Nutrition Support Protocols

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For answers to questions about nutrition management of patients with inherited metabolic disorders, call the Ross Metabolic Hotline: 1-800-986-8755.
The Ross Metabolic Formula System
Nutrition Support Protocols 4th Edition
The Ross Metabolic Formula System Nutrition Support Protocols, 4th Edition
Authors: Phyllis B. Acosta, Dr PH, RD, LD Steven Yannicelli, PhD, RD, LD
Medical Director, Medical and Regulatory Affairs Russell J. Merritt, MD, PhD
Vice President, Medical and Regulatory Affairs William C. MacLean, MD
Manuscript Processor: Christine K. Downs
Ross Products Division Division of Abbott Laboratories Columbus, Ohio 43216
Library of Congress, Catalog Card No 97-066096 2001 Abbott Laboratories Price: $500
The product information contained here, although accurate at the time of publication, is subject to change. The most current information may be obtained by referring to product labels.
A6224/(500)/June, 2001 LITHO IN USA
Acknowledgments
The shared experience of many clinicians has made possible the publication of the Ross Metabolic Formula System Nutrition Support Protocols. We are particularly indebted, however, to three clinicians listed below: Vyoone Lewis, PhD, RD, Adjunct Professor, Pediatrics and Public Health and Tropical Medicine, Tulane University, reviewed and made many excellent suggestions for improvement of Protocol 7, "Nutrition Support of Infants, Children, and Adults with -Ketothiolase Deficiency." Fran Rohr, MS, RD, in the Division of Clinical Genetics at The Children's Hospital, Boston, helped prepare Protocol 9 "Nutrition Support of Infants, Children and Adults with Glutaric Aciduria Type I." Sandy van Calcar, MS, RD, Nutritionist at the Metabolic Clinic, Biochemical Genetics Program, University of Wisconsin helped prepare Protocol 20 for nutrition support of very long-chain-, long-chain-, and long-chain-hydroxyacyl-CoA dehydrogenase deficiencies. She may be reached at 608/263-5981 if you need to discuss these disorders further. In addition, we thank the following physicians and nutritionists who reviewed and critiqued drafts of protocols:
Karen Amorde-Spalding, MS, RD Children's Hospital Oakland, CA Georgianne Arnold, MD Division of Genetics University of Rochester Medical Center Rochester, NY Paul M Fernhoff, MD Division of Medical Genetics Department of Pediatrics Emory University School of Medicine Atlanta, GA Carol Greene, MD Children's National Medical Center Washington, DC Harry Greene, MD Medical Director, Slim Fast Foods Company West Palm Beach, FL L. Lyndon Key, Jr, MD, FAAP Chief, Division of Pediatric Endocrinology Department of Pediatrics Medical University of South Carolina Charleston, SC Reuben Matalon, MD, PhD Department of Pediatrics The University of Texas Medical Branch Galveston, TX Kimberlee Matalon, PhD, RD Department of Human Development University of Houston Houston, TX Shideh Mofidi, MS, RD Westchester Institute for Human Development Valhalla, NY
Maria Nardella, MA, RD Office of Children With Special Health Care Needs Washington Department of Health Olympia, WA Vivian Shih, MD Massachusetts General Hospital Boston, MA
Ross Products Division welcomes comments for additions or changes to this manual. Please address all suggestions and inquiries to: Phyllis B. Acosta, Dr PH, RD
Director, Metabolic Diseases 614/624-7516; 800/986-8755
or
Steven Yannicelli, PhD, RD

Clinical Research Scientist 614/624-7648; 800/986-8755
Ross Products Division/Abbott Laboratories P O Box 1317 Columbus, OH 43216-1317
2001 Ross Products Division
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Contents
Page
Practical Aspects of Nutrition Support of Inborn Errors of Metabolism........................................vii DISORDERS OF AMINO ACID METABOLISM Aromatic Amino Acids PROTOCOL 1 Phenylketonuria (PKU) Nutrition Support of Infants, Children, and Adults With PHENEX-1 and PHENEX-2 Amino Acid-Modified Medical Foods................... 1 PROTOCOL 2 Maternal Phenylketonuria (MPKU) Nutrition Support of Pregnant Women With Phenylketonuria (PKU) With PHENEX-2 Amino Acid-Modified Medical Food .. 33 PROTOCOL 3 Tyrosinemia Types Ia and Ib Nutrition Support of Infants, Children and Adults With TYREX -1 and TYREX -2 Amino Acid-Modified Medical Foods.............. 49 PROTOCOL 4 Tyrosinemia Types II and III Nutrition Support of Infants, Children, and Adults With TYREX -1 and TYREX -2 Amino Acid-Modified Medical Foods ...................... 63 Branched-chain amino Acids PROTOCOL 5 Maple Syrup Urine Disease (MSUD) Nutrition Support of Infants, Children, and Adults With KETONEX -1 and KETONEX -2 Amino Acid-Modified Medical Foods..................................................................................................... 74 PROTOCOL 6 Disorders of Leucine Catabolism Nutrition Support of Infants, Children, and Adults With I-VALEX -1 and I-VALEX -2 Amino Acid-Modified Medical Foods ........ 103 PROTOCOL 7 Mitochondrial Acetoacetyl-CoA Thiolase Deficiency (-Ketothiolase Deficiency) Nutrition Support of Infants, Children, and Adults With KETONEX -1 and KETONEX -2 Amino Acid-Modified Medical Foods......................................... 123 Sulfur Amino Acids PROTOCOL 8 Homocystinuria Nutrition Support of Infants, Children, and Adults With HOMINEX -1 and HOMINEX -2 Amino Acid-Modified Medical Foods........... 137 Other Amino Acids PROTOCOL 9 Glutaric Aciduria Type I or 2-Ketoadipic Aciduria Nutrition Support of Infants, Children, and Adults With GLUTAREX -1 and GLUTAREX -2 Amino AcidModified Medical Foods .................................................................................... 166 PROTOCOL 10 Glutaric Acidemia Type II (Multiple Acyl-CoA Dehydrogenase Deficiency) Nutrition Support of Infants, Children, and Adults With PROVIMIN ProteinVitamin-Mineral Formula Component With Iron................................................. 196 PROTOCOL 11 Lysinuric Protein Intolerance Nutrition Support of Infants, Children, and Adults With PRO-PHREE Protein-Free Energy Module With Iron, Vitamins & Minerals .......................................................................................... 209 PROTOCOL 12 Nonketotic Hyperglycinemia Nutrition Support of Infants, Children, and Adults With PRO-PHREE Protein-Free Energy Module With Iron, Vitamins & Minerals .......................................................................................... 220 PROTOCOL 13 Propionic or Methylmalonic Acidemia Nutrition Support of Infants, Children, and Adults With PROPIMEX -1 and PROPIMEX -2 Amino Acid-Modified Medical Foods................................................................................................... 230 DISORDERS OF CARBOHYDRATE METABOLISM PROTOCOL 14 Galactosemia Nutrition Support of Infants, Children, and Adults With ISOMIL Soy Formula Powder With Iron ......................................................................... 262 PROTOCOL 15 Glucose Transport Protein Defect, Pyruvate Dehydrogenase Complex Deficiency, and Intractable Seizures Nutrition Support of Infants, Children, and Adults With RCF Ross Carbohydrate-Free Soy Formula Base With Iron or ProViMin Protein-Vitamin-Mineral Formula Component With Iron Powder........................ 279
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Page PROTOCOL 16 Glycogen Storage Disease Types Ia and Ib Nutrition Support of Infants, Children, and Adults With RCF Ross Carbohydrate-Free Soy Formula Base With Iron or ProViMin Protein-Vitamin-Mineral Formula Component With Iron Powder ....................................................................................................... 296 PROTOCOL 17 Hereditary Fructose Intolerance Nutrition Support of Infants, Children, and Adults .......................................................................................... 313 PROTOCOL 18 Pyruvate Carboxylase Deficiency Nutrition Support of Infants and Children With PROVIMIN Protein-Vitamin-Mineral Formula Component With Iron ............... 325 DISORDERS OF LIPID METABOLISM PROTOCOL 19 Fasting Chylomicronemia Nutrition Support of Infants, Children, and Adults With PROVIMIN Protein-Vitamin-Mineral Formula Component With Iron....... 338 PROTOCOL 20 Mitochondrial Fatty Acid Oxidation Defects Nutrition Support of Infants, Children, and Adults With PROVIMIN Protein-Vitamin-Mineral Formula Component With Iron............................................................................................................ 350 DISORDERS OF MINERAL METABOLISM PROTOCOL 21 Hypercalcemia Nutrition Support of Infants, Children, and Adults With CALCILO XD Low-Calcium/Vitamin D-Free Infant Formula With Iron.............. 366 DISORDERS OF NITROGEN METABOLISM PROTOCOL 22 Gyrate Atrophy of the Choroid and Retina Nutrition Support of Infants, Children, and Adults With CYCLINEX -1 and CYCLINEX -2 Amino Acid-Modified Medical Foods ................................................................................................... 379 PROTOCOL 23 Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome Nutrition Support of Infants, Children, and Adults With CYCLINEX -1 and CYCLINEX -2 Amino Acid-Modified Medical Foods......................................... 406 PROTOCOL 24 Urea Cycle Disorders Nutrition Support of Infants, Children, and Adults With CYCLINEX -1 and CYCLINEX -2 Amino Acid-Modified Medical Foods ......... 418 APPENDICES Nutrient Composition Tables APPENDIX 1. Fatty Acid Profile of Infant/Toddler Metabolic Medical Foods ..................................... A-2 APPENDIX 2. Fatty Acid Profile of Child/Adult Metabolic Medical Foods .......................................... A-2 APPENDIX 3. Density of Metabolic Medical Foods ........................................................................... A-3 APPENDIX 4. Nutrient Composition of Alimentum Protein Hydrolysate Formula With Iron............ A-4 APPENDIX 5. Nutrient Composition of Isomil Soy Formula With Iron............................................ A-5 APPENDIX 6. Nutrient Composition of Similac With Iron Infant Formula....................................... A-6 APPENDIX 7. Nutrient Composition of NeoSure and Similac Lactose Free ................................. A-7 APPENDIX 8. Nutrient Composition of Mature Human Milk, Skim Milk, Whole Cow's Milk, and Whole Egg......................................................................................................... A-8 APPENDIX 9. Nutrient Composition of Polycose Glucose Polymers and Pedialyte Oral Electrolyte Maintenance Solution....................................................................... A-9 APPENDIX 10. Nutrient Composition of Selected Vegetable Oils...................................................... A-9 APPENDIX 11. Nutrient Composition of Vi-Daylin Multivitamin + Iron Drops and Pro-Phree Protein-Free Energy Module with Iron, Vitamins, and Minerals.... A-10 APPENDIX 12. Nutrient Composition of Very-Low-Protein Foods per 100 g.................................... A-11 Recommended Dietary Allowances (RDIs) APPENDIX 13. Recommended Dietary Intakes (RDIs) for Minerals and Vitamins by Infants........... A-14 APPENDIX 14. Recommended Dietary Intakes (RDIs) for Minerals and Vitamins by Children, Adolescents, and Adults................................................................................... A-15
Page Technical Information APPENDIX 15. Mathematical Formula for Interconversion of Plasma Amino Acids Between mol/L and mg/dL ............................................................................................ A-17 APPENDIX 16. Molecular Weights of Amino Acids.......................................................................... A-17 APPENDIX 17. Selected Laboratory Standards ............................................................................... A-18 APPENDIX 18. Estimating Osmolarity of a Medical Food Mixture ................................................... A-20 APPENDIX 19. Approximate Osmolarity of Selected Foods ............................................................ A-21 APPENDIX 20. Potential Renal Solute Load of Medical Food Mixture ............................................. A-22 APPENDIX 21. NDC Numbers for Metabolic Medical Foods............................................................ A-23 Clinical Forms APPENDIX 22. Diet Guide .............................................................................................................. A-24 APPENDIX 23. Evaluation of Mineral/Vitamin Content of Medical Food Mixture ............................. A-25 APPENDIX 24. Diet Diary................................................................................................................ A-26 APPENDIX 25. Directions for Recording the Diet Diary ................................................................... A-27 Supplier Information APPENDIX 26. Sources of Nutrients and Drugs............................................................................... A-28 APPENDIX 27. Low-Protein Food Suppliers .................................................................................... A-29 APPENDIX 28. Products for Prescription Diet Management ............................................................ A-29 INDEX ........................................................................................................................... I-1
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Practical Aspects of Nutrition Support of Inborn Errors of Metabolism

The problem of assuring adequate nutrition for infants, children, and adults with inherited metabolic disorders may be decreased by the use of a protocol a plan for treatment because each patient requires individualized nutrition care. The protocols in this manual are intended to serve as guides for health care professionals who treat infants, children, adolescents, adults, and pregnant women with inherited metabolic disorders. The protocols have been developed for use with the Ross Metabolic Formula System (RMFS). They will be particularly useful to those who are relatively unfamiliar with nutrition support of metabolic disorders, although specialists working in treatment centers where protocols are already established should find them useful as well. Overview The protocols are organized according to disorder, with the Appendix containing information about recommended nutrient intakes for various age groups, laboratory standards, and other technical information. Also included in the Appendix are sample forms for a Diet Guide and Diet Diary, which may be photocopied for individual use. The newcomer to treatment of metabolic disorders will benefit from scanning the entire volume, giving attention not only to the protocol relevant to the disorder of interest and the Appendices, but also to the "Technical Information" section in the Appendices. Recommended Dietary Intakes (RDIs) Protein requirements are greater than Dietary Reference Intakes (DRIs) when L-amino acids are the primary protein source (2). This increased need is because of rapid amino acid absorption and subsequent oxidation (11, 16, 27), resulting in poor linear growth (7, 30), and lower than normal nitrogen retention (27), body protein, and nitrogen content of patients fed primarily L-amino acids (3). Recommended mineral and vitamin intakes suggested for patients with inherited metabolic disorders are the greatest intakes suggested for each age in the 1980 and 1989 National Academy of Sciences National Research Council (NAS-NRC) Recommended Dietary Allowances (RDAs) (10) and the DRIs (22). Reasons for choosing the greatest intakes recommended include reports of inadequate linear growth (7, 30) and poor bone mineralization (17) with Food and Agriculture Organization/World Health Organization (FAO/WHO)-recommended protein intakes (9); greater than normal energy needs when L-amino acids supply the bulk of protein equivalent (23); and depressed plasma concentrations of ferritin (5, 25), selenium (12), and zinc (1) when RDAs were achieved with chemically defined diets. Measuring Medical Foods All measures for dry powders referred to in this manual are US standard, level household measures. Cups and spoons intended for measuring liquids should not be used to measure powders. Many measuring cups and spoons sold in food markets are grossly inaccurate. If scales that read in grams are not available, US standard measuring equipment for dry materials, calibrated by the US Bureau of Standards, should be obtained (8). Professionals, parents and patients should be aware that density of medical foods varies because of settling during shipping and differences in packing. Because of this variability, medical foods should be weighed on a scale that reads in grams. Weighing takes the guesswork out of determining whether the amount of medical food ingested was the same as that prescribed. Supplying Restricted Amino Acids For infants younger than 4 months of age, restricted amino acids are normally supplied by iron-fortified proprietary infant formulas such as Similac With Iron Infant Formula or Isomil Soy Formula With Iron. Use of iron-fortified products enhances iron status of infants who may absorb less than normal amounts of iron from elemental medical foods. Similac and Isomil are available in Ready to Feed, Concentrated Liquid, and Powder forms. Baby foods (beikost) should be added slowly to the diet as the infant becomes developmentally ready sometime between 3 and 4 months of age for the developmentally normal. Prescribed amounts of selected baby foods, and, later, table foods gradually displace infant formula as the source of restricted amino acid(s).
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Meeting Water Needs Water needs of infants should be supplied by the medical food mixture. Children and adults may have additional free water when they are thirsty, if both the osmolarity and potential renal solute load of their medical food mixtures are in safe ranges. Appendices 18, 19, and 20, pp A-20 through A-22, provide help in estimating these. Recognizing the Maillard Reaction The Maillard reaction is a name given to a complex group of chemical reactions in foods in which reacting amino acids, peptides, and proteins condense with sugars, forming bonds for which no digestive enzymes are available. The Maillard reaction is accelerated by heat. It is characterized in its initial stage by a light-brown color, followed by buff yellow and then dark brown in the intermediate and final stages. Caramel-like and roasted aromas develop. Preparers of medical foods need to be able to recognize the Maillard reaction because it causes loss of some sugars and amino acids. For this reason, medical foods should not be heated beyond 100o F. For babies in the newborn nursery and at home, the aseptic technique of mixing medical foods should be used (24). Monitoring Amino Acid Concentrations Successful management of inherited disorders of metabolism requires frequent monitoring of appropriate analytes. The recommendations for plasma amino acid concentrations given here are close to the normal range because 30 years of practice have suggested that values as close to normal as possible are best. In the past, normal values were difficult to achieve because of inadequate knowledge of requirements and food composition, infrequent monitoring, and failure to recognize the effects of infection, trauma, and catabolism on plasma amino acid concentrations. Frequent monitoring of plasma amino acid concentrations and other analytes gives the physician and nutritionist data that verify the adequacy of the nutrition support prescription. These data are also useful in motivating patient/parent compliance with the prescription. Patients with insulin-dependent diabetes often monitor blood glucose three times daily, so frequent monitoring of plasma amino acids should pose no major problem. Some centers may wish to draw blood to monitor plasma amino acids at times other than those listed in these protocols. We recognize the need to take a practical approach to nutrition support. If blood cannot be drawn 2 to 4 hours after feeding, local normal standards should be developed for plasma amino acid concentrations. However, prolonged fasting may cause spurious elevations of plasma amino acid concentrations that could lead to unwarranted diet changes (13, 14), and blood drawn 15 minutes to 1 hour after a meal may also yield spuriously high values (11). Tuning the Prescription Beikost should be introduced into the diet when infants are between 3 and 4 months of age or when developmentally ready. Delay in introduction of beikost or table foods beyond this "critical period" often leads to great difficulty in getting the infant to accept them at a later age. The protocols in this manual for disorders of amino acid metabolism make use of a system of exchanges in which the primary restricted amino acid is used as the basis for providing specific amounts of food in each serving list. Serving Lists are Breads and Cereals, Fats, Fruits, Vegetables, Free Foods A, and Free Foods B. Some centers with extensive experience have developed their own food lists for each disorder; the Ross Metabolic Formula System products can be safely prescribed here as well. Amino acid intakes recommended in these protocols are ranges within which requirements for most patients will fall; however, the requirement of each patient will differ, with some patients tolerating the lower end of the range and others requiring the upper end. The specific requirement for each patient must be determined by frequent evaluation of plasma amino acid and transthyretin concentrations, growth, and skin and hair. Patients who are growing well due to adequate protein intake can normally tolerate more of the restricted amino acid(s) than can poorly growing infants and children (2, 20). When the restricted amino acid concentration(s) is (are) elevated in blood or plasma, detective work is required to determine the reason(s) for the elevation. Some questions that should be asked are given below: Is the prescribed diet ingested daily?
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Does the child fail to ingest significant amounts of prescribed medical food? Beikost or table food? Is measuring equipment accurate and are foods carefully weighed or measured? Is the appropriate form of infant formula (concentrated liquid, powder, ready-to-feed) mixed with the medical food? Do siblings, relatives, neighbors, or baby sitters feed the patient? If "yes," do they give foods not prescribed, or prescribed foods in greater than prescribed amounts? If the patient is in daycare or school, are peers, teachers, etc, giving the child food, or is the child "trading" foods? Has the patient eaten any foods NOT on the servings lists? Is the child "snitching" food? Is the child ill? Appropriate monitoring and disciplining of the child (18) on a special diet from an early age are essential to diet compliance. For additional information about this topic, see references 21 and 28. Changing Medical Foods RMFS infant/toddler medical foods are designed to supply the nutrient needs of infants and young children when they are supplemented with enough iron-fortified infant formula or foods to provide the restricted amino acid(s) in amounts necessary for normal growth and development. When a toddler's appetite is small, RMFS infant/toddler medical food should be replaced by RMFS child/adult medical food. This change may be immediate only if the RMFS medical food is promptly accepted by the child. Many children, however, are slow to accept new flavors. As infants grow into children, they become more sensitive to changes in flavors of foods, a phenomenon that often complicates ingestion of medical foods. Because nutrient requirements change gradually over time, the medical food does not need to be changed abruptly. If acceptance is slow, the amount of RMFS child/adult medical food is gradually increased as the infant/toddler medical food is gradually decreased. The change from infant/toddler to child/adult medical food may require a few days or several months. Masking the Taste of Free Amino Acids Foods with free amino acids containing sulfur and those with acidic or basic groups have a sulfurous, bitter, unpleasant taste that may make diet compliance difficult (26). Products containing free amino acids taste best when they are served very cold. Patients will accept these products containing free amino acids more easily if they are served as "slushes," that is, chilled almost to freezing. Selecting Nutrient Analysis Computer Software A number of different software packages are available for computer evaluation of nutrient intake. Many software packages appear impressive because their databases contain a large number of nutrients; however, some packages with many nutrients have significant missing data (6). For calculating diets of infants, children, and adults with inherited metabolic disorders, we recommend Amino Acid Analyzer (4) available from Ross Products Division of Abbott Laboratories. General Principles of Nutrition Support of Genetic Disease Specific enzymes produced under the direction of individual genes catalyze specific reactions as noted in the following genetic and metabolic sequences. A is converted to D through intermediates B and C using enzymes AB, BC, and CD:
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If enzyme CD were genetically impaired, at least six pathophysiologic consequences could result:
G ene A B
Gene BC
G ene C D
Enzym e A B
Enzym e B C
Enzym e C D
D E
1. A deficiency of product D or some compound derived only from D. For example, in phenylketonuria (PKU), phenylalanine (PHE) is not hydroxylated to form tyrosine (TYR). Not only is the accumulated PHE toxic, but TYR becomes an essential nutrient. TYR must be supplemented to maintain proper growth and plasma TYR concentrations in the nutrition support of patients with PKU. 2. A loss of feedback control. If product D normally functions in feedback control of enzyme AB, overproduction of an intermediate product may occur because D is not present in amounts necessary to regulate production of intermediates B and C. 3. An accumulation of C, the immediate precursor of the blocked reaction. In maple syrup urine disease (MSUD), toxic branched-chain--ketoacids accumulate because they cannot be decarboxylated and transacylated to their coenzyme A-acyl derivatives. The consequence in the neonate is severe central nervous system depression with apnea, stupor, coma, and death. If the neonate survives, mental retardation or death ensues if the child is not treated by diet restriction within 3 to 5 days of life. 4. An accumulation of A or B, remote precursors of the blocked reaction sequence CD. If the preceding reactions are freely reversible, a precursor in addition to that proximal to the block will accumulate. This process is illustrated in MSUD by increased leucine (LEU), isoleucine (ILE), and valine (VAL), which are formed by reamination of the branched-chain--ketoacids -ketoisocaproic, -keto-methylvaleric, and -ketoisovaleric acids, respectively. 5. Increased production of alternative product (eg, E, through little-used metabolic pathways. When PHE accumulates because of impaired phenylalanine hydroxylase, phenylpyruvic, phenylacetic, and phenyllactic acids are produced in greater than normal amounts through existing pathways that normally do not function at physiologic concentrations of cellular PHE. 6. Inhibition of alternative pathways by accumulated substrate (eg, C in CD impairment). For example, neurotransmitter synthesis may be depressed in PKU owing to increased blood PHE concentrations that inhibit tyrosine hydroxylase and tryptophan hydroxylase in the central nervous system. Another example is type Ia tyrosinemia. The accumulation of succinylacetone inhibits aminolevulinic acid (-ALA) dehydratase and results in secondary accumulation of -ALA, attacks of acute porphyria with peripheral neuropathy, hypertension, and bizarre behavior. Nine approaches to nutrition support of inborn errors of metabolism are discussed below. The appropriate approach depends on the biochemistry and pathophysiology of disease expression several therapeutic approaches may be used simultaneously. 1. Enhancing anabolism and depressing catabolism. This involves the use of adequate amounts of appropriate medical food and other foods to supply protein and energy, and administration of insulin,
if needed. Fasting should be prevented. This therapeutic measure should be used in all patients with an inborn error involving catabolic pathways. 2. Correcting the primary imbalance in metabolic relationships. This correction involves reducing, through diet restriction, the accumulation of substrate that is toxic. This approach is used in PKU where PHE, and MSUD where LEU, ILE, and VAL are limited. 3. Providing alternative metabolic pathways to decrease accumulated toxic precursors in blocked reaction sequences. In the treatment of isovaleric acidemia, innocuous isovalerylglycine is formed from accumulating isovaleric acid if supplemental glycine is provided to drive glycine-Ntransacylase. Isovalerylglycine is excreted in the urine. 4. Supplying products of blocked primary pathways. As examples, arginine (ARG) is supplied in most disorders of the urea cycle, cystine (CYS) is supplied in homocystinuria (HCU), TYR in PKU, tetrahydrobiopterin in biopterin synthetic defects, and ether lipids in patients with some peroxisomal disorders. 5. Supplementing "conditionally essential" nutrients. Carnitine, CYS, and TYR are supplemented in secondary liver disease, and carnitine is supplemented in organic acidemias. 6. Stabilizing altered enzyme proteins. The rate of biologic synthesis and degradation of holoenzymes depends on their structure. In some holoenzymes, saturation by coenzyme increases their biologic half-life and, thus, overall enzyme activity at the new equilibrium. This therapeutic mechanism is used in HCU and MSUD. Pharmacologic intakes of pyridoxine in HCU and thiamin in MSUD increase intracellular pyridoxal phosphate and thiamin pyrophosphate and increase the specific activity of cystathionine -synthase and branched-chain--ketoacid dehydrogenase complex. 7. Replacing deficient cofactors. Many vitamin-dependent disorders are caused by blocks in coenzyme production and are "cured" by pharmacologic intake of a specific vitamin precursor. This mechanism presumably involves overcoming a partially impaired enzyme reaction by mass action. Impairment of reactions required to produce either methylcobalamin or adenosylcobalamin result in HCU and/or methylmalonic aciduria (MMA). Daily intakes of appropriate forms of milligram quantities of vitamin B12 may cure the disease. 8. Inducing enzyme product. If the structural gene or enzyme is intact, but suppressor, enhancer, or promoter elements are not functional, abnormal amounts of enzyme may be produced. The structural gene may be "turned on" or "turned off" to enable normal enzymatic production to occur. In the acute porphyria of tyrosinemia type Ia, excessive -ALA production may be reduced by suppressing transcription of the -ALA synthase gene with excess glucose. 9. Supplementing nutrients that are inadequately absorbed or not released from their apoenzyme. Examples are zinc in acrodermatitis enteropathica and biotin in biotinidase deficiency. The Table that follows provides information, by disorder, on appropriate Ross Products or other products to use for nutrition support of a variety of inborn errors of metabolism.
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TABLE A. Nutrition Support of Selected Inborn Errors of Metabolism

Inborn Error and Defect INBORN ERRORS OF AMINO ACID METABOLISM Aromatic Amino Acids Alcaptonuria (homogentisic acid oxidase) Phenylketonuria (PKU) and Hyperphenylalaninemia (phenylalanine hydroxylase) Hyperphenylalaninemia (dihydropteridine reductase); GTP cyclohydrolase I; pyruvolyltetrahydropterin synthase) Tyrosinemia type Ia (fumarylacetoacetate hydrolyase) Tyrosinemia type Ib (maleylacetoacetate isomerase) Tyrosinemia types II and III (tyrosine aminotransferase) Branched-chain amino Acids -Ketothiolase deficiency Nutrient(s) To Modify Vitamin-Responsive Ross Metabolic Formula/Other
Restrict phenylalanine (PHE) and tyrosine (TYR). Restrict PHE and increase TYR. Maintain protein intake above NAS-NRC RDAs for age. Restrict PHE and increase TYR. Maintain protein intake above NAS-NRC RDAs for age.
No No Yes; tetrahydrobiopterin, 2 mg/kg/day.
Tyrex-2 Phenex-1 Phenex-2 Phenex-1 Phenex-2 Tyrex-1 Tyrex-2 Tyrex-1 Tyrex-2 Tyrex-1 Tyrex-2 Ketonex-1 Ketonex-2 (both must be supplemented with LEU and VAL) Ketonex-1 Ketonex-2
Restrict PHE and TYR. Maintain protein and energy No intakes above NAS-NRC RDAs for age. Restrict PHE and TYR. Maintain protein and energy No intakes above NAS-NRC RDAs for age. Restrict PHE and TYR. Maintain protein and energy No intakes above NAS-NRC RDAs for age. Restrict ILE. Maintain protein and energy intakes above NAS-NRC RDAs for age. Administer Lcarnitine No
Maple syrup urine disease (MSUD) (branched-chain- Restrict ILE, LEU, and VAL. Maintain protein and ketoacid [BCKA] dehydrogenase complex) energy intakes above NAS-NRC RDAs for age.
3-Hydroxyisobutyric aciduria (3-Hydroxyisobutyric acid dehydrogenase)
Restrict VAL. Administer L-carnitine. Maintain protein and energy intakes above NAS-NRC RDAs for age.
Isovaleric acidemia (isovaleryl-CoA dehydrogenase); Restrict LEU. Administer L-carnitine and glycine 3-Methylcrotonylglycinuria (3-methylcrotonyl-CoA (GLY). Maintain protein and energy intakes carboxylase) above NAS-NRC RDAs for age. 3-Methylglutaconic aciduria (3-methylglutaconyl-CoA Restrict LEU. Administer L-carnitine and GLY Yes, pantothenic acid, 15hydratase) Maintain protein and energy intakes above NAS150 mg/day NRC RDAs for age.
Yes; thiamin-responsive if any residual enzyme activity. Response to thiamin inadequate to alleviate need for restriction of branchedchain amino acids. 100 to 300 mg of ORAL thiamin daily. No Ketonex-1 Ketonex-2 (both must be supplemented with ILE and LEU) No I-Valex-1 I-Valex-2 I-Valex-1 I-Valex-2
2001 Ross Products Division xiii
Inborn Error and Defect 3-Hydroxy-3-methylglutaric aciduria (3-hydroxy-3methylglutaryl-CoA lyase) Sulfur Amino Acids Homocystinuria, pyridoxine nonresponsive (cystathionine -synthase) Homocystinuria, pyridoxine-responsive (Cystathionine -synthase)
Nutrient(s) To Modify Restrict LEU and fat. Maintain protein and energy intakes above NAS-NRC RDAs for age.
Vitamin-Responsive No
Ross Metabolic Formula/Other I-Valex-1 I-Valex-2
Restrict MET; increase cystine (CYS); supplement No Hominex-1 folate and betaine. Maintain protein intake above Hominex-2 NAS-NRC RDAs for age. Pyridoxine. Yes; 25 to 1,000 mg of ORAL None indicated pyridoxine daily. Use smallest amount that results in biochemical normalcy as excess may cause peripheral neuropathy. Restrict lysine (LYS) and tryptophan (TRP). Administer L-carnitine. Maintain protein intake above NAS-NRC RDAs for age. Yes; some patients may have a partial response to ORAL riboflavin, 100 to 300 mg daily in small doses administered with food. Restrict protein and fat. Administer L-carnitine, and Yes? Prescribe 100 to 300 mg GLY. Maintain energy intake above NAS-NRC ORAL riboflavin daily in RDAs for age. small doses with food. Restrict LYS and TRP. Administer L-carnitine. No Maintain protein intake above NAS-NRC RDAs for age. Restrict protein. Supplement with L-citrulline (CIT). No Maintain energy intake above NAS-NRC RDAs for age. Restrict ILE, MET, threonine (THR), VAL, oddNo chain-fatty acids, and long-chain-unsaturated fatty acids. Maintain protein and energy intakes above NAS-NRC RDAs for age. Minimum restriction of ILE, MET, THR, and VAL. Yes; 1 to 2 mg Administer L-carnitine. hydroxycobalamin daily. Restrict protein. Maintain energy intake above NAS- No NRC RDAs for age. Glutarex-1 Glutarex-2
Other Inborn Errors of Amino Acid Metabolism Glutaric aciduria type I (glutaryl-CoA dehydrogenase)
Glutaric acidemia type II (multiple acyl-CoA dehydrogenase) 2-Ketoadipic aciduria (2-ketoadipic dehydrogenase)
Pro-Phree ProViMin Glutarex-1 Glutarex-2 Pro-Phree
Lysinuric protein intolerance (defect in renal, intestinal, and hepatic membrane transport of dibasic amino acids) Methylmalonic acidemia (methylmalonyl-CoA mutase or )
Propimex-1 Propimex-2
Methylmalonic acidemia (cobalamin reductase; adenosyltransferase) Nonketotic hyperglycinemia (one of four protein components [P, H, T, or L] of a multienzyme complex in the mitochondrial GLY cleavage system)
Propimex-1 Propimex-2 Pro-Phree Similac Isomil Alimentum
xiv 2001 Ross Products Division
Inborn Error and Defect Propionic acidemia (propionyl-CoA carboxylase)
Nutrient(s) To Modify
Vitamin-Responsive Yes? Questionable; some clinicians supplement with 5 to 10 mg ORAL D-biotin daily.
Restrict ILE, MET, THR, VAL, odd-chain-fatty acids, and long-chain-unsaturated fatty acids. Administer L-carnitine. Maintain protein and energy intakes above NAS-NRC RDAs for age. INBORN ERRORS OF CARBOHYDRATE METABOLISM Galactosemias Epimerase deficiency Delete galactose, add specific known amount of galactose if no epimerase activity. Maintain protein and energy intakes at NAS-NRC RDAs for age. Galactokinase deficiency Delete galactose. Maintain protein and energy intakes at NAS-NRC RDAs for age. Galactose-1-phosphate uridyl transferase deficiency Delete galactose. Maintain protein and energy intakes at NAS-NRC RDAs for age. Glucose transport protein deficiency (GLUT1) Restrict carbohydrate (CH2O). High-fat, ketogenic diet. Glycogen Storage Diseases GSD Type Ia (glucose-6-phosphatase); Avoid lactose, fructose and sucrose. Modify type of GSD Type Ib (defective glucose-6-phosphate CH2O and frequency of feeds. Maintain protein transport) and energy intakes at NAS-NRC RDAs for age.
Ross Metabolic Formula/Other Propimex-1 Propimex-2
No
Health Source Isomil Powder
No No No
Health Source Isomil Powder Health Source Isomil Powder ProViMin RCF ProViMin Polycose RCF Raw cornstarch after 6 to 9 mos of age Polycose ProViMin RCF Raw cornstarch after 6 to 9 mos of age ProViMin RCF Polycose Raw cornstarch after 6 to 9 mos of age ProViMin RCF Pro-Phree Similac for infants Cow's milk for children
No
GSD Type III (amylo-1, 6-glucosidase)
GSD Type IV (-1, 4-Glucan -1, 4-glucan 6glucosyltransferase)
Provide high protein. Avoid lactose, fructose and sucrose. Supplement with L-alanine (ALA). Modify type of CH2O and frequency of feeds. Maintain energy intake at NAS-NRC RDAs for age. Provide high protein unless cirrhosis present. Modify type of CH2O and frequency of feeds. Maintain energy intakes at NAS-NRC RDAs for age. Provide high protein. Supplement L-ALA. Maintain energy intake at NAS-NRC RDAs for age. Restrict fructose to < 10 mg/kg of body weight; restrict protein if liver damage. Maintain energy intake at NAS-NRC RDAs for age.
No
No
GSD Type V (muscle phosphorylase) Hereditary Fructose Intolerance Hereditary fructose intolerance (aldolase B)
No
No
2001 Ross Products Division xv
Inborn Error and Defect Pyruvate Dehydrogenase Complex Deficiency (E1 or E1) Pyruvate carboxylase deficiency
Nutrient(s) To Modify Restrict CH2O. High-fat, ketogenic diet. Moderate protein, CH2O, fat. Administer thiamin, citrate, and possibly L-ASP acid, L-asparagine, L-glutamic acid, and L-glutamine. Restrict CH2O. High-fat, ketogenic diet.
Vitamin-Responsive Yes? Thiamin. No
Ross Metabolic Formula/Other ProViMin RCF ProViMin
Seizures
No
ProViMin RCF
Any tolerated
INBORN ERRORS OF CHOLESTEROL METABOLISM Supplement cholesterol, > 50 mg/kg body weight; increase Smith-Lemli-Opitz syndrome (microsomal 7energy intake to amount required for adequate weight gain dehydrocholesterol reductase) (19) INBORN ERRORS OF FATTY ACID OXIDATION Disorders of Mitochondrial Fatty Acid Oxidation Carnitine-acylcarnitine translocase deficiency (15)
No
Restrict fat; limit MCT. Provide adequate essential fatty acids. Administer L-carnitine; prevent fasting Very-long-chain and long-chain-acyl-CoA Restrict long-chain-fatty acids (> 14 carbons) to 15% dehydrogenase deficiencies; of energy. Avoid fasting. Provide adequate protein Long-chain-hydroxyacyl-CoA dehydrogenase and energy. Supplement fractionated coconut oil deficiency and L-carnitine. Supplement docosahexaenoic acid (DHA) in patients with long-chain-hydroxyacyl-CoA dehydrogenase deficiency. Medium-chain-acyl-CoA dehydrogenase deficiency Restrict fat to 20% to 30% of energy. Avoid fasting. Provide adequate protein and energy. Supplement L-carnitine. Short-chain and short-chain-hydroxyacyl-CoA Restrict fat to 20% to 30% of energy. Avoid fasting. dehydrogenase deficiencies Provide adequate protein and energy. Supplement L-carnitine INBORN ERRORS OF LIPOPROTEIN METABOLISM Abetalipoproteinemia and hypobetalipoproteinemia Restrict triglycerides with long-chain-fatty acids. (Apo B, absence and decreased) Supplement with vitamins A, D, E and K and linoleic and -linolenic acids. Maintain protein and energy intakes at NAS-NRC RDAs for age. Lecithin:cholesterol acyltransferase deficiency Restrict fat. Maintain protein and energy intakes at (LCAT) NAS-NRC RDAs for age. Hyperlipoproteinemias Type I (extrahepatic lipoprotein lipase; Apo C-II Restrict triglycerides with long-chain-fatty acids to 8% absent or decreased; lipoprotein lipase inhibitors) to 15% of energy. Maintain protein and energy intakes at NAS-NRC RDAs for age.
No No
ProViMin ProViMin
No
ProViMin
No
ProViMin
No
ProViMin Polycose
No
ProViMin Polycose ProViMin Polycose
No
xvi 2001 Ross Products Division
Inborn Error and Defect Type IIa (LDL receptors absent or defective)
Nutrient(s) To Modify
Vitamin-Responsive
Type IIb
Type III (hepatic lipoprotein lipase; homozygous for abnormal Apo E2; remnant receptor defect)
Restrict cholesterol and saturated fat; increase No polyunsaturated fatty acids (PUFAs). Maintain protein and energy intakes at NAS-NRC RDAs for age. Restrict cholesterol, saturated fat, mono- and No disaccharides, and alcohol. Increase PUFAs and fiber. Maintain protein and energy intakes at NAS-NRC RDAs for age. Restrict cholesterol, saturated fat, mono- and No disaccharides, and alcohol. Increase PUFAs and fiber. Restrict energy if patient is overweight. Maintain protein intake at NAS-NRC RDAs for age. Restrict calcium and vitamin D. Restrict calcium and vitamin D. Restrict cystine and methionine No No No No
Ross Metabolic Formula/Other Isomil ProViMin RCF Polycose ProViMin RCF Polycose ProViMin RCF Polycose
INBORN ERRORS OF MINERAL METABOLISM Idiopathic hypercalcemia with supravalvular aortic stenosis Williams syndrome. Osteopetrosis Sulphite oxidase deficiency (29) INBORN ERRORS OF NITROGEN METABOLISM Carbamylphosphate synthetase deficiency; Ornithine transcarbamylase deficiency
Calcilo XD Calcilo XD Pro-Phree Cyclinex-1 Cyclinex-2 Cyclinex-1 Cyclinex-2 Cyclinex-1 Cyclinex-2 Cyclinex-1 Cyclinex-2 Cyclinex-1 Cyclinex-2
Restrict protein. Supplement with essential amino acids (EAAs), L-carnitine, and L-CIT. Maintain energy intake above NAS-NRC RDAs for age. Citrullinemia (argininosuccinate synthetase); Restrict protein. Supplement with EAAs, L-carnitine, Argininosuccinic aciduria (argininosuccinate lyase) and L-ARG. Maintain energy intake above NASNRC RDAs for age. Argininemia (arginase) Restrict protein. Supplement with EAAs and L-carnitine. Maintain energy intake above NASNRC RDAs for age. Restrict arginine (ARG) and protein. Supplement Gyrate atrophy (ornithine--aminotransferase) with EAAs and L-carnitine. Maintain energy intake above NAS-NRC RDAs for age. Hypernornithinemia - hyperammonemia Restrict protein. Supplement with L-ARG, L-CIT, or homocitrullinuria syndrome (HHH syndrome) L-ornithine (ORN). Maintain energy intake above (defective ornithine transport across mitochondrial NAS-NRC RDAs for age. membrane) N-acetylglutamate synthetase deficiency Restrict protein. Supplement with EAAs, L-carnitine, and N-carbamylglutamate. Maintain energy intake above NAS-NRC RDAs for age.
No
No
Yes; pyridoxine.
No
No
Cyclinex-1 Cyclinex-2
References
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. Acosta PB, Fernhoff PM, Warshaw HS, et al: Zinc status and growth of children undergoing treatment for phenylketonuria. J Inher Metab Dis 1982;5:107-110. Acosta PB, Yannicelli S: Protein intake affects phenylalanine requirements and growth of infants with phenylketonuria. Acta Paediatr 1994; (Suppl):407:66-67. Allen JR, Baur LA, Waters DL, et al: Body protein in prepubertal children with phenylketonuria. Eur J Clin Nutr 1996;50:178-186. Amino Acid Analyzer is available from Ross Products Division, Appendix 28, p A-29. Bodley JL, Austin VJ, Hanley WB, et al: Low iron stores in infants and children with treated phenylketonuria: A population at risk for iron-deficiency anaemia and associated cognitive deficits. Eur J Pediatr 1993;152:140-143. Byrd-Bredbenner C: Computer nutrient analysis software packages: Considerations for selection. Nutr Today 1988; September-October:13. Dhondt JL, Largilliere C, Moreno L, Farriaux JP: Physical growth in patients with phenylketonuria. J Inher Metab Dis 1995;18:135-137. Dietetic scales that weigh in grams are available from Pelouze Scales Co, PO Box 1058, Evanston, IL 60204. For ordering information, see Appendix 28, p A-29. FAO/WHO/UNU Expert Consultation: Energy and Protein Requirements. Geneva: World Health Organization, 1985. Food and Nutrition Board, Committee on Dietary Allowances: Recommended Dietary Allowances, eds 9 and 10. Washington, DC: National Academy of Sciences, 1980 and 1989. Gropper S, Acosta PB: Effect of simultaneous ingestion of L-amino acids and whole protein on plasma amino acids and urea nitrogen concentrations in humans. JPEN 1991;15:48-53. Gropper S, Acosta PB, Clarke-Sheehan N, et al: Trace element status of children with PKU and normal children. J Amer Diet Assoc 1988;88:459-464. Gropper SS, Gropper DM, Acosta PB: Plasma amino acid response to ingestion of L-amino acids and whole protein. J Pediatr Gastroenterol Nutr 1993;16:143-150. Guttler F, Olseson ES, Wamberg E: Diurnal variations of serum phenylalanine in phenylketonuric children on low phenylalanine diet. Am J Clin Nutr 1969;22:1568-1570. Haworth JC, Demaugre F, Booth FA, et al: A typical features of the hepatic form of carnitine palmitoyltransferase deficiency in a Hutterite family. J Pediatr 1992;121;553-557. Herrmann ME, Broesicke HG, Keller M, et al: Dependence of the utilization of a phenylalanine free amino acid mixture on different amounts of a single dose ingested. A case report. Eur J Pediatr 1994;153:501-503. Hillman L, Schlotzhauer C, Lee D, et al: Decreased bone mineralization in children with phenylketonuria under treatment. Eur J Pediatr 1996;155 (Suppl 1):S148-S152. Howard BJ: Discipline in early childhood. Pediatr Clin North Am 1991;38:1351-1369. Kelly RJ: Inborn errors of cholesterol biosynthesis. Adv Pediatr 2000;47:1-53. Kindt E, Motzfeldt K, Halvorsen S, Lie S: Protein requirements in infants and children treated for phenylketonuria. Am J Clin Nutr 1983;37:778-785. Macht J: Poor Eaters: Helping Children Who Refuse to Eat. New York: Plenum Press, 1990. Monsen ER: Dietary reference intakes for antioxidant nutrients: Vitamin C, vitamin E, selenium, and carotenoids. J Amer Diet Assoc 2000;100:637-640. Pratt EL, Snyderman SE, Cheung MW, et al: The threonine requirement of the normal infant. J Nutr 1955;56:231-251. Preparation of Formula for Infants: Guidelines for Health Care Facilities. Chicago, IL: The American Dietetic Association, 1991. Scaglioni S, Zucotti G, Vedovello M, et al: Study of serum ferritin in 58 children with classic phenylketonuria and persistent hyperphenylalaninemia. J Inher Metab Dis 1985;8:160. Schiffman SS, et al: Increased taste thresholds of amino acids with age. Am J Clin Nutr 1979;32:1622. Schoeffer A, Herrmann ME, Broesicke HG, Moench E: Effect of dosage and timing of amino acid mixtures on nitrogen retention in patients with phenylketonuria. J Nutr Med 1994;4:415-418. Taylor JF, Latta RS: Why Can't I Eat That? Saratoga, CA: R & E Publishers, 1993. Touati G, Rusthoven E, Depondt E, et al: Dietary therapy in two patients with a mild form of sulphite oxidase deficiency. Evidence for clinical and biological improvement. J Inher Metab Dis 2000;23:45-53. Verkerk PH, van Spronsen FJ, Smit GPA, Sengers RCA: Impaired prenatal and postnatal growth in Dutch patients with phenylketonuria. Arch Dis Child 1994;71:114-118.
xvii
PROTOCOL 1 Phenylketonuria (PKU) Nutrition Support of Infants, Children, and Adults With PHENEX-1 and PHENEX-2 Amino Acid-Modified Medical Foods
I. Introduction
Phenylketonuria (PKU) and hyperphenylalaninemia result from a defect in the enzyme phenylalanine (PHE) hydroxylase (PAH), which is responsible for changing PHE, an essential amino acid, to tyrosine (TYR), normally a nonessential amino acid (Figure A) (19, 58). A defect in PAH activity results in accumulation of PHE in blood and body tissues from which PHE metabolites are produced. Another consequence is that blood and tissue concentrations of TYR may be deficient since TYR is an essential amino acid for patients with PKU. Hyperphenylalaninemia may also result from deficiency of tetrahydrobiopterin (H4 biopterin), a coenzyme for PAH, TYR hydroxylase, and tryptophan hydroxylase. The latter two enzymes are required for neurotransmitter synthesis. Therapy of H4 biopterin deficiency requires L-DOPA, carbidopa, and H4 biopterin in addition to a PHE-restricted diet (19, 58). Some patients with hyperphenylalaninemia may have a mutant PAH enzyme with decreased affinity for the coenzyme H4 biopterin (treat with H4 biopterin, 5-10 mg/kg) (42, 66).
GTP GTP cyclohydrolase Dihydroneopterin triphosphate NAD Dihydrobiopterin synthetase

+
NADH + H
Dihydropteridine reductase (N) Dietary protein
Dietary protein
H4 biopterin
H2 biopterin Tissue protein CO2 + H2O Melanin
Tissue protein
Phenylalanine*
Tyrosine (N) (N)
(N)
Epinephrine O2 Phenylalanine hydroxylase H2O Thyroxine
Orthohydroxyphenylacetate
Phenylpyruvate*
Phenylethylamine * Accumulates in untreated PKU (N) = several steps
Phenyllactate*
Phenylacetate* Indicates sites of possible enzyme defects
Phenylacetylglutamine
Figure A. Phenylalanine metabolism in phenylketonuria
Phenylketonuria 1
II. Screening for PKU

Newborn screening for PKU started in the mid-1960s. An elevated blood PHE concentration found on a newborn screen suggests the need for a diagnostic work-up. A positive newborn screen for elevated blood PHE concentration is NOT a positive diagnosis (19, 58). The incidence of PKU is approximately 1/10,000 to 1/25,000 live births. It is greater in people of Irish descent than in many other ethnic groups, but PKU is found in all ethnic groups (19, 58).
III. Outcome of Nutrition Support

If untreated, persons with PKU may have irreversible mental retardation and one or more of the following: neurologic abnormalities, abnormal electroencephalograms (EEGs), seizures, hyperactivity, musty odor, and eczema. Newborn screening, retrieval, diagnosis, and early nutrition intervention have resulted in children with normal intelligence. Many treated patients complete college (19, 58). Until recently, children with PKU were removed from a PHE-restricted diet at school age or younger. Because brain growth was believed to be complete, a PHE-restricted diet was thought to be no longer necessary. But data have shown that children removed from a PHE-restricted diet have decreased IQ and poorer school performance compared to the same age-matched children with PKU who remained on diet (12). Neurologic deterioration, mental aberrations, physical changes in the brain, and psychiatric problems have been reported in persons either removed from the PHE-restricted diet or in poor metabolic control (56, 68, 70, 71). For these reasons, it is now recommended that persons with PKU remain on diet for life and remain in good metabolic control. Offspring of mothers with untreated PKU or hyperphenylalaninemia (increased blood PHE without phenylketones in the urine) suffer from permanent mental retardation and may have microcephaly, congenital heart defects, and other anomalies. Although these offspring usually do not have PKU, they are exposed in utero to toxic concentrations of PHE (58).
IV. Establish Diagnosis

A. The Defect (19, 58) 1. PKU may result from defect in any of at least 3 enzymes: a. Biopterin synthetase group of enzymes. b. Dihydropteridine reductase. c. PAH. d. PAH with decreased affinity for H4 biopterin (42, 66) B. Clinical Evaluation 1. Concentration of 2 mg PHE/dL by bacterial inhibition assay of dried blood spot if test is administered before neonate is 24 hours old (18), or 4 mg/dL after 24 hours, requires differential diagnosis. C. Differential Diagnosis (19, 58) 1. Differential diagnosis will reveal false-positives and identify specific enzyme defect. 2. Therapy depends on enzyme defect present. 3. This protocol addresses nutrition support of patients with PAH deficiency.
V. Rationale for Nutrition Support

A. Correct Primary Imbalance in Metabolic Relationships 1. Restrict dietary PHE to amount tolerated by patient to maintain treatment plasma PHE concentration. B. Supply Product of Blocked Primary Pathway 1. Supplement dietary TYR as necessary to maintain normal plasma TYR concentration.
VI. Establish Goals of Nutrition Support (19, 58)

A. Plasma PHE Concentration 1. Maintain 2- to 4-hour postprandial plasma PHE concentration between 2 and 5 mg/dL when measured by bacterial inhibition assay (120 and 300 mol/L when measured by quantitative methods) (19, 46, 47, 63, 64). a. In patients >10 years of age until adulthood, plasma PHE concentration may range between 2 and 8 mg/dL (120 - 485 mol/L) (63, 64).
2 Phenylketonuria 2001 Ross Products Division
b. For adults with PKU, maintain 2- to 4-hour postprandial plasma PHE concentration between 2 and 10 mg/dL (120 - 605 mol/L) (75), although normal concentration was required in a patient to prevent complications (73). 2. In practice, obtaining blood 2 to 4 hours postprandially is not always possible. Acceptable local standards should be developed if plasma amino acids are evaluated at other times (Practical Aspects of Nutrition Support, p viii). Warning: Blood/plasma PHE concentration must be evaluated once or twice weekly, with concentrations maintained between 2 and 5 mg/dL. Otherwise, PHE deficiency may occur. PHE deficiency may result in failure to thrive and mental retardation (33, 37, 64). B. Plasma TYR Concentration 1. Maintain 2- to 4-hour postprandial plasma TYR concentration between 50 and 100 mol/L (0.9-1.8 mg/dL), or within normal range for age established by laboratory used. C. Growth, Development, and Nutrition Status 1. Support normal growth rate in infants and children and maintain appropriate weight for height in adults (3, 5, 7). 2. Support normal development (12, 24, 25, 63, 64). 3. Maintain normal nutrition status (2, 6-8, 16, 23, 28, 29, 33, 51, 53, 54, 57). 4. Prevent catabolism. D. Behavior, Mental Development, and Neurologic Status 1. Prevent behavioral abnormalities (10, 63, 64, 71). 2. Improve behavior of previously untreated adults with PKU (10, 73, 75). 3. Prevent EEG changes and neurologic deterioration in adults (20, 68, 70). E. Physical Manifestations 1. Prevent osteopenia (17, 36), eczema and offensive body odor (56).
VII. Establish Prescription

A. PHE 1. Prescribe PHE intake that promotes goals of nutrition support (Table 1-1, p 12). 2. PHE requirements vary widely: a. From patient to patient, depending on activity of PAH, which is dependent on genotype (1, 3, 4, 30, 31, 69). b. In same patient, depending on: 1) Age. 2) Growth rate (41). 3) Adequacy of energy and protein intakes (39). 4) State of health. 3. If diagnostic plasma PHE concentration is in following ranges, delete PHE from diet for hours noted:
Diagnostic Plasma PHE (mol/L) 240 < 605 605 < 1,210 1,210 < 2,420 2,420 (mg/dL) 4 < 10 10 < 20 20 < 40 > 40 Delete Dietary PHE For: (Hours) 24 48 72 96
a. To prevent PHE deficiency, plasma PHE concentration must be analyzed daily when all PHE is deleted from diet. b. When plasma PHE concentration reaches upper limit of treatment range (300 mol/L), PHE must be added to diet. 4. Dietary PHE suggested for initiating therapy after 1 to 4 days of PHE-free medical food mixture depends on maximum diagnostic quantitative plasma PHE concentration (not by bacterial inhibition assay). See values noted below for amounts of dietary PHE to begin therapy for specific plasma PHE concentrations:
2001 Ross Products Division Phenylketonuria 3
Plasma PHE (mol/L) 605 > 605 to 1210 > 1210 to 1815 > 1815 to 2420 > 2420 (mg/dL) 10 > 10 to 20 > 20 to 30 > 30 to 40 > 40
Dietary PHE (mg/kg) 70 55 45 35 25
5. Frequent monitoring of plasma PHE concentration is essential to assess patient's changing requirements. a. The closer to normal range that plasma PHE concentration is maintained, the more frequently plasma PHE concentration must be evaluated to prevent deficiency. b. See Section X, Suggested Evaluation of Nutrition Support, p 7. 6. Between 3 and 5 months of age, PHE requirements per kg body weight may decrease considerably. Warning: PHE deficiency results in following adverse effects: Low or elevated plasma PHE concentration, depending on stage of PHE deficiency (19). Bone changes and decreased growth rate in infants and children and weight loss in adults (21, 36, 40, 60). Changes in red blood cell precursors and anemia (53, 54). Generalized aminoaciduria and hypoproteinemia (37). Mental retardation (33, 64). Hair loss. Low plasma transthyretin (11). B. TYR (46) 1. Prescribe TYR intake that maintains treatment plasma TYR concentration. 2. Lowest value for dietary TYR for each age group listed in Table 1-1, p 12, is suggested to start therapy. 3. Changing requirements of patients are determined only by frequent monitoring of plasma TYR concentration. a. Prescribe TYR above amount supplied by Phenex and beikost or table foods only if plasma TYR concentration is below normal. C. Protein 1. Prescribe, initially, amount greater than Recommended Dietary Allowances (RDAs) (5, 22, 35, 41, 46, 55, 62) (Table 1-1, p 12). For neonates, use 3.50 g/kg/day. 2. Requirements are greater than RDAs when L-amino acids supply majority of protein equivalent as result of: a. Rapid amino acid absorption (26, 27). b. Early and high peak of plasma amino acid concentrations after ingestion of meals where large part of protein is supplied by L-amino acids (26, 27). c. Rapid catabolism of amino acids (35, 38). d. Possible decreased total amino acid absorption (48). Warning: Long-term inadequate protein intake will result in failure to thrive in infants, poor growth in children, weight loss in adults, low plasma transthyretin concentrations, osteopenia, hair loss, and decreased PHE tolerance. D. Energy (9) 1. Prescribe amount that should support normal weight gain in infants and children and maintain appropriate weight for height in adults (Table 1-1, p 12). 2. Requirements vary widely and may be greater than normal when L-amino acids supply majority of protein equivalent (50, 52) 3. Hyperactivity, if present, may significantly increase needs.
Warning:
Inadequate energy intake will result in failure to thrive in infants, poor growth in children, weight loss in adults, and low plasma transthyretin concentration. Weight loss will result in elevated plasma PHE concentration as result of protein catabolism. Poor growth will result in lower than expected tolerance of PHE.
E. Fluid 1. Prescribe amount that will supply water requirements (Table 1-1, p 12). Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL to children and adults for each kcal ingested. 2. Requirements may be higher than recommended secondary to increased fluid loss with fever.
VIII. Fill Prescription

A. PHE 1. Calculate amount of infant formula with iron, human milk, beikost, or table foods (Table 1-2, p 12) required to fill PHE prescription. a. Low-iron infant formula, whole cow's milk, and evaporated milk should not be used as PHE source for infants because of low iron content. 2. Measure liquid infant formula, human milk, and whole cow's milk with disposable syringe. Weigh powdered infant formula on scale that reads in grams. a. For other approaches to using human milk, see reference 76. 3. Add beikost (table foods) (Table 1-2, p 12) to gradually displace PHE provided by infant formula or human milk after infant is 3 to 4 months old or is developmentally ready. 4. Parents or patients may select any food in prescribed food lists (Table 1-3, p 13) in specified amounts to fill diet prescription. B. Protein 1. Calculate amount of infant formula with iron, human milk, beikost, whole cow's milk, or table foods (Table 1-2, p 12) required to fill the PHE prescription. 2. Subtract amount determined above from total protein prescription. 3. Supply any remaining prescribed protein with Phenex (Table 1-4, p 27). a. Phenex-1 is for infants and toddlers and Phenex-2 is for children, adolescents, and adults, but may be used by toddlers if child's appetite is small. b. Weigh Phenex powder on scale that reads in grams because of variability of household measuring equipment (Practical Approaches to Nutrition Support, p vii) and changes in density during shipping. c. See Table 1-4 (p 27, footnote 3) for approximate packed weight of Phenex powder in level, dry US standard household measures. C. TYR 1. Calculate approximate amount of TYR provided by infant formula with iron, human milk, beikost, whole cow's milk, or table foods (Table 1-2, p 12) required to fill PHE prescription. 2. Calculate amount of TYR supplied by Phenex (Table 1-4, p 27) required to fill protein prescription. 3. Added together, values calculated above should fall within range of TYR intake recommended in Table 1-1, p 12. 4. Supply remaining prescribed TYR as pure suspension. Add supplemental L-TYR only if plasma TYR concentration is below normal. a. For infants, mix weighed amounts of L-TYR powder with boiled, cooled water to yield 0.5 mg/mL (eg, 500 mg of L-TYR with enough water to yield 1 liter). b. Refrigerate suspension in sterilized, closed container until used. Discard unused suspension after 1 week, if not frozen. c. Shake well before using. Measure L-TYR (Appendix 26, p A-28) suspension into medical food mixture with disposable syringe. 5. For children or adults, L-TYR powder may be mixed with fruit pures such as applesauce, soups, pured vegetables, and mashed potatoes.
Phenylketonuria 5
6. L-TYR tablets may be used if patient can swallow them. Tablets are available at some pharmacies. D. Energy 1. Calculate energy provided by infant formula with iron, human milk, beikost, whole cow's milk, or table foods (Table 1-2, p 12) and Phenex (Table 1-4, p 27) required to fill PHE and protein prescriptions. 2. Subtract amount determined above from total energy prescription. 3. Provide remaining prescribed energy with Polycose Glucose Polymers powder (23 kcal/Tbsp, 3.8 kcal/g) or liquid (2 kcal/mL) (Appendix 9, p A-9); Pro-Phree Protein-Free Energy Module With Iron, Vitamins & Minerals (Appendix 11, p A-10); sugar (48 kcal/Tbsp); or Free Foods B (Table 1-2, p 12), depending on age of patient. a. Do not use corn syrup or table sugar for infants because of osmolarity they yield (45). b. Do not use honey for infants because it may contain botulinum toxin (67). E. Fluid and Mixing Instructions 1. Add sufficient boiled, cooled water to infant formula or human milk, Phenex, carbohydrate, and L-TYR (if needed) to yield prescribed volume. Tap water may replace boiled, cooled water when preparing Phenex for older infants, children, and adults. 2. Mix with sterilized blender at lowest speed for no longer than 3 to 4 seconds. Excess mixing may destabilize emulsion. Medical food may also be mixed in sterilized, tightly closed container by shaking vigorously for 10 to 12 seconds. 3. Refrigerate in sterilized, closed containers until used. Discard unused portion 24 hours after mixing because of nutrient loss. Store unopened cans at room temperature. Cover opened can and store in refrigerator. Use within 1 month after opening. 4. Do not use terminal sterilization or boil because of Maillard reaction (Practical Aspects of Nutrition Support, p viii). 5. Warm or cool medical food mixture to room temperature before feeding to infants. Shake well before feeding. 6. Do not warm medical food mixture in microwave oven. Unevenly heated formula can burn infants and steam can make bottles explode. 7. Notify parents or caretakers when they may discontinue using aseptic technique in preparing medical food mixture for infants. 8. For children and adults, chill Phenex medical food mixture to improve taste. F. Diet Guide 1. Provide parents, caretakers, or patient with completed Diet Guide (Appendix 22, p A-24) with each diet change. 2. Feed young infants 6 to 8 times daily (35, 55). 3. Feed older infants, children, and adults 4 to 6 times daily (35, 55).
IX. Evaluate Adequacy and Safety of Planned Nutrition Support

A. Nutrient Adequacy 1. Determine if diet provides nutrients in amounts prescribed in Section VII, Establish Prescription, p 3. a. See Table 1-4, p 27, for composition of Phenex and Table 1-2, p 12, for nutrient composition of infant formulas, human milk, and whole cow's milk. b. See Appendix 9, p A-9, for composition of Polycose and Appendix 11, p A-10, for composition of Pro-Phree. 2. Check diet to determine if it supplies Recommended Dietary Intakes (RDIs) for minerals and vitamins (Appendices 4 through 8, 13, and 14, pp A-4 through A-8, A-14, and A-15). a. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. b. If Phenex mixture provides < 100% of RDIs for infants and < 75% of RDIs for children and adults, supplement diet with needed minerals and vitamins if not provided by beikost or table foods and laboratory tests indicate need (Appendix 11, p A-10, for composition of supplements).
B. Osmolarity 1. If concentration of prescribed medical food mixture is > 24 kcal/fl oz, determine if osmolarity is in acceptable range. a. Determine osmolarity by laboratory analysis or use mathematical formula given in Appendix 18, p A-20. b. Osmolarity per gram of Phenex is listed in Appendix 19, p A-21. 2. If osmolarity is > 450 mosm/L for neonates, > 750 mosm/L for children, > 1,000 mosm/L for adults (62), or greater than tolerated by patient, increase water content of prescribed medical food mixture and recalculate its osmolarity (44, 65). C. Potential Renal Solute Load 1. Dehydration will result if renal solute load is greater than renal-concentrating ability of patient. 2. If concentration of medical food mixture prescribed is > 24 kcal/fl oz, estimate its potential renal solute load. a. This step is important to prevent dehydration of infants who may have renal-concentrating capacity as low as 600 mosm/L. b. Upper limit of renal solute load for neonates is approximately 1,100 mosm/L (61). 3. A method for estimating potential renal solute load is given in Appendix 20, p A-22. 4. If potential renal solute load is excessive, increase water content of medical food mixture and recalculate.
X. Suggested Evaluation of Nutrition Support

A. Plasma PHE and TYR Concentrations (46, 64) 1. Initial. a. Evaluate twice weekly by quantitative methods until plasma concentrations stabilize and approximate dietary PHE and TYR requirements are known. 2. Ongoing. a. Frequent evaluations help ensure adherence to nutrition support plan. b. Evaluate plasma PHE concentration weekly by bacterial inhibition assay or fluorometric method. c. Evaluate plasma PHE and TYR concentrations monthly by quantitative methods. 3. Unacceptable PHE concentrations. a. If plasma PHE concentration is not detected and patient has ingested full prescription: 1) Add 50 mg to prescribed PHE and reevaluate plasma PHE concentration in 3 days. 2) If plasma PHE concentration continues undetected, repeat above process until value is in treatment range. b. If plasma PHE concentration is < 120 mol/L (2 mg/dL) and patient has ingested full prescription: 1) Add 15 mg to prescribed PHE and reevaluate plasma PHE concentration in 3 days. 2) If plasma PHE concentration continues < 120 mol/L (2 mg/dL), repeat above process until value is in treatment range. c. If plasma PHE concentration is > 300 mol/L (5 mg/dL) and < 605 mol/L (10 mg/dL) and patient is not ill and has not ingested more PHE or significantly less protein and energy than prescribed: 1) Subtract 15 mg from prescribed PHE and reevaluate plasma PHE concentration in 3 days. 2) If plasma PHE concentration continues > 300 mol/L (5 mg/dL), repeat above process until value is in treatment range. d. If plasma PHE concentration is > 605 mol/L (10 mg/dL) and patient is not ill and has not ingested more PHE or significantly less protein and energy than prescribed: 1) Subtract 30 mg from prescribed PHE and reevaluate plasma PHE concentration in 3 days. 2) If plasma PHE concentration continues > 605 mol/L (10 mg/dL), repeat above process until value is in treatment range.
Phenylketonuria 7
B. Protein Status 1. Evaluate plasma transthyretin concentration every 3 months until patient is 1 year of age and every 6 months thereafter (Appendix 17, p A-18, for standards). a. Plasma transthyretin concentrations provide a more reliable and rapid indication of protein status than plasma albumin concentrations. b. Plasma albumin concentrations may be in the normal range when plasma transthyretin concentrations show a clear deficiency (11). 2. If plasma transthyretin concentration is below standard: a. Increase prescribed protein by 5% to 10% and reevaluate plasma transthyretin concentration in 1 month. If plasma PHE concentration is in treatment range, use Phenex to increase protein. b. If plasma transthyretin concentration continues below standard, repeat above process until value is in normal range. C. Iron Status 1. Plasma ferritin concentration (13-15). a. Evaluate at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17, p A-18, for standards). b. If plasma ferritin concentration is below standard: 1) Increase iron intake to 4 mg/kg with supplements (ferrous sulfate). 2) Evaluate plasma ferritin concentration monthly on increased iron intake. 3) Continue iron supplements until plasma ferritin concentration is in normal range. 2. Complete blood count. a. Hemoglobin and hematocrit concentrations should be evaluated at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17, p A-18, for standards). D. Serum/Erythrocyte Vitamin B12 and Folate 1. Patients who routinely fail to ingest prescribed amounts of medical food are at risk of vitamin B12 and folate deficiencies (32). 2. Serum or erythrocyte vitamin B12 and folate should be routinely analyzed if medical food prescribed is not ingested. 3. Serum and erythrocyte concentrations should be maintained between the following values:
Tissue Serum Erythrocyte Vitamin B12 (74) > 300 pg/mL --Folate (34) > 5 to < 10 ng/mL > 200 to < 300 ng/mL
4. Both vitamin B12 and folate tablets should be administered daily if the patient will not ingest prescribed amounts of medical food. E. Growth Status 1. Length/height and weight. a. Measure monthly to 1 year, every 3 months to 4 years, and every 6 months thereafter. Plot measurements on NCHS growth charts. b. Maintain length/height and weight between 10th and 90th percentiles. Some normal infants, children, and adults will fall above or below these percentiles. 2. If length/height or weight falls below usual growth channel: a. Increase prescribed protein and energy by 5% to 10% and remeasure in 1 month. b. If length/height or weight remains low, repeat above process until usual growth channel is achieved. 3. For previously untreated adult with PKU, weigh weekly after diet is initiated until weight is stabilized at appropriate weight for height, then weigh monthly. a. Liberal use of very-low-protein foods, Free Foods A (p 24), and Free Foods B (p 25) will help minimize weight loss. F. Nutrient Intake 1. Maintain records of food intake for 3 days immediately before each blood test (Appendices 24 and 25, pp A-26 and A-27).
2. For previously untreated adult with PKU who lives in an institution or group home that uses cycle menus, actual amounts of foods eaten should be noted in medical record. 3. Previously untreated adults with PKU who live independently will require help with grocery shopping, meal planning, cooking, and record keeping (75). They should be taught to use pictures or models of food to help them keep food diaries if they are illiterate, or if their guardian cannot maintain records. 4. Evaluate intakes of PHE, TYR, protein, and energy before each blood test. 5. Evaluate mineral and vitamin intakes after each diet change. a. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. b. See Appendix 28, p A-29, for information about ordering software for diet evaluation. G. Clinical Summary 1. A summary record of growth, laboratory, and nutrient intake data is useful for patient management (Table 1-5, p 29).
XI. Sample Prescriptions

A. Example 1 Establish and fill prescription for newborn weighing 3.3 kg who has diagnostic plasma PHE concentration of 1510 mol/L (41 mg/dL) using Recommended Daily Nutrient Intakes from Table 1-1, p 12, and average nutrient contents from Tables 1-2 and 1-4, pp 12 and 27. 1. Establish prescription.
PHE TYR Protein Energy Fluid 45 mg/kg 350 mg/kg 3.5 g/kg 127 kcal/kg 160 mL/kg x x x x x Measure 54 g 251 mL 199 mg 0 148 0 3.3 kg 3.3 kg 3.3 kg 3.3 kg 3.3 kg PHE (mg) 810 146 199 = = = = = 148 mg/day 1,155 mg 11.5 g 420 kcal 528 mL TYR (mg) Protein (g) 8.1 3.5 0.0 Energy (kcal) 259 171 0
2. Fill prescription.
Medical Food Mixture Phenex-1 Similac With Iron RTF L-Tyrosine
Add water to make 530 mL (18 fl oz). 148 1,155 11.6 430 Total per day 45 350 3.5 130 Total per kg Approximate osmolarity of medical food mixture is < 450 mosm/L. Estimated potential renal solute load is < 160 mosm.
B. Example 2 Establish and fill prescription for 2-year-old child weighing 13 kg using Recommended Daily Nutrient Intakes from Table 1-1, p 12, and Average nutrient contents from Tables 1-2 and 1-4, pp 12 and 27. 1. Establish prescription.
PHE TYR Protein Energy Fluid 200 mg/day 3,000 mg 30 g 1,300 kcal 1,375 mL
Phenylketonuria 9
TYR Protein (mg) (g) Phenex-1 164 g 0 2,460 24.6 L-Tyrosine 402 mg 0 402 0.0 Sugar 8 g (2 tsp) 0 0 0.0 Add water to make 710 mL (24 fl oz). Offer additional fluid ad libitum daily. Food List Servings Breads/Cereals 3 90 60 Fats 2 10 8 Fruits 2 30 20 Vegetables 5 75 50 Free Foods B 2 0 0 205 3,000 Total per day Approximate osmolarity of medical food mixture is < 700 mosm/L. Medical Food Mixture Measure PHE (mg) Energy (kcal) 787 0 32
1.8 0.2 1.0 2.5 0.0 30.1
90 120 120 50 110 1,309
C. Example 3 Establish and fill prescription for 6-year-old child using Recommended Daily Nutrient Intakes from Table 1-1, p 12, and average nutrient contents from Tables 1-2 and 1-4, pp 12 and 27. 1. Establish prescription.
PHE TYR Protein Energy Fluid 235 mg/day 3,500 mg 35.0 g 1,700 kcal 1,700 mL Energy (kcal) 398 0 336
Medical Food Measure PHE TYR Protein (mg) (mg) (g) Mixture Phenex-2 97 g 0 2,910 29.1 L-Tyrosine 430 mg 0 430 0.0 Sugar 84 g (7 Tbsp) 0 0 0.0 Add water to make 946 mL (32 fl oz). Offer additional fluid ad libitum daily. Food List Breads/Cereals Fats Fruits Vegetables Free Foods A Free Foods B Servings 4 2 3 3 3 6 2.4 0.2 1.5 1.5 0.3 0.0 35.0 120 120 180 30 195 330 1,709
120 80 10 8 45 30 45 30 15 12 0 0 235 3,500 Total per day Approximate osmolarity of medical food mixture is < 800 mosm/L.
D. Example 4 Establish and fill prescription for 20-year-old woman using Recommended Daily Nutrient Intakes from Table 1-1, p 12, and average nutrient contents from Tables 1-2 and 1-4, pp 12 and 27. 1. Establish prescription.
PHE TYR Protein Energy Fluid 220 mg/day 5,000 mg 50 g 2,100 kcal 2,100 mL
10 Phenylketonuria
Medical Food Measure PHE TYR Protein (mg) (mg) (g) Mixture Phenex-2 149 g 0 4,470 44.7 L-Tyrosine 376 mg 0 376 0.0 Sugar 60 g (5 Tbsp) 0 0 0.0 Add water to make 1183 mL (40 fl oz). Offer additional fluid ad libitum daily. Food List Servings Breads/Cereals 4 120 80 Fats 3 15 12 Fruits 3 45 30 Vegetables 2 30 20 Free Foods A 3 15 12 Free Foods B 10 0 0 225 5,000 Total per day Approximate osmolarity of medical food mixture is < 800 mosm/L. Energy (kcal) 611 0 240
2.4 0.3 1.5 1.0 0.3 0.0 50.2
120 180 180 20 195 550 2,096
XII. Nutrition Support During Febrile Illness or Following Trauma

A. Rationale 1. In normal persons, febrile illness and trauma are accompanied by catabolism of body protein (72). 2. Well-nourished patients with PKU respond to infection and trauma as do normal persons. 3. Extent of protein catabolism determines subsequent elevation in plasma PHE concentration. B. Objectives of Nutrition Support 1. Maintain hydration and electrolyte balance. a. Offer infants and toddlers Pedialyte Oral Electrolyte Maintenance Solution ad libitum (Appendix 9, p A-9). 2. Depress catabolism. a. Enhance energy intake when possible by offering fruit juices ad libitum as tolerated, liquid Jell-O , Polycose powder or liquid (Appendix 9, p A-9), or Pro-Phree (Appendix 11, p A10) added to fruit juices or Pedialyte if tolerated and caffeine-free soft drinks (not diet drinks). 1) 1/3 cup of Polycose powder may be added to liquid Pedialyte to yield 8 fl oz. b. Return patient to Phenex medical food mixture and pre-illness diet as rapidly as possible. 1) Begin with 1/2 original strength of Phenex medical food mixture. 2) Increase to original strength as tolerated. C. Parenteral Nutrition 1. If parenteral amino acid solutions are indicated, see Appendix 26, p A-28.
Phenylketonuria 11
TABLE 1-1. Recommended Daily Nutrient Intakes (Ranges) for Infants, Children, and Adults With PKU
Age PHE (mg/kg) Infants 0 to < 3 mo 3 to < 6 mo 6 to < 9 mo 9 to < 12 mo 25 - 70 20 - 45 15 - 35 10 - 35 (mg/day)
1-3 1
TYR (mg/kg) 300 - 350 300 - 350 250 - 300 250 - 300 (g/day)
Nutrient Protein4 (g/kg) 3.50 - 3.00 3.50 - 3.00 3.00 - 2.50 3.00 - 2.50 (g/day)
Energy4 (kcal/kg) 120 (145 - 95) 120 (145 - 95) 110 (135 - 80) 105 (135 - 80) (kcal/day)
Fluid5 (mL/kg) 160 - 135 160 - 130 145 - 125 135 - 120 (mL/day)
Girls and Boys 1 to < 4 yr 200 - 400 1.72 - 3.00 1,300 ( 900 - 1800) 900 - 1,800 30 4 to < 7 yr 210 - 450 2.25 - 3.50 1,700 (1300 - 2300) 1,300 - 2,300 35 7 to < 11 yr 220 - 500 2.55 - 4.00 2,400 (1650 - 3300) 1,650 - 3,300 40 Women 11 to < 15 yr 250 - 750 3.45 - 5.00 2,200 (1500 - 3000) 1,500 - 3,000 50 15 to < 19 yr 230 - 700 3.45 - 5.00 2,100 (1200 - 3000) 1,200 - 3,000 55 220 - 700 3.75 - 5.00 2,100 (1400 - 2500) 2,100 - 2,500 19 yr 60 Men 11 to < 15 yr 225 - 900 3.38 - 5.50 2,700 (2000 - 3700) 2,000 - 3,700 55 15 to < 19 yr 295 - 1,100 4.42 - 6.50 2,800 (2100 - 3900) 2,100 - 3,900 65 290 - 1,200 4.35 - 6.50 2,900 (2000 - 3300) 2,000 - 3,300 19 yr 70 1 See Section VII, Establish Prescription, p 3, for initial dietary PHE to prescribe based on diagnostic plasma PHE. Modify prescription based on frequently obtained blood and/or plasma values and growth in infants and children and frequently obtained plasma values and weight maintenance in adults. 2 PHE requirements of premature infants may be greater than highest value noted (59). 3 Modified from references 1, 3-5, 19, 43. 4 Modified from reference 22. 5 Modified from reference 13. Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL to children and adults for each kcal ingested.
TABLE 1-2. Serving Lists for PHE-Restricted Diets: Average Nutrient Content per Serving1
Food List PHE (mg) Breads/Cereals Fats Fruits Vegetables Free Foods A Free Foods B Alimentum Protein Hydrolysate Formula With Iron, Ready to Feed , 100 mL
2
Nutrient TYR (mg) 20 4 10 10 4 0 29 55 60 58 164 Protein (g) 0.6 0.1 0.5 0.5 0.1 0.0 1.86 1.07 1.66 1.40 3.39 Energy (kcal) 30 60 60 10 65 55 68 72 68 68 63
30 5 15 15 5 0 86 48 88 59 164
Human Milk, 100 mL, 3 Isomil Soy Formula With Iron, Ready to Feed, 100 mL 2 Similac With Iron Infant Formula, Ready to Feed, 100 mL 3 Whole cow's milk, 100 mL
1 2
From reference 19. See Appendices 4 through 7, pp A-4 to A-7, for complete nutrient composition of infant formulas. 3 From reference 49. See Appendix 8, p A-8, for complete nutrient composition.
12 Phenylketonuria
Phenylketonuria 13
TABLE 1-3. Serving Lists for PHE-Restricted Diets: Gerber Baby Food (Beikost)
Food Weight Approximate PHE (g) Measure (mg) For greatest accuracy, weigh food on scale that reads in grams. All measures are level. BREADS AND CEREALS Baked Finger Snacks, Graduates Animal crackers, cinnamon graham Apple cinnamon cookies Banana cookies Strawberry fruit bars Veggie crackers Cereals, Dry Barley Mixed Oatmeal Oatmeal/banana Oatmeal/mixed fruit Rice Rice/apples Rice/apple bits Rice/bananas Rice/mixed fruit Cereals, Jarred 1st Foods Oatmeal 2nd Foods Mixed/applesauce/bananas Oatmeal/applesauce/bananas Rice/applesauce 3rd Foods Mixed/apples/bananas Oatmeal/apples/cinnamon Tender Harvest Greenbeans/potatoes Spring garden vegetables Vegetables 1st Foods Peas Potatoes Sweet potatoes 2nd Foods Creamed corn Creamed spinach Garden vegetables Peas Sweet potatoes 3rd Foods Peas/rice Sweet potatoes FRUITS/JUICES Mixed fruit juice Pear juice 1st Foods Bananas 125 202 47 4 fl oz 6 2/5 fl oz 3 Tbsp + 3/4 tsp 15 15 15 6 4 8 0.3 0.6 0.5 60 99 47 TYR (mg) Protein (g) Energy (kcal)
10 10 10 12 7
1-1/2 cracker 1 cookie 1-1/4 cookie 1-1/3 bar 10 crackers
29 31 30 31 30
10 12 11 12 10
0.6 0.8 0.7 0.6 0.6
45 43 43 49 33
4 6 3 4 6 6 11 8 9 9
1 Tbsp + 1/4 tsp 1 Tbsp + 2 tsp 3/4 Tbsp 1 Tbsp + 1/4 tsp 1 Tbsp + 2 tsp 1 Tbsp + 2 tsp 3 Tbsp 2 Tbsp + 1/2 tsp 2 Tbsp + 1-1/2 tsp 2 Tbsp + 1-1/2 tsp
28 30 27 27 32 28 30 29 30 31
15 15 14 17 17 16 21 15 19 23
0.5 0.6 0.4 0.4 0.6 0.5 0.6 0.6 0.6 0.6
15 23 12 16 25 23 43 32 35 35
34 57 42 57 54 53 26 60
2 Tbsp + 1 tsp 1/4 cup 3 Tbsp 1/4 cup 3 Tbsp + 2 tsp 3 Tbsp + 2 tsp ND ND
30 30 30 30 30 30 30 30
20 15 13 15 16 16 23 18
0.6 0.6 0.5 0.4 0.6 0.6 0.6 0.9
19 49 35 52 41 36 16 21
24 75 45 31 20 30 24 48 23 48
1 Tbsp + 2 tsp 5 Tbsp + 1 tsp 3 Tbsp 2 Tbsp 1 Tbsp + 1-1/2 tsp 2 Tbsp 1 Tbsp + 2 tsp 3 Tbsp + 1 tsp 1 Tbsp + 2 tsp 3 Tbsp + 1 tsp
30 30 30 30 30 30 30 30 30 30
19 25 12 20 23 18 19 12 15 15
0.7 0.8 0.5 0.6 0.6 0.4 0.7 0.5 0.2 0.5
12 35 29 19 9 11 12 30 12 29
14 Phenylketonuria
Weight Approximate PHE (g) Measure (mg) For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Peaches 88 6 Tbsp + 1/2 tsp 15 Pears 68 1/4 cup + 2 tsp 15 Prunes 58 1/4 cup 15 2nd and 3rd Foods Applesauce/apricot 100 7 Tbsp 15 Apricots/mixed fruit 75 5 Tbsp + 1 tsp 15 Bananas 47 3 Tbsp + 3/4 tsp 15 Bananas/apples/pears 43 3 Tbsp 15 Banana/pineapple 43 3 Tbsp 15 Banana/strawberry 60 1/4 cup 15 Hawaiian delight dessert, 2nd Foods 24 1 Tbsp + 2 tsp 15 Hawaiian delight dessert, 3rd Foods 21 1 Tbsp + 1-1/2 tsp 15 Peach cobbler dessert, 2nd Foods 136 9 Tbsp + 1-1/2 tsp 15 Peach cobbler dessert, 3rd Foods 125 1/2 cup + 2 tsp 14 Peaches, 2nd Foods 88 6 Tbsp + 1/2 tsp 15 Peaches, 3rd Foods 83 5 Tbsp + 2 tsp 15 Pear/pineapple 71 1/3 cup 15 Pears 88 6 Tbsp + 1/2 tsp 15 Plums/apples, 2nd Foods 94 6 Tbsp + 2 tsp 15 Plums/apples, 3rd Foods 71 5 Tbsp 15 Prunes/apples 71 1/3 cup 15 Fruit Dices, Graduates Apples Mixed fruit Peaches Pears Fruit/Vegetable Juices Apple/carrot Apple/sweet potato Tender Harvest Apple/sweet potato Banana/oatmeal/peach Pear/wild blueberry Pears/winter squash Tropical fruit blend VEGETABLES 1st Foods Carrots Green beans Squash 2nd Foods Carrots Green beans Mixed vegetables Squash 3rd Foods Carrots Green beans/rice Squash Tender Harvest Butternut squash/corn Garden carrots/brown rice
Food
TYR (mg) 9 4 5 6 7 8 5 6 8 9 8 7 4 9 7 4 8 5 4 6
Protein (g) 0.6 0.3 0.6 0.3 0.4 0.5 0.4 0.4 0.6 0.3 0.3 0.7 0.6 0.6 0.6 0.3 0.4 0.4 0.3 0.4
Energy (kcal) 38 39 58 52 45 42 36 32 54 20 18 103 54 56 53 39 65 66 49 55
136 115 94 136
ND ND ND ND
15 15 15 15
4 6 6 7
0.3 0.3 0.5 0.4
65 56 46 73
214 125 125 27 100 25 68
6-3/4 fl oz 4 fl oz ND ND ND ND ND
15 15 15 15 15 15 15
11 9 8 6 5 6 7
0.2 0.4 0.3 0.3 0.4 0.3 0.4
89 62 72 20 61 13 50
75 23 50 75 31 27 33 65 28 71 25 47
5 Tbsp + 1 tsp 1 Tbsp + 2 tsp 3 Tbsp + 1-1/2 tsp 5 Tbsp + 1 tsp 2 Tbsp 1 Tbsp + 2 tsp 2 Tbsp + 1 tsp 4 Tbsp + 1-1/2 tsp 2 Tbsp 1/3 cup ND ND
15 15 15 15 15 15 15 15 15 15 15 15
10 9 14 10 11 11 7 10 11 11 10 9
0.7 0.4 0.4 0.6 0.4 0.3 0.2 0.5 0.3 0.6 0.5 0.4
26 9 17 22 10 11 10 19 12 23 12 20
Phenylketonuria 15
Weight Approximate PHE (g) Measure (mg) For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Vegetable Dices, Graduates ND Carrots 38 15 ND Green beans 28 15 FREE FOODS A Apple juice Apple/banana juice Apple/cherry juice Apple/cranberry juice Apple/grape juice Apple/prune juice Fruit medley tropical fruit dessert Guava tropical fruit dessert Mango/banana/passion fruit juice Mango tropical fruit dessert Mixed fruit juice Orange juice Papaya tropical fruit dessert Peach/mango dessert 1st and 2nd Foods Applesauce Apple/blueberry 3rd Foods Fruit salad Beverages, Graduates Berry punch Fruit punch Tender Harvest Apple/mango/kiwi Apple/strawberry
1
Food
TYR (mg)
Protein (g)
Energy (kcal)
8 12
0.2 0.3
9 7
218 93 124 93 218 124 100 83 57 50 163 100 83 78 86 83 50
7 fl oz 3 fl oz 4 fl oz 3 fl oz 7 fl oz 4 fl oz 7 Tbsp 1/3 cup + 2-1/2 tsp 1-3/4 fl oz 3 Tbsp + 1-1/2 tsp 5 fl oz 3-1/5 fl oz 1/3 cup + 2-1/2 tsp 1/3 cup + 1 tsp 1/4 cup + 2 Tbsp 5 Tbsp + 2 tsp 3 Tbsp + 1-1/2 tsp
5 5 5 5 5 5 5 5 6 5 5 7 5 5 5 5 5
5 4 3 4 5 4 2 2 3 3 2 3 2 3 3 3 3
0.2 0.2 0.3 0.2 0.2 0.3 0.2 0.1 0.1 0.1 0.5 0.6 0.2 0.2 0.2 0.2 0.2
109 50 62 46 112 69 64 58 34 43 80 47 53 47 48 42 32
218 218 100 100
7 fl oz 7 fl oz 7 Tbsp 7 Tbsp
5 5 5 5
5 5 3 3
0.2 0.2 0.1 0.1
111 113 60 60
Prepared from 1998 and 1999 data from Gerber Products Co, Fremont, MI 49413. ND = No data. Weights and Measures Except for Dry Cereals and Food Dices, the following weights apply: Level = Level 1 tsp = 1/3rd Tbsp = 4.8 g 1 Tbsp = 1/16th cup = 14.3 g 1/4 cup = 4 Tbsp = 57.2 g 1/3 cup = 5-1/3rd Tbsp = 76.2 g 1/2 cup = 8 Tbsp = 114.3 g 2/3 cup = 10 2/3rd Tbsp = 152.5 g 3/4 cup = 12 Tbsp = 171.5 g 1 cup = 16 Tbsp = 228.6 g
16 Phenylketonuria
TABLE 1-3. Serving Lists for PHE-Restricted Diets: Table Foods

Food
Weight Approximate PHE (g) Measure (mg) For greatest accuracy, weigh food on scale that reads in grams. All measures are level. BREADS AND CEREALS Cereals, Cooked. Measure after cooking. Corn grits instant cheese flavor plain regular, quick (plain) Cream of Rice Cream of Wheat instant Mix'n Eat flavored plain quick regular Farina Maltex Malt-o-Meal Maypo Oat Oats, regular, quick, and instant Pettijohns Ralston Roman Meal (plain) Wheatena Whole Wheat Hot Natural Cereals, Ready To Eat All Bran Alpha-Bits Apple Jacks 100% Bran Bran Buds Bran Chex Cap'n Crunch Cap'n Crunch's Crunch Berries Cap'n Crunch's Peanut Butter Cheerios Cinnamon Toast Crunch Cocoa Krispies Cocoa Pebbles Cocoa Puffs Cookie Crisp Corn Bran Corn Chex Corn Flakes Crispy Rice Crispy Wheat 'n Raisins C W Post plain w/ raisins Fortified Oat Flakes 40% Bran Flakes (Post ) Froot Loops
TYR (mg)
Protein (g)
Energy (kcal)
36 34 45 81 30 38 36 30 30 44 31 35 30 20 30 32 22 30 30
1/4 packet 1/4 packet 3 Tbsp 1/3 cup 2 Tbsp 1/4 packet 1/4 packet 2 Tbsp 2 Tbsp 3 Tbsp 2 Tbsp 2 Tbsp + 1 tsp 2 Tbsp 1 Tbsp + 1 tsp 2 Tbsp 2 Tbsp 1 Tbsp + 1-1/2 tsp 2 Tbsp 2 Tbsp
36 27 33 30 30 33 37 25 30 34 33 29 34 28 24 32 31 29 29
29 22 28 40 18 20 22 14 18 20 19 16 20 18 14 19 22 17 17
0.7 0.5 0.6 0.7 0.6 0.6 0.7 0.4 0.5 0.6 0.7 0.5 0.7 0.5 0.5 0.7 0.6 0.6 0.6
27 20 28 42 19 33 26 16 19 22 22 18 21 12 20 17 14 22 19
5 7 9 6 5 6 12 12 9 4 19 12 16 19 10 9 7 7 9 11 6 7 3 6 9
1 Tbsp 1/4 cup 1/3 cup 1 Tbsp + 1-1/2 tsp 1 Tbsp 2 Tbsp 1/3 cup 1/3 cup 1/4 cup 3 Tbsp 1/2 cup 1/3 cup 1/2 cup 2/3 cup 1/3 cup 1/4 cup 1/4 cup 1/3 cup 1/3 cup 1/4 cup 1 Tbsp 1 Tbsp 1 Tbsp 2 Tbsp 1/3 cup
29 29 26 30 28 29 33 32 33 35 30 27 33 31 26 32 26 31 26 35 29 29 29 30 29
22 20 18 22 21 23 25 25 27 23 18 34 42 26 19 24 22 26 34 21 21 21 21 20 20
0.8 0.5 0.5 0.8 0.7 0.6 0.6 0.6 0.6 0.6 0.7 0.6 0.8 0.7 0.5 0.6 0.5 0.6 0.6 0.7 0.5 0.6 0.6 0.7 0.6
13 28 36 17 14 20 51 49 38 17 80 46 66 73 39 31 28 29 37 37 27 28 11 19 37
Phenylketonuria 17
Food
Weight Approximate PHE (g) Measure (mg) For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Frosted Mini-Wheats 8 1 biscuit 38 Frosted Rice Krinkles 16 1/2 cup 34 Frosted Rice Krispies 14 1/2 cup 28 Fruit Wheat Squares 10 2 Tbsp 32 Fruity Pebbles 16 1/2 cup 28 Golden Grahams 10 1/4 cup 28 Grape Nuts Flakes 6 3 Tbsp 33 Honey Nut Cheerios 5 2 Tbsp 27 Honey Nut Corn Flakes 9 1/4 cup 31 Honeycomb 11 1/2 cup 33 King Vitaman 11 1/2 cup 29 Kix 6 1/3 cup 29 Life 3 1 Tbsp 28 Lucky Charms 6 3 Tbsp 30 Nutri-Grain barley 5 2 Tbsp 31 corn 8 3 Tbsp 32 rye 8 3 Tbsp 31 wheat 5 2 Tbsp 25 Oat Flakes 3 1 Tbsp 29 Product 19 6 3 Tbsp 31 Quisp 11 6 Tbsp 30 Raisin Bran (Post ) 7 2 Tbsp 26 Rice Chex 13 1/2 cup 29 Rice Krispies 9 1/3 cup 27 Rice, puffed 10 3/4 cup 28 Special K 4 2 Tbsp 31 Sugar Frosted Flakes 12 1/3 cup 30 Sugar Pops 11 6 Tbsp 29 Sugar Smacks 9 1/4 cup 34 Sugar Sparkled Flakes 13 1/2 cup 35 Super Sugar Crisp 8 1/4 cup 28 Team 11 1/4 cup 32 Toasties (Post ) 7 1/3 cup 29 Total 6 3 Tbsp 30 Trix 9 1/3 cup 27 Wheat puffed 4 1/3 cup 30 shredded 5 1 Tbsp + 1-1/2 tsp 28 Wheat Chex 6 2 Tbsp 30 Wheaties 7 1/4 cup 33 Grains Corn cob (medium ear) cooked cream style whole kernel Rice, prepared brown, cakes fried pilaf Rice-A-Roni Spanish
TYR (mg) 22 44 37 19 37 22 20 18 25 26 23 23 20 20 19 27 21 15 21 23 23 17 38 36 37 34 25 24 20 29 16 31 24 18 21 17 17 17 20
Protein (g) 0.8 0.8 0.6 0.7 0.6 0.5 0.7 0.5 0.6 0.6 0.5 0.6 0.5 0.5 0.6 0.6 0.7 0.5 0.6 0.6 0.6 0.7 0.7 0.6 0.7 0.7 0.6 0.6 0.7 0.7 0.5 0.7 0.6 0.6 0.5 0.6 0.6 0.6 0.7
Energy (kcal) 28 62 54 35 66 38 22 18 38 43 43 24 10 23 19 30 27 20 11 24 47 22 50 37 42 14 44 43 35 64 31 41 27 22 35 14 19 21 25
21 32 20 25 9 23 15 21 30
1/3 ear 2 Tbsp 2 Tbsp 2 Tbsp 1 cake 1 Tbsp + 2 tsp 1 Tbsp 1 Tbsp + 1 tsp 2 Tbsp
30 26 32 32 34 30 30 28 26
25 21 26 24 45 23 20 20 21
0.6 0.6 0.7 0.6 0.8 0.7 0.6 0.7 0.5
19 23 22 27 35 30 23 27 26
18 Phenylketonuria
Weight Approximate PHE (g) Measure (mg) For greatest accuracy, weigh food on scale that reads in grams. All measures are level. white long-grain 26 2 Tbsp 36 long-grain, instant 31 3 Tbsp 34 medium- and short-grain 26 2 Tbsp 32 Pasta, cooked Macaroni Noodles Ramen Noodles Spaghetti Tubers Potatoes, sweet baked, w/ skin, mashed boiled, no skin, mashed canned, packed in syrup Potatoes, white baked, no skin boiled no skin w/ skin canned French fries (1/2" x 1/2" x 2") hash browns, frozen/cooked microwaved, w/ skin pan fried Tater Tots Yams, baked or boiled Miscellaneous Chocolate sauce (Hershey's ) Chow mein noodles Flour, cake Jell-O , w/ sugar Snack Foods Barnum's Animal Crackers Cookies fig bar Ho Ho's Oreo Social Tea Biscuit Sugar Wafer (Nabisco ) vanilla wafer Crackers Goldfish , original graham cracker (2" x 2") Ritz Ritz Bits (cheese) Rye Thins Rykrisp saltine soda Waverly Wheat Thins Doodads
Food
TYR (mg)
Protein (g)
Energy (kcal)
23 21 20
0.7 0.6 0.6
33 30 33
12 13 10 19
1 Tbsp + 1-1/2 tsp 1 Tbsp + 1 tsp 1 Tbsp 2 Tbsp
31 26 25 33
18 14 15 17
0.6 0.5 0.6 0.6
18 17 22 21
25 31 49 30 39 40 45 20 20 29 29 37 42
2 Tbsp 1 Tbsp + 1-1/2 tsp 1/4 cup 1/4 cup 1/4 cup 1/4 cup 1/4 cup 4 fries 2 Tbsp 3 Tbsp 3 Tbsp 4 pieces 1/3 cup
26 30 26 31 30 32 28 32 26 27 30 33 29
18 21 18 26 25 28 24 19 15 23 18 19 17
0.4 0.5 0.4 0.7 0.7 0.8 0.3 0.7 0.6 0.6 0.7 0.8 0.6
26 32 67 33 34 34 27 64 43 29 61 61 49
20 7 8 80
1 Tbsp 2 Tbsp 1 Tbsp + 1 tsp 1/3 cup
25 35 31 30
18 21 19 3
0.5 0.8 0.6 0.6
49 38 30 65
10 16 14 11 11 17 12 9 7 10 6 8 6 6 7 7 9 7
4 crackers 1 cookie 1/2 Ho Ho 1 cookie 2 biscuits 3 wafers 3 wafers 15 crackers 1 cracker 3 crackers 8 crackers 3 crackers 1 cracker 2 crackers 1 cracker 1 cracker 5 crackers 2 Tbsp
34 33 27 24 28 30 32 29 28 32 28 27 30 27 35 24 31 34
21 21 17 15 17 18 19 19 17 19 18 12 21 16 19 15 19 22
0.7 0.6 0.6 0.5 0.6 0.7 0.6 0.6 0.6 0.7 0.5 0.6 0.6 0.5 0.7 0.5 0.7 0.8
45 57 60 53 48 80 55 44 27 50 28 39 23 26 30 35 43 35
Phenylketonuria 19
Food
Weight Approximate PHE (g) Measure (mg) For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Doritos 9 5 chips 28 Doughnuts, Ener-G Banana 84 2 doughnuts 31 Fritos 10 5 chips 30 Ice cream cone, wafer type 4 1 (cone only) 22 Popcorn buttered 6 2/3 cup 31 caramel 9 1/4 cup 28 plain 4 2/3 cup 26 Potato chips (2" diameter) 10 5 chips 29 Rice cakes 9 1 cake 34 Tortillas chips 8 1 chip 36 corn (6" diameter) 8 1/4 tortilla 36 flour (6" diameter) 8 1/4 tortilla 33
TYR (mg) 17 10 22 13 26 23 22 24 45 29 29 19
Protein (g) 0.7 0.8 0.7 0.4 0.6 0.5 0.5 0.6 0.8 0.7 0.7 0.7
Energy (kcal) 44 309 55 17 27 34 15 52 35 27 27 27
FATS Butter, stick Gravy mushroom, canned mushroom mix, dry onion mix, dry Margarine liquid soft stick or brick Nondairy creamers, w/ sodium caseinate liquid powder Rich's Coffee Rich Polyrich Olives, black or green Salad dressings, commercial French Italian mayonnaise Thousand Island Toppings, commercial Cool Whip extra creamy regular Richwhip pressurized prewhipped Whipped cream, pressurized 14 10 1 1 5 14 14 10 2 29 29 10 16 15 9 16 1 Tbsp 2 tsp 2 tsp 2 tsp 1 tsp 1 Tbsp 1 Tbsp 2 tsp 1 tsp 2 Tbsp 2 Tbsp 2 olives 1 Tbsp 1 Tbsp 2 tsp 1 Tbsp 6 6 4 5 4 5 6 6 5 4 4 4 4 4 5 6 6 4 3 3 4 5 6 4 5 3 3 4 4 4 4 6 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.2 0.1 0.1 0.1 0.1 101 5 3 3 34 102 101 14 11 44 44 15 67 69 66 59
5 8 22 8 4
1 Tbsp 2 Tbsp 3 Tbsp 2 Tbsp 1 Tbsp
6 6 5 5 6
6 6 4 4 6
0.1 0.1 0.1 0.1 0.1
15 22 60 24 10
FRUITS Fruits are raw unless otherwise noted. Weight of raw fruits is only for parts that can be eaten. Drain canned, cooked, and frozen fruits before measuring or weighing. Do not use any fruits that contain NutraSweet, SweetMate, or aspartame. Apricots canned, heavy syrup dried, halves frozen, sweetened nectar, canned whole Avocados, all varieties, mashed Bananas, sliced
64 11 60 94 35 23 42
1/4 cup 3 1/4 cup 3 fl oz 1 fruit 1 Tbsp + 2 tsp 3 Tbsp
14 16 16 15 18 17 16
8 9 9 9 10 12 10
0.3 0.4 0.4 0.3 0.5 0.5 0.4
54 25 60 53 17 38 39
20 Phenylketonuria
Weight Approximate PHE (g) Measure (mg) For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Blackberries canned, heavy syrup 25 2 Tbsp + 1-1/2 tsp 16 frozen 50 1/2 cup 17 raw 72 1/2 cup 15 Blueberries canned, heavy syrup 64 1/4 cup 15 frozen, sweetened 115 1/2 cup 16 raw 72 1/2 cup 17 Boysenberries, canned, heavy syrup 64 1/4 cup 18 Cherries canned, heavy syrup sour red 77 1/3 cup 12 sweet 86 1/3 cup 15 raw 48 1/3 cup 13 Dates 25 3 fruits 14 Figs canned, heavy syrup 168 3/4 cup 15 dried, uncooked 19 1 fruit 14 whole, large 83 1-2/3 fruit 15 Fruit cocktail, canned, heavy syrup 128 1/2 cup 14 Fruit salad, canned, heavy syrup 128 1/2 cup 14 Gooseberries, canned, light syrup 63 1/4 cup 15 Grapefruit, all varieties canned, light syrup 85 1/3 cup 15 juice, canned, unsweetened 124 4 fl oz 19 sections 77 1/3 cup 16 Grapes adherent skin 120 3/4 cup 16 juice, canned 126 4 fl oz 15 slipskin 92 1 cup 12 Thompson, seedless, canned, heavy syrup 128 1/2 cup 13 Kiwi fruit 50 2/3 piece 16 Mangoes, sliced 82 1/2 cup 14 Melons, cubed cantaloupe 53 1/3 cup 13 casaba 57 1/3 cup 15 honeydew 85 1/2 cup 11 Mixed fruit, canned, heavy syrup 127 1/2 cup 14 Nectarines, sliced 52 6 Tbsp 16 Oranges juice canned 249 8 fl oz 17 frozen, diluted 187 6 fl oz 15 sections 45 1/4 cup 14 Papaya, cubed 140 1 cup 13 Passion fruit juice 124 4 fl oz 14 whole, small 18 1 fruit 12 Peaches canned, heavy syrup 128 1/2 cup 18 dried 13 1/2 cup 15 frozen, sweetened 83 1/3 cup 17 nectar 187 6 fl oz 16 sliced 85 1/2 cup 18 spiced, canned, heavy syrup 121 1/2 cup 16 Pears canned, heavy syrup 255 1 cup 13 2001 Ross Products Division
Food
TYR (mg)
Protein (g)
Energy (kcal)
19 20 17 5 6 6 13
0.6 0.6 0.5 0.4 0.5 0.5 0.6
39 32 38 56 93 41 56
5 10 5 8 32 25 27 9 10 5 8 13 8 14 4 10 10 13 9 8 10 8 10 12
0.6 0.5 0.6 0.5 0.7 0.6 0.6 0.4 0.4 0.4 0.5 0.6 0.5 0.8 0.7 0.6 0.6 0.5 0.4 0.5 0.5 0.4 0.5 0.5
70 67 34 68 180 48 61 93 94 46 50 48 24 86 78 58 93 31 54 18 15 30 92 25
7 8 7 7 10 8 16 12 13 13 16 13 5
1.5 1.3 0.4 0.9 0.5 0.4 0.6 0.5 0.5 0.5 0.6 0.5 0.5
105 84 21 54 63 73 95 31 78 100 37 90 188
Phenylketonuria 21
Food
Weight Approximate PHE (g) Measure (mg) For greatest accuracy, weigh food on scale that reads in grams. All measures are level. halves, dried 35 2 17 sliced 165 1 cup 17 Persimmons, Japanese 56 1/3 fruit 15 Pineapple canned, heavy syrup, chunks, tidbits, or crushed 191 3/4 cup 17 diced 116 3/4 cup 14 frozen, sweetened, chunks 122 1/2 cup 15 juice, canned, frozen, diluted 125 4 fl oz 15 Plantains, cooked 51 1/3 cup 14 Plums cubed 82 1/2 cup 14 purple, canned, heavy syrup 194 3/4 cup 16 Prunes juice 128 4 fl oz 17 whole, dried 25 3 fruits 15 Raisins, seedless 18 2 Tbsp 12 Raspberries canned, heavy syrup 64 1/4 cup 15 raw 62 1/2 cup 16 red, frozen, sweetened 83 1/3 cup 17 Rhubarb, cooked, sweetened 120 1/2 cup 14 Strawberries, sliced frozen, sweetened 85 1/3 cup 13 raw 74 1/2 cup 13 Tangerines canned, light syrup 84 1/3 cup 13 juice canned, sweetened 249 8 fl oz 15 frozen, diluted 241 8 fl oz 12 whole, medium 84 1 fruit 18 Watermelon, cubed 120 3/4 cup 18
TYR (mg) 6 5 9 15 14 16 13 10 5 6 6 6 11 18 19 20 9 15 16 7 7 5 9 14
Protein (g) 0.7 0.6 0.4 0.8 0.4 0.5 0.5 0.4 0.7 0.7 0.8 0.7 0.6 0.5 0.6 0.6 0.5 0.5 0.5 0.4 1.2 1.0 0.5 0.7
Energy (kcal) 92 97 39 149 58 104 65 60 45 172 90 60 55 58 30 85 139 82 23 51 125 110 37 38
VEGETABLES Vegetables are raw unless otherwise noted. Weight of raw vegetables is only for parts that can be eaten. Drain canned and cooked vegetables before measuring or weighing. Asparagus canned green white fresh or frozen, cooked raw Bamboo shoots, canned, sliced Beans, snap, green canned fresh, cooked frozen, cooked sprouts mung (seed attached to sprout) cooked raw soy cooked raw yellow wax canned
30 38 22 21 25
2 Tbsp or 2 spears 2 spears 1-1/2 spears 1-1/2 spears 3 Tbsp
15 19 16 16 15
9 13 10 10 12
0.6 0.6 0.6 0.7 0.4
6 7 6 7 5
34 16 34
1/4 cup 2 Tbsp 1/4 cup
14 14 17
9 9 11
0.4 0.4 0.5
7 7 9
16 13 8 6 34
2 Tbsp 2 Tbsp 1 Tbsp 1 Tbsp 1/4 cup
14 15 13 12 14
6 7 12 11 9
0.3 0.4 0.4 0.4 0.4
3 4 3 3 7
22 Phenylketonuria
Weight Approximate PHE (g) Measure (mg) For greatest accuracy, weigh food on scale that reads in grams. All measures are level. frozen, cooked 34 1/4 cup 14 Beets red, sliced fresh or canned, cooked 50 1/3 cup 15 pickled 50 1/3 cup 15 greens, cooked 18 2 Tbsp 12 Broccoli, fresh or frozen cooked 20 2 Tbsp 18 raw 16 3 Tbsp 14 Brussels sprouts, fresh or frozen, cooked 21 1 sprout 16 Cabbage, shredded Chinese (Pak-choi) cooked 32 3 Tbsp 15 raw 35 1/2 cup 15 red cooked 37 1/4 cup 13 raw 35 1/2 cup 15 white cooked 52 1/3 cup 15 raw 35 1/2 cup 14 Carrots canned 50 1/2 cup 15 fresh or cooked 39 1/4 cup 14 sliced 55 1/2 cup 18 Cauliflower cooked 23 3 Tbsp 16 frozen, cooked 22 2 Tbsp 13 raw 25 1/4 cup 18 Celery, diced cooked 75 1/2 cup 11 raw 60 1/2 cup 11 Chard, cooked 14 1 Tbsp + 1 tsp 15 Chayote, fruit, cooked 40 1/4 cup 14 Collards, cooked, chopped fresh 48 1/4 cup 18 frozen 14 1 Tbsp + 1 tsp 14 Cucumber, pared, sliced 104 1 cup 16 Eggplant, cubed cooked 48 1/2 cup 17 raw 31 6 Tbsp 14 Endive, raw, shredded 25 1/2 cup 13 Kale, cooked fresh 16 2 Tbsp 16 frozen 11 1 Tbsp + 1 tsp 15 Kohlrabi, sliced cooked 41 1/4 cup 17 raw 35 1/4 cup 14 Lettuce bibb and Boston, raw 30 4 leaves 16 iceberg, shredded 28 1/2 cup 14 Romaine and cos, raw 20 2 leaves 14 Mushrooms, Agaricus bisporus cooked or canned 19 1/4 cup 15 raw, sliced 18 1 mushroom 15 Shitake cooked 18 2 Tbsp 12
Food
TYR (mg) 11
Protein (g) 0.5 9
Energy (kcal)
12 12 11 13 7 12
0.5 0.5 0.5 0.6 0.3 0.5
15 15 5 6 3 8
10 10 7 8 8 7 9 8 11 10 8 11 5 5 11 10 15 11 9 11 9 10 11 11 12 17 10 8 8
0.5 0.5 0.4 0.5 0.5 0.4 0.5 0.4 0.6 0.4 0.4 0.5 0.4 0.4 0.2 0.2 0.5 0.4 0.6 0.4 0.3 0.3 0.3 0.3 0.7 0.6 0.4 0.3 0.3 17 18 24 6 4 6 11 9 3 10 6 5 14 13 8 4 5 4 12 10 4 4 4
4 5 8 10 10 8
8 8 8
0.4 0.4 0.3
5 5 10
Phenylketonuria 23
Food
Weight Approximate PHE (g) Measure (mg) For greatest accuracy, weigh food on scale that reads in grams. All measures are level. dried 4 1 mushroom 17 Mustard greens, cooked 26 3 Tbsp 16 Okra, pods or sliced, cooked 23 2 Tbsp 16 Onions cooked 75 1/3 cup 15 raw, chopped 50 1/3 cup 15 rings, canned 25 1/2 cup 18 Parsnips, cooked 58 6 Tbsp 15 Peas, green, canned or frozen, cooked 10 1 Tbsp 17 Peppers, green, diced cooked 68 1/2 cup 13 raw 50 1/2 cup 13 Pickles, cucumber dill 104 1 large 16 dill relish 83 1/3 cup 12 sweet 83 1/3 cup 12 Pumpkin, canned 46 3 Tbsp 16 Radish red, small 67 15 radishes 15 white icicle, sliced 50 1/2 cup 18 Rutabagas cooked, mashed 60 1/4 cup 17 raw, cubed 44 1/3 cup 14 Sauerkraut 59 1/4 cup 17 Shallots, chopped 20 2 Tbsp 16 Spinach fresh or frozen, cooked 12 1 Tbsp 16 raw, chopped 14 1/4 cup 18 Squash, summer, all varieties fresh or frozen, cooked 45 1/4 cup 15 sliced 33 1/4 cup 14 Squash, winter acorn baked, cubed 38 3 Tbsp 17 boiled, mashed 61 1/4 cup 16 butternut baked, cubed 51 1/4 cup 18 boiled, mashed 30 2 Tbsp 15 Hubbard baked, cubed 26 2 Tbsp 15 boiled, mashed 30 2 Tbsp 17 spaghetti, cooked 51 1/3 cup 12 Taro, cooked 66 1/2 cup 18 leaves 18 2 Tbsp 20 root, sliced Tomato canned or fresh, cooked 60 1/4 cup 17 catsup 31 2 Tbsp 15 fresh juice 92 3 fl oz 15 paste 16 1 Tbsp 13 pure 47 3 Tbsp 16 sauce canned, w/ onions, green pepper, and celery 61 1/4 cup 17 marinara 47 3 Tbsp 16 whole, small 66 1/2 tomato 14
TYR (mg) 12 31 21 15 15 12 12 10 9 9 9 7 7 21 9 11 13 10 9 14 13 15 11 10
Protein (g) 0.3 0.6 0.5 0.7 0.6 0.4 0.6 0.5 0.4 0.4 0.6 0.4 0.4 0.5 0.4 0.6 0.7 0.5 0.5 0.5 0.4 0.4 0.4 0.4
Energy (kcal) 11 4 8 20 15 90 48 7 12 13 14 14 114 15 10 7 20 16 11 14 2 3 9 7
15 14 16 12 13 15 10 13 18
0.4 0.4 0.5 0.4 0.6 0.4 0.3 0.3 0.5
21 20 20 12 13 9 15 94 4
12 8 9 8 10 11 10 9
0.7 0.6 0.7 0.6 0.8 0.8 0.8 0.5
15 33 16 14 19 19 32 12
24 Phenylketonuria
Weight Approximate PHE (g) Measure (mg) For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Turnips greens canned 25 2 Tbsp 17 fresh or frozen, cooked 18 2 Tbsp 12 root, diced cooked 78 3/4 cup 16 raw 65 3/4 cup 16 Vegetable juice cocktail 91 3 fl oz 12 Soups, Campbell's Condensed. Weigh or measure before diluting and dilute with water only. Asparagus, Cream of 21 1 Tbsp + 1 tsp 16 Celery, Cream of 31 2 Tbsp 20 Chicken Gumbo 21 1 Tbsp + 1 tsp 16 Chicken Vegetable 16 1 Tbsp 17 Mushroom, Cream of 20 1 Tbsp + 1 tsp 16 Onion 20 1 Tbsp + 1 tsp 16 Potato, Cream of 24 1 Tbsp + 1-1/2 tsp 15 Tomato 32 2 Tbsp 18 Tomato Bisque 26 1 Tbsp + 2 tsp 16 Tomato Rice 32 2 Tbsp 18 Vegetable, Old Fashioned 15 1 Tbsp 13 Vegetarian, Vegetable 15 1 Tbsp 13
Food
TYR (mg)
Protein (g)
Energy (kcal)
10 8 12 12 7
0.4 0.2 0.9 0.9 0.6
4 4 21 27 17
12 14 12 12 12 15 12 11 12 11 6 6
0.4 0.4 0.4 0.5 0.4 0.7 0.3 0.5 0.5 0.5 0.3 0.3
15 22 9 9 20 9 14 21 25 30 9 9
FREE FOODS A Limit to prescribed number of servings. Do not use beverages or foods that contain NutraSweet , SweetMate , or aspartame. Desserts Butterscotch chips Gelatin pop Marmalade Marshmallow M&M candy, plain Mocha Mix, frozen chocolate vanilla Raisins, chocolate covered Sorbet peach pineapple strawberry Fruits/Fruit Products Apple butter canned, sweetened, sliced chips (Nature's Favorite ) dried dried, cooked juice, frozen, diluted sauce, sweetened, canned whole, small Cranberry sauce, canned Fruit bars, frozen orange pineapple strawberry Fruit ice
5 22 19 8 2 8 8 2 30 59 59
5 pieces 1/2 pop 1 Tbsp 1 large 2 pieces 1 Tbsp 1 Tbsp 2 raisins 2 Tbsp 1/4 cup 1/4 cup
5 5 3 4 6 7 5 6 4 7 7
5 1 2 1 4 5 4 6 4 7 8
0.1 0.3 0.1 0.2 0.2 0.2 0.1 0.2 0.1 0.2 0.2
15 16 50 26 8 17 17 12 30 58 58
40 102 15 21 64 120 128 100 69 37 37 74 48
2 Tbsp 1/2 cup 1/4 cup 1/4 cup 1/4 cup 2 fl oz 1/2 cup 1 fruit 1/4 cup 1/2 bar 1/2 bar 1 bar 1/4 cup
4 5 6 6 4 4 6 5 5 5 4 6 6
3 3 4 4 3 3 4 4 1 2 4 7 3
0.2 0.2 0.2 0.2 0.1 0.2 0.2 0.2 0.1 0.1 0.1 0.2 0.2
74 68 60 52 36 56 97 59 104 35 35 60 62
Phenylketonuria 25
Food
Weight Approximate PHE (g) Measure (mg) For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Fruit pie filling apple 123 1/2 cup 4 cherry 47 3 Tbsp 5 peach 50 3 Tbsp 5 strawberry 31 2 Tbsp 5 Fruit Roll-Ups 14 1 piece 4 Lemonade 125 4 fl oz 4 Nectar papaya 250 8 fl oz 5 peach 62 2 fl oz 5 pear 125 4 fl oz 4
TYR (mg)
Protein (g)
Energy (kcal)
3 2 4 5 3 2 3 4 1
0.1 0.2 0.2 0.2 0.2 0.1 0.4 0.2 0.1
135 49 54 34 55 55 142 34 75
Miscellaneous Barbecue sauce Chocolate drink powder pudding mix syrup Coconut, dried, sweetened w/ sugar Coffee, instant, powder Horseradish
16 3 7 6 3 2 2
1 Tbsp 1 tsp 2 tsp 1 tsp 2 tsp 1 tsp 2 tsp
6 4 6 5 5 5 4
4 3 4 4 3 3 4
0.3 0.1 0.1 0.1 0.1 0.2 0.1
12 11 23 14 15 4 2
FREE FOODS B These foods contain little or no PHE or TYR. They may be used as desired if patient is not overweight and they do not depress appetite for prescribed foods. Do not use beverages or foods that contain NutraSweet , SweetMate , or aspartame. Beverages Apple juice, canned Beer, regular Carbonated beverages, caffeine-free Cranberry juice cocktail Exceed Energy Drink Gatorade Kool-Aid , sweetened w/ sugar Liquor Limeade, sweetened w/ sugar Tang Tea, instant, powder Wine Desserts/Sweeteners Candies Candy corn Gumdrops Hard candy Jelly beans Lollipop Frosting, strawberry and vanilla Honey Lemon pudding, canned (Hunt's ) Molasses Popsicle , twin Sugar brown powdered table
124 28 113 126 124 125 125 28 125 125 1 28
4 fl oz 1 fl oz 4 fl oz 4 fl oz 4 fl oz 4 fl oz 4 fl oz 1 fl oz 4 fl oz 4 fl oz 1 Tbsp 1 fl oz
2 2 0 1 0 0 0 0 0 0 1 1
2 4 0 1 0 0 0 0 0 0 1 1
0.1 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.1
60 12 52 72 35 25 48 70 51 59 3 21 1
16 4 10 28 28 16 21 121 21 128 14 8 12
10 pieces 2 pieces 2 pieces 10 pieces 1 medium 1 Tbsp 1 Tbsp 1 can 1 Tbsp 1 popsicle 1 Tbsp 1 Tbsp 1 Tbsp
0 0 0 0 0 0 3 0 0 0 0 0 0
0 0 0 0 0 0 2 0 0 0 0 0 0
0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.0 0.0 0.0 0.0 0.0 0.0
58 14 39 103 108 69 64 151 48 95 52 31 48
26 Phenylketonuria
Weight Approximate PHE (g) Measure (mg) For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Syrup corn 20 1 Tbsp 0 maple 20 1 Tbsp 0 table 20 1 Tbsp 0 Fruits/Fruit Products Fruit butters Fruit ices Fruit juice bar Fun Fruits Guava raw sauce Jams Jellies Miscellaneous Cornstarch Lard Oil, vegetable Richwhip , liquid Shortening Tapioca, dry Vinegar/oil dressing Wheat starch
Food
TYR (mg)
Protein (g)
Energy (kcal)
0 0 0
0.0 0.0 0.0
58 50 50
7 52 26 90 119 7 20
1 tsp 1/2 cup 1 bar 1 piece 1 fruit 1/2 cup 1 tsp 1 Tbsp
1 0 2 2 2 1 1 0
1 0 1 1 9 5 1 0
< 0.1 trace 0.1 0.1 0.7 0.4 < 0.1 0.0
13 69 43 100 45 43 18 50
8 13 14 14 13 10 16 8
1 Tbsp 1 Tbsp 1 Tbsp 1 Tbsp 1 Tbsp 1 Tbsp 1 Tbsp 1 Tbsp
0 0 0 0 0 1 0 1
0 0 0 0 0 1 0 1
trace 0.0 0.0 0.0 0.0 0.1 0.0 trace
29 115 120 40 113 36 70 25
For nutrient composition of very-low-protein foods, see Appendix 12, p A-11.
Phenylketonuria 27
TABLE 1-4. Nutrient Composition of PHENEX-1 1, 3 and PHENEX-2 2, 3

Phenex-1 Per 100 g pwd Per g protein equiv 480 32 Energy, kcal 15.00 1.000 Protein equiv, g 2.40 0.160 Nitrogen, g 15.79 1.053 Amino acids, g Cystine, g 0.15 0.010 Histidine, g 0.42 0.028 Isoleucine, g 1.08 0.072 Leucine, g 1.68 0.112 Lysine, g 1.00 0.067 Methionine, g 0.30 0.020 Phenylalanine, g trace 0 Threonine, g 0.70 0.047 Tryptophan, g 0.17 0.011 Tyrosine, g 1.50 0.100 Valine, g 1.22 0.081 Other Nitrogen-Containing Compounds Carnitine, mg 20 1.33 Taurine, mg 40 2.67 53.0 3.53 Carbohydrate, g 21.7 1.45 Fat, g Linoleic acid, g 2.00 4 0.133 0.36 6 0.024 -Linolenic acid, g Minerals Calcium, mg 575 38 Chloride, mg/mEq 325/9.17 21.7/0.61 Chromium, g 11 0.73 Copper, mg 1.10 0.073 Iodine, g 65 4.33 Iron, mg 9.0 0.60 Magnesium, mg 50 3.33 Manganese, mg 0.50 0.033 Nutrient Phenex-2, Unflavored Per 100 g pwd Per g protein equiv 410 13.7 30 1.000 4.80 0.160 31.58 1.053 0.30 0.010 0.84 0.028 2.16 0.072 3.36 0.112 2.00 0.067 0.60 0.020 trace 0 1.40 0.047 0.34 0.011 3.00 0.100 2.44 0.081 40 50 35 14 1.50 5 0.17 7 880 940/26.51 27 1.00 100 13 225 0.80 1.33 1.67 1.17 0.47 0.050 0.006 29 31.33/0.88 0.90 0.033 3.33 0.43 7.50 0.027 Phenex-2, Flavored Per 100 g pwd Per g protein equiv 410 13.7 30 1.000 4.80 0.160 31.58 1.053 0.30 0.010 0.84 0.028 2.16 0.072 3.36 0.112 2.00 0.067 0.60 0.020 trace 0 1.40 0.047 0.34 0.011 3.00 0.100 2.44 0.081 40 50 36 13.5 1.50 5 0.17 7 880 940/26.51 27 1.00 100 13 225 0.80 1.33 1.67 1.20 0.45 0.050 0.006 29 31.33/0.88 0.90 0.033 3.33 0.43 7.50 0.027
Nutrient Molybdenum, g Phosphorus, mg Potassium, mg/mEq Selenium, g Sodium, mg/mEq Zinc, mg Vitamins A, g RE D, g E, mg -TE K, g Ascorbic acid, mg Biotin, g B6, mg B12, g Choline, mg Folate, g Inositol, mg Niacin equiv, mg Pantothenic acid, mg Riboflavin, mg Thiamin, mg
1 3
Phenex-1 Per 100 g pwd Per g protein equiv 12 0.80 400 27 675/17.26 45./1.15 20 1.33 190/8.26 12.7/0.55 8.0 0.53 420 7.50 10.10 50 50 65 0.75 4.90 80 230 40 12.80 6.90 0.90 1.90
2
Phenex-2, Unflavored Per 100 g pwd Per g protein equiv 30 1.00 760 25 1,370/35.04 45.7/1.17 35 1.17 880/38.28 29.3/1.28 13 0.43 660 7.50 12.10 60 60 100 1.30 5.00 100 450 70 21.7 8.00 1.80 3.25 22 0.25 0.40 2.00 2.00 3.33 0.043 0.167 3.33 15 2.33 0.72 0.267 0.060 0.108
Phenex-2, Flavored Per 100 g pwd Per g protein equiv 30 1.00 760 25 1,370/35.04 45.7/1.17 35 1.17 880/38.28 29.3/1.28 13 0.43 660 7.50 12.10 60 60 100 1.30 5.0 100 450 70 21.7 8.0 1.80 3.25 22 0.25 0.40 2.00 2.00 3.33 0.043 0.167 3.33 15 2.33 0.72 0.267 0.060 0.108
28 0.50 0.67 3.33 3.33 4.33 0.050 0.327 5.33 15 2.67 0.850 0.460 0.060 0.127
Designed for infants and toddlers. Designed for children, adolescents, and adults. Approximate packed weights in level, dry US standard household measures: Phenex-1 Phenex-2, unflavored Phenex-2, flavored
1 Tbsp = 7g 8g 9g 1/4 cup = 26 g 32 g 30 g 1/3 cup = 35 g 41 g 40 g 1/2 cup = 53 g 61 g 59 g 1 cup = 105 g 117 g 116 g 4 Analytical data at manufacture = 4.32 g/100 g powder. 5 Analytical data at manufacture = 2.66 g/100 g powder in flavored. 6 Analytical data at manufacture = 0.40 g/100 g powder. 7 Analytical data at manufacture = 0.28 g/100 g powder in unflavored, 0.27 g/100 g powder in flavored.
TABLE 1-5. PKU Clinical Summary Sheet Name: Date of Birth: __________/__________/__________
Mo Day Year
Hospital Number:
Date
Age Length/ Height (cm)
(mo/d/yr)
(yrs/mo)
Physical Data Weight Head Circum (kg) (cm)
Hgb (g/dL)
Ferritin (ng/mL)
Laboratory Data Transthyretin (mg/dL)
PHE1
TYR1
PHE (mg)
Nutrient Intake Data TYR Protein (mg) (g)
Energy (kcal)
Indicate if mg/dL or mol/L.
REFERENCES
1. Acosta PB: The contribution of therapy of inherited amino acid disorders to knowledge of amino requirements. In Wapnir RA (ed): Congenital Metabolic Diseases: Diagnosis and Treatment. New York: Marcel Dekker Inc, 1985, (review), pp 115-135. Acosta PB, Fernhoff PM, Warshaw HS, et al: Zinc status and growth of children undergoing treatment for phenylketonuria. J Inher Metab Dis 1982;5:107-110. Acosta PB, Trahms C, Wellman NS, Williamson MW: Phenylalanine intakes of one to six year old children undergoing therapy for PKU. Am J Clin Nutr 1983;38:694-700. Acosta PB, Wenz E, Williamson M: Nutrient intakes of treated infants with phenylketonuria. Am J Clin Nutr 1977;30:198-208. Acosta PB, Yannicelli S: Protein intake affects phenylalanine requirements and growth of infants with phenylketonuria. Acta Paediatr 1994;407 (Suppl):66-67. Acosta PB,Yannicelli S: Plasma micronutrient concentrations in infants undergoing therapy for phenylketonuria. Biol Tr Elem Res 1999;67:75-84. Acosta PB, Yannicelli S, Marriage B, et al: Nutrient intake and growth of infants with phenylketonuria undergoing therapy. J Pediatr Gastroent Nutr 1998;27:287-291. Acosta PB, Yannicelli S, Marriage B, et al: Protein status of infants with phenylketonuria undergoing nutrition management. J Am Col Nutr 1999;18:102-107. Allen JR, McCauley JC, Waters DL, et al: Fasting energy expenditure in children with phenylketonuria. Am J Clin Nutr 1995;62:797-801. Anderson VE, Siegel FS: Behavioral and biochemical correlates of diet change in phenylketonuria. Pediatr Res 1976;10:10-17. Arnold GL, Vladutiu CJ, Kirby RS: Protein insufficiency and impaired growth in children with PKU. J Inher Metab Dis 2000;23 (Suppl 1):29A. Azen CG, Koch R, Friedman EG, et al: Intellectual development in 12-year-old children treated for phenylketonuria. Am J Dis Child 1991;145:35-39. Behrman RE, Kleigman RM, Arvin AA (eds): Nelson Textbook of Pediatrics, ed 15. Philadelphia: WB Saunders Co, 1996. Bodley JL, Austin VJ, Hanley WB, et al: Low iron stores in infants and children with treated phenylketonuria: A population at risk for iron-deficiency anaemia and associated cognitive defects. Eur J Pediatr 1993;152:140-143. Bohles H, Ullrich K, Endres W, et al: Inadequate iron availability as a possible cause of low serum carnitine concentrations in patients with phenylketonuria. Eur J Pediatr 1991;150:425-428. Calomme MR, Vanderpas JB, Francois B, et al: Thyroid function parameters during a selenium repletion/depletion study in phenylketonuric subjects. Experientia 1995;51:1208-1215. Carson DJ, Greeves LG, Sweeney LE, Crone MD: Osteopenia and phenylketonuria. Pediatr Radiol 1990;20:598-599. Doherty LB, Rohr R, Levy HL: Detection of phenylketonuria in the very early newborn blood specimen. Pediatrics 1991;87:240-244. Elsas LJ, Acosta PB: Nutrition support of inherited metabolic diseases. In Shils ME, et al (eds): Modern Nutrition in Health and Disease, ed 9. Baltimore: Williams & Wilkins, 1999, pp 1003-1056. Epstein CM, Trotter JF, Averbook A, et al: EEG mean frequencies are sensitive indices of phenylalanine effects on normal brain. Electroencephalog Clin Neurophys 1989;72:133-139. Fisch RO, Gravem HJ, Feinberg SB: Growth and bone characteristics of phenylketonurics: Comparative analysis of treated and untreated phenylketonuric children. Am J Dis Child 1966;112:3-10. Food and Nutrition Board, Committee on Dietary Allowances: Recommended Dietary Allowances, eds 9 and 10. Washington, DC: National Academy of Sciences, 1980 and 1989. Greeves LG, Carson DJ, Craig BG, McMaster D: Potentially life-threatening cardiac dysrhythmia in a child with selenium deficiency and phenylketonuria. Acta Paediatr Scand 1990;79:1259-1262. Greeves LG, Patterson CC, Carson DJ, et al: Effect of genotype on changes in intelligence quotient after dietary relaxation in phenylketonuria and hyperphenylalaninaemia. Arch Dis Child 2000;82:216-221. Griffiths PV, Demellweek C, Fay N, et al: Wechsler subscale IQ and subtest profile in early treated phenylketonuria. Arch Dis Child 2000;82:209-215. Gropper S, Acosta PB: Effect of simultaneous ingestion of L-amino acids and whole protein on plasma amino acid and urea nitrogen concentrations in humans. JPEN 1991;15:48-53. Gropper SS, Gropper DM, Acosta PB: Plasma amino acid response to ingestion of L-amino acids and whole protein. J Pediatr Gastroent Nutr 1993;16:143-150. Gropper SS, Trahms C, Cloud HA, et al: Iron deficiency without anemia in children with phenylketonuria. Int'l Pediatr 1994;9:237-243. Gropper SS, Yannicelli S: Plasma molybdenum concentrations in children with and without phenylketonuria. Biol Trace Elem Res 1993;38:227-231.
2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29.
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30. Guldberg P, Mikkelsen I, Henriksen KF, et al: In vivo assessment of mutations in the phenylalanine hydroxylase gene by phenylalanine loading: Characterization of seven common mutations. Eur J Pediatr 1995;154:551-556. 31. Guttler F, Guldberg P: Mutations in the phenylalanine hydroxylase gene: Phenotypic variability of hyperphenylalaninemia. Acta Paediatr 1996;407 (Suppl):49-56. 32. Hanley WB, Feigenbaum ASJ, Clarke JTR, et al: Vitamin B12 deficiency in adolescents and young adults with phenylketonuria. Eur J Pediatr 1996;S155:S145-S147. 33. Hanley WB, Linsao L, Davidson W, et al: Malnutrition with early treatment of phenylketonuria. Pediatr Res 1970;4:318-327. 34. Herbert V: Folic acid. In Shils ME, et al (eds): Modern Nutrition in Health and Disease, ed 9. Baltimore: Williams & Wilkins, 1999, pp 433-446. 35. Herrmann ME, Broesicke HG, Keller M, et al: Dependence of the utilization of a phenylalanine-free amino acid mixture on different amounts of single dose ingested. A case report. Eur J Pediatr 1994;153:501-503. 36. Hillman L, Schlotzhauer C, Lee D, et al: Decreased bone mineralization in children with phenylketonuria under treatment. Eur J Pediatr 1996;155 (Suppl 1):S148-S152. 37. Ingall D, Sherman JD, Cockburn F: Immediate effects of phenylalanine-deficient diet in young infants. J Pediatr 1964;65:1073A. 38. Jones BJM, Lees R, Andrews J, et al: Comparison of an elemental and polymeric enteral diet in patients with normal gastrointestinal function. Gut 1983;24:78-84. 39. Kindt E, Lunde HA, Gjessing LR, et al: Fasting plasma amino acid concentrations in PKU children on two different levels of protein intake. Acta Paediatr Scand 1988;77:60-66. 40. Kindt E, Motzfeldt K, Halvorsen S, Lie S: Protein requirements in infants and children treated for phenylketonuria. Am J Clin Nutr 1983;37:778-785. 41. Kindt E, Motzfeldt K, Halvorsen S, Lie SO: Is phenylalanine requirement in infants and children related to protein intake? Br J Nutr 1984;51:435-442. 42. Kure S, Hou DC, Ohura T, et al: Tetrahydrobiopterin-responsive phenylalanine-hydroxylase deficiency. J Pediatr 1999;135:375-378. 43. Leverton RM, Johnson N, Ellison J, et al: The quantitative amino acid requirements of young women. IV. Phenylalanine, with and without tyrosine. J Nutr 1956;58:341-353. 44. MacLean W, Graham G: Pediatric Nutrition in Clinical Practice. Menlo Park, Calif: Addison-Wesley Publishing Co, 1982. 45. Martin SB, Acosta PB: Osmotic behaviors of components of chemically-defined formulas. J Pediatr Perinat Nutr 1987;1:1-17. 46. Medical Research Council Working Party on Phenylketonuria: Recommendations on the dietary management of phenylketonuria. Arch Dis Child 1993;68:426-427. 47. Michals K, Lopus M, Matalon R: Phenylalanine metabolites as indicators of dietary compliance in children with phenylketonuria. Biochem Med 1988;39:18-23. 48. Ohkohchi N, Andoh T, Ohi R, Mori S: Defined formula diets alter characteristics of the intestinal transport of amino acids and peptides in growing rats. J Pediatr Gastroenterol Nutr 1990;10:490-496. 49. Posati LP, Orr ML: Composition of Foods: Dairy and Egg Products, Agriculture Handbook No. 8-1. Washington, DC: US Dept of Agriculture, Agricultural Research Service, 1976. 50. Pratt EL, Snyderman SE, Cheung MW, et al: The threonine requirement of the normal infant. J Nutr 1955;56:231-251. 51. Reilly C, Barrett JE, Patterson CM, et al: Trace element nutrition status and dietary intake of children with phenylketonuria. Am J Clin Nutr 1990;52:159-165. 52. Rose WC, Wixom RL: The amino acid requirements of man. XIV. The sparing effect of tyrosine on the phenylalanine requirement. J Biol Chem 1955;217:95-101. 53. Rouse BM: Phenylalanine deficiency syndrome. J Pediatr 1966;69:246-249. 54. Royston NJ, Parry TE: Megaloblastic anaemia complicating dietary treatment of phenylketonuria in infancy. Arch Dis Child 1962;37:430-435. 55. Schoeffer A, Herrmann ME, Broesicke HG, Moench E: Effect of dosage and timing of amino acid mixtures on nitrogen retention in patients with phenylketonuria. J Nutr Med 1994;4:415-418. 56. Schuett VE, Brown ES, Michals K: Reinstitution of diet therapy in PKU patients from twenty-two US clinics. Am J Publ Health 1985;75:39-42. 57. Schulpis KH, Nounopoulos C, Scarpalezou A, et al: Serum carnitine level in phenylketonuric children under dietary control in Greece. Acta Paediatr Scand 1990;79:920-934. 58. Scriver CR, Kaufman S: Hyperphenylalaninemias. Phenylalanine hydroxylase deficiency. In Scriver CR, et al (eds): The Metabolic and Molecular Bases of Inherited Disease, ed 8. New York: McGraw-Hill Medical Publishing Division, 2001, pp 1667-1724. 59. Shortland D, Smith I, Francis DEM, et al: Amino acid and protein requirements in a preterm infant with classic phenylketonuria. Arch Dis Child 1985;60:263-265. 60. Sibinga MS, Friedman CJ, Steisel IM, Baker EC: The depressing effect of diet on physical growth in phenylketonuria. Develop Med Child Neurol 1971;13:63-70.
61. Smith CA, Nelson NM (eds): The Physiology of the Newborn Infant, ed 4. Springfield, IL: Charles C Thomas Publisher, 1976. 62. Smith JL, Arteaga C, Heymsfield SB: Increased ureagenesis and impaired nitrogen use during infusion of a synthetic amino acid formula - A controlled trial. N Engl J Med 1982;306:1013-1018. 63. Smith I, Beasley MG, Ades AE: Effect on intelligence of relaxing the low phenylalanine diet in phenylketonuria. Arch Dis Child 1990;65:311-316. 64. Smith I, Beasley MG, Ades AE: Intelligence and quality of dietary treatment in phenylketonuria. Arch Dis Child 1990;65:462-478. 65. Smith JL, Heymsfield SB: Enteral nutrition support: Formula preparation from modular ingredients. JPEN 1983;7:280-288. 66. Spaapen LJM, Bakker JA, Velter C, et al: Tetrahydrobiopterin-responsive hyperphenylalaninemia (HPA) in Dutch neonates. J Inher Metab Dis 2000;23 (Suppl 1):45A. 67. Spika JS, Shaffer N, Hargrett-Bean N, et al: Risk factors for infant botulism in the United States. Am J Dis Child 1989;143:828-832. 68. Thompson AJ, Smith I, Brenton D, et al: Neurological deterioration in young adults with phenylketonuria. Lancet 1990;336:602-605. 69. Trefz F, Burgard P, Konig T, et al: Genotype-phenotype correlations in phenylketonuria. Clin Chim Acta 1993;217:15-21. 70. Villasana D, Butler IJ, Williams JC, Roongta SM: Neurological deterioration in adult phenylketonuria. J Inher Metab Dis 1989;12:451-457. 71. Waisbren SE, Levy HL: Agoraphobia in phenylketonuria. J Inher Metab Dis 1991;14:755-764. 72. Wannemacher RW: Key role of various individual amino acids in host response to infection. Am J Clin Nutr 1977;30:1269-1280. 73. Williams K: Benefits of normalizing plasma phenylalanine: Impact on behavior and health. A case report. J Inher Metab Dis 1998;21:785-790. 74. Weir D, Scott JM: Vitamin B12 "cobalamin". In Shils ME, et al (eds): Modern Nutrition in Health and Disease, ed 9. Baltimore: Williams & Wilkins, 1999, pp 447-458. 75. Yannicelli S, Davidson AJ, Van Doorninck WJ: Nutrition support for the late-treated adult with phenylketonuria. Metabolic Currents 1990;2:9-14. Columbus, Ohio: Ross Laboratories. 76. Yannicelli S, Ernest A, Neifert MR, McCabe ERB: Guide to Breastfeeding the Infant With PKU, ed 2. Dept of Health and Human Services Publication No. HRS-M-CH88-12, October 1988.
Phenylketonuria 33
PROTOCOL 2 Maternal Phenylketonuria (MPKU) Nutrition Support of Pregnant Women With Phenylketonuria (PKU) With PHENEX-2 Amino Acid-Modified Medical Food
I. Introduction
Phenylketonuria (PKU) that is untreated at conception and during gestation is associated with poor reproductive outcomes. Intrauterine growth retardation and congenital anomalies, often severe and incompatible with life, are common. Most investigators attribute these effects to elevated maternal plasma phenylalanine (PHE) concentrations. Lenke and Levy (25) described outcomes of 524 pregnancies in 155 women with PKU. The incidence of low birth weight, microcephaly, congenital anomalies, and mental retardation in offspring was significantly higher than in the normal population. The pathogenesis of fetal damage is uncertain, but is believed to be related to an elevated maternal blood concentration of PHE (12, 20, 27) because PHE is actively transported across the placenta to the fetus (24). Fetal blood PHE concentrations usually are significantly greater than those of maternal blood (15) and interfere with embryonic development, although the mechanism of effect is not yet known (12, 20, 27). Offspring who survive fail to grow and develop normally. In fact, Kirkman (21) predicted that if these women have normal fertility and dietary PHE intake is not controlled, the incidence of PKU-related mental retardation could return to the prescreening level after only one generation.
II. Effects of Nutrition Support on Reproductive Outcome

A PHE-restricted diet and the gestational age at which it is initiated affect reproductive outcome. Of 576 pregnancies in the Maternal PKU Collaborative Study (MPKUCS), 414 resulted in live births (22, 37). Only 125 women achieved and maintained blood PHE concentration < 600 mol by 10 weeks gestation. Women who started the PHE-restricted diet before conception had a mean plasma PHE concentration of 461 mol/L ( SD of 233) during their 1st trimester of pregnancy. Those who started the diet during the 1st trimester had a mean concentration of 661 mol/L ( SD of 267). Both mean concentrations were greater than the target range of 120 to 360 mol/L. Mean median head circumference percentile of offspring of the 25 women whose plasma PHE concentration was less than 360 mol/L by 10 weeks' gestation was significantly greater (58%) than that of offspring of 35 women whose plasma PHE concentration was between 360 and 600 mol/L by 10 weeks (41%). The mean General Cognitive Index (GCI) (McCarthy score) of offspring of women who achieved control of plasma PHE concentration before 10 weeks' gestation was 94. Offspring of women achieving control of plasma PHE concentration between 10 and 20 weeks' gestation had a mean GCI of 87 and offspring of women not achieving control until after 20 weeks had a mean GCI of 72 (22, 23). Rouse, et al (40) reported incidence of facial dysmorphology and major malformations in 35 infants in the MPKUCS. Abnormally shaped ears, a wide palpebral fissure, epicanthical folds, and a long philtrum were manifested in 50% to 70% of the offspring of mothers whose blood PHE concentration was between 240 and 600 mol/L. Fifteen percent of offspring of treated mothers had cardiac defects. Intrauterine growth retardation ranged from 10% in offspring of women whose plasma PHE concentration was between 240 and 600 mol/L, to 100% in infants whose mother's PHE concentration was more than 1200 mol/L. Rouse, et al suggested that the mother's blood PHE concentration should be lower than 360 mol/L during pregnancy for the best outcome. Smith et al (43) studied 94 infants of women with PKU, evaluating subjects by maternal blood PHE concentration around the time of conception. Regression analysis of data from all 94 infants indicated that birth weight decreased by 98 g and head circumference decreased by 0.46 cm for each 200 mol/L increase in maternal blood PHE concentration above the normal range. Smith, et al advised that a PHE-restricted diet should be started before conception and that blood PHE concentration should be maintained between 60 and 180 mol/L (43).
III. Establish Diagnosis

A. This protocol addresses nutrition support of women diagnosed with PHE hydroxylase deficiency. See Protocol 1, p 2.
34 Maternal Phenylketonuria
IV. Rationale for Nutrition Support

A. Correct Primary Imbalance in Metabolic Relationships 1. Restrict dietary PHE to amount tolerated by patient to maintain treatment plasma PHE concentration. B. Supply Product of Blocked Primary Pathway 1. Supplement dietary tyrosine (TYR) as necessary to maintain normal plasma TYR concentration.
V. Establish Goals of Nutrition Support

A. Plasma PHE Concentration 1. Maintain 2- to 4-hour postprandial plasma PHE concentration between 2 and 4 mg/dL when measured by bacterial inhibition assay and 120 and 240 mol/L when measured by quantitative methods) (10, 11, 29, 43, 46) or within normal range established by laboratory used. a. Frequent assessment of plasma PHE concentration is necessary for optimal nutrition support and fetal outcome. 2. In practice, obtaining blood 2 to 4 hours postprandially is not always possible. Acceptable local standards should be developed if plasma amino acids are evaluated at other times (Practical Aspects of Nutrition Support, p viii). 3. Differences of opinion exist as to best concentrations of plasma PHE and TYR for support of normal fetal development and growth. Concentrations of plasma PHE and TYR as close to normal as possible without restricting fetal growth are recommended (10, 30, 40, 43). B. Plasma TYR Concentration 1. Maintain 2- to 4-hour postprandial plasma TYR concentration between 50 and 100 mol/L (0.9 and 1.8 mg/dL) or within normal range established by laboratory used. C. Weight and Nutrition Status 1. Support normal and appropriate weight gain based on height, prepregnancy weight, and gestational age (Table 2-1, p 41). 2. Recommended weight gain depends on weight at conception (47). a. Normal-weight women should gain: 1) 1.60 kg (3.50 lb) in 1st trimester. 2) 0.44 kg (0.97 lb) per week during remainder of pregnancy. 3) 11 to 16 kg (25 to 35 lb) by 40 weeks' gestation. b. Underweight women should gain: 1) 2.30 kg (5 lb) in 1st trimester. 2) 0.49 kg (1.08 lb) per week during remainder of pregnancy. 3) 15 to 18 kg (34 to 40 lb) by 40 weeks' gestation. c. Overweight women should gain: 1) 0.9 kg (2 lb) in 1st trimester. 2) 0.3 kg (0.66 lb) per week during remainder of pregnancy. 3) 7 to 11.5 kg (15 to 25 lb) by 40 weeks' gestation. 3. Maintain normal nutrition status for pregnant woman (3, 8).
VI. Establish Prescription

A. PHE 1. Prescribe PHE intake that promotes goals of nutrition support. 2. PHE requirements vary widely: a. From patient to patient, depending on activity of PHE hydroxylase which is dependent on genotype (9). b. In same patient, depending on: 1) Age. 2) Weight gain (39). 3) Trimester of pregnancy (39). 4) Adequacy of energy and protein intakes. 5) State of health.
2001 Ross Products Division Maternal Phenylketonuria 35
3. Lowest value for PHE in Table 2-2, p 41, is suggested to begin therapy. a. Changing requirements are established only by frequent monitoring of plasma PHE concentration of patient. b. See Section IX, Suggested Evaluation of Nutrition Support, p 37. 4. PHE requirements usually increase at approximately 20 weeks' gestation (39, 46). Warning: Inadequate PHE intake may lead to low maternal weight gain and poor reproductive outcome. B. TYR 1. Prescribe TYR intake that maintains treatment plasma TYR concentration. 2. Lowest value for TYR listed in Table 2-2, p 41, is suggested to start therapy. 3. Changing requirements of patients are determined only by frequent monitoring of plasma TYR concentration. C. Protein 1. See Table 2-2, p 41, for Recommended Protein Intakes. 2. Requirements are greater than Recommended Dietary Allowances (RDAs) when L-amino acids supply majority of protein equivalent as result of: a. Rapid amino acid absorption (14). b. Early and high peak of plasma amino acid concentrations after ingestion of meals where large part of protein is supplied by L-amino acids (14). c. Rapid catabolism of amino acids (18, 19, 42, 44). d. Possible decreased total amino acid absorption (34) Warning: Inadequate protein intake is correlated with low birth length and poor weight gain of offspring (1, 2, 30, 33). 3. Total protein intake of women in the MPKUCS was negatively correlated with plasma PHE concentration throughout pregnancy and positively correlated with offspring birth measures (2, 33). 4. Inadequate protein intake by women in the MPKUCS was associated with very low intakes of folate and vitamin B12 and congenital heart defects in offspring (16, 17, 31,49). D. Fat 1. Fat should supply 35% to 40% of energy. a. 7% to 10% of energy should be obtained from linoleic acid (C18:2,n-6) (13). b. 0.7% to 2.5% of energy should be obtained from -linolenic acid (C18:3,n-3) (13). 2. Fat intake of women in the MPKUCS was negatively correlated with plasma PHE concentration during pregnancy and positively correlated with offspring birth measures (2, 33). E. Energy 1. Prescribe amount that should support appropriate weight gain (Table 2-2, p 41). Infant birth measures are influenced by maternal energy intake and maternal weight gain (1, 2, 30, 33). 2. Requirements vary widely and may be greater than normal when L-amino acids supply majority of protein equivalent (38). 3. Energy intake was negatively correlated with plasma PHE concentration during the last two trimesters of pregnancy (2, 33). Warning: Inadequate energy intake is associated with poor maternal weight gain, decreased birth length and birth weight of offspring (1, 2, 31, 33), and decreased maternal PHE tolerance. F. Fluid 1. Prescribe amount that will supply water requirements (Table 2-2, p 41). Under normal circumstances offer minimum of 1.0 mL for each kcal ingested.
VII. Fill Prescription

A. PHE 1. Calculate amount of table foods required to fill PHE prescription (Table 2-3, p 42). a. Patients may select any food in prescribed Servings Lists for PHE-Restricted Diets (Protocol 1, pp 16-26) in specified amounts to fill diet prescription.
36 Maternal Phenylketonuria 2001 Ross Products Division
2. If patient's appetite is small and PHE requirement is high: a. Use bread, cheese, eggs, or whole cow's milk to help fill PHE prescription (Tables 2-3 and 2-4, p 42). These high-PHE foods usually are not required before 3rd trimester. b. Measure whole cow's milk with large disposable syringe or standard volumetric flask. B. Protein 1. Calculate amount of protein provided by table foods, bread, cheese, egg, or whole cow's milk (Table 2-3, p 42) required to fill PHE prescription. 2. Subtract amount determined above from total protein prescription. 3. Supply any remaining prescribed protein with Phenex-2 (Table 2-5, p 43). a. Weigh Phenex-2 powder on scale that reads in grams because of variability of household measuring equipment (Practical Aspects of Nutrition Support, p vii) and changes in density during shipping. b. See Table 2-5 (p 43, footnote 1) for approximate packed weight of Phenex-2 powder in level, dry US standard household measures. C. TYR 1. Calculate approximate amount of TYR provided by table foods, breads, whole cow's milk, or whole egg (Table 2-3, p 42) required to fill PHE prescription. 2. Calculate amount of TYR supplied by Phenex-2 (Table 2-5, p 43) required to fill protein prescription. 3. Subtract amounts determined above from total TYR prescription. 4. Provide any remaining prescribed TYR as L-TYR (Appendix 26, p A-28). a. Supplement with L-TYR only if plasma TYR concentration is below 50 mol/L (0.9 mg/dL). 5. Make suspension of L-TYR of known TYR content per milliliter: a. Weigh L-TYR powder and add sufficient boiled, cooled water to yield known volume. b. Refrigerate in closed container until used. May be stored up to 1 week, if not frozen. c. Shake well before using. Measure L-TYR into medical food mixture with disposable syringe. d. Solubility of L-TYR in water is low, about 50 mg/100 mL. Because of its low solubility, some L-TYR may be mixed with fruit pures such as applesauce, sauces, soups, and juices from Free Foods A and B in Servings Lists for PHE-Restricted Diets (Protocol 1, pp 16-26). 6. L-TYR tablets (500 mg) are available at some pharmacies. D. Fat 1. Use fats containing canola or soy oil as first ingredient to help supply -linolenic acid. E. Energy 1. Calculate energy provided by table foods, bread, cheese, egg, whole cow's milk (Table 2-3, p 42), and Phenex-2 (Table 2-5, p 43) required to fill PHE and protein prescriptions. 2. Subtract amount of energy determined above from total energy prescription. 3. Provide any remaining prescribed energy with Free Foods B (Table 2-3, p 42), Polycose Glucose Polymers Powder (23 kcal/Tbsp, 3.8 kcal/g), sugar (48 kcal/Tbsp), or other nitrogenfree energy sources. F. Fluid and Mixing Instructions 1. Add sufficient tap water or other fluid to ingredients to yield prescribed volume of medical food mixture. 2. Mix with blender at lowest speed no longer than 4 seconds. Excess mixing may destabilize emulsion. Medical food mixture may also be mixed in tightly closed container by shaking vigorously for 10 to 12 seconds. 3. Place in container, cap, and store in refrigerator until used. Discard unused portion 24 hours after mixing because of nutrient loss. 4. Do not heat because of Maillard reaction (Practical Aspects of Nutrition Support, p viii). 5. Chill Phenex-2 medical food mixture to improve taste. 6. Shake well before using.
G. Diet Guide 1. Provide patient with completed Diet Guide (Table 2-6, p 44) with each diet change. 2. Six small meals, including late-evening snack, may be better tolerated than three meals. 3. Late-evening snack containing at least 12 g of protein equivalent and 400 kcal may be helpful in preventing usual early morning rise in blood PHE concentration (11).
VIII. Evaluate Adequacy and Safety of Planned Nutrition Support

A. Nutrient Adequacy (29) 1. Determine if diet provides nutrients in amounts prescribed in Section VI, Establish Prescription, p 34. 2. Check Phenex-2 medical food mixture to determine if it supplies Recommended Dietary Intakes (RDIs) for minerals and vitamins. a. See Table 2-7, p 45, for RDIs. b. See Appendix 8, p A-8, for complete nutrient composition of whole cow's milk and eggs. c. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. d. If medical food used contains inadequate or no selenium, selenium deficiency and decreased active thyroid concentration may occur (6). 3. If Phenex-2 mixture provides < 80% of RDIs, supplement diet with needed minerals and vitamins if not supplied by table foods and laboratory tests indicate need. a. Trace- and ultra-trace mineral deficiencies may occur if Phenex-2 fails to supply adequate amounts (3). b. Vitamin A from diet plus supplements should not exceed 400% of RDIs. c. Folate and vitamin B12 supplementation are necessary prior to conception and during trimester 1 if ingested medical food fails to supply requirements (31, 41). d. Prenatal vitamin supplements are contraindicated if adequate medical food is ingested due to the vitamin A they supply. B. Osmolarity 1. If concentration of Phenex-2 is > 19 g mixed with water to yield 100 mL (3.3 fl oz), determine if osmolarity is in acceptable range. a. Determine osmolarity by laboratory analysis or use mathematical formula given in Appendix 18, p A-20. b. Osmolarity per gram of Phenex-2 is listed in Appendix 19, p A-21. 2. If osmolarity is > 1,000 mosm/L, or if patient does not tolerate initial feeds, dilute subsequent feeds by equal volume of water (45). a. Gradually increase concentration over 3 days, as tolerated.
IX. Suggested Evaluation of Nutrition Support

A. Plasma PHE Concentration 1. Evaluate twice weekly by quantitative methods. 2. Unacceptable PHE concentrations. a. If plasma PHE concentration is not detected and patient has ingested full prescription: 1) Increase prescribed PHE by 25% and reevaluate plasma PHE concentration in 3 days. 2) If plasma PHE concentration continues undetected, repeat above process until value is in treatment range. b. If plasma PHE concentration is < 120 mol/L (2 mg/dL) and patient has ingested full prescription: 1) Increase prescribed PHE by 5% to 10% and reevaluate plasma PHE concentration in 3 days. 2) If plasma PHE concentration continues < 120 mol/L (2 mg/dL), repeat above process until value is in treatment range. c. If plasma PHE concentration is > 240 mol/L (4 mg/dL) and patient is not ill and has not ingested more PHE or significantly less protein and energy than prescribed: 1) Decrease prescribed PHE by 5% to 10% and reevaluate plasma PHE concentration in 3 days.
2) If plasma PHE concentration continues > 240 mol/L (4 mg/dL), repeat above process until value is in treatment range. B. Plasma amino acid concentrations (all) should be evaluated monthly by quantitative analysis. 1. Follow appropriate steps in Section IX, Suggested Evaluation of Nutrition Support, p 37, Plasma PHE Concentration, if plasma PHE concentration is not in appropriate range. C. Protein Status 1. Evaluate plasma transthyretin concentration monthly (Appendix 17, p A-18, for standards). a. Plasma transthyretin concentrations provide a more reliable and rapid indication of protein status than plasma albumin concentrations. b. Plasma albumin concentrations may be in the normal range when plasma transthyretin concentrations show a clear deficiency (4). 2. If plasma transthyretin concentration is below standard: a. Increase prescribed protein by 5% to 10% and reevaluate plasma transthyretin concentration in 1 month. If plasma PHE concentration is in treatment range, use Phenex-2 to increase protein. b. Repeat above process until transthyretin concentration is in treatment range. D. Iron Status 1. Plasma ferritin concentration. a. Evaluate monthly (Appendix 17, p A-18, for standards). b. If plasma ferritin concentration is below standard: 1) Add 60 mg elemental iron as ferrous sulfate daily and reevaluate in 1 month. 2) Continue iron supplements until plasma ferritin concentration is in treatment range. 2. Complete blood count a. Hemoglobin and hematocrit should be evaluated each trimester (Appendix 17, p A-18, for standards). E. Erythrocyte Folate and Serum Vitamin B12 Concentrations 1. Evaluate preconception, at first visit after conception, and each trimester (8, 16, 17, 39, 49). 2. If erythrocyte folate concentration is < 200 ng/mL (17): a. Supplement with 400 to 800 g of folacin daily and reevaluate in 1 month. b. If folacin concentration is not in normal range, continue supplement and reevaluate in 1 month. 3. If serum vitamin B12 is < 300 pg/mL (49): a. Supplement with 2.2 to 4.0 g vitamin B12 per day and reevaluate in 1 month. b. If vitamin B12 concentration is not in normal range, continue supplement and reevaluate again after 1 month. F. Weight Gain 1. Evaluate weekly during 1st month of treatment and monthly thereafter. 2. If weight gain is below recommended (Section V, Establish Goals of Nutrition Support, p 34) and all prescribed diet has been regularly ingested: a. Increase prescribed energy by 5% to 10% and reevaluate weight gain in 1 week. b. If weight gain is still inadequate, repeat above process until appropriate weight gain occurs. G. Nutrient Intake 1. Maintain records of food intake for 3 days immediately before each blood test (Appendices 24 and 25, pp A-26 and A-27). 2. Evaluate intakes of PHE, TYR, protein, energy, minerals, and vitamins for 3 days immediately before each blood test. a. Vitamin A intakes > 4500 g RE (15,000 IU) daily MUST be avoided (48) because excess vitamin A is a teratogen. 3. After each diet change, evaluate mineral and vitamin intakes: a. See Table 2-7, p 45, for normal standards for pregnant women. b. See Appendix 28, p A-29, for information about ordering software for diet evaluation. c. See Appendix 8, p A-8, for nutrient composition of whole cow's milk and eggs. 4. For further information on nutrition support of pregnant women, see reference 32.
H. Clinical Summary 1. A summary record of weight gain, laboratory, and nutrient intake data is useful for patient management (Table 2-8, p 46).
X. Sample Prescriptions
A. Example 1 Establish and fill prescription for pregnant 24-year-old woman who is 167.6 cm tall and weighs 56 kg (normal weight) at beginning of pregnancy and 63.3 kg at 27 weeks' gestation using Recommended Daily Nutrient Intakes from Table 2-2, p 41, and average nutrient contents from Tables 2-3 and 2-5, pp 42 and 43. 1. Establish prescription for 1st trimester.
PHE TYR Protein Energy Fluid 200 mg/day 7,000 mg (7.0 g) 70 g 2,500 kcal 2,500 mL Measure PHE (mg) TYR (mg) Protein (g) Energy (kcal)
2. Fill prescription for 1st trimester.

Medical Food Mixture
Phenex-2 217 g 0 6,510 65.1 890 L-TYR 352 mg 0 352 0.0 0 Add water to make 1183 mL (40 fl oz). Additional fluid should be consumed ad libitum daily. Food List Breads/Cereals Fats Fruits Vegetables Free Foods A Free Foods B Total per day Servings 3 5 3 2 2 16 90 25 45 30 10 0 200 60 20 30 20 8 0 7,000 1.8 0.5 1.5 1.0 0.2 0.0 70.1 90 300 180 30 130 880 2,500
Approximate osmolarity of medical food mixture is < 960 mosm/L.
3. Establish prescription for 3rd trimester.

PHE TYR Protein Energy Fluid 875 mg/day 7,000 mg (7.0 g) 70 g 2,500 kcal 2,500 mL
4. Fill prescription for 3rd trimester.

Medical Food Mixture Measure PHE (mg) TYR (mg) Protein (g) Energy (kcal)
Phenex-2 169 g 0 5,070 Whole cow's milk 195 mL 320 320 Sugar 2 tsp 0 0 1 L-TYR 1,234 mg 0 1,234 Add water to make 1183 mL (40 fl oz). Additional fluid should be consumed Food List Breads/Cereals Fats Fruits Vegetables Free Foods B Total per day 13 9 4 4 8 Servings 390 45 60 60 0 875 260 36 40 40 0 7,000
50.7 693 6.6 123 0 32 0 0 ad libitum daily.
7.8 0.9 2.0 2.0 0.0 70.0
390 540 240 40 440 2,498
Approximate osmolarity of medical food mixture is < 800 mosm/L. 1 Mix with soups, pures, and juices from Free Foods B in Servings Lists for PHE-Restricted Diets (Protocol 1, pp 13-26), or use L-TYR tablets.
XI. Management of Problems During Pregnancy (7)

A. Nausea 1. Suggest patient try one or more of following: a. Eat small amounts of prescribed food hourly while awake. b. Eat some prescribed low-protein crackers before rising in morning. c. Drink fluids (except medical food mixture) between meals. d. Avoid fried foods. e. Eat lightly seasoned foods. f. Eat plain fruits and vegetables. g. Eat some prescribed food before preparing meal. h. Avoid strong, unpleasant odors. B. Heartburn 1. Suggest patient try one or more of following: a. Eat slowly. b. Chew food well. c. Eat small, frequent meals. d. Avoid spicy and/or fried foods. e. Sit straight up or walk after eating. f. Avoid bending or stooping after eating. C. Constipation 1. Suggest patient try one or more of following: a. Drink more water. b. Eat some fruits with skins and raw vegetables. c. Increase fiber by selecting cereal with fiber. d. Drink some prune juice daily (may be mixed with soft drinks, not diet, to improve flavor). e. Exercise daily.
Maternal Phenylketonuria 41
TABLE 2-1. Prepregnancy Weights for Heights

Height Without Shoes (ft/in) 4'10" 4'11" 5' 5'1" 5'2" 5'3" 5'4" 5'5" 5'6" 5'7" 5'8" 5'9" 5'10" 5'11" 6'
1
(cm) 147.32 149.86 152.40 154.94 157.48 160.02 162.56 165.10 167.64 170.18 172.72 175.26 177.8 180.34 182.88
Underweight If This Weight or Less (lb) (kg) 88 40.0 91 94 99 104 108 113 118 123 127 132 137 142 146 151 41.4 42.7 45.0 47.3 49.0 51.4 53.6 55.9 57.7 60.0 62.3 64.5 66.4 68.6
Normal Weight Range1
(lb) 89 - 108 92 - 112 95 - 115 100 - 121 105 - 127 109 - 132 114 - 138 119 - 144 124 - 150 128 - 155 133 - 161 138 - 167 143 - 173 147 - 178 152 - 184
(kg) 40.4 - 49.0 41.8 - 50.9 43.2 - 52.3 45.5 - 55.0 47.7 - 57.7 49.5 - 60.0 51.8 - 62.7 54.1 - 64.5 56.4 - 68.2 58.2 - 70.5 60.5 - 73.2 62.7 - 75.9 65.0 - 78.6 66.8 - 80.9 69.1 - 83.6
Midpoint of Normal Weight Range (lb) (kg) 98.5 44.7 102.0 105.0 110.5 116.0 120.5 126.0 131.5 137.0 141.5 147.0 152.5 158.0 162.5 168.0 46.4 47.7 50.2 52.7 54.8 57.3 59.8 62.3 64.3 66.8 69.3 71.8 73.0 76.4
Overweight If This Weight or More (lb) (kg) 109 49.5 113 116 122 128 133 139 145 151 156 162 168 174 179 185 51.4 52.7 55.5 58.2 60.5 63.2 65.9 68.6 70.9 73.6 76.4 79.1 81.4 84.1
Normal weight for "thin-boned" women will be closer to lower end of range. For "big-boned" women, weight will be closer to higher end.
TABLE 2-2. Recommended Daily Nutrient Intakes (Ranges) for Pregnant Women With PKU
Trimester and Age
(yrs)
PHE1,2 (mg/day) 200 - 600 200 - 600
TYR 1, 2 (g/day) 5.75 - 7.50 4.50 - 7.00
Nutrient Protein3 (g/day) 75 70 75 70
Energy 3, 4 (kcal/day) 2,500 (2000 - 3500) 2,500 (2000 - 3000)
Fluid5 (mL/day) 2,000 - 3,500 2,000 - 3,000
1st Trimester 15 to < 19 19 2nd Trimester 15 to < 19 19
200 - 900 200 - 900
5.75 - 7.50 4.50 - 7.00
2,500 (2000 - 3500) 2,500 (2000 - 3000)
2,000 - 3,500 2,000 - 3,000
3rd Trimester 15 to < 19 300 - 1200 5.75 - 7.50 2,500 (2000 - 3500) 2,000 - 3,500 75 300 - 1200 4.50 - 7.00 2,500 (2000 - 3000) 2,000 - 3,000 19 70 1 Initiate prescription with lowest value for age and trimester. Actual requirement may vary considerably. Modify prescription based on frequently obtained plasma values and maternal weight gain. 2 From references 1, 2, 26, 30, 32, 33. 3 Modified from reference 13. 4 For 15- to < 19-year-old, energy intake should never be < 45 kcal/kg of ideal pregnancy weight. For women 19 years of age, energy intake should never be < 35 kcal/kg of ideal pregnancy weight (35). Adequate energy to support recommended weight gain (Section V, Establish Goals of Nutrition Support, p 34) should be prescribed even if number is greater than highest number listed for trimester and age. 5 Under normal circumstances, offer minimum of 1 mL fluid for each kcal ingested (5).
TABLE 2-3. Serving Lists for PHE-Restricted Diets: Average Nutrient Content per Serving1
Food List PHE (mg) TYR (mg) 0.6 0.1 0.5 0.5 0.1 0.0 2.2 6.8 6.2 3.39 Nutrient Protein (g) 30 60 60 10 65 55 79 95 74 63 Energy (kcal)
Breads/Cereals 30 20 Fats 5 4 Fruits 15 10 Vegetables 15 10 Free Foods A 5 4 Free Foods B 0 0 Breads 116 67 Cheeses 365 337 Egg, whole, 1 large (~50 g), 2 332 255 Whole cow's milk, 100 mL 2 164 164 1 From reference 10. 2 From reference 36. See Appendix 8, p A-8, for complete nutrient composition.
TABLE 2-4. Serving Lists for PHE-Restricted Diets: Supplemental Foods

Food Weight (g) Approximate Measure PHE (mg) TYR (mg) Protein (g) Energy (kcal)
For greatest accuracy, weigh food on scale that reads in grams. BREADS Biscuit, commercially baked Bun, hamburger and hot dog, plain Cracked wheat French, Vienna or sourdough Italian Pumpernickel Raisin Rye, American White Whole wheat Mean CHEESE American, processed Blue (3/4" x 1" x 1") Camembert Cheddar Colby Cottage, creamed Gouda Monterey Jack Mozzarella, low-moisture, part skim Muenster Parmesan, grated Provolone Swiss Mean 35 43 25 25 20 26 26 32 25 28 1 biscuit 1 bun 1 slice 1 slice 1 slice 1 slice 1 slice 1 slice 1 slice 1 slice 108 179 105 109 87 110 94 132 101 130 116 67 106 63 62 50 62 53 68 59 81 67 2.2 3.6 2.2 2.2 1.8 2.3 2.0 2.7 2.0 2.7 2.2 127 123 65 68 54 65 71 83 67 69 79
28 28 28 28 28 56 28 28 28 28 16 28 28
1 slice 1 piece 1 slice 1 slice 1 slice 1/4 cup 1 slice 1 slice 1 slice 1 slice 3 Tbsp 1 slice 1 slice
319 308 313 372 355 378 406 365 407 352 336 365 471 365
344 367 325 341 325 374 412 335 450 318 348 431 480 337
6.3 6.1 5.6 7.1 6.7 7.0 7.0 6.9 7.8 6.6 6.2 7.2 8.1 6.8
106 100 85 114 112 58 101 106 79 104 68 100 106 95
TABLE 2-5. Nutrient Composition of PHENEX-2 1

Nutrient Phenex-2, Unflavored Per 100 g pwd Per g protein equiv Energy, kcal 410 13.7 Protein equiv, g 30.00 1.000 Nitrogen, g 4.80 0.160 Amino acids, g 31.58 1.053 Cystine, g 0.30 0.010 Histidine, g 0.84 0.028 Isoleucine, g 2.16 0.072 Leucine, g 3.36 0.112 Lysine, g 2.00 0.067 Methionine, g 0.60 0.020 Phenylalanine, g trace 0 Threonine, g 1.40 0.047 Tryptophan, g 0.34 0.011 Tyrosine, g 3.00 0.100 Valine, g 2.44 0.081 Other Nitrogen-Containing Compounds Carnitine, mg 40 1.33 Taurine, mg 50 1.67 Carbohydrate, g 35 1.17 Fat, g 14 0.47 2 Linoleic acid, g 1.50 0.050 3 0.17 0.006 -Linolenic acid, g Minerals Calcium, mg 880 29 Chloride, mg/mEq 940/26.51 31.33/0.88 Chromium, g 27 0.90 Copper, mg 1.00 0.033 Iodine, g 100 3.33 Iron, mg 13 0.43 Magnesium, mg 225 7.50 Manganese, mg 0.80 0.027 Molybdenum, g 30 1.00 Phosphorus, mg 760 25 Potassium, mg/mEq 1,370/35.04 45.7/1.17 Selenium, g 35 1.17 Sodium, mg/mEq 880/38.28 29.3/1.28 Zinc, mg 13 0.43 Vitamins A, g RE 660 22 D, g 7.50 0.25 12.10 0.40 E, mg -TE K, g 60 2.00 Ascorbic acid, mg 60 2.00 Biotin, g 100 3.33 B6, mg 1.30 0.043 5.0 0.167 B12, g Choline, mg 100 3.33 Folate, g 450 15 Inositol, mg 70 2.33 Niacin equiv, mg 21.7 0.72 Pantothenic acid, mg 8.00 0.267 Riboflavin, mg 1.80 0.06 Thiamin, mg 3.25 0.108 1 Approximate packed weight in level, dry US standard household measures: Phenex-2, Flavored Per 100 g pwd Per g protein equiv 410 13.7 30.00 1.000 4.80 0.160 31.58 1.053 0.30 0.010 0.84 0.028 2.16 0.072 3.36 0.112 2.00 0.067 0.60 0.020 trace 0 1.40 0.047 0.34 0.011 3.00 0.100 2.44 0.081 40 50 36 13.5 2 1.50 3 0.17 880 940/26.51 27 1.00 100 13 225 0.80 30 760 1,370/35.04 35 880/38.28 13 660 7.50 12.10 60 60 100 1.30 5.0 100 450 70 21.7 8.00 1.80 3.25 1.33 1.67 1.20 0.45 0.050 0.006 29 31.33/0.88 0.90 0.033 3.33 0.43 7.50 0.027 1.00 25 45.7/1.17 1.17 29.3/1.28 0.43 22 0.25 0.40 2.00 2.00 3.33 0.043 0.167 3.33 15 2.33 0.72 0.267 0.06 0.108
Phenex-2, unflavored Phenex-2, flavored 1 Tbsp = 8g 9g 1/4 cup = 32 g 30 g 1/3 cup = 41 g 40 g 1/2 cup = 61 g 59 g 1 cup = 117 g 116 g 2 Analytical data at manufacture = 2.75 g/100 g powder in unflavored and 2.66 g/100 g powder in flavored. 3 Analytical data at manufacture = 0.28 g/100 g powder in unflavored and 0.27 g/100 g powder in flavored.
TABLE 2-6. PHE-Restricted Diet Guide

Name: _____________________________________________________ Date: ______ _/__ _____/_ ______ Mo Day Year Weight: ______________________(kg)
Medical Food Phenex-2, unflavored, flavored
Amount
Tbsp/cup/g Tbsp/cup/g Tbsp/cup/g Add water to make ____________________ mL (__________________ fl oz). Daily Intake Servings PHE (mg) TYR (mg) Protein (g) Energy (kcal)
BREAKFAST Medical Food Mixture, fl oz Breads/Cereals Fats Fruits Cheese/Eggs/Regular Bread Free Foods A Free Foods B MIDMORNING SNACK LUNCH Medical Food Mixture, fl oz Breads/Cereals Fats Fruits Vegetables Cheese/Eggs/Regular Bread Free Foods A Free Foods B MIDAFTERNOON SNACK DINNER Medical Food Mixture, fl oz Breads/Cereals Fats Fruits Vegetables Cheese/Eggs/Regular Bread Free Foods A Free Foods B BEDTIME SNACK
DAILY TOTAL
Comments:
_____________________________________________ Nutritionist
TABLE 2-7. Recommended Dietary Intakes (RDIs) for Pregnant Women1

Nutrient 15 to <19 Minerals Calcium, mg Chloride, mEq Copper, mg Iodine, g Iron 2, mg Magnesium, mg Manganese, mg Phosphorus, mg Potassium, mEq Selenium, g Sodium, mEq Zinc, mg 1,300 40 - 117 2.5 175 48 450 3.75 1,250 39 - 117 65 39 - 117 20 1,000 48 - 144 2.5 175 48 450 3.75 1,250 48 - 144 65 48 - 144 20 Age (yr) > 19
Vitamins A, g RE 1,000 D, g 5 15 E, mg -TE K, g 65 Ascorbic acid, mg 80 Biotin, g 30 B6, mg 2.6 B12, g 4 Folate, g 800 Niacin equiv3, mg 18 Pantothenic acid, mg 6.0 Riboflavin, mg 1.6 Thiamin, mg 1.5 1 Modified from references 13, 50. 2 From reference 3. 3 From reference 28.
1,000 5 15 65 85 30 2.6 4 800 18 6.0 1.6 1.5
TABLE 2-8. MPKU Clinical Summary Sheet Name: Date of Birth: __________/__________/__________ Age: _______(yrs) Mo Day Year Date of Last Menstrual Period: _________/__________/_________ Mo Day Year Mo Hospital Number: Usual Prepregnancy Weight: __________ kg Height:________ (cm)
Diet Started: _________/__________/_________ Day Year
Wks Preconception: _________________ Wks Gestation: _________________ When Diet Initiated: _________________
Date Physical Data Weight Weight Gestation Age Gain (wk) (kg) (kg) Hgb (g/dL) Hct (%) Laboratory Data Transthyretin Ferritin Folate1 (mg/dL) (g/L) PHE2 TYR2 PHE (mg) Nutrient Intake Data TYR Protein Energy (mg) (g) (kcal)
(mo/d/yr)
1 2
Indicate if RBC or serum and method. Indicate if mg/dL or mol/L.
REFERENCES
1. 2. Acosta PB: Nutrition support of maternal PKU. Sem Perinat 1995;19;182-190. Acosta PB, Michals-Matalon K, Austin V, et al: Nutrition findings and requirements in pregnant women with phenylketonuria. In Platt L (ed): Effects of Genetic Disorders on Pregnancy Outcome. London: Parthenon Publ, 1997, pp 21-32. Acosta PB, Stepnick-Gropper S, Clarke-Sheehan N, et al: Trace element status of PKU children ingesting an elemental diet. JPEN 1987;11:287. Arnold GL, Vladutiu CJ, Kirby RS: Protein insufficiency and impaired growth in children with PKU. J Inher Metab Dis 2000;23 (Suppl 1):29A. Behrman RE, Kliegman RM, Arvin AA (eds): Nelson Textbook of Pediatrics, ed 15. Philadelphia: WB Saunders Co, 1996. Calomme MR, Vanderpas JB, Francois B, et al: Thyroid function parameters during a selenium repletion/depletion study. Experientia 1995;51:1208-1215. Castiglioni LL, Rouse BM: The Young Woman With PKU. Galveston, Texas: University of Texas, 1986. Committee on Nutrition of the Mother and Preschool Child, Food and Nutrition Board, National Research Council: Laboratory Indices of Nutritional Status in Pregnancy. Washington, DC: National Academy of Sciences, 1978. Danks DM, Cotton RGH: Future developments in phenylketonuria. In Tada T, et al (eds): Recent Advances in Inborn Errors of Metabolism. New York: S Karger, 1987. Elsas LJ, Acosta PB: Nutrition support of inherited metabolic diseases. In Shils ME, et al (eds): Modern Nutrition in Health and Disease, ed 9. Baltimore: Williams & Wilkins, 1999, pp 1003-1056. Farquhar DL, Steven F, Westwood A: Preliminary report on inverse diurnal variation of phenylalanine: Implications in maternal phenylketonuria. Hum Nutr Appl Nutr 1985;39A:224-226. Fisch RO, Burke B, Bass J, et al: Maternal phenylketonuria Chronology of the detrimental effects on embryogenesis and fetal development: Pathological report, survey, clinical application Pediatr Pathol 1986;5:449-461. Food and Nutrition Board, Committee on Dietary Allowances: Recommended Dietary Allowances, eds 9 and 10. Washington, DC: National Academy of Sciences, 1980 and 1989. Gropper S, Acosta PB: Effect of simultaneous ingestion of L-amino acids and whole protein on plasma amino acid and urea nitrogen concentrations in humans. JPEN 1991;15:48-53. Hanley WB, Clarke JTR, Schoonheyt W: Maternal phenylketonuria (MPKU): A review. Clin Biol 1986:20:149-56. Hanley WB, Feigenbaum ASJ, Clarke JTR, et al: Vitamin B12 deficiency in adolescents and young adults with phenylketonuria. Eur J Pediatr 1996;S155:S145-S147. Herbert V: Folic acid. In Shils ME, et al (eds): Modern Nutrition in Health and Disease, ed 9. Baltimore: Williams & Wilkins, 1999, pp 433-446. Herrmann ME, Broesicke HG, Keller M, et al: Dependence of the utilization of a phenylalanine-free amino acid mixture on different amounts of a single dose ingested. A case report. Eur J Pediatr 1994;153:501-503. Jones BJM, Lees R, Andrews J, et al: Comparison of an elemental and polymeric enteral diet in patients with normal gastrointestinal function. Gut 1983;24:78-84. Kirby ML, Miyagawa ST: The effects of high phenylalanine concentration on chick embryonic development. J Inher Metab Dis 1990;13:634-640. Kirkman HN: Projections of a rebound in frequency of mental retardation from phenylketonuria. Appl Res Mental Retard 1982;3:319-328. Koch R, Friedman E, Azen C, et al: The international collaborative study of maternal phenylketonuria status report 1998. Mental Retard Devpt Disabilities Research Rev 1999;5:117-121. Koch R, Friedman EG, Wenz E, et al: Maternal phenylketonuria. J Inher Metab Dis 1986;9 (Suppl 2):159-168. Kudo Y, Boyd CAR: Transport of amino acids by the human placenta: Predicted effects thereon of maternal hyperphenylalaninemia. J Inher Metab Dis 1990;13:617-626. Lenke RR, Levy HL: Maternal phenylketonuria and hyperphenylalaninemia. An international survey of the outcome of untreated and treated pregnancies. N Engl J Med 1980;303:1202-1208. Leverton RM, Johnson N, Ellison J, et al: The quantitative amino acid requirements of young women. IV. Phenylalanine, with and without tyrosine. J Nutr 1956;58:341-353. Levy HL: Maternal phenylketonuria: Review with emphasis on pathogenesis. Enzyme 1987;38:312-320. Lewis JS, Loskill S, Bunker ML, et al: N-Methylnicotinamide excretion of phenylketonuric children and a child with Hartnup disease before and after phenylalanine and tryptophan load. Fed Proc 1974;33:666A. Lynch BC, Pitt DB, Maddison TG, et al: Maternal phenylketonuria: Successful outcome in four pregnancies treated prior to conception. Eur J Pediatr 1988;148:72-75. Matalon R, Michals K, Azen C, et al: Maternal PKU collaborative study: The effect of nutrient intake on pregnancy outcome. J Inher Metab Dis 1991;14:371-374. Matalon KM, Acosta PB, Azen C, Matalon R: Congenital heart disease in maternal phenylketonuria: Effects of blood phenylalanine and nutrient intake. Mental Retard Devpt Disabilities Research Rev 1999;5:122-124.
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13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31.
32. Matalon K, Acosta PB, Castiglioni L, et al: Protocol for Nutrition Support of Maternal Phenylketonuria. Bethesda. The National Institute of Child health and Human Development, 1999. 33. Michals K, Acosta PB, Austin V, et al: Nutrition and reproductive outcome in maternal phenylketonuria. Eur J Pediatr 1996;155 (Suppl 1): S165-S168. 34. Ohkohchi N, Andoh T, Ohi R, Mori S: Defined formula diets alter characteristics of the intestinal transport of amino acids and peptides in growing rats. J Pediatr Gastroenterol Nutr 1990;10:490-496. 35. Oldham H, Sheft BB: Effect of caloric intake on nitrogen utilization during pregnancy. J Amer Diet Assoc 1951;27:847-854. 36. Posati LP, Orr ML: Composition of Foods: Dairy and Egg Products, Agriculture Handbook No. 8-1. Washington, DC: US Dept of Agriculture, Agricultural Research Service, 1976. 37. Platt LD, Koch R, Hanley WB, et al: The international study of pregnancy outcome in women with maternal phenylketonuria. Report of a 12-year study. Am J Obstet Gynecol 2000;182:1-8. 38. Pratt EL, Snyderman SE, Cheung MW, et al: The threonine requirement of the normal infant. J Nutr 1955;56:231-251. 39. Rohr FJ, Doherty LB, Waisbren SE, et al: New England maternal PKU project: Prospective study of untreated and treated pregnancies and their outcomes. J Pediatr 1987;110:391-398. 40. Rouse B, Azen C, Koch R, et al: Maternal phenylketonuria collaborative study (MPKUCS) offspring: Facial anomalies, malformations, and early neurological sequelae. Am J Med Genet 1997;69:89-95. 41. Rouse B, Matalon R, Koch R, et al: Maternal phenylketonuria syndrome: Congenital heart defects, microcephaly, and developmental outcomes. J Pediatr 2000;136:57-61. 42. Schoeffer A, Herrmann ME, Broesicke HG, Moench E: Effect of dosage and timing of amino acid mixtures on nitrogen retention in patients with phenylketonuria. J Nutr Med 1994;4:415-418. 43. Smith I, Glossop J, Beasley M: Fetal damage due to maternal phenylketonuria: Effects of dietary treatment and maternal phenylalanine concentrations around the time of conception. J Inher Metab Dis 1990;13:651-657. 44. Smith JL, Arteaga C, Heymsfield SB: Increased ureagenesis and impaired nitrogen use during infusion of a synthetic amino acid formula - A controlled trial. N Engl J Med 1982;306:1013-1018. 45. Smith JL, Heymsfield SB: Enteral nutrition support: Formula preparation from modular ingredients. JPEN 1983;7:280-288. 46. Soeters RP, Sengers RC, van Dongen PW, et al: Maternal phenylketonuria: Comparison of two treated full-term pregnancies. Eur J Pediatr 1986;145:221-223. 47. Subcommittee on Nutritional Status and Weight Gain During Pregnancy: Nutrition and Pregnancy. Washington, DC: National Academy Press, 1990. 48. Rothman KJ, Moore LL, Singer MR, et al: Teratogenicity of high vitamin A intake. N Engl J Med 1995;333:1369-1373. 49. Weir D, Scott JM: Vitamin B12 "cobalamin". In Shils ME, et al (eds): Modern Nutrition in Health and Disease, ed 9. Baltimore: Williams & Wilkins, 1999, pp 447-458. 50. Yates AA, Schlicker SA, Suitor CW: Dietary reference intakes: The new basis for recommendations for calcium and related nutrients, B vitamins, and choline. J Amer Diet Assoc 1998;98;699-706.
PROTOCOL 3 Tyrosinemia Types Ia and Ib Nutrition Support of Infants, Children and Adults With TYREX -1 and TYREX -2 Amino Acid-Modified Medical Foods
I. Introduction
Five clinical forms of hereditary tyrosinemia have been reported. Type Ia is caused by a primary defect of hepatic fumarylacetoacetate hydrolyase (FAH) (13) with production of an abnormal metabolite, succinylacetone, which is formed from the accumulated substrate fumarylacetoacetate (Figure B). If maleylacetoacetic acid isomerase is functional, succinylacetone is also formed from maleylacetoacetate. Succinylacetone is extremely toxic and is associated with impaired active transport functions and disordered hepatic enzymes, including p-hydroxyphenylpyruvic acid dioxygenase (p-OHPPAD) and -aminolevulinic acid (-ALA) dehydratase (30). Decreased activity of both hepatic and erythrocyte -ALA dehydratase has been reported in these patients and is postulated as the mechanism by which acute porphyric-like episodes develop (30). Inhibition of p-OHPPAD using the drug 2 (2-nitro-4-trifluoromethylbenzoyl)-1, 3-cyclo-hexanedione (NTBC) has prevented acute porphyric episodes and decreased rates of progression of cirrhosis and Fanconi syndrome (20, 21).
Dietary protein
Tissue protein catabolism
Phenylalanine*
Tissue protein synthesis CO2 + H2O Melanin Epinephrine Thyroxine
Tyrosine*
p-Hydroxyphenylpyruvic acid* p-OH phenylpyruvic acid dioxygenase Homogentisic acid Maleylacetoacetic acid isomerase (type Ib) Maleylacetoacetic acid* Succinylacetoacetic acid*
Fumarylacetoacetic acid*
Fumarylacetoacetic acid hydrolyase (type Ia) * Accumulates In untreated tyrosinemia type Ia Inhibited by NTBC Enzyme malfunction Succinylacetone*
Fumaric acid + Acetoacetic acid
Figure B. Tyrosine metabolism in tyrosinemia types Ia and Ib Tyrosinemia type Ia is characterized by generalized renal tubular impairment with hypophosphatemic rickets, progressive liver failure producing cirrhosis and hepatic cancer, hypertension, episodic behavioral and peripheral nerve deficiencies, and elevated concentrations of blood phenylalanine (PHE) and tyrosine (TYR) with succinylacetone and -ALA excretion in urine (30). FAH is expressed in amniotic and chorionic villus cells and prenatal diagnosis is available by biochemical or molecular techniques (30). Soon after birth, infants with the acute form of tyrosinemia type Ia develop progressive liver and kidney failure, vomiting, diarrhea, and a "cabbage-like" odor.
50 Tyrosinemia Types Ia and Ib 2001 Ross Products Division
Because some of these symptoms are similar to other inborn errors of metabolism, accurate diagnosis is essential. Increased concentrations of PHE and TYR are found in the blood (13, 30). The chronic form of tyrosinemia type Ia is similar to the acute form, but symptoms are usually milder and appear later in infancy. Symptoms include rickets, liver and kidney dysfunction, high blood pressure, and nervous system dysfunction. Liver hepatomas often develop on or before 10 years of age, even in well-treated patients (13, 30). Incidence of tyrosinemia type Ia varies. Overall incidence in Quebec, Canada, is 1/12,500 live births (30). Therapy with a PHE and TYR-restricted diet and administration of NTBC to prevent succinylacetone accumulation is now the standard of care for tyrosinemia type Ia. Tyrosinemia type Ib, believed to be due to deficiency of maleylacetoacetate isomerase (Figure B), has been reported in 1 infant (8, 30). Liver failure, renal tubular disease, and progressive psychomotor retardation occurred prior to death at 1 year of age. Succinylacetone did not accumulate.
II. Outcome of Nutrition Support

Liver transplantation has significantly improved outcome in patients with tyrosinemia type Ia. Without liver transplantation, patients develop hepatomas (12), usually within the 1st or 2nd decade of life. NTBC has dramatically improved the course of patients with tyrosinemia type I (20, 21, 23, 26, 33). Whether hepatomas will develop in patients treated with NTBC is unknown (23). If hepatomas do not develop, liver transplantation may be unnecessary. Medical and nutrition support are essential to maintain optimal health and nutrition status until a suitable liver is found. Long-term data on patients with a liver transplant are not yet available.

A. The Defect 1. Tyrosinemia may result from defect in 1 of several enzymes. a. Type Ia: Fumarylacetoacetate hydrolyase (17, 30). b. Type Ib: Maleylacetoacetate isomerase (8). c. Type II: Tyrosine aminotransferase (Protocol 4, p 63). d. Type III: Parahydroxyphenylpyruvic acid dioxygenase (14, 30) (Protocol 4, p 63). 1) No liver enzyme activity (30). 2) Hawkinsinuria (30). 3) Transient, neonatal. B. Clinical Screening 1. Concentration of > 4 mg TYR/dL (13) by bacterial inhibition assay of dried blood spot requires differential diagnosis. 2. Because few states screen for tyrosinemia, infants or children with any of following clinical findings associated with hepatosplenomegaly and nephropathy should be evaluated for tyrosinemia types Ia and Ib (7, 12, 30): a. Failure to thrive. b. Vomiting and/or diarrhea. c. Jaundice. d. Fanconi syndrome. e. Rickets. f. Some patients may not develop renal tubular dysfunction or rickets (43). C. Differential Diagnosis 1. Differential diagnosis will reveal false-positives and identify specific enzyme defect. 2. Therapy depends on enzyme defect present. 3. This protocol addresses nutrition support for patients with deficiency of FAH or maleylacetoacetate isomerase.

A. Correct Primary Imbalance in Metabolic Relationships 1. Restrict dietary PHE and TYR to amounts tolerated by patient to maintain treatment plasma amino acid concentrations.
Tyrosinemia Types Ia and Ib 51
B. Reduce Transcription of Gene 1. Reduce transcription of -ALA dehydratase gene with high-carbohydrate diet if -ALA is present in urine (9). 2. The high-carbohydrate diet may be unnecessary with use of NTBC.

A. Plasma PHE and TYR Concentrations 1. Maintain 2- to 4-hour postprandial plasma PHE and TYR concentrations in ranges noted below when measured by quantitative methods, or within normal range for age established by laboratory used.
Amino Acid PHE TYR mol/L 35 - 90 40 - 80 mg/dL 0.58 - 1.49 0.72 - 1.45
2. In practice, obtaining blood 2 to 4 hours postprandially is not always possible. Acceptable local standards should be developed if plasma amino acids are evaluated at other times (Practical Aspects of Nutrition Support, p viii). 3. Differences of opinion exist as to best concentrations of plasma PHE and TYR to support normal growth and development in infants and children with tyrosinemia types Ia and 1b and to prevent development of hepatomas. a. In this protocol, concentrations as close to normal as possible are assumed to be best. b. With use of NTBC, plasma TYR concentrations will be greater than without its use but should be maintained as close to normal range as possible. c. With plasma PHE and TYR concentrations in normal range, plasma amino acids must be measured frequently to prevent deficiency (11). B. Growth, Development, and Nutrition Status 1. Support normal growth rate in infants and children. 2. Support normal development. 3. Maintain normal nutrition status (10). 4. Prevent catabolism. 5. Maintain plasma bicarbonate, phosphate, and potassium in normal range for age. 6. Maintain plasma and urine free of, or containing only traces of, succinylacetone and parahydroxyphenyl organic acids. 7. Maintain urine free of, or containing only traces of, -ALA. 8. Prevent rickets (19). C. Neurologic Status 1. Prevent neurologic crises (31, 36). D. Hepatic and Renal Status 1. Maintain normal liver and renal function (23-25, 37, 38, 43, 45). 2. Support patient nutritionally until appropriate liver can be found to transplant (37), if indicated.

A. PHE Plus TYR (5) 1. Prescribe PHE plus TYR intake that promotes goals of nutrition support. 2. PHE plus TYR requirement varies widely: a. From patient to patient, depending on activity of fumarylacetoacetate hydrolyase. b. In same patient, depending on age, growth rate, adequacy of protein and energy intakes, and state of health. 3. Lowest value for age for PHE plus TYR listed in Table 3-1, p 58, is suggested for initiating therapy. 4. Changing requirements of patients are determined by frequent monitoring of: a. Plasma PHE and TYR concentrations. b. Plasma and urine concentrations of succinylacetone and parahydroxyphenyl organic acids. c. See Section IX, Suggested Evaluation of Nutrition Support, p 54.
Warning:
Inadequate PHE plus TYR intake results in anorexia, lethargy, hypotonia, decreased growth rate in infants and children, decreased plasma fibrogen, and increased plasma amino acid concentrations (except PHE and TYR) (11).
B. Protein 1. Prescribe, initially, amount greater than Recommended Dietary Allowances (RDA) (15) (Table 3-1, p 58). 2. Requirements are greater than RDAs when L-amino acids supply majority of protein equivalent as result of: a. Rapid amino acid absorption (16). b. Early and high peak of plasma amino acid concentrations after ingestion of meals where large part of protein is supplied by L-amino acids (16). c. Rapid catabolism of amino acids (18, 22, 39, 41). d. Possible decreased total amino acid absorption (32). 3. If blood ammonia concentration is elevated, protein intake may need to be restricted until ammonia level returns to normal range. Warning: Inadequate protein intake will result in failure to thrive, weight loss, low plasma transthyretin concentrations, osteopenia, hair loss, and decreased PHE and TYR tolerance. C. Energy 1. Prescribe amount that should support normal weight gain for infants and toddlers (Table 3-1, p 58). 2. Requirements vary widely and may be greater than normal when L-amino acids supply majority of protein equivalent (18, 35). 3. To help prevent neurologic crises if NTBC is not used, 50-65% of energy should be derived from carbohydrate (9). 4. See Appendix 26, p A-28, for source of NTBC. Warning: Inadequate energy intake may precipitate metabolic and neurologic crises as result of muscle protein catabolism. D. Fluid 1. Prescribe amount that will supply water requirements (Table 3-1, p 58). Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL fluid to children and adults for each kcal ingested. 2. Supply greater than normal amounts because of greater than normal energy intake. E. 1,25 Dihydroxycholecalciferol (Rocaltrol ) 1. Use in presence of elevated alkaline phosphatase and/or decreased plasma phosphate, or radiographic evidence of rickets. 2. Prescribe 0.25-1.0 g of Rocaltrol daily, if needed.

A. PHE Plus TYR 1. Calculate amount of infant formula with iron, beikost, whole cow's milk, or table foods (Table 3-2, p 58) required to fill PHE plus TYR prescription. a. Low-iron infant formula, whole cow's milk, or evaporated milk should not be used as PHE plus TYR source for infants because of low iron content. 2. Measure liquid infant formula, and whole cow's milk with disposable syringe. Weigh powdered infant formula on scale that reads in grams. 3. Add beikost or table foods to gradually displace PHE plus TYR provided by infant formula after infant is 3 to 4 months old or is developmentally ready. 4. Parents or patients may select any food in prescribed Servings Lists for PHE-Restricted Diets (Protocol 1, pp 13-26) in specified amounts to fill diet prescription. B. Protein 1. Calculate amount of infant formula with iron, beikost, whole cow's milk, or table foods (Table 3-2, p 58) required to fill PHE plus TYR prescription.
2001 Ross Products Division Tyrosinemia Types Ia and Ib 53
2. Subtract amount determined above from total protein prescription. 3. Supply remaining prescribed protein with Tyrex (Table 3-3, p 59). a. Tyrex-1 is for infants and toddlers and Tyrex-2 is for children and adults. b. Weigh Tyrex powder on scale that reads in grams because of variability of household measuring equipment (Practical Aspects of Nutrition Support, p vii) and changes in density during shipping. c. See Table 3-3 (p 59, footnote 3) for approximate packed weight of Tyrex powder in level, dry US standard household measures. C. Energy 1. Calculate energy provided by infant formula with iron, beikost, whole cow's milk, or table foods (Table 3-2, p 58), and Tyrex (Table 3-3, p 59) required to fill PHE plus TYR and protein prescriptions. 2. Subtract amount determined above from total energy prescription. 3. Provide remaining prescribed energy with Polycose Glucose Polymers powder (23 kcal/Tbsp, 3.8 kcal/g) or liquid (2 kcal/mL) (Appendix 9, p A-9); Pro-Phree Protein-Free Energy Module With Iron, Vitamins & Minerals (Appendix 11, p A-10); sugar (48 kcal/Tbsp); or Free Foods B (Table 3-2, 58), depending on age of patient. a. Do not use corn syrup or table sugar for infants because of osmolarity they yield (28). b. Do not use honey for infants because it may contain botulinum toxin (44). 4. At least 50% of energy prescription should be derived from carbohydrate (9) if patient tolerates osmolarity of medical food mixture. D. Fluid and Mixing Instructions 1. Add sufficient boiled, cooled water to infant formula, Tyrex, and carbohydrate to yield prescribed volume. Tap water may replace boiled, cooled water when preparing Tyrex for older infants and children. 2. Mix with sterilized blender at lowest speed no longer than 3 to 4 seconds. Excess mixing may destabilize emulsion. Medical food may also be mixed in tightly closed container by shaking vigorously for 10 to 12 seconds. 3. Refrigerate in sterilized, closed containers until used. Discard unused portion 24 hours after mixing because of nutrient loss. 4. Do not use terminal sterilization or boil because of Maillard reaction (Practical Aspects of Nutrition Support, p viii). 5. Warm or cool medical food mixture to room temperature before feeding to infants. Shake mixture well before feeding. 6. Do not warm medical food mixture for infants in microwave oven. Unevenly heated formula can burn infants, and steam can make bottles explode. 7. Notify parents or caretakers when they may discontinue using aseptic technique in preparing medical food mixture for infants. 8. For children and adults, chill Tyrex medical food mixture to improve taste. E. Diet Guide 1. Provide parents or caretakers with completed Diet Guide (Appendix 22, p A-24) with each diet change. 2. Feed infant 6 to 8 times daily (18, 39). 3. Feed children and adults 4 to 6 times daily (18, 39).

A. Nutrient Adequacy 1. Determine if diet provides nutrients in amounts prescribed in Section VI, Establish Prescription, p 51. a. See Table 3-3, p 59, for composition of Tyrex. b. See Table 3-2, p 58, for average composition of infant formulas and whole cow's milk. 2. Check diet to determine if it supplies Recommended Dietary Intakes (RDIs) for minerals and vitamins (Appendices 13 and 14, pp A-14 and A-15). a. See Appendices 4 through 7, pp A-4 to A-7, for average nutrient composition of infant formulas.
b. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. c. If Tyrex mixture provides < 100% of RDIs for infants and < 75% for children and adults, supplement diet with needed minerals and vitamins if not provided by beikost or table foods and laboratory tests indicate need (Appendix 11, p A-10, for composition of supplements). B. Osmolarity 1. If concentration of prescribed medical food mixture is > 24 kcal/fl oz, determine if osmolarity is in acceptable range. a. Determine osmolarity by laboratory analysis or use mathematical formula given in Appendix 18, p A-20. b. Osmolarity per gram of Tyrex is listed in Appendix 19, p A-21. 2. If osmolarity is > 450 mosm/L for neonates, > 750 mosm/L for children, or is greater than that tolerated by patient, increase water content of prescribed medical food mixture and recalculate its osmolarity (27). C. Potential Renal Solute Load 1. Dehydration will result if renal solute load is greater than renal-concentrating ability of patient. 2. If concentration of medical food mixture prescribed is > 24 kcal/fl oz, estimate its potential renal solute load. a. This step is important to prevent dehydration of infants who may have renal-concentrating capacity as low as 600 mosm/L. b. Upper limit of renal solute load for neonates is approximately 1,100 mosm/L (40). 3. A method for estimating potential renal solute load is given in Appendix 20, p A-22. 4. If potential renal solute load is excessive, increase water content of medical food mixture and recalculate.
IX. Suggested Evaluation of Nutrition Support (13)

A. Plasma PHE and TYR Concentrations 1. Initial. a. Evaluate twice weekly by quantitative methods until plasma concentrations stabilize and approximate dietary PHE and TYR requirements are known. 2. Ongoing. a. Frequent evaluations help ensure adherence to nutrition support plan. b. Evaluate plasma PHE and TYR concentrations weekly until infant is 1 year old and once or twice monthly thereafter. 3. Unacceptable plasma PHE or TYR concentrations. a. If plasma PHE or TYR concentration is not detected and patient has ingested full prescription: 1) Increase prescribed amount of undetected amino acid(s) by 25% and reevaluate plasma concentrations in 3 to 4 days. 2) If plasma PHE or TYR concentration continues undetected, repeat above process until value is in treatment range. b. If plasma PHE concentration is < 35 mol/L (0.58 mg/dL) or plasma TYR concentration is < 40 mol/L (0.72 mg/dL) and patient has ingested full prescription: 1) Increase prescribed amount of amino acid(s) that is low by 5% to 10% and reevaluate plasma concentration in 3 to 4 days. 2) If plasma PHE or TYR concentration continues to be low, repeat above process until value is in treatment range. c. If plasma PHE is > 90 mol/L (1.49 mg/dL) or plasma TYR is > 80 mol/L (1.45 mg/dL) and the patient is not ill and has not ingested more or less protein and energy than prescribed: 1) Decrease prescribed amount of elevated amino acid(s) by 5% to 10% and reevaluate plasma concentration in 3 to 4 days. 2) If plasma PHE or TYR concentration continues to be high, repeat above process until value is in treatment range.
2001 Ross Products Division Tyrosinemia Types Ia and Ib 55
B. Organic Acids in Urine 1. Evaluate succinylacetone and parahydroxyphenyl organic acids monthly or if plasma TYR is elevated. C. Protein Status 1. Evaluate plasma transthyretin concentration every 3 months in infants and twice yearly in children and adults (Appendix 17, p A-18, for standards). a. Plasma transthyretin concentrations provide a more reliable and rapid indication of protein status than plasma albumin concentrations. b. Plasma albumin concentrations may be in the normal range when plasma transthyretin concentrations show a clear deficiency (3). 2. If plasma transthyretin concentration is below standard: a. Increase prescribed protein by 5% to 10% if blood ammonia is normal and reevaluate in 1 month. If plasma PHE and TYR concentrations are in treatment range, use Tyrex to increase protein. b. If plasma transthyretin concentration continues below standard, repeat above process until value is in normal range. D. Iron Status 1. Plasma ferritin concentration. a. Evaluate at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17, p A-18, for standards). b. If plasma ferritin concentration is below standard: 1) Increase iron intake to 4 mg/kg body weight with supplements (ferrous sulfate). 2) Evaluate plasma ferritin concentration monthly on increased iron intake. 3) Continue iron supplements until plasma ferritin concentration is in normal range. 2. Complete blood count. a. Hemoglobin and hematocrit concentrations should be evaluated at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17, p A-18, for standards). E. Plasma and Urine Biochemistries 1. Plasma and urine phosphate, potassium, and bicarbonate concentrations. a. Evaluate monthly. b. Maintain in normal range for age as established by laboratory used. 2. Plasma chloride, sodium, liver enzymes, and alkaline phosphatase concentrations. a. Maintain in normal range for age and laboratory standards (29). b. Evaluate every 3 months. c. If alkaline phosphatase concentration is elevated, obtain radiographs of bones for evaluation of rickets (2). F. Growth Status 1. Length/height and weight. a. Measure monthly to 1 year and every 6 months thereafter until adulthood. Plot measurements on NCHS growth charts. b. Maintain length/height and weight between 10th and 90th percentiles. Some normal infants and children will fall above or below these percentiles. 2. If length/height or weight falls below usual growth channel: a. Increase prescribed protein (from Tyrex) and energy by 5% to 10% and remeasure in 1 month. b. If length/height or weight remains low, repeat above process until usual growth channel is achieved. G. Nutrient Intake 1. Maintain records of food intake for 3 days immediately before each blood test (Appendices 24 and 25, pp A-26 and A-27). 2. Evaluate intakes of PHE, TYR, protein, and energy before each blood test.
56 Tyrosinemia Types Ia and Ib
3. Evaluate mineral and vitamin intakes after each diet change. a. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. b. See Appendix 28, p A-29, for information about ordering software for diet evaluation. I. Special Concern 1. Because of the high risk of hepatomas, periodic serum -fetoprotein concentrations and liver imaging studies (by computer-assisted tomography, ultrasonography, or magnetic resonance imaging) should be obtained.
H. Clinical Summary 1. A summary record of growth, laboratory, and nutrient intake data is useful for patient management (Table 3-4, p 60).
A. Example 1 Establish and fill prescription for newborn weighing 3.3 kg using Recommended Daily Nutrient Intakes from Table 3-1, p 58, and nutrient contents from Tables 3-2 and 3-3, pp 58 and 59. 1. Establish prescription.
PHE and TYR Protein Energy Fluid 65 mg/kg 3.5 g/kg 120 kcal/kg 148 mL/kg x x x x 3.3 kg 3.3 kg 3.3 kg 3.3 kg = 214 mg = 11.6 g = 396 kcal = 488 mL PHE (mg) 0 110 0 108 TYR (mg) Protein (g) 9.2 2.6 Energy (kcal) 293 126
Medical Food Mixture Tyrex-1 Similac With Iron RTF Add water to make 488 mL (17 fl oz). 110 108 11.8 419 Total per day 33 33 3.6 127 Total per kg Total PHE plus TYR 218 Approximate osmolarity of medical food mixture is < 450 mosm/L. Estimated potential renal solute load is < 130 mosm. Measure 61 g 186 mL
B. Example 2 Establish and fill prescription for 3-year-old child weighing 13 kg using Recommended Daily Nutrient Intakes from Table 3-1, p 58, and average nutrient contents from Tables 3-2 and 3-3, pp 58 and 59. 1. Establish prescription.
PHE and TYR Protein Energy Fluid 380 mg 30 g 1,300 kcal 1,365 mL
Medical Food Mixture Tyrex-2 Sugar Measure 80 g 102 g (8.5 Tbsp) 0 0 PHE (mg) 0 0 TYR (mg) Protein (g) 24.0 0.0 Energy (kcal) 328 408
Add water to make 1000 mL (34 fl oz). Offer additional fluid ad libitum daily. Food List Breads/Cereals Fruits Vegetables Free Foods A Servings 3 4 4 3 90 60 60 15 225 377 60 40 40 12 152 1.8 2.0 2.0 0.3 30.1 90 240 40 195 1,301
Total per day Total PHE plus TYR Approximate osmolarity is < 750 mosm/L.
XI. Nutrition Support During Febrile Illness or Following Trauma

A. Rationale 1. In normal persons, febrile illness and trauma are accompanied by catabolism of body protein (46). 2. Well-nourished patients with tyrosinemia respond to infection and trauma as do normal persons. 3. Extent of protein catabolism determines subsequent elevations in plasma PHE and TYR concentrations. B. Objectives of Nutrition Support 1. Maintain hydration and electrolyte balance. a. Offer infants and toddlers Pedialyte Oral Electrolyte Maintenance Solution ad libitum (Appendix 9, p A-9). 2. Depress catabolism. a. Enhance energy intake when possible by offering fruit juices ad libitum as tolerated, liquid Jell-O , Polycose powder or liquid (Appendix 9, p A-9), or Pro-Phree (Appendix 11, p A-10) added to fruit juices or Pedialyte if tolerated and caffeine-free soft drinks (not diet drinks). 1) 1/3 cup of Polycose powder may be added to liquid Pedialyte to yield 8 fl oz. b. Return patient to Tyrex medical food mixture and pre-illness diet as rapidly as possible. 1) Begin with 1/2 original strength of Tyrex medical food mixture. 2) Increase to original strength as tolerated. C. Parenteral Nutrition 1. If parenteral amino acid solutions are indicated, see Appendix 26, p A-28.
TABLE 3-1. Recommended Daily Nutrient Intakes (Ranges) for Infants and Children With Tyrosinemia Types Ia and Ib
Age
Nutrient PHE plus TYR (mg/kg)

1
Protein (g/kg) 3.50 - 3.00 3.50 - 3.00 3.00 - 2.50 3.00 - 2.50
Energy2 (kcal/kg) 120 (145 120 (145 110 (135 105 (135 - 95) - 95) - 80) - 80)
Fluid3 (mL/kg) 160 - 135 160 - 130 145 - 125 135 - 120 (mL/day) 900 - 1,800 1,300 - 2,300 1,650 - 3,300
Infants 0 to < 3 mo 3 to < 6 mo 6 to < 9 mo 9 to < 12 mo
65 - 155 55 - 135 50 - 120 40 - 105 (mg/day)
(g/day) 30 35 40
(kcal/day) 1,300 ( 900 - 1800) 1,700 (1300 - 2300) 2,400 (1650 - 3300)
Girls and Boys 1 to < 4 yr 4 to < 7 yr 7 to < 11 yr Women 11 to < 15 yr 15 to < 19 yr > 19 yr
380 - 800 390 - 900 400 - 1,000
800 - 1,200 800 - 1,200 800 - 1,000
> 50 > 55 > 60
2,200 (1500 - 3000) 2,100 (1200 - 3000) 2,100 (1400 - 2500)
1,500 - 3,000 1,200 - 3,000 1,400 - 2,500
Men 11 to < 15 yr 990 - 1,200 > 55 2,700 (2000 - 3700) 2,000 - 3,700 15 to < 19 yr 1,000 - 1,500 > 65 2,800 (2100 - 3900) 2,100 - 3,900 > 19 yr 1,000 - 1,500 > 70 2,900 (2000 - 3300) 2,000 - 3,300 1 Modified from references 1, 4, 13, 42. Initiate therapy with lowest value for age range. Modify prescription based on frequently obtained plasma values and growth. 2 Modified from reference 15. 3 Modified from reference 6. Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL fluid to children and adults for each kcal ingested.
TABLE 3-2. Serving Lists for PHE- and TYR-Restricted Diets: Average Nutrient Content per Serving1
Food List PHE (mg) Nutrient TYR (mg) Protein (g) 0.6 0.1 0.5 0.5 0.1 0.0 1.86 1.66 1.40 3.39 Energy (kcal) 30 60 60 10 65 55 68 68 68 63
Breads/Cereals 30 20 Fats 5 4 Fruits 15 10 Vegetables 15 10 Free Foods A 5 4 Free Foods B 0 0 Alimentum Protein Hydrolysate Formula With Iron, Ready to Feed, 100 mL 2 86 29 2 Isomil Soy Formula With Iron, Ready to Feed, 100 mL 88 60 2 Similac With Iron Infant Formula, Ready to Feed, 100 mL 59 58 Whole cow's milk, 100 mL 3 164 164 1 From reference 13. 2 See Appendices 4 through 7, pp A-4 to A-7, for complete nutrient composition of infant formulas. 3 From reference 34. See Appendix 8, p A-8, for complete nutrient composition.
TABLE 3-3. Nutrient Composition of TYREX -11, 3 and TYREX -22, 3

Tyrex-1 Tyrex-2 (per 100 g pwd) (per g protein equiv) (per 100 g pwd) (per g protein equiv) Energy, kcal 480 32.0 410 13.7 Protein equiv, g 15.00 1.000 30.00 1.000 2.40 0.160 0.160 Nitrogen, g 4.80 14.73 0.982 0.982 Amino acids, g 29.46 Cystine, g 0.15 0.010 0.30 0.010 Histidine, g 0.42 0.028 0.84 0.028 Isoleucine, g 1.08 0.072 2.16 0.072 Leucine, g 1.68 0.112 3.36 0.112 Lysine, g 1.00 0.067 2.00 0.067 Methionine, g 0.30 0.020 0.60 0.020 Phenylalanine, g trace 0 trace 0 Threonine, g 0.70 0.047 1.40 0.047 Tryptophan, g 0.17 0.011 0.34 0.011 Tyrosine, g trace 0 trace 0 Valine, g 1.22 0.081 2.44 0.081 Other Nitrogen-Containing Compounds Carnitine, mg 20 1.33 40 1.33 Taurine, mg 40 2.67 50 1.67 Carbohydrate, g 53.0 3.53 35 1.17 Fat, g 21.7 1.45 14.0 0.47 4 5 Linoleic acid, g 2.00 0.133 1.50 0.050 6 7 0.36 0.024 0.17 0.006 -Linolenic acid, g Minerals Calcium, mg 575 38 880 29 Chloride, mg/mEq 325/9.17 21.7/0.61 940/26.51 31.33/0.88 Chromium, g 11 0.73 27 0.90 Copper, mg 1.10 0.073 1.00 0.033 Iodine, g 65 4.33 100 3.33 Iron, mg 9.0 0.60 13 0.43 Magnesium, mg 50 3.33 225 7.50 Manganese, mg 0.50 0.033 0.80 0.027 Molybdenum, g 12 0.80 30 1.00 Phosphorus, mg 400 27 760 25 Potassium, mg/mEq 675/17.26 45/1.15 1,370/35.04 45.7/1.17 Selenium, g 20 1.33 35 1.17 Sodium, mg/mEq 190/8.26 12.7/0.55 880/38.28 29.3/1.28 Zinc, mg 8.0 0.53 13 0.43 Vitamins A, g RE 420 28 660 22 D, g 7.50 0.50 7.50 0.25 10.10 0.67 12.10 0.40 E, mg -TE K, g 50 3.33 60 2.00 Ascorbic acid, mg 50 3.33 60 2.00 Biotin, g 65 4.33 100 3.33 B6, mg 0.75 0.050 1.30 0.043 B12, g 4.90 0.327 5.00 0.167 Choline, mg 80 5.33 100 3.33 Folate, g 230 15 450 15 Inositol, mg 40 2.67 70 2.33 Niacin equiv, mg 12.80 0.850 21.7 0.72 Pantothenic acid, mg 6.90 0.460 8.00 0.267 Riboflavin, mg 0.90 0.060 1.80 0.060 Thiamin, mg 1.90 0.127 3.25 0.108 1 2 Designed for infants and toddlers. Designed for children and adults. 3 Approximate packed weights of Tyrex-1 and Tyrex-2 in level, dry US standard household measures: Tyrex-1 Tyrex-2 1 Tbsp = 7g 8g 1/4 cup = 26 g 32 g 1/3 cup = 35 g 41 g 1/2 cup = 53 g 61 g 1 cup = 105 g 117 g 4 5 Analytical data at manufacture = 4.32 g/100 g powder. Analytical data at manufacture = 2.66 g/100 g powder. 6 7 Analytical data at manufacture = 0.40 g/100 g powder. Analytical data at manufacture = 0.28 g/100 g powder. Nutrient
TABLE 3-4. Tyrosinemia Type I Clinical Summary Sheet Name: Date of Birth: __________/__________/__________ Mo Day Year Mo
Date
(mo/d/yr)
Hospital Number: Age Diagnosed: __________/__________/__________ Day Year

Laboratory Data
Na
+
Physical Data
Length/ Height (cm) Weight (kg) Head Circum (cm) K
+
Nutrient Intake Data

Succinyl acetone (mol/L) Transthyretin (mg/dL) PHE (mol/L) TYR (mol/L) PHE (mg) TYR (mg) Protein (g) Energy (kcal)
Cl
HCO3 (mEq/L )
P (mg/dL)
(mEq/L)
(mEq/L)
(mEq/L)
Alkaline Phos (U/L)
SGOT (U/L)
SGPT (U/L)
REFERENCES
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Acosta PB: The contribution of therapy of inherited amino acid disorders to knowledge of amino acid requirements. In Wapnir RA (ed): Congenital Metabolic Diseases: Diagnosis and Treatment. New York: Marcel Dekker Inc, 1985, pp 115-135. Ameen VZ, Powell GK, Rassin DK: Cholestasis and hypermethioninemia during dietary management of hereditary tyrosinemia type 1. J Pediatr 1986;108:949-952. Arnold GL, Vladutiu CJ, Kirby RS: Protein insufficiency and impaired growth in children with PKU. J Inher Metab Dis 2000;23 Suppl 1:29. Bain MD, Purkiss P, Jones M, et al: Dietary treatment eliminates succinylacetone from the urine of a patient with tyrosinemia type 1. Eur J Pediatr 1990;149:637-639. Balint JP, Lindstadt S, Holme E, Balistreri WF: Long-term follow-up: Treatment of acute hereditary tyrosinemia type I without liver transplantation. J Pediatr Gastroenterol Nutr 1994;19:345A. Behrman RE, Kliegman RM, Arvin AA (eds): Nelson Textbook of Pediatrics, ed 15. Philadelphia: WB Saunders Co, 1996. Berger R: Biochemical aspects of type I hereditary tyrosinemia. In Bickel H, et al (eds): Inherited Diseases of Amino Acid Metabolism. New York: Thieme Inc, 1985, pp 192-202. Berger R, Michals K, Galbraeth J, Matalon R: Tyrosinemia type Ib caused by maleylacetoacetate isomerase deficiency: A new enzyme deficiency. Pediatr Res 1988;23:328A. Bonkowsky HL, Magnussen CR, Collins AR, et al: Comparative effects of glycerol and dextrose on porphyrin precursor excretion in acute intermittent porphyria. Metabolism 1976;25:405-414. Calomme MR, Vanderpas JB, Francois B, et al: Thyroid function parameters during a selenium repletion/depletion study in phenylketonuric subjects. Experientia 1995;51:1208-1215. Cohn RM, Yudkoff M, Yost B, et al: Phenylalanine-tyrosine deficiency syndrome as a complication of the management of hereditary tyrosinemia. Am J Clin Nutr 1977;30:209-214. Dubois J, Garel L, Patriquin H,et al: Imaging features of type I hereditary tyrosinemia: A review of 30 patients. Pediatr Radiol 1996;26:845-851. Elsas LJ, Acosta PB: Nutrition support of inherited metabolic diseases. In Shils ME, et al (eds): Modern Nutrition in Health and Disease, ed 9. Baltimore: Williams & Wilkins, 1999, pp 1003-1056. Endo F, Kitano K, Uehara I, et al: Four-hydroxyphenylpyruvic acid oxidase deficiency with normal fumarylacetoacetase: A new variant form of hereditary tyrosinemia. Pediatr Res 1983;17:92-96. Food and Nutrition Board, Committee on Dietary Allowances: Recommended Dietary Allowances, eds 9 and 10. Washington, DC: National Academy of Sciences, 1980 and 1989. Gropper S, Acosta PB: Effect of simultaneous ingestion of L-amino acids and whole protein on plasma amino acid and urea nitrogen concentrations in humans. JPEN 1991;15:48-53. Haber BA, Chuang E, Lee W, Taub R: Variable gene expression within human tyrosinemia type I liver may reflect region-specific dysplasia. Hepatology 1996;24:65-71. Herrmann ME, Broesicke HG, Keller M, et al: Dependence of the utilization of a phenylalanine-free amino acid mixture on different amounts of single dose ingested. A case report. Eur J Pediatr 1994;153:501-503. Hillman L, Schlotzhauer C, Lee D, et al: Decreased bone mineralization in children with phenylketonuria under treatment. Eur J Pediatr 1996;155 (Suppl 1):S148-S152. Holme E, Lindstedt S: Tyrosinaemia type I and NTBC (2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione). J Inher Metab Dis 1998;21:507-517. Holme E, Lindstedt S, Lock EA: Treatment of tyrosinemia type I with an enzyme inhibitor. Intl Pediatr 1995;10:41-43. Jones BJM, Lees R, Andrews J, et al: Comparison of an elemental and polymeric enteral diet in patients with normal gastrointestinal function. Gut 1983;24:78-84. Kvittingen EA: Tyrosinemia type I: An update. J Inher Metab Dis 1991;14:554-562. Kvittingen EA, Talseth T, Halvorsen S, et al: Renal failure in adult patients with hereditary tyrosinemia type I. J Inher Metab Dis 1991;14:53-62. Laine J, Salo MK, Krogerus L, et al: The nephropathy of type I tyrosinemia after liver transplantation. Pediatr Res 1995;37:640-645. Lindstedt S, Holme E, Lock EA, et al: Treatment of hereditary tyrosinemia type I by inhibition of 4-hydroxyphenylpyruvate dioxygenase. Lancet 1992;340:813-817. MacLean W, Graham G: Pediatric Nutrition in Clinical Practice. Menlo Park, Calif: Addison-Wesley Publishing Co, 1982. Martin SB, Acosta PB: Osmotic behaviors of components of chemically-defined formulas. J Pediatr Perinat Nutr 1987;1:1-17. Meites S (ed): Pediatric Clinical Chemistry: Reference Normal Values, ed 3. Washington, DC: AAAP Press, 1989.
30. Mitchell GA, Grompe M, Lambert M, Tanguay RM: Hypertyrosinemia. In Scriver CR, et al (eds): The Metabolic and 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46.
Molecular Bases of Inherited Disease, ed 8. New York, McGraw-Hill Medical Publishing Division, 2001, pp 1777-1806. Mitchell G, LaRochelle J, Lambert M, et al: Neurologic crises in hereditary tyrosinemia. N Engl J Med 1990;322:432-437. Ohkohchi N, Andoh T, Ohi R, Mori S: Defined formula diets alter characteristics of the intestinal transport of amino acids and peptides in growing rats. J Pediatr Gastroenterol Nutr 1990;10:490-496. Paradis K: Tyrosinemia: the Quebec experience. Clin Invest Med 1996;19:11-16. Posati LP, Orr ML: Composition of Foods: Dairy and Egg Products, Agriculture Handbook No. 8-1. Washington, DC: US Dept of Agriculture, Agricultural Research Service, 1976. Pratt EL, Snyderman SE, Cheung MW, et al: The threonine requirement of the normal infant. J Nutr 1955;56:231-251. Rank JM, Pascual-Leone A, Payne W, et al: Hematin therapy for the neurologic crisis of tyrosinemia. J Pediatr 1991;118:136-139. Riudor E, Ribes A, Lloret J, et al: Liver transplantation in two children with tyrosinemia type I: Biochemical aspects. J Inher Metab Dis 1991;14:281-284. Roth KS, Carter BE, Higgins ES: Succinylacetone effects on renal tubular phosphate metabolism: A model for experimental renal Fanconi syndrome. Proc Soc Exp Biol Med 1991;196:428-431. Schoeffer A, Herrmann ME, Broesicke HG, Moench E: Effect of dosage and timing of amino acid mixtures on nitrogen retention in patients with phenylketonuria. J Nutr Med 1994;4:415-418. Smith CA, Nelson NM (eds): The Physiology of the Newborn Infant, ed 4. Springfield, IL: Charles C Thomas Publisher, 1976. Smith JL, Arteaga C, Heymsfield SB: Increased ureagenesis and impaired nitrogen use during infusion of a synthetic amino acid formula - A controlled trial. N Engl J Med 1982;306:1013-1018. Snyderman SE, Boyer A, Norton PM, et al: The essential amino acid requirements of infants. X. Methionine. Am J Clin Nutr 1964;15:322-330. Sovik O, Kvittingen EA, Steen-Johnsen J, Halvorsen S: Hereditary tyrosinemia of chronic course without rickets and renal tubular dysfunction. Acta Paediatr Scand 1990;79:1063-1068. Spika JS, Shaffer N, Hargrett-Bean N, et al: Risk factors for infant botulism in the United States. Am J Dis Child 1989;143:828-832. Suzuki Y, Konda M, Imai I, et al: Effect of dietary treatment on the renal tubular function in a patient with hereditary tyrosinemia. Int J Pediatr Nephrol 1987;8:171-176. Wannemacher RW: Key role of various individual amino acids in host response to infection. Am J Clin Nutr 1977;30:1269-1280.
PROTOCOL 4 Tyrosinemia Types II and III Nutrition Support of Infants, Children, and Adults With TYREX -1 and TYREX -2 Amino Acid-Modified Medical Foods
I. Introduction
Tyrosinemia type II is characterized by greatly elevated concentrations of blood and urine tyrosine (TYR) and by increases in urinary phenolic acids, N-acetyltyrosine, and tyramine. Deficiency of hepatic cytosolic tyrosine aminotransferase (TAT) has been demonstrated (Figure C). Characteristic physical findings include stellate corneal erosions and plaques and bullous lesions of the soles and palms. Persistent keratitis and hyperkeratosis occur on the fingers and palms of the hands and on the soles of the feet. These skin abnormalities respond to restriction of dietary phenylalanine (PHE) and TYR (33, 39, 43). Intracellular crystallization of TYR is thought to cause these inflammatory responses. Mental retardation may occur (42). Two clinical subsets of hereditary tyrosinemia type III result from dysfunction of p-hydroxyphenylpyruvic acid dioxygenase (p-OHPPAD) (Figure C). The most severe is type IIIa with no hepatic p-OHPPAD activity. Neurologic abnormalities, including seizures, ataxia, and mental retardation, have been reported in untreated patients with type IIIa. Hawkinsinuria (Type IIIb) is named for the 2-L-cysteinyl 5-1,4-dihydroxycyclohexenyl-5, 1-acetic acid which presumably is formed from an intermediate resulting from the impaired p-OHPPAD reaction. Metabolic acidosis and failure to thrive with a "swimming pool"-like odor are described (42). Restriction of TYR and PHE improves the critical condition (47).
Dietary protein
Phenylalanine Tissue protein catabolism Tyrosine* Tyrosine aminotransferase (tyrosinemia type II)
Tissue protein synthesis CO2 + H2O Melanin Epinephrine Thyroxine
p-Hydroxyphenylpyruvic acid* p-OH phenylpyruvic acid dioxygenase Homogentisic acid (Tyrosinemia type III) * Accumulates in untreated tyrosinemia types II and III Inhibited by NTBC Maleylacetoacetic acid Enzyme malfunction
Fumarylacetoacetic acid
Fumaric acid + Acetoacetic acid
Figure C. Tyrosine metabolism in tyrosinemia types II and III

The PHE- and TYR-restricted diet has been successfully used in several patients, including a pregnant woman (24), with tyrosinemia types II and III, with rapid resolution of clinical symptoms (33, 39, 43, 47).
64 Tyrosinemia Types II and III 2001 Ross Products Division

A. The Defect 1. Tyrosinemia may result from defect in 1 of several enzymes: a. Type Ia: Fumarylacetoacetate hydrolyase (Protocol 3, p 49). b. Type Ib: Maleylacetoacetate isomerase (Protocol 3, p 49). c. Type II: TAT (16, 27, 29, 33, 42). d. Type III: p-OHPPAD (16-18, 26,42, 47). e. Transient: p-OHPPAD immaturity (16). B. Clinical Screening 1. Concentration > 4 mg/dL of TYR by bacterial inhibition assay of dried blood spot requires differential diagnosis (16) 2. Because few states screen for tyrosinemia, infants, children, or adults with any of following clinical findings should be evaluated for tyrosinemia type II (3, 5-7, 9, 10, 13, 15, 25, 27-29, 36, 48, 50): a. Eye lesions. 1) Photophobia, redness, and/or lacrimation. 2) Persistent herpetiform dendritic ulcers. 3) Ulcerations and thick corneal or conjunctival plaques with neovascularization. b. Skin lesions. 1) Hyperkeratosis of fingers, palms, toes, and/or soles of feet. 2) Blisters. 3) Erosions. c. Seizures. d. Mental retardation. 3. Patients with tyrosinemia type III have been reported with immunologic abnormalities (19, 20), intermittent ataxia (26), neurologic abnormalities (42), and no symptoms (53). C. Differential Diagnosis (42) 1. Differential diagnosis will reveal false-positives and identify specific enzyme defect. 2. Therapy depends on enzyme defect present. 3. This protocol addresses nutrition support for patients with TAT or p-OHPPAD deficiency.

A. Correct Primary Imbalance in Metabolic Relationships 1. Restrict dietary PHE and TYR to amounts tolerated by patient to maintain treatment plasma amino acid concentrations.
V. Establish Goals of Nutrition Support (3, 5-7, 9, 10, 12, 13, 15, 17-20, 22, 25-29, 33, 36, 39, 47,
48) A. Plasma PHE and TYR Concentrations 1. Maintain 2- to 4-hour postprandial plasma PHE and TYR concentrations in ranges noted below, when measured by quantitative methods, or within normal range for age established by laboratory used.
Amino Acid PHE TYR mol/L 35 - 90 40 - 80 mg/dL 0.58 - 1.49 0.72 - 1.45
2. In practice, obtaining blood 2 to 4 hours postprandially is not always possible. Acceptable local standards should be developed if plasma amino acids are evaluated at other times (Practical Aspects of Nutrition Support, p viii). 3. With plasma PHE and TYR concentrations in normal range, plasma amino acids must be measured frequently to prevent deficiency (10). B. Growth, Development, and Nutrition Status (11, 30, 35) 1. Support normal growth rate in infants and children and maintain appropriate weight for height in adults. 2. Support normal development.
2001 Ross Products Division Tyrosinemia Types II and III 65
3. Maintain normal nutrition status. 4. Prevent catabolism. 5. Maintain plasma and urine free of, or containing only traces, of N-acetyltyrosine, p-tyramine, and parahydroxyphenyl organic acids. C. Physical Manifestations 1. Prevent oculocutaneous and/or palmo-plantar lesions.

A. PHE Plus TYR 1. Prescribe PHE plus TYR intake that promotes goals of nutrition support. 2. PHE plus TYR requirement varies widely: a. From patient to patient, depending on activity of TAT or p-OHPPAD. b. In same patient, depending on: 1) Age 2) Growth rate 3) Adequacy of protein and energy intakes 4) State of health. 3. Lowest value for age for PHE plus TYR listed in Table 4-1, p 70, is suggested for initiating therapy. 4. Changing requirements of patients are determined by frequent monitoring of : a. Plasma PHE and TYR concentrations. b. Plasma and urine concentrations of N-acetyltyrosine, p-tyramine, and parahydroxyphenyl organic acids. c. See Section IX, Suggested Evaluation of Nutrition Support, p 67. Warning: Inadequate PHE plus TYR intake results in anorexia, lethargy, and hypotonia; decreased growth rate in children; weight loss in adults; decreased plasma fibrogen concentration; and increased plasma amino acid concentrations (except PHE and TYR) (14). B. Protein 1. Prescribe, initially, amount greater than Recommended Dietary Allowances (RDAs) (23) (Table 4-1, p 70). 2. Requirements are greater than RDAs when L-amino acids supply majority of protein equivalent as a result of: a. Rapid amino acid absorption (31, 32). b. Early and high peak of plasma amino acid concentrations after ingestion of meals where large part of protein is supplied by L-amino acids (31, 32). c. Rapid catabolism of amino acids (31, 32, 34, 37, 52). d. Possible decreased total amino acid absorption (44). Warning: Inadequate protein intake will result in failure to thrive in infant, weight loss in children and adults, low plasma transthyretin, osteopenia, hair loss, and decreased PHE and TYR tolerance. C. Energy 1. Prescribe amount that should support normal weight gain for infants and children and maintain weight for height in adults (Table 4-1, p 70). 2. Requirements vary and may be greater than normal when L-amino acids supply majority of protein equivalent (46, 49). Warning: Inadequate energy intake results in failure to thrive in infants and weight loss in children and adults with elevated plasma PHE and TYR concentrations resulting from muscle protein catabolism. D. Fluid 1. Prescribe amount that will supply water requirements (Table 4-1, p 70). Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL to children and adults for each kcal ingested.
66 Tyrosinemia Types II and III

A. PHE Plus TYR 1. Calculate amount of infant formula with iron, beikost, whole cow's milk, or table foods (Table 4-2, p 70) required to fill PHE plus TYR prescription. a. Low-iron infant formula, whole cow's milk, and evaporated milk should not be used as PHE and TYR source for infants because of low iron content. 2. Parents or patients may select any food in prescribed Servings Lists for PHE-Restricted Diets (Protocol 1, pp 13-26) in specified amounts to fill diet prescription. B. Protein 1. Calculate amount of protein provided by infant formula with iron, beikost, whole cow's milk, or table foods (Table 4-2, p 70) required to fill PHE plus TYR prescription. 2. Subtract amount determined above from total protein prescription. 3. Supply remaining prescribed protein with Tyrex (Table 4-2, p 70). a. Weigh Tyrex powder on scale that reads in grams because of variability of household measuring equipment (Practical Aspects of Nutrition Support, p vii) and changes in density during shipping. b. See Table 3-3 (p 59, footnote 3) for approximate packed weight of Tyrex powder in level, dry US standard household measures. C. Energy 1. Calculate energy provided by infant formula with iron, beikost, whole cow's milk, or table foods and Tyrex (Table 4-2, p 70) required to fill PHE plus TYR and protein prescriptions. 2. Subtract amount determined above from total energy prescription. 3. Provide remaining prescribed energy with Polycose Glucose Polymers powder (23 kcal/Tbsp, 3.8 kcal/g) or liquid (2 kcal/mL) (Appendix 9, p A-9); Pro-Phree Protein-Free Energy Module with Iron, Vitamins & Minerals (Appendix 11, p A-10); sugar (48 kcal/Tbsp); or Free Foods B (Table 4-2, p 70). D. Fluid and Mixing Instructions 1. Add sufficient boiled, cooled water to infant formula, Tyrex, and carbohydrate to yield prescribed volume. Tap water may replace boiled, cooled water when preparing Tyrex for older infants, children, and adults. 2. Mix with sterilized blender at lowest speed for 3 to 4 seconds. Excess mixing may destabilize emulsion. Medical foods may also be mixed in sterilized, tightly closed container by shaking vigorously for 10 to 12 seconds. 3. Place in sterilized formula bottles. Cap and store in refrigerator until used. Discard unused portion 24 hours after mixing because of nutrient loss. 4. Do not use terminal sterilization or boil because of Maillard reaction (Practical Aspects of Nutrition Support, p viii). 5. Warm or cool medical food mixture to room temperature before feeding to infants. Shake well before feeding. 6. Do not warm medical food mixture for infants in microwave oven. Unevenly heated formula can burn infant and steam can make bottles explode. 7. Notify parents or caretakers when they may discontinue using aseptic technique in preparing medical food mixture for infants. 8. For children and adults, chill Tyrex medical food mixture to improve taste. E. Diet Guide 1. Provide parents, caretakers, or patient with completed Diet Guide (Appendix 22, p A-24) with each diet change. 2. Feed young infants 6 to 8 times daily (34, 37, 51). 3. Feed older infants, children, and adults 4 to 6 times daily (34, 37, 51).
Tyrosinemia Types II and III 67

A. Nutrient Adequacy 1. Determine if diet provides nutrients in amounts prescribed in Section VI, Establish Prescription, p 65. a. See Table 4-2, p 70, for composition of Tyrex and average nutrient content of beikost or table foods. b. See Appendix 9, p A-9, for composition of Polycose and Appendix 11, p A-10, for composition of Pro-Phree. 2. Check diet to determine if it supplies Recommended Dietary Intakes (RDIs) for minerals and vitamins (Table 3-3, p 59, and Appendices 13 and 14, pp A-14 and A-15). a. See Appendices 4 through 7, pp A-4 to A-7, for complete nutrient composition of infant formulas and Appendix 8, p A-8, for composition of whole cow's milk. b. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. c. If Tyrex mixture provides < 100% of RDIs for infants and < 75% for children and adults, supplement diet with needed minerals and vitamins if not provided by beikost or table foods and laboratory tests indicate need (Appendix 11, p A-10, for composition of supplements) (11, 30, 35). B. Osmolarity 1. If concentration of prescribed medical food mixture is > 24 kcal/oz, determine if osmolarity is in acceptable range. a. Determine osmolarity by laboratory analysis or use mathematical formula given in Appendix 18, p A-20. b. Osmolarity per gram of Tyrex is listed in Appendix 19, p A-21. 2. If osmolarity is > 450 mosm/L for neonates, > 750 mosm/L for children, > 1,000 mosm/L for adults, or greater than tolerated by patient, increase water content of prescribed medical food mixture and recalculate its osmolarity (40, 41). C. Potential Renal Solute Load 1. Dehydration will result if renal solute load is greater than renal-concentrating ability of patient. 2. If concentration of medical food mixture prescribed is > 24 kcal/fl oz, estimate its potential renal solute load. a. This step is important to prevent dehydration of infants who may have renal-concentrating capacity as low as 600 mosm/L. b. Upper limit of renal solute load for neonates is approximately 1,100 mosm/L. 3. A method for estimating potential renal solute load is given in Appendix 20, p A-22. 4. If potential renal solute load is excessive, increase water content of medical food mixture and recalculate.
IX. Suggested Evaluation of Nutrition Support (16)

A. Plasma PHE and TYR Concentrations 1. Initial. a. Evaluate weekly by quantitative methods until 6 months of age. 2. Ongoing. a. Evaluate monthly. b. Frequent evaluations help ensure adherence to nutrition support plan. 3. Unacceptable PHE and TYR concentrations. a. If plasma PHE or TYR concentration is not detected and patient has ingested full prescription: 1) Increase prescribed amount of PHE plus TYR by 25% and reevaluate plasma concentration in 3 to 4 days. 2) If plasma PHE or TYR concentration continues undetected, repeat above process until value is in treatment range. b. If plasma PHE concentration is < 35 mol/L (0.58 mg/dL) or plasma TYR concentration is < 40 mol/L (0.72 mg/dL) and patient has ingested full prescription: 1) Increase prescribed amount of PHE plus TYR by 5% to 10% and reevaluate plasma concentration in 7 days.
c.
2) If plasma PHE or TYR concentration continues to be low, repeat above process until value is in treatment range. If plasma PHE concentration is > 90 mol/L (1.49 mg/dL) or plasma TYR concentration is > 80 mol/L (1.45 mg/dL) and patient is not ill and has not ingested more or less protein and energy than prescribed: 1) Decrease prescribed amount of PHE plus TYR by 5% to 10% and reevaluate plasma concentrations in 7 days. 2) If plasma PHE or TYR concentration continues to be high, repeat above process until value is in treatment range.
B. Organic Acids in Urine 1. Evaluate N-acetyltyrosine, p-tyramine, and p-hydroxyphenyl organic acids monthly or if plasma TYR concentration is elevated. C. Protein Status 1. Evaluate plasma transthyretin concentration at 3, 6, 9, and 12 months in infants and twice yearly in children and adults (Appendix 17, p A-18, for standards). a. Plasma transthyretin concentrations provide a more reliable and rapid indication of protein status than plasma albumin concentrations. b. Plasma albumin concentrations may be in the normal range when plasma transthyretin concentrations show a clear deficiency (4). 2. If plasma transthyretin concentration is below standard: a. Increase prescribed protein by 5% to 10% and reevaluate plasma transthyretin concentration in 1 month. If plasma PHE and TYR concentrations are in treatment range, use Tyrex to increase protein. b. If plasma transthyretin concentration remains low, repeat above process until value is in normal range. D. Iron Status 1. Plasma ferritin concentration. a. Evaluate at 6, 9, and 12 months in infants and twice yearly in children and adults (Appendix 17, p A-18, for standards). b. If plasma ferritin concentration is below standard: 1) Increase iron intake to 4 mg/kg body weight with supplements (ferrous sulfate). 2) Evaluate plasma ferritin concentration monthly on increased iron intake. 3) Continue iron supplements until plasma ferritin concentration is in normal range. 2. Complete blood count a. Hemoglobin and hematocrit concentrations should be evaluated at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17, p A-18, for standards). E. Growth Status 1. Height and weight. a. Measure infants every 3 months and children and adults every 6 months. Plot measurements on NCHS growth charts. b. Maintain height and weight between 10th and 90th percentiles. Some normal children and adults will fall above or below these percentiles. 2. If height or weight falls below usual growth channel: a. Increase prescribed protein and energy by 5% to 10% and remeasure in 1 month. b. If height or weight remains low, repeat above process until usual growth channel is achieved. F. Nutrient Intake 1. Maintain records of food intake for 3 days immediately before each blood test (Appendices 24 and 25, pp A-26 and A-27). 2. Evaluate intakes of PHE, TYR, protein, and energy before each blood test. 3. Evaluate mineral and vitamin intakes after each diet change. a. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. b. See Appendix 28, p A-29, for information about ordering software for diet evaluation.
G. Clinical Summary 1. A summary record of growth, laboratory, and nutrient intake data is useful for patient management (Table 4-3, p 71).
X. Sample Prescription
A. Example Establish and fill prescription for 5-year-old weighing 20 kg who has tyrosinemia type II using Recommended Daily Nutrient Intakes in Table 4-1, p 70, and average nutrient contents from Table 4-2, p 70. Plasma PHE concentration is 100 mol/L and plasma TYR is 500 mol/L. 1. Establish prescription.
PHE and TYR Protein Energy Fluid 510 mg 35 g 1,300 kcal 1,300 mL Measure PHE (mg) TYR (mg) Protein (g) 27.9 Energy (kcal) 381
Tyrex-2 93 g 0 0 Add water to make 946 mL (32 fl oz). Offer additional fluid ad libitum daily. Food List Breads/Cereals Fats Fruits Vegetables Free Foods A Free Foods B Total per day 6 6 4 2 1 1 Servings 180 30 60 30 5 0 305 120 24 40 20 4 0 208
3.6 0.6 2.0 1.0 0.1 0.0 35.2
180 360 240 20 65 55 1,301
513 Total PHE plus TYR Approximate osmolarity of medical food mixture is < 600 mosm/L.

A. Rationale 1. In normal person, febrile illness and trauma are accompanied by catabolism of body protein (54). 2. Well-nourished patients with tyrosinemia type II or III respond to infection and trauma as do normal persons. 3. Extent of protein catabolism determines subsequent elevation in blood PHE and TYR concentrations. B. Objectives of Nutrition Support 1. Maintain hydration and electrolyte balance. 2. Depress catabolism. a. Enhance energy intake when possible by offering fruit juices ad libitum as tolerated; liquid Jell-O ; Polycose liquid or powder (Appendix 9, p A-9) added to fruit juices if tolerated; and caffeine-free soft drinks (not diet). b. 1/3 cup Polycose powder may be added to liquid Pedialyte to yield 8 fl oz. c. Return patient to Tyrex medical food mixture and pre-illness diet as rapidly as possible. 1) Begin with 1/2 original strength of Tyrex medical food mixture. 2) Increase to original strength, as tolerated. C. Parenteral Nutrition 1. If parenteral amino acid solutions are indicated, see Appendix 26, p A-28.
TABLE 4-1. Recommended Daily Nutrient Intakes (Ranges) for Infants, Children, and Adults With Tyrosinemia Types II or III
Age PHE 1, 2 (mg/kg) Infants 0 to < 3 mo 3 to < 6 mo 6 to < 9 mo 9 to < 12 mo 30 - 90 30 - 70 25 - 50 20 - 40 (mg/day) Girls and Boys 1 to < 4 yr 4 to < 7 yr 7 to < 11 yr Women 11 to < 15 yr 15 to < 19 yr > 19 yr 250 - 500 260 - 550 270 - 600 TYR 1,2 (mg/kg) 35 - 90 30 - 70 25 - 50 20 - 40 (mg/day) 200 - 450 250 - 500 260 - 550 Nutrient Protein 3 (g/kg) 3.50 - 3.00 3.50 - 3.00 3.00 - 2.50 3.00 - 2.50 (g/day) > 30.0 > 35.0 > 40.0 Energy 3 (kcal/kg) 120 (145 115 (145 110 (135 105 (135 - 95) - 95) - 80) - 80) Fluid 4 (mL/kg) 150-125 160-130 145-125 135-120 (mL/day) 900 - 1,800 1,300 - 2,300 1,730 - 3,300
(kcal/day) 1,300 ( 900 - 1800) 1,700 (1300 - 2300) 2,400 (1650 - 3300)
300 - 650 280 - 700 270 - 700
290 - 500 270 - 450 260 - 450
> 50.0 > 55.0 > 60.0
2,200 (1500 - 3000) 2,100 (1200 - 3000) 2,100 (1400 - 2500)
1,500 - 3,000 1,200 - 3,000 1,400 - 2,500
Men 11 to < 15 yr 275 - 700 260 - 550 > 55.0 2,700 (2000 - 3700) 2,000 - 3,700 15 to < 19 yr 350 - 750 340 - 550 > 65.0 2,800 (2100 - 3900) 2,100 - 3,900 > 19 yr 340 - 750 330 - 550 > 70.0 2,900 (2000 - 3300) 2,000 - 3,300 1 Initiate therapy with lowest value for age range. Modify prescription based on frequently obtained plasma values and growth in infants and children and frequently obtained plasma values and weight maintenance in adults. 2 From references 1, 2, 16, 38, 49. 3 From references 21, 23. 4 From reference 8. Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL fluid to children and adults for each kcal ingested.
TABLE 4-2. Serving Lists for PHE- and TYR-Restricted Diets: Average Nutrient Content per Serving
Food List PHE (mg) Breads/Cereals Fats Fruits Vegetables Free Foods A Free Foods B Alimentum Protein Hydrolysate Formula With Iron, Ready to Feed, 100 mL
2 2
30 5 15 15 5 0 86
Nutrient TYR Protein (mg) (g) 20 0.6 4 0.1 10 0.5 10 0.5 4 0.1 0 0.0 29 1.86
Energy (kcal) 30 60 60 10 65 55 68 68 68 480 410 63
Isomil Soy Formula With Iron, Ready to Feed, 100 mL 88 60 1.66 2 Similac With Iron Infant Formula, Ready to Feed, 100 mL 59 58 1.40 Tyrex-1 0 0 15.00 Tyrex-2 0 0 30.00 3 Whole cow's milk, 100 mL 164 164 3.39 1 From reference 16. 2 See Appendices 4 through 7, pp A-4 to A-7, for complete nutrient composition of infant formulas. 3 From reference 45. See Appendix 8, p A-8, for complete nutrient composition.
TABLE 4-3. Tyrosinemia Types II and III Clinical Summary Sheet Name: Date of Birth: __________/__________/__________
Mo Day Year
Hospital Number:
Date
(mo/d/yr)
Age
(yrs/mos) Length/ Height (cm)
Physical Data
Weight (kg) Head Circum (cm) Hgb (g/dL) Ferritin (ng/mL)
Laboratory Data
Transthyretin (mg/dL) Urine 1 p-OHPOA PHE
2

TYR
3
PHE (mg)
TYR (mg)
Protein (g)
Energy (kcal)
1 2
Urine p-hydroxyphenyl organic acids. Indicate if mg/dL or mol/L.
REFERENCES
1. Acosta PB: The contribution of therapy of inherited amino acid disorders to knowledge of amino acid requirements. In Wapnir RA (ed): Congenital Metabolic Diseases: Diagnosis and Treatment. New York: Marcel Dekker Inc, 1985, 115-135. Acosta PB, Yannicelli S: Protein intake affects phenylalanine requirements and growth of infants with phenylketonuria. Acta Paediatr 1994;407 (Suppl):66-67. Al-Hemidan A, Al-Hazzaa SAF: Richner-Hanhart syndrome (tyrosinemia type II). Ophthal Genet 1995;16:21-26. Arnold GL, Vladutiu CJ, Kirby RS: Protein insufficiency and impaired growth in children with PKU. J Inher Metab Dis 2000;23 (Suppl 1):29A. Balato N, Cusano F, Lembo G, Santoianni P: Tyrosinemia type II in two cases previously reported as RichnerHanhart syndrome. Dermatologica 1986;173:66-74. Bardelli AM, Borgogni P, Farnetani MA, et al: Familial tyrosinemia with eye and skin lesions. Opthalmologica (Basel) 1977;175:5-9. Barr DGB, Kirk JM, Laing SC: Outcome in tyrosinaemia type II. Arch Dis Child 1991;66:1249-1250. Behrman RE, Kleigman RM, Arvin AA (eds): Nelson Textbook of Pediatrics, ed 15. Philadelphia: WB Saunders Co, 1996. Benoldi D, Orsoni JB, Allegra F: Tyrosinemia type II: A challenge for ophthalmologists and dermatologists. Pediatr Dermat 1997;14:110-112. Billson FA, Danks DM: Corneal and skin changes in tyrosinemia. Aust J Opthalmol 1975;3:112-115. Calomme MR, Vanderpas JB, Francois B, et al: Thyroid function parameters during a selenium repletion/depletion study in phenylketonuric subjects. Experientia 1995;51:1208-1215. Cerone R, Holme E, Schiaffino MC, et al: Tyrosinemia type III: Diagnosis and ten-year follow-up. Acta Paediatr 1997;86:1013-1015. Charlton KH, Binder PS, Wozniak L, Digby DJ: Pseudodendritic dermatitis and systemic tyrosinemia. Ophthalmology 1981;88:355-360. Cohn RM, Yudkoff M, Yost B, et al: Phenylalanine-tyrosine deficiency syndrome as a complication of the management of hereditary tyrosinemia. Am J Clin Nutr 1977;30:209-214. Colditz PB, Yu JS, Billson FA, et al: Tyrosinemia II. Med J Aust 1984;141:244-245. Elsas LJ, Acosta PB: Nutrition support of inherited metabolic diseases. In Shils ME, et al (eds): Modern Nutrition in Health and Disease, ed 9. Baltimore: Williams & Wilkins, 1999, pp 1003-1056. Endo F, Awata H, Tanoue A, et al: Tyrosinaemia type III: Immunochemical studies on 4-hydroxyphenylpyruvic acid dioxygenase and molecular cloning of cDNA for the enzyme. J Inher Metab Dis 1991;14:783-786. Endo F, Kitano K, Uehara I, et al: Four-hydroxy-phenylpyruvic acid oxidase deficiency with normal fumarylacetoacetase: A new variant form of hereditary tyrosinemia. Pediatr Res 1983;17:92-96. D'Eufemia P, Finocchiaro R, Celli M, et al: Immunological abnormalities in a patient with tyrosinemia type II. J Inher Metab Dis 1995;18:355-356. D'Eufemia P, Giardini O, Cantani F, et al: Autoimmune thyroiditis in a case of tyrosinemia type II. J Inher Metab Dis 1992;15:861-862. FAO/WHO/UNU Expert Consultation: Energy and Protein Requirements. Geneva: World Health Organization, 1985. Faull KF, Gan I, Halpern B, et al: Metabolic studies on two patients with nonhepatic tyrosinemia using deuterated tyrosine loads. Pediatr Res 1977;11:631-637. Food and Nutrition Board, Committee on Dietary Allowances: Recommended Dietary Allowances, eds 9 and 10. Washington, DC: National Academy of Sciences, 1980 and 1989. Francis DEM, Kirby DM, Thompson GN: Maternal tyrosinemia type II: Management and successful outcome. Eur J Pediatr 1992;151:196-199. Garibaldi IR, Siliato F, DeMartini I, et al: Oculocutaneous tyrosinosis. Helv Paediatr Acta 1977;32:173-180. Giardini O, Cantani A, Kennaway NG, D'eufemia P: Chronic tyrosinemia associated with 4-hydroxy-phenylpyruvate dioxygenase deficiency with acute intermittent ataxia and without visceral and bone involvement. Pediatr Res 1983;17:25-29. Goldsmith LA: Tyrosinemia II: Lessons in molecular pathophysiology. Pediatr Dermatol 1983;1:25-34. Goldsmith LA, Reed J: Tyrosine-induced eye and skin lesions. JAMA 1976;236:382-384. Goldsmith LA, Thorpe J, Roe CR: Hepatic enzymes of tyrosine metabolism in tyrosinemia II. J Invest Dermatol 1979;73:530-532. Greeves LG, Carson DJ, Craig BG, McMaster D: Potentially life-threatening cardiac dysrhythmia in a child with selenium deficiency and phenylketonuria. Acta Paediatr Scand 1990;79:1259-1262. Gropper S, Acosta PB: Effect of simultaneous ingestion of L-amino acids and whole protein on plasma amino acid and urea nitrogen concentrations in humans. JPEN 1991;15:48-53. Gropper SS, Gropper DM, Acosta PB: Plasma amino acid response to ingestion of L-amino acids and whole protein. J Pediatr Gastroenterol Nutr 1993;16:143-150.
2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26.
27. 28. 29. 30. 31. 32.
33. Halvorsen S, Skjelkvale L: Tyrosine aminotransferase deficiency (TATD): First case diagnosed on newborn screening and successfully treated with PHE-TYR restricted diet from early age. Pediatr Res 1977;11:1017A. 34. Herrmann ME, Broesicke HG, Keller M, et al: Dependence of the utilization of a phenylalanine-free amino acid mixture on different amounts of single dose ingested. A case report. Eur J Pediatr 1994;153:501-503. 35. Hillman L, Schlotzhauer C, Lee D, et al: Decreased bone mineralization in children with phenylketonuria under treatment. Eur J Pediatr 1996;155 (Suppl 1):S148-S152. 36. Hunziker N: Richner-Hanhart syndrome and tyrosinemia type II. Dermatologica 1980;160:180-189. 37. Jones BJM, Lees R, Andrews J, et al: Comparison of an elemental and polymeric enteral diet in patients with normal gastrointestinal function. Gut 1983;24:78-84. 38. Leverton RM, Johnson N, Dazur J, Ellison J: Amino acid requirements of young adults. In Albanese AA (ed): Protein and Amino Acid Nutrition. New York: Academic Press, 1959. 39. Machino H, Miki Y, Kawatsu T, et al: Successful dietary control of tyrosinemia II. Am Acad Dermatol 1983;9:533-539. 40. MacLean W, Graham G: Pediatric Nutrition in Clinical Practice. Menlo Park, Calif: Addison-Wesley Publishing Co, 1982. 41. Martin SB, Acosta PB: Osmotic behaviors of components of chemically-defined formulas. J Pediatr Perinat Nutr 1987;1:1-17. 42. Mitchell GA, Grompe M, Lambert M, Tanguay RM: Hypertyrosinemia. In Scriver CR, et al (eds): The Metabolic and Molecular Bases of Inherited Disease, ed 8. New York, McGraw-Hill Medical Publishing Division, 2001, pp 1777-1806. 43. Ney D, Bay C, Schneider JA, et al: Dietary management of oculocutaneous tyrosinemia in an 11-year-old child. Am J Dis Child 1983;137:995-1000. 44. Ohkohchi N, Andoh T, Ohi R, Mori S: Defined formula diets alter characteristics of the intestinal transport of amino acids and peptides in growing rats. J Pediatr Gastroenterol Nutr 1990;10:490-496. 45. Posati LP, Orr ML: Composition of Foods: Dairy and Egg Products, Agriculture Handbook No. 8-1. Washington, DC: US Dept of Agriculture, Agricultural Research Service, 1976. 46. Pratt EL, Snyderman SE, Cheung MW, et al: The threonine requirement of the normal infant. J Nutr 1955;56:231-251. 47. Preece MA, Rylance GW, MacDonald A, et al: A new case of tyrosinaemia type III detected by neonatal screening. J Inher Metab Dis 1996;19 (Suppl 1):32. 48. Rabinowitz LG, Williams LR, Anderson CE, et al: Painful keratoderma and photophobia: Hallmarks of tyrosinemia type II. J Pediatr 1995;126;266-269. 49. Rose WC, Wixom RL: The amino acid requirements of man. XIV. The sparing effect of tyrosine on the phenylalanine requirement. J Biol Chem 1955;217:95-101. 50. Sandberg HO: Bilateral keratopathy and tyrosinosis. Acta Ophthalmol 1975;53:760-764. 51. Schoeffer A, Herrmann ME, Broesicke HG, Moench E: Effect of dosage and timing of amino acid mixtures on nitrogen retention in patients with phenylketonuria. J Nutr Med 1994;4:415-418. 52. Smith JL, Arteaga C, Heymsfield SB: Increased ureagenesis and impaired nitrogen use during infusion of a synthetic amino acid formula - A controlled trial. N Engl J Med 1982;306:1013-1018. 53. Stoppoloni, G, Santinelli R, Priscof, et al: Benign tyrosinemia: An 18-year follow-up. J Inher Metab Dis 1995;18:641-642. 54. Wannemacher RW: Key role of various individual amino acids in host response to infection. Am J Clin Nutr 1977;30:1269-1280.
74 Tyrosinemia Types II and III
PROTOCOL 5 Maple Syrup Urine Disease (MSUD) Nutrition Support of Infants, Children, and Adults With KETONEX -1 and KETONEX -2 Amino Acid-Modified Medical Foods
I. Introduction
The branched-chain amino acids (BCAAs) isoleucine (ILE), leucine (LEU), and valine (VAL) are essential nutrients. In newborns, 75% of BCAAs ingested are used for protein synthesis. Those present in excess of need for synthetic purposes are degraded through many steps to provide energy (Figure D). The initial step in catabolism is reversible transamination, requiring a specific transaminase and the coenzyme pyridoxal phosphate. The second step is irreversible oxidative decarboxylation which uses the branched-chain--ketoacid dehydrogenase (BCKAD) complex. This complex is located in the inner mitochondrial membrane and requires the coenzymes thiamin pyrophosphate, lipoic acid, CoA, and NAD+ (36). The Figure below schematizes this overall reaction, which is impaired in maple syrup urine disease (MSUD) (8).
Dietary protein Tissue protein catabolism
Branched-chain amino acids
Leucine * Tissue protein synthesis
Isoleucine * Tissue protein synthesis -Keto-3-methylvaleric acid *
Valine *
-Ketoacids
-Ketoisocaproic acid *
-Ketoisovaleric acid *
Branched-chain -ketoacid dehydrogenase complex
Thiamin (4n) Acetyl-CoA + Acetoacetate
Thiamin (4n) Acetyl-coA + Propionyl-CoA (n) Succinyl-CoA Propionyl-CoA (n) Succinyl-CoA
Thiamin (4n)
Enzyme defect (n) = several steps * Accumulates in the body in untreated MSUD.
Figure D. Branched-chain amino acid metabolism in maple syrup urine disease When thiamin pyrophosphate saturates its site on BCKAD, biologic turnover of BCKAD is decreased because the multienzyme complex undergoes a conformational change, making it more resistant to chymotrypsin and heat degradation. The biologic half-life of the enzyme and overall activity are increased when a new equilibrium of enzyme synthesis and degradation is reached (11, 12). MSUD is a group of inherited disorders of ILE, LEU, and VAL metabolism (8, 11) resulting from several mutations that impair various components of the multienzyme BCKAD (Figure D). An autosomal recessive mode of inheritance is defined for all reported cases. The incidence of MSUD is approximately 1/100,000 to 1/300,000 live births in the general population, and 1/760 live births in the Mennonite population (8, 11). Infants with MSUD appear normal at birth and are clinically well until after eating a protein-containing feed. The most severely impaired enzymes may produce seizures, apnea, and death within 10 days of birth. The disorder is characterized by elevated blood, urine, and cerebrospinal fluid concentrations of the branched-chain-ketoacids (BCKAs), their amino acid precursors, and alloisoleucine (ALLO). Progressive neurologic dysfunction and production of urine with the odor of maple syrup follow. The sweet smell may only be evident in earwax, sensed after otoscopic
2001 Ross Products Division Maple Syrup Urine Disease 75
examination. Neurologic impairment in the newborn is manifested by poor sucking, irregular respiration, rigidity alternating with flaccidity, opisthotonos, progressive loss of Moro reflex, and seizures (8, 11). Immune suppression may occur as a result of elevated plasma organic acid concentrations (53). Several variants with a spectrum of impaired mitochondrial BCKAD complex have been reported. Clinical manifestations are expressed intermittently upon protein loading or with febrile illness in patients with partial enzyme activity between 5% and 30% of normal. A thiamin-responsive form with expression similar to the intermediate form has been described (8, 11). Untreated patients with classic MSUD (0-2% BCKAD activity) who survive beyond early infancy have retarded physical and mental development (8, 11). If death occurs within the 1st few days of life, few unique abnormalities are seen in the brain. With prolonged survival, deficient myelination is thought to be due to inhibition of enzymes involved in myelin formation, inhibition of amino acid transport, and inhibition by BCKAs of oxidative phosphorylation (8, 11). Early diagnosis and adequate nutrition support lead to normal growth and development.

Patients diagnosed 5 days of age had an IQ (97 13 SD) greater than that of normal siblings or parents (24). Factors influencing IQ were age at diagnosis, neonatal condition, and long-term metabolic control (32). Reproductive outcome of a woman with classic MSUD whose blood BCAAs were controlled by diet was excellent (52). The first attempt to manage an 8-month old infant with MSUD used pure amino acids totaling approximately 50 g daily and 1,500 kcal/day. Mineral and vitamin mixtures were also provided. Plasma concentrations of BCAAs decreased significantly. During the course of the diet trial, length and weight increased from the 3rd percentile to the 50th percentile (2). Nutrition support of a neonate with MSUD was subsequently described (2). Protein intake ranged from 3.5-3.0 g/kg/day between 3 and 8 months of age. Energy intake was about 125 kcal/kg/day. At birth, the infant was at the 10th percentile for length and weight; during the 1st year of life, length increased toward the 50th percentile but weight remained at about the 10th percentile. At 55 weeks of age, the patient had a developmental quotient of 97, which is in the normal range (2). A number of investigators have reported poor growth in treated children with MSUD (2). Intakes of both protein and energy by children with MSUD have been reported to be below that of comparable aged normal children (19) and below RDA (15). Whether failure to thrive is due to the underlying disease or to dietary deficiency is unclear. However, some investigators reported normal growth in patients fed adequate protein and energy (2). Selenium deficiency has been found in treated patients with MSUD who received selenium-free medical foods (21, 28). B-vitamin deficiencies resulting in anemia, angular stomatitis, and lesions of the skin occurred in one baby when the B-vitamin mixture was not added to the diet for 6 weeks (2). Folic acid deficiency was reported in an infant after about 4 months on a synthetic diet (2). Metabolic acidosis occurred in an infant treated with an amino acid mix in which several amino acids were provided as the HCl salt (2).

A. The Defect 1. MSUD may result from 1 of several defects in the BCKAD complex. B. Clinical Screening 1. Concentration 4 mg LEU/dL by bacterial inhibition assay requires differential diagnosis (11). 2. Infants who develop poor suck, shrill cry, lethargy, and vomiting; followed by loss of normal tendon reflexes, alternating periods of hypertonia and hypotonia, seizures, loss of consciousness, irregular respiration, apnea, metabolic acidosis, or maple syrup odor in warm urine or ear wax should be evaluated (44). C. Vitamin Responsive 1. Evaluate thiamin responsiveness in patients with any BCKAD complex activity. 2. Prescribe 100-500 mg oral thiamin per day for up to 3 months (8, 14).
76 Maple Syrup Urine Disease

A. Correct Primary Imbalance in Metabolic Relationships 1. Restrict dietary BCAAs (ILE, LEU, and VAL) to amounts tolerated by patient to maintain treatment plasma amino acid concentrations. B. Stabilize Altered Enzyme Protein 1. Supplement with oral thiamin if patient has any BCKAD activity (12, 14).
V. Nutrition Support During Acute Illness or at Diagnosis (20, 53-55)

A. Initiation of Nutrition Support 1. Initiate nutrition support immediately. Do not wait for confirmation of diagnosis. 2. Evaluate plasma concentrations of ILE, LEU, and VAL daily. B. Patients Without Severe Neurologic Involvement 1. Begin high-energy feeds (120-150 kcal/kg for infants, 80-100 kcal/kg for children, and 40-50 kcal/kg for adults) that supply adequate water (Table 5-1, p 85) (11, 50). a. Depending on clinical status, feed patient by nipple, nasogastric tube, intravenous infusion, or combine these methods (44, 45). 1) For nipple or nasogastric feeds, use Ketonex (Table 5-2, p 86). 2) For intravenous feeds via central line, use hypertonic D-glucose and Liposyn II (Appendix 26, p A-28). 3) For intravenous feeds via peripheral line, use isotonic glucose and Liposyn II (Appendix 26, p A-28). 2. Introduce nutrition support with Ketonex as rapidly as possible. a. See Table 5-1, p 85, for Recommended Protein, Energy, and Fluid Intakes. b. See Table 5-2, p 86, for composition of Ketonex. Warning: Add L-ILE to Ketonex feeds when plasma ILE concentration reaches upper limit of treatment range (105 mol/L), usually within 1-3 days of starting nutrition support (45). Plasma LEU concentrations will NOT decrease to normal range if intake of either ILE or VAL is deficient. c. Order L-ILE and L-VAL immediately when nutrition support is initiated. d. See Table 5-1, p 85, for Recommended ILE Intakes and Appendix 26, p A-28, for source of L-ILE. e. Mix weighed amount of L-ILE powder with boiled, cooled water to make known volume that supplies 10 mg/mL (eg, 1 g L-ILE with enough water to yield 100 mL). f. Refrigerate in closed container until used. Discard unused mixture after 1 week, if not frozen. g. Measure into Ketonex medical food mixture with disposable syringe. Warning: Patient will develop severe skin and eye lesions if ILE deficiency occurs (16, 26, 33, 51). 3. Add L-VAL (Table 5-1, p 85) to Ketonex feeds when plasma VAL concentration reaches upper limit of treatment range (318 mol/L), usually within 2 to 4 days of starting nutrition support (45). a. Mix weighed amount of L-VAL powder (Appendix 26, p A-28) with boiled, cooled water to make known volume that supplies 10 mg/mL (1 g L-VAL powder with enough water to yield 100 mL). b. Refrigerate in closed container until used. Discard unused mixture after 1 week, if not frozen. c. Measure into Ketonex medical food mixture with disposable syringe. 4. Add LEU (Table 5-1, p 85) to Ketonex feeds when plasma LEU concentration reaches upper limit of treatment range (185 mol/L). May require 7-10 days if L-ILE and L-VAL are supplemented as noted in steps 3 and 4 above (44, 45). Warning: LEU, the last amino acid to become normal in plasma, remains elevated for prolonged period if ILE and/or VAL are deficient (10). a. Use infant formula with iron or whole cow's milk (Table 5-3, p 87), depending on age, to fill LEU prescription. 1) Determine amounts of ILE and VAL in infant formula or whole cow's milk required to supply LEU.
2) Decrease volumes of L-ILE and L-VAL solutions added to medical food mixture by amount of ILE and VAL in infant formula or whole cow's milk. 3) Use disposable syringe to measure liquid infant formula or whole cow's milk. Weigh powdered infant formula on scale that reads in grams. C. Comatose Patients (10, 11) 1. See References 54 and 55 for medical management. 2. Begin BCAA-free parenteral (6) or nasogastric feeding of amino acids and energy within 36 to 48 hours of initiation of dialysis using nitrogen-free (amino acid-free) dialysate. a. See Table 5-1, p 85, for Recommended Protein and Energy Intakes b. See Table 5-2, p 86, for Ketonex composition. 3. Begin intravenous infusion of Liposyn II (Appendix 26, p A-28) and 10% D-glucose during nasogastric feeding, continuing until major neurologic signs subside. 4. When plasma ILE concentration reaches upper limit of treatment range (105 mol/L), usually within 1 to 3 days of starting nutrition support, add L-ILE (Table 5-1, p 85) to Ketonex feeds. a. See Section VB2, p 76. 5. When plasma VAL concentration reaches upper limit of treatment range (318 mol/L), usually within 2 to 4 days of starting nutrition support, add L-VAL (Table 5-1, p 85) to Ketonex feeds. a. See Section VB3, p 76. 6. When plasma LEU concentration reaches upper limit of treatment range (185 mol/L), add LEU (Table 5-1, p 85) to Ketonex feeds. a. See Section VB4, p 76. 7. If parenteral amino acid solutions are indicated, see Appendix 26, p A-28.
VI. Establish Goals of Long-Term Nutrition Support

A. Plasma Amino Acid Concentrations 1. Maintain 2- to 4-hour postprandial (40) plasma concentrations of alanine (ALA), ALLO, and BCAAs in ranges noted below when measured by quantitative methods (modified from reference 11), or within normal range for age established by laboratory used.
Amino Acid ALA ALLO ILE LEU VAL mol/L 275 - 450 0-0 50 - 105 50 - 185 130 - 318 mg/dL 2.4 - 4.0 0.0 - 0.0 0.6 - 1.4 0.6 - 2.4 1.5 - 3.7
2. In practice, obtaining blood 2 to 4 hours postprandially is not always possible. Acceptable local standards should be developed if plasma amino acids are evaluated at other times (Practical Aspects of Nutrition Support, p viii). B. Growth, Development, and Nutrition Status 1. Support normal growth rates in infants and children and maintain appropriate weight for height in adults. 2. Support normal development. 3. Maintain normal nutrition status (7, 21, 28). 4. Prevent catabolism. 5. Maintain urine free of branched-chain-ketoacids.
VII. Establish Prescription for Long-Term Nutrition Support

A. ILE, LEU, and VAL (1, 9, 13, 25, 27, 46-48) 1. Prescribe intakes that promote goals of nutrition support. 2. ILE, LEU, and VAL requirements vary widely: a. From patient to patient, depending on activity of BCKAD complex. b. In same patient, depending on: 1) Age. 2) Growth rate. 3) Adequacy of energy and protein intakes. 4) State of health.
78 Maple Syrup Urine Disease 2001 Ross Products Division
3. Lowest values for ILE, LEU, and VAL for each age group listed in Table 5-1, p 85, are suggested for initiating therapy. 4. Changing requirements of patient are determined by frequent monitoring of: a. Plasma ILE, LEU, and VAL concentrations. b. Urine concentrations of branched-chain -ketoacids. c. See Section X, Suggested Evaluation of Nutrition Support, p 80. d. With ILE, LEU, and VAL concentrations in normal range, plasma amino acids must be measured frequently to prevent deficiency. Warning: ILE, LEU, and VAL deficiencies result in the following adverse effects: ILE deficiency (16, 26, 46, 51): Weight loss or no weight gain; redness of buccal mucosa; fissures at corners of mouth; tremors of extremities; decreased plasma cholesterol and ILE concentrations; increased plasma lysine, phenylalanine, serine, tyrosine, and VAL concentrations; and skin desquamation. LEU deficiency (48): Loss of appetite, apathy, irritability; weight loss or poor weight gain; decreased plasma LEU concentration; and increased plasma ILE, methionine, serine, threonine, and VAL concentrations. VAL deficiency (47): Poor appetite, drowsiness; excess irritability and crying in infants; weight loss or decrease in weight gain; and decreased plasma albumin concentration. Prolonged exclusion, over-restriction, or imbalance of BCAAs result in adverse effects (31): Anemia, desquamation of skin, diarrhea, and failure to thrive in infants. B. Protein 1. Prescribe, initially, amount greater than Recommended Dietary Allowances (RDAs) (15) (Table 5-1, p 85). 2. Requirements are greater than RDAs when L-amino acids supply majority of protein equivalent as a result of: a. Rapid amino acid absorption (17, 18). b. Early and high peak of plasma amino acid concentrations after ingestion of meals where large part of protein is supplied by L-amino acids (17). c. Rapid catabolism of amino acids (17, 22, 23, 39, 42). d. Possible decreased total amino acid absorption (34). Warning: Long-term inadequate protein intake will result in failure to thrive in infants, poor growth in children, weight loss in adults, low plasma albumin and transthyretin concentrations, osteopenia, and hair loss. 3. Adequate protein intake that supports normal growth results in greater tolerance to restricted BCAAs (3). C. Energy 1. Prescribe amount that should support normal weight gain in infants and children and maintain appropriate weight for height in adults (Table 5-1, p 85). 2. Requirements vary widely and may be greater than normal when L-amino acids supply majority of protein equivalent (38). 3. At diagnosis and during metabolic acidosis resulting from infection, energy needs may be 25% to 40% higher than values listed in Table 5-1, p 85. Warning: Inadequate energy intake may result in failure to thrive in infants, poor growth in children, weight loss in adults, depressed tolerance of BCAAs, and increased concentrations of plasma BCAAs. D. Fluid 1. Prescribe amount that will supply water requirements (Table 5-1, p 85). Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL to children and adults for each kcal ingested.
Maple Syrup Urine Disease 79

A. LEU 1. Calculate amount of infant formula with iron, beikost, whole cow's milk, or table foods (Table 5-3, p 87) required to fill LEU prescription. a. Low-iron infant formula, whole cow's milk, and evaporated milk should not be used as BCAA source for infants because of low iron content. 2. Measure liquid infant formula and whole cow's milk with disposable syringe. Weigh powdered infant formula on scale that reads in grams. 3. Add beikost or table foods to gradually displace LEU provided by infant formula after infant is 3 to 4 months old or is developmentally ready. 4. Parents or patients may select any food in prescribed food lists (Table 5-4, p 88) in specified amounts to fill LEU prescription. B. ILE and VAL 1. Calculate approximate amounts of ILE and VAL provided by infant formula with iron, beikost, whole cow's milk, or table foods (Table 5-3, p 87). 2. Subtract amount determined in step B1 from total ILE and VAL prescriptions. 3. Supply any remaining prescribed ILE and VAL as individual pure solutions. If plasma concentrations of ILE and VAL are in normal range, supplements are not required (Appendix 26, p A-28). a. Mix weighed amounts of L-ILE and L-VAL powders with boiled, cooled water to make known volume of each that supplies 10 mg/mL (eg, 1 g with enough water to yield 100 mL). b. Refrigerate solutions in separate, closed containers until used. Discard unused suspensions after 1 week, if not frozen. c. Measure solutions into medical food mixture with disposable syringe. C. Protein 1. Calculate amount provided by infant formula with iron, beikost, whole cow's milk, or table foods (Table 5-3, p 87) required to fill LEU prescription. 2. Subtract amount determined in step C1 from total protein prescription. 3. Supply any remaining prescribed protein with Ketonex (Table 5-2, p 87). a. Ketonex-1 is for infants and toddlers and Ketonex-2 is for children, adolescents, and adults. b. Weigh Ketonex powder on scale that reads in grams because of variability of household measuring equipment (Practical Aspects of Nutrition Support, p vii) and changes in density during shipping. c. See Table 5-2 (p 86, footnote 3) for approximate packed weight of Ketonex powder in level, dry US standard household measures. D. Energy 1. Calculate energy provided by Ketonex (Table 5-2, p 86) and infant formula with iron, beikost, whole cow's milk, or table foods (Table 5-3, p 87) required to fill LEU and protein prescriptions. 2. Subtract amount determined in step D1 from total energy prescription. 3. Provide any remaining prescribed energy with Polycose Glucose Polymers powder (23 kcal/Tbsp, 3.8 kcal/g) or liquid (2 kcal/mL) (Appendix 9, p A-9); Pro-Phree Protein-Free Energy Module With Iron, Vitamins & Minerals (Appendix 11, p A-10); sugar (48 kcal/Tbsp); or Free Foods B (Table 5-2, p 86). a. Do not use corn syrup or table sugar for infants because of osmolarity they yield (30). b. Do not use honey for infants because it may contain botulinum toxin (49). E. Fluid and Mixing Instructions 1. Add sufficient boiled, cooled water to infant formula, Ketonex, and carbohydrate (if needed) to yield prescribed volume. Tap water may replace boiled, cooled water when preparing Ketonex for older infants, children, and adults. 2. Mix with sterilized blender at lowest speed for no longer than 3 to 4 seconds. Excess mixing may destabilize emulsion. Medical food may also be mixed in sterilized, tightly closed container by shaking vigorously for 10 to 12 seconds. 3. Refrigerate in sterilized, closed containers until used. Discard unused portion 24 hours after mixing because of nutrient loss.
4. Do not use terminal sterilization or boil because of Maillard reaction (Practical Aspects of Nutrition Support, p viii). 5. Warm or cool medical food mixture to room temperature before feeding to infants. Shake well before feeding. 6. Do not warm medical food mixture for infants in microwave oven. Unevenly heated formula can burn infants, and steam can make bottles explode. 7. Notify parents or caretakers when they may discontinue using aseptic technique in preparing medical food mixture for infants. 8. For children and adults, chill Ketonex medical food mixture to improve taste. F. Diet Guide 1. Provide parents, caretakers, or patient with completed Diet Guide (Appendix 22, p A-24) with each diet change. 2. Feed young infants 6 to 8 times daily (22, 39). 3. Feed older infants, children, and adults 4 to 6 times daily (22, 39).

A. Nutrient Adequacy 1. Determine if diet provides nutrients in amounts prescribed in Section VII, Establish Prescription for Long-Term Nutrition Support, p 77. 2. Check diet to determine if it supplies Recommended Dietary Intakes (RDIs) of minerals and vitamins (Appendices 13 and 14, pp A-14 and A-15). a. See Table 5-2, p 86, for composition of Ketonex and Appendices 4 through 7, pp A-4 to A-7, for complete nutrient composition of infant formulas. b. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. c. If Ketonex mixture provides < 100% of RDIs for infants and < 75% for children and adults, supplement diet with needed minerals and vitamins if not provided by beikost or table foods and laboratory test results indicate need. See Appendix 11, p A-10, for composition of supplements. B. Osmolarity 1. If concentration of prescribed medical food mixture is > 24 kcal/fl oz, determine if osmolarity is in acceptable range. a. Determine osmolarity by laboratory analysis or use mathematical formula given in Appendix 18, p A-20. b. Osmolarity per gram of Ketonex is listed in Appendix 19, p A-21. 2. If osmolarity is > 450 mosm/L for neonates, > 750 mosm/L for children, > 1,000 mosm/L for adults, or greater than tolerated by patient, increase water content of prescribed medical food mixture and recalculate its osmolarity (29, 43). C. Potential Renal Solute Load 1. Dehydration will result if renal solute load is greater than renal-concentrating ability of patient. 2. If concentration of medical food mixture prescribed is > 24 kcal/fl oz, estimate its potential renal solute load. a. This step is important to prevent dehydration of infants who may have renal-concentrating capacity as low as 600 mosm/L. b. Upper limit of renal solute load for neonates is approximately 1,100 mosm/L (41). 3. A method for estimating potential renal solute load is given in Appendix 20, p A-22. 4. If potential renal solute load is excessive, increase water content of medical food mixture and recalculate.

A. Plasma ALA, ALLO, and BCAAs (40) 1. Initial. a. Evaluate daily by quantitative methods until plasma concentrations stabilize and approximate BCAA requirements are known.
2. Ongoing. a. Use bacterial inhibition assay for blood LEU evaluation - from state laboratory if available. b. Evaluate blood LEU concentration twice weekly by bacterial inhibition assay and twice monthly by quantitative methods until patient is 6 months old. c. From 6 months onward, evaluate blood LEU concentration weekly by bacterial inhibition assay and monthly by quantitative method. 3. Unacceptable amino acid concentrations. a. If plasma ILE, LEU, or VAL concentration is not detected and patient has ingested full prescription: 1) Increase prescribed amount of undetected amino acid(s) by 25% and reevaluate plasma concentrations in 3 days. 2) If plasma ILE, LEU, or VAL concentration continues undetected, repeat above process until value is in treatment range. b. If plasma ILE concentration is < 50 mol/L, plasma LEU concentration is < 50 mol/L, or plasma VAL concentration is < 95 mol/L, and patient has ingested full prescription: 1) Increase prescribed amount for amino acid(s) that is low by 5% to 10% and reevaluate plasma concentration in 1 week. 2) If plasma ILE, LEU, or VAL concentration continues low, repeat above process until amino acid(s) concentration is in treatment range. c. If plasma ILE concentration is > 105 mol/L, plasma LEU concentration is > 185 mol/L, or plasma VAL concentration is > 318 mol/L, and patient is not ill and has not ingested more or less protein and energy than prescribed: 1) Decrease prescribed amount of elevated amino acid(s) by 5% to 10% and reevaluate plasma BCAA concentrations in 1 week. 2) If plasma ILE, LEU, or VAL concentration continues high, repeat above process until amino acid(s) concentration is in treatment range. B. Urine Ketoacids by Ketostix or Dinitrophenylhydrazine (DNPH) 1. Evaluate once daily to 6 months of age and twice weekly thereafter. 2. If patient is ill, evaluate daily. 3. Urine should be free of ketoacids at all times (negative Ketostix or DNPH result). 4. If urine contains ketoacids (positive Ketostix or DNPH result): a. Immediately obtain blood sample for evaluation of LEU by bacterial inhibition assay or evaluation of BCAAs by quantitative methods. b. Brief metabolic physician immediately on patient's illness. C. Protein Status 1. Evaluate plasma transthyretin concentration every 3 months until 1 year of age and twice yearly thereafter (Appendix 17, p A-18, for standards). a. Plasma transthyretin concentrations provide a more reliable and rapid indication of protein status than plasma albumin concentrations. b. Plasma albumin concentrations may be in the normal range when plasma transthyretin concentrations show a clear deficiency (4). 2. If plasma transthyretin concentration is below standard: a. Increase prescribed protein by 5% to 10% and reevaluate plasma transthyretin concentration in 1 month. If ILE, LEU and VAL concentrations are in treatment range, use Ketonex to increase protein. b. If plasma transthyretin concentration continues below standard, repeat above process until value is in normal range. D. Iron Status 1. Plasma ferritin concentration. a. Evaluate at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17, p A-18, for standards). b. If plasma ferritin concentration is below standard: 1) Increase iron intake to 4 mg/kg of body weight with supplements (ferrous sulfate). 2) Evaluate plasma ferritin concentration monthly on increased iron intake. 3) Continue iron supplements until plasma ferritin concentration is in normal range.
2. Complete blood count and differential. a. Hemoglobin and hematocrit concentrations and differential should be evaluated at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17, p A-18, for standards). E. Growth Status 1. Length/height and weight. a. Measure monthly to 1 year and every 3 months thereafter until final growth is achieved. Plot measurements on NCHS growth charts. b. Maintain length/height and weight between 10th and 90th percentiles. Some normal infants, children, and adults will fall above or below these percentiles. 2. If length/height or weight falls below usual growth channel: a. Increase protein and energy prescriptions by 5% to 10% and remeasure after 1 month. b. If length/height or weight remains low, repeat above process until usual growth channel is achieved. F. Nutrient Intake 1. Maintain records of food intake for 3 days immediately before each blood test (Appendices 24 and 25, pp A-26 and A-27). 2. Evaluate intakes of BCAAs, protein, and energy before each blood test. 3. Evaluate mineral and vitamin intakes after each diet change. a. See Table 5-2, p 86, for composition of Ketonex and Appendices 4 through 7, pp A-4 to A-7, for complete nutrient composition of infant formulas. b. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. c. See Appendix 28, p A-29, for information about ordering software for diet evaluation. G. Clinical Summary 1. A summary record of growth, laboratory, and nutrient intake data is useful for patient management (Table 5-5, p 100).

A. Example 1 Establish and fill prescription for newborn weighing 3.3 kg using Recommended Daily Nutrient Intakes from Table 5-1, p 85, and nutrient contents from Tables 5-2 and 5-3, pp 86 and 87. 1. Establish prescription.
ILE LEU VAL Protein Energy Fluid 60 mg/kg 80 mg/kg 70 mg/kg 3.5 g/kg 140 kcal/kg 150 mL/kg x x x x x x Measure 3.3 kg 3.3 kg 3.3 kg 3.3 kg 3.3 kg 3.3 kg ILE (mg) 0 137 61 0 0 = = = = = = 198 mg 264 mg 231 mg 11.6 g 462 kcal 495 mL LEU (mg) 0 264 0 0 0 VAL (mg) 0 152 0 79 0 Protein (g) 9.0 2.6 0.0 0.0 0.0 Energy (kcal) 288 124 0 0 50
Ketonex-1 60.0 g Similac With Iron RTF 183.0 mL ILE solution1 6.1 mL VAL solution1 7.9 mL Polycose Liquid 25.0 mL Add water to make 569 mL (19 fl oz).
198 264 231 11.6 462 Total per day 60 80 70 3.5 140 Total per kg Approximate osmolarity of medical food mixture is < 400 mosm/L. Estimated potential renal solute load is < 100 mosm. 1 Solution is 10 mg/mL.
B. Example 2 Establish and fill prescription for 2-year-old child weighing 13 kg using Recommended Daily Nutrient Intakes from Table 5-1, p 85, and nutrient contents from Tables 5-2 and 5-3, pp 86 and 87. 1. Establish prescription.
ILE LEU VAL Protein Energy Fluid 325 mg/day 535 mg 400 mg 30 g 1,300 kcal 1,300 mL Measure 71 g 1 mL 0 10 ILE (mg) 0 0 LEU (mg) 0 0 VAL (mg) Protein (g) 21.3 0.0 Energy (kcal) 291 0
Medical Food Mixture Ketonex-2 ILE solution
Add water to make 710 mL (24 fl oz). Offer additional fluid ad libitum daily. Food List Breads/Cereals Fats Fruits Vegetables Servings 9 6 4 2 162 42 68 44 315 60 100 60 225 42 88 48 4.5 0.6 2.4 1.2 30.0 270 420 300 30 1,311
326 535 403 Total per day Approximate osmolarity of medical food mixture is < 550 mosm/L. 1 Solution is 10 mg/mL.
C. Example 3 Establish and fill prescription for 15-year-old boy weighing 60 kg using Recommended Daily Nutrient Intakes from Table 5-1, p 85 , and nutrient contents from Tables 5-2 and 5-3, pp 86 and 87. 1. Establish prescription.
ILE LEU VAL Protein Energy Fluid 330 mg/day 550 mg 410 mg 55 g 2,800 kcal 2,800 mL
Medical Food Mixture Ketonex-2 Sugar ILE solution 1 VAL solution 1 Measure 155 g 96 g (1/2 cup) 1.5 mL 1.4 mL 0 0 15 0 ILE (mg) 0 0 0 0 LEU (mg) 0 0 0 14 VAL (mg) Protein (g) 46.5 0.0 0.0 0.0 Energy (kcal) 708 384 0 0
Add water to make 1100 mL (36 fl oz). Offer additional fluid ad libitum daily. Food List Breads/Cereals Fats Fruits Vegetables Free Foods A Free Foods B Servings 9 9 2 2 4 8 162 63 34 44 12 0 315 90 50 60 20 0 225 63 44 48 16 0 4.5 0.9 1.2 1.2 0.4 0.0 54.7 270 630 150 30 200 440 2,812
326 550 410 Total per day Approximate osmolarity of medical food mixture is < 1,000 mosm/L.

A. Rationale 1. In normal persons, febrile illness and trauma are accompanied by catabolism of body protein. 2. Well-nourished patients with MSUD respond to infection and trauma as do normal persons. 3. Febrile illnesses and trauma are life-threatening if not diagnosed and treated promptly. B. Management of Nutrition Support 1. See Section V, Nutrition Support During Acute Illness or at Diagnosis, p 76.
TABLE 5-1. Recommended Daily Nutrient Intakes (Ranges) for Infants, Children, and Adults With MSUD
Age ILE (mg/kg) Infants 0 to < 3 mo 3 to < 6 mo 6 to < 9 mo 9 to < 12 mo 36 - 60 30 - 50 25 - 40 18 - 33 (mg/day) Girls and Boys 1 to < 4 yr 4 to < 7 yr 7 to < 11 yr Women 11 to < 15 yr 15 to < 19 yr 19 yr Men 11 to < 15 yr 15 to < 19 yr
1 1,2
Nutrient LEU (mg/kg) 60 - 100 50 - 85 40 - 70 30 - 55 (mg/day) 275 - 535 360 - 695 410 - 785
1
VAL (mg/kg) 42 - 70 35 - 60 28 - 50 21 - 38 (mg/day) 190 - 400 250 - 490 285 - 550
1,3
Protein 4 (g/kg) 3.50 - 3.00 3.50 - 3.00 3.00 - 2.50 3.00 - 2.50 (g/day) 30.0 35.0 40.0
Energy 4 (kcal/kg) 120 (145 115 (145 110 (135 105 (135 - 95) - 95) - 80) - 80)
Fluid 5 (mL/kg) 150 - 125 160 - 130 145 - 125 135 - 120 (mL/day) 900 - 1,800 1,300 - 2,300 1,650 - 3,300
(kcal/day) 1,300 ( 900 - 1800) 1,700 (1300 - 2300) 2,400 (1650 - 3300)
165 - 325 215 - 420 245 - 470
330 - 445 330 - 445 300 - 450
550 - 740 550 - 740 400 - 620
385 - 520 385 - 520 420 - 650
50.0 55.0 60.0
2,200 (1500 - 3000) 2,100 (1200 - 3000) 2,100 (1400 - 2500)
1,500 - 3,000 1,200 - 3,000 1,400 - 2,500
325 - 435 425 - 570
540 - 720 705 - 945
375 - 505 495 - 665
55.0 65.0
2,700 (2000 - 3700) 2,800 (2100 - 3900)
2,000 - 3,700 2,100 - 3,900
2 3 4 5
575 - 700 800 - 1100 560 - 800 2,900 (2000 - 3300) 2,000 - 3,300 19 yr 70.0 From references 1, 2, 9, 11, 25, 27, 35. Initiate prescription as noted in Section V, p 76. After 2 to 3 days of BCAAfree feeds, begin diet with lowest recommended intake for age. Modify prescription based on frequently obtained plasma values and growth in infants and children and frequently obtained plasma values and weight maintenance in adults. In general, ILE should be approximately 60% of LEU prescription. In general, VAL should be approximately 70% of LEU prescription. From reference 15. From reference 5. Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL fluid to children and adults for each kcal ingested. Fluid intake should be higher during illness to enhance urinary ketoacid excretion.
TABLE 5-2. Nutrient Composition of KETONEX -1 1, 3 and KETONEX -2 2, 3,

Nutrient (per 100 g pwd) Ketonex-1 (per g protein equiv) 32 1.000 0.160 0.963 0.010 0.028 0.000 0.000 0.067 0.020 0.059 0.047 0.011 0.059 0.000 Ketonex-2 (per 100 g pwd) (per g protein equiv) 410 13.7 30.00 1.000 4.80 0.160 0.963 28.90 0.30 0.010 0.84 0.028 trace 0.000 trace 0.000 2.00 0.067 0.60 0.020 1.76 0.059 1.40 0.047 0.34 0.011 1.78 0.059 trace 0.000 6.67 1.67 1.17 0.47 0.050 0.006 29 31.33/0.88 0.90 0.033 3.33 0.43 7.50 0.027 1.00 25 45.7/1.17 1.17 29.3/1.28 0.43 22 0.25 0.40 2.00 2.00 3.33 0.043 0.167 3.33 15 2.33 0.72 0.267 0.060 0.108
Energy, kcal 480 Protein equiv, g 15.00 Nitrogen, g 2.40 14.45 Amino acids, g Cystine, g 0.15 Histidine, g 0.42 Isoleucine, g trace Leucine, g trace Lysine, g 1.00 Methionine, g 0.30 Phenylalanine, g 0.88 Threonine, g 0.70 Tryptophan, g 0.17 Tyrosine, g 0.89 Valine, g trace Other Nitrogen-Containing Compounds Carnitine, mg 100 6.67 200 Taurine, mg 40 2.67 50 Carbohydrate, g 53.0 3.53 35 Fat, g 21.7 1.45 14 4 5 Linoleic acid, g 2.00 0.133 1.50 6 7 0.36 0.024 0.17 -Linolenic acid, g Minerals Calcium, mg 575 38 880 Chloride, mg/mEq 325/9.17 21.7/0.61 940/26.51 Chromium, g 11 0.73 27 Copper, mg 1.10 0.073 1.00 Iodine, g 65 4.33 100 Iron, mg 9.0 0.60 13 Magnesium, mg 50 3.33 225 Manganese, mg 0.50 0.033 0.80 Molybdenum, g 12 0.80 30 Phosphorus, mg 400 27 760 Potassium, mg/mEq 675/17.26 45/1.15 1,370/35.04 Selenium, g 20 1.33 35 Sodium, mg/mEq 190/8.26 12.7/0.55 880/38.28 Zinc, mg 8.0 0.53 13 Vitamins A, g RE 420 28 660 D, g 7.50 0.50 7.50 10.10 0.67 12.10 E, mg -TE K, g 50 3.33 60 Ascorbic acid, mg 50 3.33 60 Biotin, g 65 4.33 100 B6, mg 0.75 0.050 1.30 B12, g 4.90 0.327 5.00 Choline, mg 80 5.33 100 Folate, g 230 15 450 Inositol, mg 40 2.67 70 Niacin equiv, mg 12.80 0.850 21.7 Pantothenic acid, mg 6.90 0.460 8.00 Riboflavin, mg 0.90 0.060 1.80 Thiamin, mg 1.90 0.127 3.25 1 2 Designed for infants and toddlers. Designed for children, adolescents, and adults. 3 Approximate packed weight of Ketonex in level, dry US standard household measures: Ketonex-1 Ketonex-2 1 Tbsp = 7g 8g 1/4 cup = 26 g 32 g 1/3 cup = 35 g 41 g 1/2 cup = 53 g 61 g 1 cup = 105 g 117 g 4 5 Analytical data at manufacture = 4.32 g/100 g powder. Analytical data at manufacture = 2.66 g/100 g powder. 6 7 Analytical data at manufacture = 0.40 g/100 g powder. Analytical data at manufacture = 0.28 g/100 g powder.
TABLE 5-3. Serving Lists for BCAA-Restricted Diets: Average Nutrient Content per Serving1
Food List ILE (mg) Breads/Cereals 18 Fats 7 Fruits 17 Vegetables 22 Free Foods A 3 Free Foods B 0 Alimentum Protein-Hydrolysate Formula With Iron, Ready to Feed, 100 mL 108
2
Nutrient LEU (mg) 35 10 25 30 5 0 173 VAL (mg) 25 7 22 24 4 0 140 Protein Energy (g) (kcal) 0.5 0.1 0.6 0.6 0.1 0.0 1.86 1.66 1.40 3.39 30 70 75 15 50 55 68 68 68 63
Isomil Soy Formula With Iron, Ready to Feed, 100 mL 2 74 135 76 Similac With Iron Infant Formula, Ready to Feed, 100 mL 2 75 144 83 Whole cow's milk, 100 mL 3 205 332 227 1 Reference 11. 2 See Appendices 4 through 7, pp A-4 to A-7, for complete nutrient composition of infant formulas. 3 From reference 37. See Appendix 8, p A-8, for complete nutrient composition.
TABLE 5.4. Equivalency Lists for BCAA-Restricted Diets: Gerber Baby Foods (Beikost) 1
Weight Approximate ILE (g) Measure (mg) For greatest accuracy, weigh food on scale that reads in grams. All measures are level. BREADS AND CEREALS Baked Finger Snacks Animal crackers, cinnamon graham Banana cookies Strawberry fruit bars Veggie crackers Cereals, Dry Barley Mixed Oatmeal Oatmeal/banana Oatmeal/mixed fruit Rice Rice/apple bits Rice/apples Rice/banana Rice/mixed fruit Cereals, Jarred 1st Foods Oatmeal 2nd Foods Mixed/applesauce/bananas Oatmeal/applesauce/bananas Rice/applesauce 3rd Foods Mixed/apples/bananas Oatmeal/apples/cinnamon Vegetables 1st Foods Peas Potatoes Sweet potatoes 2nd Foods Creamed corn Garden vegetables Mixed vegetables Peas Sweet potatoes 3rd Foods Green beans/rice Peas/rice Sweet potatoes FRUITS/JUICES Mixed fruit juice Orange juice Pear juice 1st Foods Bananas Peaches Pears 125 188 156 27 100 132 4 fl oz 6 fl oz 5 fl oz 2 Tbsp 7 Tbsp 1/2 cup + 1 Tbsp 13 14 13 7 14 13 24 25 24 25 25 25 18 22 16 16 19 17 0.3 1.4 0.5 0.3 0.7 0.5 70 92 76 27 43 75 Food LEU (mg) VAL (mg) Protein (g) Energy (kcal)
8 8 9 8
1 cracker 1 cookie 1 bar 11 crackers
17 19 20 20
34 38 37 37
20 23 23 23
0.5 0.5 0.5 0.5
35 35 35 35
4 5 3 4 4 5 6 8 6 6
1 Tbsp 1 Tbsp + 1 tsp 1 Tbsp 1 Tbsp 1 Tbsp 1 Tbsp + 1 tsp 1 Tbsp + 2 tsp 1 Tbsp + 2 tsp 1 Tbsp + 2 tsp 1 Tbsp + 2 tsp
18 16 17 18 16 18 16 16 15 16
35 38 33 34 35 34 33 35 33 35
24 21 23 23 22 24 21 23 21 23
0.5 0.5 0.5 0.5 0.4 0.4 0.4 0.5 0.4 0.4
15 19 12 15 17 19 25 31 23 24
27 55 38 52 44 41
2 Tbsp 3 Tbsp + 2-1/2 tsp 2 Tbsp + 2 tsp 3 Tbsp + 2 tsp 3 Tbsp 2 Tbsp + 2-1/3 tsp
18 19 18 17 16 16
35 35 35 35 35 35
26 26 24 23 21 22
0.5 0.6 0.5 0.4 0.5 0.5
15 47 32 47 33 27
16 67 69 20 24 41 17 61 42 20 49
1 Tbsp 1/4 cup + 2 tsp 1/4 cup + 2-1/2 tsp 1 Tbsp + 1 tsp 1 Tbsp + 2 tsp 2 Tbsp + 2-1/2 tsp 1 Tbsp + 1/2 tsp 1/4 cup + 1 tsp 3 Tbsp 1 Tbsp + 1 tsp 3 Tbsp + 1-1/4 tsp
21 21 21 14 19 19 21 21 18 20 23
36 35 35 35 36 35 36 35 35 35 35
26 34 33 18 24 27 26 30 23 24 32
0.5 0.7 0.8 0.4 0.6 0.6 0.5 0.6 0.5 0.4 0.7
8 31 45 13 9 19 8 38 18 10 39
Food
Weight Approximate ILE (g) Measure (mg) For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Prunes 119 1/2 cup + 1 tsp 14 2nd Foods Apricot/mixed fruit 100 7 Tbsp 13 Bananas 27 2 Tbsp 7 Bananas/apples/pears 36 2 Tbsp + 1-1/2 tsp 9 Hawaiian delight 25 1 Tbsp + 2-1/4 tsp 13 Peaches 100 7 Tbsp 14 Pears 125 1/2 cup + 2 tsp 15 Pear/pineapple 139 1/2 cup + 1-1/2 Tbsp 14 Plums/apple 156 1/2 cup + 3 Tbsp 14 Prunes/apple 119 1/2 cup + 1 tsp 13 3rd Foods Apricots/mixed fruit 100 7 Tbsp 13 Bananas 27 2 Tbsp 7 Banana/pineapple 34 2 Tbsp + 1 tsp 8 Banana/strawberry 34 2 Tbsp + 1 tsp 8 Hawaiian delight dessert 25 1 Tbsp + 2-1/4 tsp 13 Peaches 125 1/2 cup + 2 tsp 15 Pears 125 1/2 cup + 2 tsp 15 Fruit/Vegetable Juices Apple/sweet potato Graduates, Fruit Dices Peaches Pears Tender Harvest Apple/sweet potato Banana/oatmeal/peach Pears/winter squash Tropical fruit blend VEGETABLES 1st Foods Carrots Green beans Squash 2nd Foods Carrots Green beans Squash 3rd Foods Carrots Squash Graduates, Vegetable Dices Carrots Green beans Mixed vegetables Tender Harvest Butternut squash/corn Garden carrots/brown rice Green beans/potatoes Spring garden vegetables FREE FOODS A Apple juice 94 3 fl oz 3
LEU (mg) 25 26 25 25 25 25 25 25 25 25 26 25 25 25 25 25 25 20 19 16 15 16 19 20 18 19 15 19 16 15 16 16 20 20
VAL (mg)
Protein (g) 1.2 0.6 0.3 0.3 0.3 0.7 0.6 0.6 0.6 0.7 0.6 0.3 0.3 0.3 0.3 0.9 0.6
Energy (kcal) 120 60 24 30 21 64 92 76 109 92 60 24 26 32 21 80 92
179 192 208 156 28 58 58
5-3/4 fl oz ND ND 1/2 cup + 3 Tbsp 2 Tbsp 1/4 cup 1/4 cup
16 13 12 14 10 15 9
25 25 25 25 25 25 25
23 19 19 19 16 19 17
0.5 1.0 0.6 0.5 0.3 0.6 0.3
93 94 112 98 21 30 43
91 30 55 91 37 62 77 81 60 29 19 29 73 16 41
6 Tbsp + 1 tsp 2 Tbsp 4 Tbsp 6 Tbsp + 1 tsp 2 Tbsp + 1-1/2 tsp 1/4 cup + 1 tsp 1/3 cup + 1 tsp 1/3 cup + 2 tsp ND ND ND 2 Tbsp 1/3 cup 1 Tbsp 2 Tbsp + 2-1/3 tsp
20 15 23 20 16 19 20 18 17 17 13 13 17 16 18
30 30 30 30 30 30 30 30 30 30 30 30 30 30 30
27 20 21 27 21 21 27 21 23 21 16 16 24 20 23
0.8 0.4 0.4 0.7 0.5 0.5 0.6 0.6 0.4 0.3 0.4 0.6 0.7 0.4 0.6
32 9 19 27 6 38 22 27 14 7 9 14 34 10 14
0.1
47
Food
Weight Approximate ILE (g) Measure (mg) For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Apple/banana juice 39 1-1/4 fl oz 3 Apple/carrot juice 71 2-1/3 fl oz 4 Apple/cherry juice 62 2 fl oz 3 Apple/cranberry juice 62 2 fl oz 3 Apple/grape juice 125 4 fl oz 3 Apple/prune juice 62 2 fl oz 3 Fruit medley tropical dessert 55 3 Tbsp + 2-1/2 tsp 3 Guava tropical dessert 50 3 tbsp + 1-1/2 tsp 3 Mango tropical dessert 31 2 Tbsp + 1/2 tsp 3 Papaya tropical dessert 64 1/4 cup + 1-1/2 tsp 3 White grape juice 78 2-1/2 fl oz 3 1st Foods Applesauce 43 3 Tbsp 3 2nd Foods Apple/blueberry 45 3 Tbsp 3 Applesauce 29 2 Tbsp 3 Fruit medley dessert 43 3 Tbsp 3 Peach cobbler 31 2 Tbsp + 1/3 tsp 2 3rd Foods Fruit salad 28 2 Tbsp 3 Peach cobbler 26 1 Tbsp + 2-1/2 tsp 2 Plums/apples 29 2 Tbsp 3 Graduates Beverages Apple 93 3 fl oz 3 Apple banana 39 1-1/4 fl oz 3 Apple grape 124 4 fl oz 3 Berry punch 124 4 fl oz 3 Fruit punch 124 4 fl oz 3
LEU (mg) 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 3 6 4 4 7 4 4 4 4 4 4 4 4 3 4 3 4 3 3 3 3 7 7 7
VAL (mg)
Protein (g) 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.2 0.1 0.1 0.1 0.2 0.2 0.1 0.2 0.1 0.1 0.1 0.1 0.1 0.1
Energy (kcal) 21 30 31 27 64 34 35 35 23 40 54 23 22 14 35 24 19 23 21 42 20 58 63 60
Fruit Dices Graduates Apples Mixed fruit Tender Harvest Pear/wild blueberry
1
71 50 31
ND ND 2 Tbsp + 1/2 tsp
2 3 2
5 5 5
4 4 3
0.1 0.1 0.1
34 25 9
Prepared from 1998 and 1999 data from Gerber Products Co, Fremont, MI 49413.
ND = no data.
Weights and Measures: Except for Dry Cereals and Food Dices, the following weights apply: Level Level 1 tsp = 1/3rd Tbsp = 4.8 g 1 Tbsp = 1/16th cup = 14.3 g 1/4 cup = 4 Tbsp = 57.2 g 1/3 cup = 5-1/3rd Tbsp = 76.2 g 1/2 cup = 8 Tbsp = 114.3 g 2/3 cup = 10 2/3rd Tbsp = 152.5 g 3/4 cup = 12 Tbsp = 171.5 g 1 cup = 16 Tbsp = 228.6 g
TABLE 5-4. Equivalency Lists for BCAA-Restricted Diets: Table Foods

Food
Weight Approximate ILE (g) Measure (mg) For greatest accuracy, weigh food on scale that reads in grams. All measures are level. BREADS AND CEREALS Cereals, Cooked. Measure after cooking Corn Grits, regular and quick Cream of Rice Cream of Wheat instant quick regular Farina Malt-o-Meal Oats, regular, quick, and instant Ralston Wheatena Whole Wheat Hot Natural Cereals, Ready To Eat Alpha-Bits Apple Jacks 100% Bran Bran Chex 40% Bran Flakes (Post ) Cap'n Crunch Cap'n Crunch's Crunch Berries Cap'n Crunch's Peanut Butter Cheerios Cinnamon Toast Crunch Cocoa Krispies Cocoa Pebbles Cocoa Puffs Cookie Crisp Corn Bran Corn Chex Corn Flakes Crispy Rice Crispy Wheat'n Raisins Froot Loops Frosted Rice Krinkles Frosted Rice Krispies Fruity Pebbles Golden Grahams Grape Nuts Flakes Honeycomb Honey Nut Cheerios Honey Nut Corn Flakes King Vitaman Kix Lucky Charms Nutri-Grain corn rye wheat Product 19 Quisp Raisin Bran (Post ) Rice Chex 92 Maple Syrup Urine Disease
LEU (mg)
VAL (mg)
Protein (g)
Energy (kcal)
15 46 25 30 31 29 15 15 20 23 20
1 Tbsp 3 Tbsp 1 Tbsp + 2 tsp 2 Tbsp 2 Tbsp 2 Tbsp 1 Tbsp 1 Tbsp 1 Tbsp + 1 tsp 1 Tbsp + 1-1/2 tsp 1 Tbsp
8 7 20 20 21 18 17 17 20 21 18
32 33 35 34 36 32 29 29 34 36 31
11 26 22 22 23 20 22 22 22 23 20
0.2 0.4 0.4 0.4 0.5 0.4 0.4 0.4 0.4 0.5 0.4
9 24 16 16 17 14 9 9 11 13 12
5 5 5 3 5 5 5 5 3 17 8 9 8 7 4 3 3 7 8 6 9 9 11 5 5 5 3 5 5 3 5 3 6 5 3 6 7 8
3 Tbsp 1/4 cup 1 Tbsp + 1/2 tsp 1 Tbsp 1 Tbsp + 1-1/2 tsp 2 Tbsp 2 Tbsp 2 Tbsp 2 Tbsp 1/4 cup + 3 Tbsp 1/4 cup 1/4 cup 1/4 cup 1/4 cup 1 Tbsp + 1-1/2 tsp 2 Tbsp 2 Tbsp 1/4 cup 3 Tbsp 3 Tbsp 1/4 cup 1/4 cup 1/3 cup 2 Tbsp + 3/4 tsp 2 Tbsp + 1 tsp 3 Tbsp + 1-1/4 tsp 1 Tbsp + 2/3 tsp 2 Tbsp 1/4 cup 2 Tbsp + 1-1/2 tsp 3 Tbsp 1 Tbsp 2 Tbsp + 1 tsp 2 Tbsp 1 Tbsp + 1-1/4 tsp 3 Tbsp + 1-1/2 tsp 2 Tbsp 1/3 cup
18 17 19 12 21 10 10 13 20 18 22 22 10 14 13 8 9 8 21 14 22 22 23 12 21 11 14 11 12 11 21 8 22 20 11 12 22 7
35 35 37 34 35 30 29 32 33 36 35 35 35 35 38 35 35 36 37 35 35 35 35 35 36 35 39 32 35 34 35 36 34 35 34 36 38 34
23 22 28 16 28 13 12 16 25 21 27 27 14 18 16 11 11 28 26 17 28 26 28 15 26 14 19 14 15 14 27 11 27 23 14 15 28 26
0.4 0.4 0.6 0.3 0.6 0.2 0.2 0.3 0.4 0.6 0.4 0.4 0.3 0.4 0.3 0.2 0.2 0.4 0.5 0.3 0.4 0.4 0.4 0.3 0.5 0.3 0.3 0.3 0.3 0.3 0.5 0.2 0.5 0.5 0.3 0.3 0.6 0.4
21 16 13 10 16 20 18 19 11 70 31 37 31 28 16 12 11 28 28 21 35 34 43 19 18 18 11 19 21 12 19 10 21 20 11 23 22 31
Food
Weight Approximate ILE (g) Measure (mg) For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Rice Krispies 6 1/4 cup 22 Rice, puffed 7 1/2 cup 23 Special K 2 1 Tbsp + 1/2 tsp 20 Sugar Frosted Flakes 5 1 Tbsp + 3/4 tsp 9 Sugar Pops 5 2 Tbsp + 2 tsp 9 Sugar Smacks 7 3 Tbsp 21 Super Sugar Crisp 8 1/4 cup 23 Team 7 1/4 cup 20 Toasties 3 2 Tbsp 9 Total 4 2 Tbsp + 1/2 tsp 18 Trix 4 2 Tbsp + 1-1/2 tsp 10 Wheat Chex 5 1 Tbsp + 2 tsp 20 Wheat puffed 3 1/4 cup 19 shredded 5 1/5 large biscuit 20 Wheaties 5 3 Tbsp 20
LEU (mg) 35 37 32 35 36 36 38 36 34 31 33 34 32 36 36
VAL (mg) 30 29 23 11 12 24 26 25 12 22 13 23 21 25 26
Protein (g) 0.5 0.5 0.4 0.2 0.2 0.5 0.5 0.4 0.2 0.4 0.2 0.5 0.5 0.5 0.5
Energy (kcal) 24 28 8 17 18 26 31 26 11 16 17 18 11 17 19
Grains Corn, cooked cream style whole kernel Rice, prepared brown fried Rice-A-Roni white long grain glutinous medium grain Pasta, cooked Macaroni Noodles Ramen noodles Spaghetti Tubers Potatoes, sweet baked, in skin, mashed candied or canned in syrup Potatoes, white baked or boiled in skin French fries (1/2" x 1/2" x 2") hash browns, frozen, cooked Tater Tots Yams, baked or boiled. mashed Miscellaneous Chow mein noodles Jell-O , prepared w/ sugar Snack Foods Arrowroot Barnum's Animal Crackers Cookies Oreo Social Tea Biscuits 2001 Ross Products Division
16 10 18 14 16 16 21 18
1 Tbsp 1 Tbsp 1 Tbsp + 2 tsp 1 Tbsp 1 Tbsp 1 Tbsp + 2 tsp 1-1/2 Tbsp 1-1/2 Tbsp
11 14 18 17 17 18 18 19
30 37 35 29 32 36 35 35
16 20 26 22 21 26 25 26
0.3 0.3 0.5 0.4 0.5 0.4 0.4 0.4
11 11 22 18 20 21 20 23
10 13 10 9
1 Tbsp + 3/4 tsp 1 Tbsp + 1/2 tsp 1 Tbsp 1 Tbsp
18 27 18 16
35 36 35 31
20 32 20 18
0.5 0.5 0.6 0.5
15 17 22 14
25 49 29 15 20 28 34
1/4 small 1/4 cup 3 Tbsp 3 fries 2 Tbsp 3 pieces 1/4 cup
25 22 22 26 27 25 17
37 32 33 37 37 34 32
33 28 31 31 31 29 20
0.5 0.4 0.5 0.6 0.6 0.6 0.5
30 67 25 47 43 46 39
5 73
1 Tbsp + 1-1/2 tsp 1/4 cup
18 16
36 35
21 29
0.6 1.1
28 43
5 8 11 11
1 biscuit 3 crackers 1 cookie 2 biscuits
16 18 17 21
35 35 32 39
224 21 21 24
0.4 0.5 0.5 0.6
21 33 53 48
Food
Weight Approximate ILE (g) Measure (mg) For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Sugar Wafers (Nabisco ) 14 2-1/2 wafers 18 vanilla wafer 8 2 wafers 15 Crackers Goldfish , original 7 12 crackers 18 graham crackers (2" x 2") 7 1 cracker 20 Ritz 7 2 crackers 15 saltine 6 2 crackers 19 Triangle Thins 4 2 crackers 20 Waverly 7 1 cracker 17 Wheat Thins 7 4 crackers 17 Doritos 4 2 chips 8 Fritos 4 2 chips 10 Ice cream cone (wafer type) 4 1 (cone only) 15 Popcorn buttered 2 1/4 cup 9 caramel 4 1 Tbsp + 2 tsp 9 plain 2 1/3 cup 9 Potato chips (2" diameter) 8 4 chips 21 Rice cakes 5 1/2 cake 21 FATS Butter stick whipped Gravy mushroom, canned mushroom mix, dry onion mix, dry Margarine soft in tub stick or brick Nondairy creamers w/ sodium caseinate liquid powder Rich's Coffee Rich Polyrich Olives black green Salad dressings, commercial French Italian mayonnaise Miracle Whip ranch Russian Thousand Island Toppings, commercial Cool Whip extra creamy regular Richwhip pressurized prewhipped
LEU (mg) 34 30 34 38 29 37 34 33 34 31 34 30 34 34 36 31 33
VAL (mg) 20 17 20 23 17 22 22 20 20 12 13 18 13 12 12 29 26
Protein (g) 0.6 0.4 0.5 0.6 0.5 0.6 0.4 0.5 0.5 0.3 0.3 0.4 0.3 0.2 0.2 0.5 0.4
Energy (kcal) 67 37 35 27 33 26 20 35 34 18 22 17 10 14 7 42 17
15 11 11 1 1 14 14 11 2 43 43 15 10 18 15 9 28 5 8 13
1 Tbsp 1 Tbsp + 1-1/2 tsp 2-1/4 tsp 1 Tbsp 1 Tbsp 1 Tbsp 1 Tbsp 2-1/4 tsp 1 tsp 3 Tbsp 3 Tbsp 3 olives 2 olives 1 Tbsp + 1 tsp 1 Tbsp 2 tsp 2 Tbsp 1 tsp 1-1/2 tsp 2-1/2 tsp
9 6 5 5 5 6 6 6 6 6 6 6 4 6 6 6 7 6 7 7
12 9 10 9 9 9 12 10 9 10 10 10 8 9 9 9 10 9 10 10
9 6 6 6 5 6 9 6 7 6 6 7 6 7 6 7 7 7 8 7
0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.2 0.2 0.1 0.1 0.1 0.1 0.1 0.1 0.1
108 79 6 4 5 101 101 15 11 66 66 28 12 78 69 66 140 26 38 49
4 7 25 10
2-1/2 tsp 1 Tbsp + 2-1/4 tsp 3 Tbsp + 1-1/4 tsp 2 Tbsp + 1-1/2 tsp
6 6 6 6
10 10 10 10
7 7 6 6
0.1 0.1 0.1 0.1
13 19 69 30
Food
Weight Approximate ILE (g) Measure (mg) For greatest accuracy, weigh food on scale that reads in grams. All measures are level.
LEU (mg)
VAL (mg)
Protein (g)
Energy (kcal)
FRUITS Fruits are raw unless otherwise noted. Weight of raw fruits is only for parts that can be eaten. Drain canned, cooked, and frozen fruits before measuring or weighing. Apple canned, sweetened, sliced dried cooked, sweetened uncooked sauce, canned, sweetened whole, large Apricots canned, heavy syrup dried cooked, sweetened uncooked frozen, sweetened nectar, canned whole Avocados, all varieties, mashed Bananas Blackberries canned, heavy syrup raw Blueberries canned, heavy syrup frozen, sweetened raw Boysenberries, canned, heavy syrup Cherries sour red, canned, heavy syrup sweet canned, heavy syrup raw Dates, dried Figs canned, heavy syrup dried cooked uncooked whole Fruit cocktail, canned, heavy syrup Fruit salad, canned, heavy syrup Gooseberries, canned, light syrup Grapefruit, all varieties canned, light syrup juice, canned, unsweetened sections Grapes adherent skin juice, canned or bottled slipskin
204 210 43 255 230 86 31 10 60 126 35 19 38 32 72 64 115 72 48 117 97 72 25 130 49 19 75 130 128 63 125 185 115 160 210 184
1 cup 3/4 cup 1/2 cup 1 cup 1 fruit 1/3 cup 2 Tbsp 3 halves 1/4 cup 4 fl oz 1 fruit 1 Tbsp + 1 tsp 1/3 small 2 Tbsp 1/2 cup 1/4 cup 1/2 cup 1/2 cup 3 Tbsp 1/2 cup 6 Tbsp 1/2 cup 3 dates 1/2 cup 3 Tbsp 1 fig 1-1/2 medium 1/2 cup 1/2 cup 1/4 cup 1/2 cup 6 fl oz 1/2 cup 1 cup 6 2/3 fl oz 2 cups
14 16 16 18 18 14 12 12 12 14 14 13 13 10 12 13 14 15 14 16 17 17 12 16 19 17 18 12 13 13 23 26 19 8 15 10
22 26 25 28 28 27 23 22 24 26 27 23 27 21 26 25 26 29 21 23 26 24 22 22 27 25 26 22 23 25 21 23 26 22 25 24
16 19 19 20 21 16 14 14 15 16 17 18 18 12 15 17 20 20 18 21 22 22 16 18 24 22 21 20 18 17 37 41 31 29 21 32
0.4 0.4 0.4 0.5 0.4 0.5 0.4 0.4 0.4 0.5 0.5 0.4 0.4 0.4 0.5 0.4 0.4 0.5 0.5 0.9 0.6 0.9 0.5 0.5 0.6 0.6 0.6 0.5 0.4 0.4 0.9 1.0 0.7 1.1 1.2 1.2
136 174 104 194 136 71 38 25 60 72 17 31 35 30 37 66 94 41 42 106 80 52 68 114 52 48 56 93 94 46 46 46 37 114 129 484
Food
Weight Approximate ILE (g) Measure (mg) For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Thompson, seedless, canned, heavy syrup 256 1 cup 10 Guava, common and strawberry diced 41 1/4 cup 12 sauce 119 1/2 cup 15 Kiwi fruit 38 1/2 fruit 11 Loquats 100 10 fruits 15 Mangoes, diced 82 1/2 cup 15 Melon, cubed cantaloupe 53 1/3 cup 14 casaba 57 1/3 cup 15 honeydew 113 2/3 cup 14 Mixed fruit, canned, heavy syrup 128 1/2 cup 14 Nectarines, sliced 69 1/2 cup 19 Oranges, all varieties juice canned 249 8 fl oz 15 frozen, diluted 187 3/4 cup 13 sections 90 1/2 cup 23 Orange-grapefruit juice, canned 187 6 fl oz 30 Papaya, diced 140 1 cup 14 Peaches canned, heavy syrup, sliced 85 1/3 cup 11 dried, uncooked 13 1/2 fruit 14 frozen, sweetened 62 1/4 cup 11 nectar, canned 187 6 fl oz 15 sliced 57 1/3 cup 11 spiced, canned, heavy syrup 121 1/2 cup 15 Pears canned, heavy syrup 255 1 cup 15 sliced 165 1 cup 33 Persimmons Japanese 56 1/3 fruit 14 native 42 1-2/3 fruit 15 Pineapple chunks canned, heavy syrup 196 3/4 cup 17 frozen, sweetened 122 1/2 cup 16 diced 155 1 cup 20 juice canned 188 6 fl oz 20 frozen, diluted 156 5 fl oz 20 Plantains, cooked, sliced 77 1/2 cup 17 Plums purple, canned, heavy syrup 258 1 cup 18 sliced 124 3/4 cup 20 Prunes dried cooked, unsweetened 71 1/3 cup 16 uncooked 34 4 fruits 17 juice, canned or bottled 160 5 fl oz 18 Raisins, seedless 41 1/4 cup 10 Raspberries canned, heavy syrup 64 1/4 cup 15 red, frozen, sweetened 83 1/3 cup 17 raw 62 1/2 cup 16 Rhubarb, frozen, cooked, sweetened 120 1/2 cup 14
LEU (mg) 26 23 25 22 26 26 21 23 23 24 29
VAL (mg) 33 12 13 21 21 22 18 19 18 21 25
Protein (g) 1.2 0.3 0.4 0.4 0.4 0.4 0.5 0.5 0.5 0.5 0.6
Energy (kcal) 186 21 44 23 47 54 19 15 38 92 34
27 24 22 28 22 22 26 22 29 23 28 26 23 24 25
22 20 36 49 11 21 26 21 27 22 28 18 23 17 18
1.5 1.3 0.9 1.1 0.9 0.4 0.5 0.4 0.5 0.4 0.5 0.5 0.6 0.3 0.3
104 84 42 96 54 63 31 59 100 24 90 188 97 39 43
26 25 29 26 29 27 26 25
22 20 25 25 25 22 23 23
0.7 0.5 0.6 0.6 0.6 0.6 0.9 1.0
98 104 77 104 80 90 230 68
23 24 26 30 24 26 25 21
20 22 23 38 20 22 21 18
0.8 0.9 0.9 1.4 0.5 0.6 0.6 0.5
76 80 115 124 58 85 30 139
Food
Weight Approximate ILE (g) Measure (mg) For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Sapodilla, pulped 100 7 Tbsp 15 Strawberries, sliced frozen, sweetened 85 1/3 cup 10 raw 75 1/2 cup 11 Tangerines canned, light syrup 252 1 cup 30 juice canned, sweetened 249 8 fl oz 121 fresh 247 8 fl oz 12 whole 168 2 medium 28 Watermelon, diced 160 1 cup 30
LEU (mg) 24 23 23 28 25 25 26 29
VAL (mg) 16 13 13 48 20 20 46 26
Protein (g) 0.4 0.4 0.5 1.1 1.2 1.2 1.1 1.0
Energy (kcal) 83 82 22 153 125 106 74 50
VEGETABLES Vegetables are raw unless otherwise noted. Weight of raw vegetables is only for parts that can be eaten. Drain canned and cooked vegetables before measuring or weighing. Asparagus green, raw, canned, cooked Bamboo shoots, canned Beans, green, snap, or yellow wax canned, cooked frozen, cooked Bean sprouts mung cooked raw soya cooked raw Beets, canned, cooked greens roots, pickled, diced Broccoli fresh or frozen, cooked raw, diced Brussels sprouts fresh, cooked frozen, cooked whole Cabbage Chinese cooked raw, shredded red, raw, shredded white, shredded cooked raw Carrots fresh or frozen, cooked, shredded Cauliflower fresh or frozen, cooked diced Celery, diced cooked raw Chard, Swiss, chopped cooked 33 37 26 34 2 Tbsp or 2 spears 1/3 cup 3 Tbsp + 1 tsp 1/4 cup 18 19 18 17 32 31 30 28 26 23 24 23 0.7 0.6 0.5 0.5 9 4 5 9
23 17 14 12 27 74 20 22 21 22 19
3 Tbsp 2 Tbsp + 2 tsp 1 Tbsp + 2 tsp 2 Tbsp 3 Tbsp 7 Tbsp 2 Tbsp 4 Tbsp 1 sprout 1 sprout 1 sprout
23 23 27 27 14 24 22 24 21 30 25
30 31 32 32 31 33 27 29 24 31 29
22 23 27 27 21 27 27 28 25 31 29
0.5 0.5 0.7 0.7 0.7 0.8 0.6 0.6 0.5 0.6 0.6
5 4 5 6 8 23 6 6 8 8 8
32 35 39 61 52 68 73 26 25 112 90 22
3 Tbsp 1/2 cup 1/3 cup 6 Tbsp 2/3 cup 7 Tbsp 2/3 cup 3 Tbsp + 1-1/4 tsp 1/4 cup 3/4 cup 3/4 cup 2 Tbsp
28 30 28 29 31 29 30 19 19 18 18 34
29 31 28 30 33 31 31 30 29 27 28 30
22 23 23 25 27 31 32 25 25 23 23 25
0.5 0.5 0.5 0.6 0.8 0.7 0.7 0.5 0.5 0.6 0.6 0.4
4 5 11 13 12 31 31 6 6 17 14 4
Food
Weight Approximate ILE (g) Measure (mg) For greatest accuracy, weigh food on scale that reads in grams. All measures are level. raw 25 3 Tbsp 26 Chayote fruit, cubed cooked 53 1/3 cup 18 raw 33 1/4 cup 16 Collards, cooked, diced 47 1/4 cup 21 Cucumber, sliced 130 1-1/4 cup 22 Eggplant, cooked, diced 54 1/2 cup + 1 Tbsp 19 Endive, shredded 28 1/2 cup + 1 Tbsp 20 Kale, cooked, chopped 24 3 Tbsp 28 Kohlrabi, cooked 41 1/4 cup 34 Lettuce, shredded bibb, Boston, or iceberg 42 3/4 cup 33 leaf 37 2/3 cup 31 Romaine or cos 28 1/2 cup 29 Mushrooms, Agaricus bisporus cooked 20 2 Tbsp 17 raw, sliced 23 1/3 cup 19 Mustard greens, cooked, chopped 44 1/3 cup 36 Okra, cooked, sliced 30 3 Tbsp 21 Onions, mature cooked, diced 105 1/2 cup 34 rings 10 1 ring 21 Parsnips, cooked, chopped 59 3/4 cup 32 Peas, green, fresh, or frozen, canned, cooked 10 1 Tbsp 19 Pepper, green, diced cooked 85 3/4 cup 17 raw 66 2/3 cup 18 Pickle, cucumber dill 100 1 large 22 sweet 100 1 large 22 Pumpkin, cooked 61 1/4 cup 21 Radishes, Oriental, cooked, sliced 74 1/2 cup 21 Rutabagas, cubed cooked 85 1/2 cup 39 raw 70 1/2 cup 35 Sauerkraut, canned 58 1/4 cup 27 Shallots, chopped 20 2 Tbsp 21 Spinach, chopped canned 13 1 Tbsp 19 fresh, cooked 11 1 Tbsp 17 frozen, cooked 12 1 Tbsp 18 raw 14 1/4 cup 20 Squash, summer, all varieties, sliced fresh, cooked 56 1/3 cup 19 frozen, cooked 50 1/4 cup 22 raw 43 1/3 cup 18 winter, all varieties baked, boiled, or mashed 54 1/4 cup 19 Tomatoes canned 84 1/3 cup 19 catsup 39 2 Tbsp + 1-1/2 tsp 23 cooked 75 1/3 cup 20 juice 137 41/2 fl oz 21 paste 29 1 Tbsp + 2-1/4 tsp 21 pure 62 1/4 cup 20
LEU (mg) 32 31 28 32 30 28 28 32 29 31 29 28 27 30 30 29 34 35 28 32 28 29 30 30 31 26 30 27 27 30 29 26 29 31
VAL (mg) 23 25 23 26 22 23 18 25 22 28 26 24 20 23 39 26 22 22 25 23 22 24 24 22 23 23 37 34 23 22 21 19 21 22
Protein (g) 0.6 0.3 0.3 0.5 0.7 0.4 0.4 0.5 0.7 0.5 0.5 0.5 0.4 0.5 1.0 0.6 0.9 0.5 0.8 0.5 0.5 0.6 0.7 0.7 0.7 0.5 0.9 0.8 0.5 0.5 0.4 0.3 0.4 0.4
Energy (kcal) 6 13 8 7 17 15 5 8 12 5 7 4 5 6 7 10 29 41 47 8 15 17 11 146 21 13 29 25 11 14 3 3 8 3
30 32 30 27 29 31 31 29 30 29
23 26 23 21 20 23 22 21 22 21
0.5 0.7 0.5 0.5 0.8 0.8 0.8 1.0 1.1 1.0
11 10 9 21 22 41 19 23 24 26
Food
Weight Approximate ILE (g) Measure (mg) For greatest accuracy, weigh food on scale that reads in grams. All measures are level. raw, diced 90 1/2 cup 19 sauce, no meat 81 1/3 cup 21 Turnips greens, canned, chopped 27 3 Tbsp 16 root, diced cooked 117 3/4 cup 34 raw 98 3/4 cup 35 Vegetable juice cocktail 182 6 fl oz 22 Soups, Campbell's , Condensed. Measure before diluting and dilute with water only. Asparagus, Cream of 26 1 Tbsp + 2 tsp Celery, Cream of 31 2 Tbsp Chicken Gumbo 21 1 Tbsp + 1 tsp Chicken Vegetable 15 1 Tbsp Minestrone 15 1 Tbsp Mushroom, Cream of 26 1 Tbsp + 2 tsp Onion 31 2 Tbsp Potato, Cream of 31 2 Tbsp Tomato 42 2 Tbsp + 2 tsp Tomato Bisque 31 2 Tbsp Vegetarian Old-Fashioned 26 1 Tbsp + 2 tsp Vegetarian Vegetable 25 1 Tbsp + 2 tsp
LEU (mg) 30 30 28 30 32 31
VAL (mg) 21 22 21 27 29 22
Protein (g) 0.8 1.1 0.3 0.8 0.9 1.1
Energy (kcal) 17 24 5 21 26 35
20 19 17 17 16 20 33 19 20 19 21 20
34 31 28 29 30 33 33 29 33 32 31 30
24 22 20 20 22 22 22 23 22 21 21 20
0.5 0.5 0.4 0.4 0.5 0.4 0.9 0.4 0.7 0.5 0.5 0.4
18 22 9 9 10 27 14 18 29 30 14 15
FREE FOODS A Limit to prescribed number of servings. Desserts Apple butter Fruit Ice Fruit bars, frozen orange pineapple Gelatin Pop Marmalade Marshmallow M&M candy, plain Raisins, chocolate covered Sorbet peach pineapple strawberry Fruits/Juices Apple juice, frozen, diluted Cranberry juice cocktail Fruit juice bar Fruit pie filling apple cherry peach strawberry Jams Nectar papaya pear
20 61 56 24 15 39 8 1 1 17 26 25
1 Tbsp 1/3 cup 3/4 bar 1/3 bar 1/3 pop 2 Tbsp 1 large 1 piece 1 raisin 1 Tbsp + 1/2 tsp 1 Tbsp + 2-1/4 tsp 1 Tbsp + 2 tsp
3 6 6 3 2 5 2 3 3 2 3 2
5 6 5 5 5 5 5 5 6 5 5 5
4 10 9 4 4 8 4 3 4 5 4 3
0.1 0.2 0.2 0.1 0.2 0.2 0.2 0.1 0.1 0.1 0.1 0.1
37 78 53 23 10 100 26 4 6 17 25 24
171 253 104 81 81 29 18 20 126 78
5-1/2 fl oz 8 fl oz 2 bars 1/3 cup 2 Tbsp 1 Tbsp + 2-1/4 tsp 1 Tbsp + 1/2 tsp 1 Tbsp 4 fl oz 2-1/2 fl oz
3 3 2 3 3 29 2 3 3 2
5 5 4 5 4 3 5 6 5 5
3 3 3 4 4 5 3 3 4 3
0.1 0.1 0.2 0.1 0.2 0.1 0.1 0.1 0.2 0.1
80 144 86 89 33 31 20 54 71 47
Food
Weight Approximate ILE (g) Measure (mg) For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Miscellaneous Chocolate drink powder Chocolate syrup Honey Vegetables Chives, chopped Cucumbers, sliced Horseradish Leeks, chopped Onions, spring, chopped Peppers, jalapeo, canned, chopped Radishes, sliced
LEU (mg)
VAL (mg)
Protein (g)
Energy (kcal)
3 6 42 3 26 1 6 6 8 14
1 tsp 1 tsp 2 Tbsp 1 Tbsp 1/4 cup 1-1/4 tsp 1 Tbsp 1 Tbsp 1 Tbsp 2 Tbsp
3 4 4 4 5 3 4 4 2 4
5 6 5 5 6 5 6 6 4 5
3 6 4 4 5 4 4 5 3 5
0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1
11 14 128 1 4 1 4 2 2 3
FREE FOODS B These foods contain little or no branched-chain amino acids. They may be used as desired if patient is not overweight and if they do not depress appetite for prescribed foods. Beverages Carbonated beverages, caffeine-free Exceed Energy Drink Gatorade Kool-Aid , sweetened w/ sugar Lemonade Limeade, sweetened w/ sugar Strawberry drink powder Tang Tea, instant, powder Desserts/Sweeteners Candies candy corn gum drops hard candy jelly beans lollipop Frosting, strawberry or vanilla Jellies Lemon pudding, canned (Hunt's ) Molasses Popsicle , twin Sugar brown powdered table Syrup corn maple table Miscellaneous Salad dressing, oil/vinegar
1
113 124 125 125 125 125 8 125 1
4 fl oz 4 fl oz 4 fl oz 4 fl oz 4 fl oz 4 fl oz 1 Tbsp 4 fl oz 1 Tbsp
0 0 0 0 1 1 0 0 0
0 0 0 0 1 1 0 0 0
0 0 0 0 1 1 0 0 0
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
52 35 25 70 49 59 33 59 3
16 16 15 14 28 16 20 121 21 128 14 8 12 20 20 20
10 pieces 8 pieces 3 pieces 5 pieces 1 medium 1 Tbsp 1 Tbsp 1 can 1 Tbsp 1 popsicle 1 Tbsp 1 Tbsp 1 Tbsp 1 Tbsp 1 Tbsp 1 Tbsp
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
58 56 58 51 108 69 54 151 48 95 52 31 48 58 50 50
16
1 Tbsp
0.0
70
See Appendix 12, p A-11, for composition of very-low-protein foods.
TABLE 5-5. MSUD Clinical Summary Sheet
Name: Date of Birth: __________/__________/__________

Mo Day Year
Hospital Number:
Date
(mo/d/yr)
Age
(yrs/mos)
Physical Data
Length/ Height (cm) Weight (kg) Head Circum (cm) Allo1 isoleucine ILE
1
Laboratory Data
LEU
1

Transthyretin Ketostix or DNPH (mg/dL) (ng/mL) Ferritin ILE (mg) LEU (mg) VAL (mg) Protein (g) Energy (kcal)
VAL
Hgb (g/dL)
Hct (%)
Indicate if mol/L or mg/dL.
REFERENCES
1. Acosta PB: The contribution of therapy of inherited amino acid disorders to knowledge of amino acid requirements. In Wapnir RA (ed): Congenital Metabolic Diseases: Diagnosis and Treatment. New York: Marcel Dekker Inc, 1985, 115-135. Acosta PB, Yannicelli S: Nutrition support of inherited disorders of amino acids metabolism: Part 2. Top Clin Nutr 1995;10:48-72 (review). Acosta PB, Yannicelli S: Protein intake affects phenylalanine requirements and growth of infants with phenylketonuria. Acta Paediatr 1994;407 (Suppl):66-67. Arnold GL, Vladutiu CJ, Kirby RS: Protein insufficiency and impaired growth in children with PKU. J Inher Metab Dis 2000;23 (Suppl) 1:29A. Behrman RE, Kliegman RM, Arvin AA (eds): Nelson Textbook of Pediatrics, ed 15. Philadelphia: WB Saunders Co, 1996. Berry GT, Heidenreich R, Kaplan P, et al: Branched-chain amino acid free parenteral nutrition in the treatment of acute metabolic decompensation in patients with maple syrup urine disease. N Engl J Med 1991;324:175-179. Calomme MR, Vanderpas JB, Francois B, et al: Thyroid function parameters during a selenium repletion/depletion study in phenylketonuric subjects. Experientia 1995;51:1208-1215. Chuang DT, Shih VE: Maple syrup urine disease (Branched-chainketoaciduria). In Scriver CR, et al (eds): The Metabolic and Molecular Bases of Inherited Disease, ed 8. New York: McGraw-Hill Medical Publishing Division, 2001, pp 1971-2005. Clow CL, Reade TM, Scriver CR: Outcome of early and long-term management of classical maple syrup urine disease. Pediatrics 1981;68:856-862. DiGeorge AM, Rezvani I, Garibaldi LR, et al: Prospective study of maple syrup urine disease for the first four days of life. N Engl J Med 1982;307:1492-1495. Elsas LJ, Acosta PB: Nutrition support of inherited metabolic diseases. In Shils ME, et al (eds): Modern Nutrition in Health and Disease, ed 9. Baltimore: Williams & Wilkins, 1999, pp 1003-1056. Elsas LJ, Danner DJ: The role of thiamine in maple syrup urine disease. Ann NY Acad Sci 1982;378:404-421. Elsas LJ, Ellerine NP, Klin PD: Practical methods to estimate whole body leucine oxidation in maple syrup urine disease. Pediatr Res 1993;33:445-451. Fernhoff PM, Lubitz D, Danner DJ, et al: Thiamine response in maple syrup urine disease. Pediatr Res 1985;19:1011-1016. Food and Nutrition Board, Committee on Dietary Allowances: Recommended Dietary Allowances, eds 9 and 10. Washington, DC: National Academy of Sciences, 1980 and 1989. Giacoia GP, Berry GT: Acrodermatitis enteropathica-like syndrome secondary to isoleucine deficiency during treatment of maple syrup urine disease. Am J Dis Child 1993;147;954-956. Gropper S, Acosta PB: Effect of simultaneous ingestion of L-amino acids and whole protein on plasma amino acid concentrations and urea nitrogen in humans. JPEN 1991;15:48-53. Gropper SS, Gropper DM, Acosta PB: Plasma amino acid response to ingestion of L-amino acids and whole protein. J Pediatr Gastroenterol Nutr 1993;16:143-150. Gropper SS, Naglak MC, Nardella M, et al: Nutrient intakes of adolescents with PKU and infants and children with MSUD on semisynthetic diets. J Am Col Nutr 1993;12:108-114. Hammerson G, Wille L, Schmidt H, et al: Maple syrup urine disease: Treatment of the acutely ill newborn. Eur J Pediatr 1978;129:157-165. Henstenburg JD, Mazur AT, Kaplan PB, et al: Nutritional assessment and body composition in children with maple syrup urine disease (MSUD). J Amer Diet Assoc 1990;90:A-32. Herrmann ME, Broesicke HG, Keller M, et al: Dependence of the utilization of a phenylalanine-free amino acid mixture on different amounts of single dose ingested. A case report. Eur J Pediatr 1994;153:501-503. Jones BJM, Lees R, Andrews J, et al: Comparison of an elemental and polymeric enteral diet in patients with normal gastrointestinal function. Gut 1983;24:78-84. Kaplan P, Mazur A, Field M, et al: Intellectual outcome in children with maple syrup urine disease. J Pediatr 1991;119:46-50. Kindt E, Halvorsen S: The need of essential amino acids in children: An evaluation based on the intake of phenylalanine, tyrosine, leucine, isoleucine, and valine in children with phenylketonuria, tyrosine amino transferase defect, and maple syrup urine disease. Am J Clin Nutr 1980;33:279-286. Koch SE, Packman S, Koch TK, Williams ML: Dermatitis in treated maple syrup urine disease. J Am Acad Dermatol 1993;28:289-292. Leverton RM, Johnson N, Dazur J, Ellison J: Amino acid requirements of young adults. In Albanese AA (ed): Protein and Amino Acid Nutrition. New York: Academic Press, 1959. Lombeck I, Kasperek K, Harbisch HD, et al: The selenium state of children. II. Selenium content of serum, whole blood, hair and the activity of erythrocyte glutathione peroxidase in dietetically treated patients with PKU and MSUD. Eur J Pediatr 1978;128:213-223.
2. 3. 4. 5. 6. 7. 8.
9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25.
26. 27. 28.
29. MacLean W, Graham G: Pediatric Nutrition in Clinical Practice. Menlo Park, Calif: Addison-Wesley Publishing Co, 1982. 30. Martin SB, Acosta PB: Osmotic behaviors of components of chemically-defined formulas. J Pediatr Perinat Nutr 1987;1:1-17. 31. Naglak ME, Elsas LJ: Nutrition support of maple syrup urine disease. Metabolic Currents 1988;1:15-18. 32. Nord A, van Doorninck WJ, Greene C: Developmental profile of patients with maple syrup urine disease. J Inher Metab Dis 1991;14:881-889. 33. Northrup H, Sigman ES, Herbert AA: Exfoliative erythroderma resulting from inadequate intake of branched-chain amino acids in infants with MSUD. Arch Dermatol 1993;129:384-385. 34. Ohkohchi N, Andoh T, Ohi R, Mori S: Defined formula diets alter characteristics of the intestinal transport of amino acids and peptides in growing rats. J Pediatr Gastroenterol Nutr 1990;10:490-496. 35. Parsons HG, Carter RJ, Unrath M, Snyder FF: Evaluation of branched chain amino acid intake in children with maple syrup urine disease and methylmalonic aciduria. J Inher Metab Dis 1990;13:125-136. 36. Peinemann F, Danner DJ: Maple syrup urine disease 1954 to 1993. J Inher Metab Dis 1994;17:3-15. 37. Posati LP, Orr ML: Composition of Foods: Dairy and Egg Products, Agriculture Handbook No. 8-1. Washington, DC: US Dept of Agriculture, Agricultural Research Service, 1976. 38. Pratt EL, Snyderman SE, Cheung MW, et al: The threonine requirement of the normal infant. J Nutr 1955;56:231-251. 39. Schoeffer A, Herrmann ME, Broesicke HG, Moench E: Effect of dosage and timing of amino acid mixtures on nitrogen retention in patients with phenylketonuria. J Nutr Med 1994;4:415-418. 40. Schwahn B, Wendel U, Schadewaldt P, et al: Diurnal changes in plasma amino acids in maple syrup urine disease. Acta Paediatr 1998;87:1245-1246. 41. Smith CA, Nelson NM (eds): The Physiology of the Newborn Infant, ed 4. Springfield, IL: Charles C Thomas Publisher, 1976. 42. Smith JL, Arteaga C, Heymsfield SB: Increased ureagenesis and impaired nitrogen use during infusion of a synthetic amino acid formula - A controlled trial. N Engl J Med 1982;306:1013-1018. 43. Smith JL, Heymsfield SB: Enteral nutrition support: Formula preparation from modular ingredients. JPEN 1983;7:280-288. 44. Snyderman SE: Maple syrup urine disease. In Wapnir RA (ed): Congenital Metabolic Diseases: Diagnosis and Treatment. New York: Marcel Dekker Inc, 1985. 45. Snyderman SE: The treatment of branched chain ketoacidemia. In Nutrition Committee: Diet Therapy for MSUD and Organic Acidurias. Elk Grove Village, Ill: American Academy of Pediatrics, 1978. 46. Snyderman SE, Boyer A, Norton PM, et al: The essential amino acid requirements of infants: IX. Isoleucine. Am J Clin Nutr 1964;15:313-321. 47. Snyderman SE, Holt LE, Smellie F, et al: The essential amino acid requirements of infants: Valine. Am J Dis Child 1959;97:186-191. 48. Snyderman SE, Roitman EL, Boyer A, et al: The essential amino acid requirements of infants: Leucine. Am J Dis Child 1961;102:157-162. 49. Spika JS, Shaffer N, Hargrett-Bean N, et al: Risk factors for infant botulism in the United States. Am J Dis Child 1989;143:828-832. 50. Thompson GN, Francis DEM, Halliday D: Acute illness in maple syrup urine disease: Dynamics of protein metabolism and implications for management. J Pediatr 1991;119:33-41. 51. Tornqvist K, Tornqvist H: Corneal deepithelialization caused by acute deficiency of isoleucine during treatment of a patient with maple syrup urine disease. Acta Ophthalmol Scand 1996;74 (Suppl 219):48-49. 52. van Calcar S, Harding CO, Davidson SR, et al: Case reports of successful pregnancy in women with maple syrup urine disease and propionic acidemia. Am J Med Genet 1992;44:641-646. 53. Wajner M, Schlottfeldt JL, Kless C, Wannmacher CMD: Immunosuppresive effects of organic acids accumulating in patients with maple syrup urine disease. J Inher Metab Dis 1995;18:165-168. 54. Wendel U, Becker K, Przyrembel H, et al: Peritoneal dialysis in maple syrup urine disease: Studies on branchedchain amino and ketoacids. Eur J Pediatr 1980;134:57-63. 55. Wendel U, Langenbeck U, Lombeck I, et al: Exchange transfusion in acute episodes of maple syrup urine disease. Eur J Pediatr 1982;138:293.
PROTOCOL 6 Disorders of Leucine Catabolism Nutrition Support of Infants, Children, and Adults With I-VALEX -1 and I-VALEX -2 Amino Acid-Modified Medical Foods
I. Introduction
Five mitochondrial enzyme defects have been identified in the catabolic pathway for essential leucine (LEU) which normally produces acetoacetic acid and acetyl-CoA: branched-chain--ketoacid dehydrogenase complex deficiency (Protocol 5); isovaleryl-CoA dehydrogenase deficiency; 3-methylcrotonyl-CoA carboxylase deficiency; 3-methylglutaconyl-CoA hydratase deficiency; and 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (HMG-CoA lyase deficiency) (20, 68). Isovaleric acidemia was first described in 1967 and was identified by urinary excretion of isovaleric acid (IVA). Subsequently, a deficiency of isovaleryl-CoA dehydrogenase (IVD) was defined in cultured skin fibroblasts. This enzyme is a mitochondrial flavoprotein and uses electron transfer factor. Deficiency of IVD results in a block in catabolism of LEU at the step after branched-chain-ketoacid dehydrogenase complex (Figure E) (20, 68). IVA, 3-hydroxyisovaleric acid (3-OHIVA), and isovalerylglycine (IVG) accumulate in body fluids. The phenotypic abnormalities result from toxic accumulation of free IVA. An alternate pathway producing IVG reduces accumulation of toxic precursors. Carnityl adducts offer an additional alternate pathway to detoxify free IVA (20, 23, 68).
Dietary protein Tissue protein Isovaleric acid Isovalerylglycine 3-Hydroxyisovaleric acid 4-Hydroxyisovaleric acid Mesaconic acid Methylsuccinic acid Isovalerylglucuronide Isovalerylglutamic acid Isovalerylalanine Isovalerylsarcosine 3-Hydroxyisoheptanoic acid Isovalerylcarnitine 3-Methylcrotonic acid 3-Methylcrotonylglycine 3-Hydroxyisovaleric acid 3-Methylglutaconic acid 3-Methylglutaric acid 3-Methylglutarylcarnitine 3-Hydroxy-3-Methylglutaric acid 3-Hydroxy-3-methylglutaryl-CoA reductase
Transaminase
L-Leucine
2-Keto-isocaproic acid Branched-chain -ketoacid dehydrogenase
Isovaleryl-CoA
Isovaleryl-CoA dehydrogenase 3-Methylcrotonyl-CoA 3-Methylcrotonyl-CoA carboxylase 3-Methylglutaconyl-CoA 3-Methylglutaconyl-CoA hydratase 3-Hydroxy-3-methylglutaryl-CoA 3-Hydroxy-3-methylglutaryl-CoA lyase
Acetoacetic acid Site of enzyme defect Modified from reference 68.
Acetyl-CoA
Mevalonic acid Cholesterol
Mevalonic acid (Mevalonolactone)
Figure E. Metabolism of leucine in disorders of leucine catabolism (excluding MSUD) Two forms of isovaleric acidemia are reported: acute and chronic intermittent. Those patients with acute isovaleric acidemia appear to be normal full-term infants. Within the 1st days of life, poor feeding, tachypnea, vomiting, and a characteristic sweaty-feet odor of the blood and urine are frequently noted. Diarrhea, lethargy, hypotonia, and tremors may also be found. Some patients fail to respond to treatment and expire. The exact cause of death is frequently unknown. Severe metabolic acidosis, hyperammonemia, central nervous system (CNS) hemorrhage, cardiac arrest, and sepsis
104 Disorders of Leucine Catabolism 2001 Ross Products Division
are some probable causes. Infants who are detected early and respond to treatment survive the neonatal period and develop appropriately. If acute neonatal disease is prevented, they progress into chronic intermittent isovaleric acidemia (20, 68). In the chronic intermittent form, babies are normal at birth. During late infancy, they may develop episodes of vomiting, metabolic acidosis, stupor, and coma. Sweaty-feet odor is usually present, and transient alopecia is occasionally seen. Episodes may begin as early as 2 weeks of age and the frequency of attacks seems to decrease with age. Urinary tract and upper respiratory infections frequently trigger episodes, as do excessive intake of protein and aspirin. Many children affected by the intermittent form have a stronger preference for fruits and vegetables over meat and milk (20, 68). Several patients with either acute or chronic isovaleric acidemia have had moderate to severe hematologic abnormalities, including leukopenia and thrombocytopenia, with pancytopenia most common. IVA is an inhibitor of granulopoietic progenitor cell proliferation in bone marrow cell cultures and may account for the neutropenia often seen in isovaleric acidemia (39). Depressed hemoglobin concentrations were also seen in several patients. Transient alopecia seems to be more common with the chronic intermittent form than with the acute form of the disease and may be nutritionally related. Hyperammonemia (up to 1200 mol) has also been reported during neonatal crisis (72).

A male infant with isovaleric acidemia, treated from the neonatal period with medical food designed for MSUD with added L-isoleucine and L-valine and whole protein to supply essential restricted LEU, had normal growth and development. Height and weight were between the 25th and 50th percentiles. Head circumference was at 50th percentile. On average, diet supplied 2.5-3.0 g protein/kg/day and 100 mg LEU/kg/day (44). L-carnitine and glycine (GLY) were not a part of the diet regimen. Growth of a male infant with isovaleric acidemia diagnosed prenatally has been reported (47). At birth, this infant was breastfed ad libitum and 250 mg GLY/kg/day was administered. In spite of low protein intake from human milk and the GLY supplement, the patient became acidotic and began to vomit and hyperventilate at 3 days of age. Breastfeeding was discontinued and a LEU-free diet providing 125 kcal/kg supplemented with 380 mg GLY/kg/day was begun. His clinical status improved rapidly. Dietary LEU at 45 mg/kg/day with GLY at 250 mg/kg/day and protein at 2.0 g/kg was introduced at 5 days of age. At 2 years of age, the patient was developmentally normal and was > 95th percentile for height and weight. Diet at 2 years of age supplied per kg: 46 mg LEU, 1.7 g protein and 72 kcal. Only one hospitalization for vomiting and dehydration was required during the 2-year period. Outcomes in 9 patients with isovaleric acidemia managed by protein restriction (1.5-2.0 g/kg in infancy, 0.8-1.5 g/kg thereafter) and 250 mg GLY/kg/day have been reported (12). Since all patients had secondary carnitine deficiency (total serum carnitine 19 3 mol/L), 4 children were supplemented with 50 mg/kg/day L-carnitine. In these patients serum carnitine returned to normal (51 5 mol). Actual height, weight, and head circumference of patients were not reported although growth velocities were stated to be normal after diet initiation. Developmental quotients or IQ scores of 5 subjects in whom diet was initiated during the neonatal period ranged from 49 to 115. Food refusal has been reported in a patient with isovaleric acidemia (35). Both physiologic and behavioral components to feeding problems were reported. The physiologic component involved altered serotonin metabolism. Any factor such as hyperammonemia or a high-carbohydrate, lowprotein diet that stimulates the transport of tryptophan, a precursor of serotonin, into the brain, could lead to anorexia. A low-tryptophan diet was suggested as one alternative to treatment of anorexia. Of 11 reported French cases of isovaleric acidemia, 8 were alive after the neonatal period. LEU restriction and GLY supplementation were used to manage patients. Six of 8 surviving patients had normal development (58).

A. Isovaleric Acidemia Resulting From Isovaleryl-CoA Dehydrogenase Deficiency 1. Diagnostic studies should be conducted in any infant or child with poor feeding, vomiting, metabolic acidosis, hyperammonemia, hypocalcemia, coma, seizures, neutropenia, thrombocytopenia, pancytopenia, alloisoleucine in plasma, tachypnea and/or sweaty-feet or aged-cheese odor (4, 5, 13, 39, 54, 68). 2. See reference 68 for methods of diagnosis.
2001 Ross Products Division Disorders of Leucine Catabolism 105
B. 3-Methylcrotonylglycinuria Resulting From 3-Methylcrotonyl-CoA Carboxylase Deficiency 1. Diagnostic studies should be conducted in any infant or child who has hypotonia and lethargy progressing to coma, or symptoms resembling Reye's syndrome (hypoglycemia, hyperammonemia, metabolic acidosis, elevated transaminases, and seizures or incoordination) (8, 9, 27, 42, 51, 57, 58). 2. See references 8 and 68 for methods of diagnosis. C. 3-Methylglutaconic Aciduria Resulting From 3-Methylglutaconyl-CoA Hydratase Deficiency. 1. Diagnostic studies should be conducted in any infant or child who presents with mental retardation, retarded speech, or fasting hypoglycemia with metabolic acidosis (15, 18, 25, 26 33, 34, 48). 2. See references 48 and 68 for methods of diagnosis. D. 3-Hydroxy-3-Methylglutaric Aciduria Resulting From HMG-CoA Lyase Deficiency 1. Diagnostic studies should be conducted in any infant who has convulsions, coma, cyanosis, dehydration, dyspnea, hyperpnea, hypotonia, lethargy, myoclonic jerks, opisthotonos, strokelike encephalopathy, respiratory distress, vomiting, hypoglycemia, metabolic acidosis, and absent ketonuria, hyperammonemia, elevated transaminases, hepatomegaly (19, 22, 24, 28, 31, 34, 40, 43, 62, 67). 2. See reference 68 for methods of diagnosis.

A. Correct Primary Imbalance in Metabolic Relationships 1. Restrict dietary LEU to amount tolerated by patient to maintain treatment plasma LEU concentration (12, 44). 2. For patients with HMG-CoA lyase deficiency, also restrict fat to between 20% and 25% of energy and avoid fasting (6, 11). B. Provide Alternative Metabolic Pathways 1. Prescribe adequate L-carnitine and GLY to decrease accumulated toxic compounds formed in blocked reaction sequences (12, 14, 16, 17, 23, 37, 56).
V. Nutrition Support During Acute Illness

A. Initiation of Nutrition Support 1. Initiate nutrition support immediately. Do not wait for confirmation of diagnosis. 2. Evaluate plasma LEU concentrations and urine organic acid concentrations daily. B. Medical Care 1. For medical management during diagnosis and acute illness, see references 4, 5, 16, 17, 23, 39, 41, 55, 74. C. Patients Without Severe Neurologic Involvement 1. Begin high-energy LEU-free feeds (120-150 kcal/kg for infants and young children, 80-100 kcal/kg for children, and 40-50 kcal/kg for adults) that supply adequate water (Table 6-1, p 115). a. Depending on clinical status and age of patient, feed orally or by nipple, nasogastric tube, intravenous infusion, or combine these methods. 1) For nipple or nasogastric feeds: i. Use I-Valex (Table 6-2, p 116), L-carnitine (100-300 mg/kg), and GLY (150-300 mg/kg (7) (Appendix 26, p A-28). 2) For intravenous feeds via central line: i. Use hypertonic D-glucose, LEU-free parenteral amino acid solution (Appendix 26, p A-28), L-carnitine (100-300 mg/kg) (14, 54, 69), and GLY (150-300 mg/kg) (6, 16, 17, 36, 41, 46, 47, 59, 60, 70, 71). ii. Add Liposyn II (Appendix 26, p A-28) after 2 to 3 days, when response to glucose is seen. For 3-hydroxy-3 methylglutaric aciduria, Liposyn II should be restricted to between 20% and 25% of energy (11, 24).
106 Disorders of Leucine Catabolism
3) For intravenous feeds via peripheral line: i. Use isotonic D-glucose, LEU-free parenteral amino acid solution, L-carnitine (100-300 mg/kg) (55, 70) and GLY (150-300 mg/kg). Add Liposyn II (Appendix 26, p A-28) when response to glucose is seen. For 3-hydroxy-3-methylglutaric aciduria, Liposyn II should be restricted to between 20% and 25% of energy (11, 24). 2. Introduce nutrition support with I-Valex orally or by nasogastric tube as soon as possible. a. See Table 6-1, p 115, for Recommended LEU, Protein, Energy, and Fluid intakes. b. See Table 6-2, p 116 , for composition of I-Valex. 3. Add LEU (Table 6-1, p 115) to I-Valex feeds when plasma LEU concentration drops to upper limit of treatment range (185 mol/L). a. Use Similac With Iron Infant Formula to fill LEU prescription for very young infants (Table 6-3, p 117); Similac and beikost or table foods (Table 6-3, p 117) to fill prescription for older infants; and whole cows milk (Table 6-3, p 117) or table foods to fill LEU prescription for children and adults. b. For patients with HMG-CoA lyase deficiency, use ProViMin Protein-Vitamin-Mineral Formula Component With Iron to supply LEU (Table 6-4, p 118). c. Measure liquid infant formula and whole cows milk with disposable syringe. Weigh powdered infant formula on scale that reads in grams. D. Comatose Patients 1. For medical management during diagnosis and acute illness, see references 16, 39, 41, 55, 68-74. 2. Begin LEU-free nasogastric feeding of protein and energy (I-Valex) (Tables 6-1 and 6-2, pp 115 and 116) 36 to 48 hours after beginning dialysis with amino acid-free dialysate. 3. Begin intravenous infusion of 10% D-glucose, L-carnitine (100-300 mg/kg), and GLY (150-300 mg/kg) during nasogastric feeding. Add L-carnitine and GLY only if amounts provided by I-Valex are inadequate. a. GLY is not beneficial in HMG-CoA lyase deficiency. b. Add Liposyn II (Appendix 26, p A-28) to intravenous infusion in 2 to 3 days when response to glucose is seen, continuing until major neurologic signs subside. c. For HMG-CoA lyase deficiency, Liposyn II should provide between 20% and 25% of energy. 4. Add LEU (Table 6-1, p 115) to I-Valex nasogastric feeding when plasma LEU concentration drops to upper limit of range (185 mol/L). a. Use Similac to fill LEU prescription for infants (Table 6-3, p 117) and whole cows milk to fill LEU prescription for children and adults. b. For patients with HMG-CoA lyase deficiency, use ProViMin to supply LEU (Table 6-4, p 118) for infants and skim milk for children and adults. c. Measure liquid infant formula and whole or skim cows milk with disposable syringe. Weigh powdered infant formula on scale that reads in grams. 5. If parenteral amino acid solutions are indicated, see Appendix 26, p A-28.
VI. Establish Goals of Long-Term Nutrition Support (18)

A. Plasma LEU and GLY Concentrations 1. Maintain 2- to 4-hour postprandial plasma LEU concentrations between 50 and 100 mol/L (0.66 to 1.31 mg/dL) when measured by quantitative methods or between 2 and 4 mg/dL when measured by bacterial inhibition assay. 2. Maintain 2- to 4-hour postprandial plasma GLY concentrations between 200 and 400 mol/L (1.5-3.0 mg/dL) when measured by quantitative methods. 3. In practice, obtaining blood 2 to 4 hours postprandially is not always possible. Acceptable local standards should be developed if plasma amino acids are evaluated at other times (Practical Aspects of Nutrition Support, p viii). B. Growth, Development, and Nutrition Status 1. Maintain normal osseous mineralization (41). Osteopenia may occur despite treatment. 2. Support normal growth rate in infants and children and maintain appropriate weight for height in adults.
3. Maintain normal nutrition status. 4. Prevent catabolism (46, 69). b. Avoid extended periods of fasting in patients with HMG-CoA lyase deficiency (68). 5. Maintain normal blood hemoglobin, leukocyte, and platelet concentrations (39). 6. Maintain normal plasma anion gap. 7. Maintain plasma concentration of free carnitine > 30 mol/L. 8. Maintain organic acid concentrations in urine in normal range (4). a. Concentrations of organic acids in urine may be increased somewhat above normal even when blood organic acids are in normal range. 9. Prevent alopecia. C. Mental Development and Neurologic Status 1. Prevent developmental delay and mental retardation (12, 18).

A. LEU (1) 1. Prescribe LEU intake that promotes goals of nutrition support (Table 6-1, p 115). 2. LEU requirements vary widely: a. From patient to patient, depending on activity of enzyme involved. b. In same patient, depending on 1) Age. 2) Growth rate. 3) Adequacy of energy and protein intakes. 4) State of health. 5) GLY and L-carnitine intakes. 3. Values for LEU listed in Table 6-1, p 115, are suggested for initiating therapy. 4. Frequent monitoring of plasma LEU concentration and urinary excretion of organic acids is essential to assess each patients changing requirements. a. Compare results of plasma and urine monitoring with LEU intake. b. See Section X, Suggested Evaluation of Nutrition Support, p 110. Warning: Inadequate LEU intake will result in weight loss or poor weight gain, skin rash progressing to desquamation, hair loss, below normal plasma LEU concentration, loss of appetite, irritability, apathy, and increased concentrations of plasma isoleucine, methionine, serine, threonine, and valine (66). B. GLY 1. Prescribe 150-300 mg/kg (47). C. Protein (2) 1. Prescribe amount greater than Recommended Dietary Allowances (RDAs) (Table 6-1, p 115). 2. Requirements may be greater than RDAs when L-amino acids supply majority of protein equivalent as result of: a. Rapid amino acid absorption (29, 30). b. Early and high peak of plasma amino acids after ingestion of meals where large part of protein is supplied by L-amino acids (29, 30). c. Rapid catabolism of amino acids (32, 38, 61, 64). d. Possible decreased total amino acid absorption (49). Warning: Inadequate protein intake will result in weight loss or poor weight gain, skin rash, hair loss, low plasma protein concentration, and decreased tolerance of LEU. D. Energy 1. Prescribe amount that should support normal weight gain for infants and children and maintain appropriate weight for height of adults (Table 6-1, p 115). 2. Requirements vary widely and may be greater than normal when L-amino acids supply majority of protein equivalent (53).
3. At diagnosis and during metabolic acidosis precipitated by infection or trauma, energy needs may be 25% to 40% greater than values listed in Table 6-1, p 115. 4. Maintenance of adequate energy intake is essential for normal growth and prevention of catabolism (47, 69). Warning: Inadequate energy intake results in poor weight gain or weight loss and depressed tolerance of LEU. E. L-Carnitine 1. Prescribe amount that will maintain plasma free carnitine concentration > 30 mol/L. Most patients require between 100 and 300 mg/kg (17, 23). F. Fluid 1. Prescribe amount that will supply water requirements (Table 6-1, p 115). 2. Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL to children and adults for each kcal ingested (10). G. Fat 1. Restrict fat to between 20% and 25% of energy in patients with HMG-CoA lyase deficiency (11, 24). H. Pantothenic Acid 1. Supplements of 15 to 150 mg/day in three divided doses may be beneficial in 3-methylglutaconic aciduria (50).

A. LEU 1. Calculate amount of infant formula with iron, beikost, whole or skim milk, or table foods required to fill LEU prescription (Table 6-3, p 117). a. Low-iron infant formula, whole cow's milk, skim milk, and evaporated milk should not be used as LEU source for infants because of low iron content. b. Use ProViMin (Table 6-4, p 118) to supply LEU for infants with HMG-CoA lyase deficiency. 2. Measure liquid infant formula or whole or skim milk with disposable syringe. Weigh powdered infant formula on scale that reads in grams. 3. Add beikost or table foods to gradually replace LEU provided by infant formula after infant is 3 to 4 months old or is developmentally ready. 4. Parents or patients may select any food in prescribed Servings Lists for BCAA-Restricted Diets (Protocol 5, pp 88-99) in specified amounts to fill diet plan. B. Protein 1. Calculate amount of protein provided by infant formula with iron, beikost, whole or skim milk, or table foods (Table 6-3, p 117) required to fill LEU prescription. a. Supplemental GLY is not included in protein calculation. 2. Subtract amount determined above from protein prescription. 3. Provide remaining prescribed protein with I-Valex (Table 6-2, p 116). a. I-Valex is for infants and toddlers and I-Valex-2 is for children, adolescents, and adults. b. Weigh I-Valex powder on scale that reads in grams because of variability of household measuring equipment (Practical Aspects of Nutrition Support, p vii) and changes in density during shipping. c. See Table 6-2 (p 116, footnote 3) for approximate packed weight of I-Valex powder in level, dry US standard household measures. C. GLY (Appendix 26, p A-28) (7) 1. Supply GLY as pure solution if amount present in I-Valex does not provide amount prescribed. a. Add GLY powder to boiled, cooled water to yield 100 mg/mL (eg, 100 g GLY with enough water to yield 1 liter). b. Refrigerate in sterilized, closed container until used. Discard unused suspension after 1 week, if not frozen.
c.
Shake well before using. Measure GLY solution into medical food mixture with disposable syringe.
D. Energy 1. Calculate energy provided by I-Valex (Table 6-2, p 116) and infant formula with iron, beikost, whole or skim milk, or table foods (Table 6-3, p 117) required to fill LEU and protein prescriptions. 2. Subtract amount of energy supplied by these sources from energy prescription. 3. Provide remaining prescribed energy with Polycose Glucose Polymers powder (23 kcal/Tbsp, 3.8 kcal/g) or liquid (2 kcal/mL) (Appendix 9, p A-9); Pro-Phree Protein-Free Energy Module With Iron, Vitamins & Minerals (Appendix 11, p A-10), except for patients with HMG-CoA lyase deficiency; sugar (48 kcal/Tbsp); or Free Foods B (Table 6-3, p 117). a. Do not use corn syrup or table sugar for infants because of osmolarity they yield. b. Do not use honey for infants because it may contain botulinum toxin. 4. Nasogastric or gastrostomy feeds may be required to maintain energy intake. E. L-Carnitine (Appendix 26, p A-28) 1. If L-carnitine in I-Valex is inadequate to fill prescription, supply as pure solution. 2. Measure L-carnitine solution into medical food mixture with disposable syringe if entire contents of container are not used. 3. L-carnitine tablets may be used if patient is old enough to swallow them (Appendix 26, p A-28). F. Fluid and Mixing Instructions 1. Add sufficient boiled, cooled water to infant formula, GLY solution (if needed), L-carnitine (if needed), I-Valex, and energy source (if needed) to yield prescribed volume. 2. Mix with sterilized blender at lowest speed for 3 to 4 seconds. Excess mixing may destabilize emulsion. Medical foods may also be mixed in sterilized, tightly closed container by shaking vigorously for 10 to 12 seconds. 3. Place in sterilized formula bottles. Cap and store in refrigerator until used. Discard unused portion 24 hours after mixing because of nutrient loss. 4. Do not use terminal sterilization or boil because of Maillard reaction (Practical Aspects of Nutrition Support, p viii). 5. Warm or cool medical food mixture to room temperature before feeding to infants. Shake well before feeding. 6. Do not warm medical food mixture for infants in microwave oven. Unevenly heated formula can burn infant and steam can make bottles explode. 7. Notify parents or caretakers when they may discontinue using aseptic technique in preparing medical food mixture for infants. 8. For children and adults, chill I-Valex medical food mixture to improve taste. G. Diet Guide 1. Provide parents, caretakers, or patient with completed Diet Guide (Appendix 22, p A-24) with each diet change. 2. Feed infants 6 to 8 times daily (32, 61). 3. Feed children and adults 4 to 6 times daily (32, 61).

A. Nutrient Adequacy 1. Determine if diet provides nutrients in amounts prescribed in Section VII, Establish Prescription, p 107. a. See Table 6-2, p 116, for composition of I-Valex and Table 6-3, p 117, for nutrient composition of beikost or table foods, infant formula, and whole or skim milk. 2. Check diet to determine if it supplies Recommended Dietary Intakes (RDIs) for minerals and vitamins (Appendices 13 and 14, pp A-14 and A-15). a. See Appendices 4 through 7, pp A-4 to A-7, for composition of infant formulas. b. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available.
c.
If I-Valex mixture provides < 100% of RDIs for infants and < 75% for children and adults, supplement diet with needed minerals and vitamins if not provided by beikost or table foods and laboratory test results indicate need (Appendix 11, p A-10, for composition of supplements).
B. Osmolarity 1. If concentration of prescribed medical food mixture is > 24 kcal/fl oz, determine if osmolarity of I-Valex mixture is in acceptable range. a. Determine osmolarity by laboratory analysis or use mathematical formula given in Appendix 18, p A-20. b. Osmolarity per gram of I-Valex is listed in Appendix 19, p A-21. 2. If osmolarity is > 450 mosm/L for infants, > 750 mosm/L for children, > 1,000 mosm/L for adults, or greater than tolerated by patient, increase water content of prescribed medical food mixture and recalculate its osmolarity (45, 65). C. Renal Solute Load 1. Dehydration will result if renal solute load is greater than renal-concentrating ability of patient. 2. If concentration of medical food mixture prescribed is > 24 kcal/fl oz, estimate its potential renal solute load. a. This step is important to prevent dehydration of infants who may have renalconcentrating capacity as low as 600 mosm/L. b. Upper limit of renal solute load for neonates is approximately 1,100 mosm/L (63). 3. A method for estimating potential renal solute load is given in Appendix 20, p A-22. 4. If potential renal solute load is excessive, increase water content of medical food mixture and recalculate.

A. Plasma LEU Concentration 1. Initial. a. Evaluate every 2 to 3 days by quantitative methods until plasma concentrations stabilize and approximate dietary LEU requirement is known. 2. Ongoing. a. Evaluate weekly until patient is 1 year old if bacterial inhibition assay for LEU is available in state laboratory. b. Evaluate at least monthly by quantitative methods if weekly evaluations by bacterial inhibition assay are conducted. 3. Unacceptable LEU concentrations. a. If plasma LEU concentration is not detected and patient has ingested full prescription: 1) Increase prescribed LEU by 25% and reevaluate plasma LEU concentration in 3 days. 2) If LEU concentration remains undetected, repeat above process until value is in treatment range. b. If plasma LEU concentration is < 50 mol/L or < 0.66 mg/dL and patient is ingesting full prescription: 1) Increase prescribed LEU by 5% to 10%, then evaluate plasma LEU concentration in 1 week. 2) If plasma LEU concentration remains low, repeat above process until value is in treatment range. c. If plasma LEU concentration is > 100 mol/L or > 1.31 mg/dL and patient is not ill and is ingesting full prescription for LEU, protein, and energy: 1) Decrease prescribed LEU by 5% to 10% and reevaluate plasma LEU concentration in 1 week. 2) If plasma LEU concentration remains high, repeat above process until value is in treatment range. B. Urinary Organic Acid Excretion 1. Isovaleric acidemia. a. Assess urinary IVA, 3-OHIVA, and IVG weekly to monthly when patient is well and every 1 to 3 days when patient is ill.
2. 3-Methylcrotonylglycinuria. a. Assess urinary 3-OHIVA and 3-methylcrotonylglycine weekly to monthly when patient is well and daily or every 2 to 3 days when patient is ill. 3. 3-Methylglutaconic aciduria. a. Assess urinary 3-OHIVA, 3-methylglutaconic acid, and 3-methylglutaric acid weekly to monthly when patient is well and daily or every 2 to 3 days when patient is ill. 4. 3-Hydroxy-3-methylglutaric aciduria. a. Assess urinary 3-OHIVA, 3-methylglutaconic acid, 3-methylglutaric acid and 3-hydroxy-3methylglutaric acid weekly to monthly when patient is well and every 1 to 3 days when patient is ill. C. Urine Ketoacids by Ketostix 1. Evaluate daily for acetoacetic and -hydroxybutyric acids when patient is ill. 2. Results for urine ketoacids should be negative at all times. 3. If results for urine ketoacids are positive: a. Immediately obtain blood sample for evaluation of LEU concentration by bacterial inhibition assay or quantitative methods. b. Brief metabolic physician on patients illness. D. Protein Status 1. Evaluate plasma transthyretin concentration every 3 months until patient is 1 year of age and every 6 months thereafter (Appendix 17, p A-18, for standards). a. Plasma transthyretin concentrations provide a more reliable and rapid indication of protein status than plasma albumin concentrations. b. Plasma albumin concentrations may be in the normal range when plasma transthyretin concentrations show a clear deficiency (3). 2. If plasma transthyretin concentration is below standard: a. Increase prescribed protein by 5% to 10% and reevaluate plasma transthyretin concentration in 1 month. If LEU concentration is in treatment range, use I-Valex to increase protein. b. If plasma transthyretin concentration continues below standard, repeat above process until value is in normal range. E. Carnitine Status 1. Evaluate plasma free carnitine concentration weekly until amount of L-carnitine required to maintain concentration > 30 mol/L is determined, then evaluate every 3 months. a. If free carnitine concentration in plasma is < 30 mol/L: 1) Increase prescribed L-carnitine by 5-10%, then evaluate free carnitine concentration in 1 week. 2) If free carnitine concentration remains low, repeat above process until value is in treatment range. F. Iron Status 1. Plasma ferritin concentration. a. Evaluate at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17, p A-18, for standards). b. If plasma ferritin concentration is below standard: 1) Increase iron intake to 4 mg/kg with supplements (ferrous sulfate). 2) Evaluate plasma ferritin concentration monthly on increased iron intake. 3) Continue iron supplements until plasma ferritin concentration is in normal range. 2. Complete blood count and differential. a. Hemoglobin and hematocrit concentrations and differential should be evaluated at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17, p A-18, for standards).
G. Growth Status 1. Length/height and weight. a. Measure monthly to 1 year, every 3 months to 4 years, and every 6 months until full growth is achieved. Plot measurements on NCHS growth charts. b. Maintain length/height and weight between 10th and 90th percentiles. Some normal infants, children, and adults will fall above or below these percentiles. 2. If length/height or weight falls below usual growth channel: a. Increase prescribed protein and energy by 5% to 10% and remeasure after 1 month. b. If length/height or weight remains low, repeat above process until usual growth channel is achieved. H. Bone Mineralization 1. Assess bone age and mineralization and look for signs of osteoporosis via yearly radiographs of lumbar vertebrae. I. Nutrient Intake 1. Maintain records of food intake for 3 days immediately before each blood test (Appendices 24 and 25, pp A-26 and A-27). 2. Evaluate intakes of LEU, GLY, carnitine, protein, and energy (plus fat in HMG-CoA lyase deficiency). 3. Evaluate mineral and vitamin intake after each diet change. a. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. b. See Appendix 28, p A-29, for information about ordering software for diet evaluation.
J. Clinical Summary 1. A summary record of growth, laboratory, and nutrient intake data is useful for patient management (Table 6-5, p 119).

A. Example 1 Establish and fill prescription for 3-month-old infant weighing 4.5 kg who has isovaleric acidemia, using Recommended Daily Nutrient Intakes from Table 6-1, p 115, and nutrient contents from Tables 6-2 and 6-3, pp 116 and 117. 1. Establish prescription.
LEU GLY L-Carnitine Protein Energy Fluid 80 mg/kg 150 mg/kg 150 mg/kg 3.5 g/kg 120 kcal/kg 150 mL/kg Measure x x x x x x 4.5 kg 4.5 kg 4.5 kg 4.5 kg 4.5 kg 4.5 kg LEU (mg) 0 360 = = = = = = GLY (mg) 810 70 360 mg/day 675 mg 675 mg 15.8 g 540 kcal 675 mL L-Carnitine (mg) 729 3 Protein (g) 12.2 3.5 Energy (kcal) 389 170
I-Valex-1 81 g 1 Similac With Iron RTF 250 mL Add water to make 675 mL (23 fl oz). Total per day Total per kg
360 80
880 196
732 162
15.7 3.5
559 124
Approximate osmolarity of medical food mixture is < 450 mosm/L. Estimated potential renal solute load is 100 mosm. 1 RTF = Ready To Feed
Disorders of Leucine Catabolism 113
B. Example 2 Establish and fill prescription for 2-year-old child weighing 13 kg using Recommended Daily Nutrient Intakes from Table 6-1, p 115, and nutrient contents from Tables 6-2 and 6-3, pp 116 and 117. 1. Establish prescription.
LEU GLY L-Carnitine Protein Energy Fluid 500 mg/day 1,300 mg 1,300 mg 30 g 1,300 kcal 1,300 mL Measure 140 g 0 LEU (mg) GLY (mg) 1,400 L-Carnitine (mg) 1,260 Protein (g) 21.0 Energy (kcal) 672
Medical Food Mixture I-Valex-1
Add water to make 800 mL (27 fl oz). Offer additional fluid ad libitum daily.
Food List Breads/Cereals Fats Fruits Vegetables
Servings 5 1 4 7 175 10 100 210 0 0 0 0 0 0 0 0 2.5 0.1 2.4 4.2 30.2 150 70 300 105 1,297
495 1,400 1,260 Total per day Approximate osmolarity of medical food mixture is < 500 mosm/L.
C. Example 3 Establish and fill prescription for 3-year-old child weighing 17 kg who has 3-methylcrotonylglycinuria. Use the Recommended Daily Nutrient Intakes from Table 6-1, p 115, and nutrient contents from Tables 6-2 and 6-3, pp 116 and 117. 1. Establish prescription.
LEU GLY L-Carnitine Protein Energy Fluid 600 mg/day 1,700 mg 1,275 mg 30 g 1,300 kcal 1,300 mL Amount LEU (mg) GLY (mg) L-Carnitine (mg) Protein (g) 20.1 Energy (kcal) 275
I-Valex-2 67 g 0 2,023 1,206 Add water to make 710 mL (24 fl oz). Offer additional fluid ad libitum daily. Food List Breads/Cereals Fats Fruits Vegetables Servings 8 4 6 4 280 40 150 120 0 0 0 0 0 0 0 0
4.0 0.4 3.6 2.4 30.5
240 280 450 60 1,305
590 2,023 1,206 Total per day Approximate osmolarity of medical food mixture is < 600 mosm/L.
D. Example 4 Establish and fill prescription for 6-month-old child weighing 7 kg who has 3-hydroxy-3methylglutaric aciduria. Use Recommended Daily Nutrient Intakes from Table 6-1, p 115, average nutrient contents from Tables 6-2 through 6-4, pp 116-118. 1. Establish prescription.
LEU L-Carnitine Protein Energy Fat Fluid 490 mg/day 700 mg 19.2 g 805 kcal 18 g 910 mL Measure 81 g 2.9 g 8 g (2 tsp) LEU (mg) 0 196 0 L-Carnitine (mg) 729 1 0 Fat (g) 17.6 0.0 0.0 Protein (g) 12.2 2.1 0.0 Energy (kcal) 389 9 32
Medical Food Mixture I-Valex-1 ProViMin Sugar
Add water to make 710 mL (24 fl oz). Offer additional water ad libitum daily.
Food List Breads/Cereals Fruits Vegetables 3 3 4
Servings 105 75 120 0 0 0 0.0 0.0 0.0 17.6 1.5 1.8 2.4 20.0 90 225 60 805
496 730 Total per day Approximate osmolarity of medical food mixture is < 400 mosm/L.

A. Rationale 1. In normal persons, febrile illness and trauma are accompanied by catabolism of body protein. 2. Well-nourished patients with disorders of leucine catabolism respond to infection and trauma as do normal persons. 3. Febrile illness and trauma are life-threatening if not diagnosed and treated promptly. 4. See Section V, Nutrition Support During Acute Illness, p 105.
XIII. Contraindicated Medications

A. Benzoic acid (sodium benzoate) (55). 1. However, benzoic acid may be used for short periods if patient is hyperammonemic. B. Salicylates (41, 55).
TABLE 6-1. Recommended Daily Nutrient Intakes (Average and Range) for Infants, Children and Adults With Disorders of LEU Catabolism
Age LEU (mg/kg) Infants 0 to < 3 mo 3 to < 6 mo 6 to < 9 mo 9 to < 12 mo 80 - 150 70 - 140 60 - 130 50 - 120 (mg/day) Girls and Boys 1 to < 4 yr 4 to < 7 yr 7 to < 11 yr Women 11 to < 15 yr 15 to < 19 yr > 19 yr 500 - 900 600 - 900 700 - 900 > 30.0 > 35.0 > 40.0
1,2
Nutrient Protein (g/kg) 3.50 - 3.00 3.50 - 3.00 3.00 - 2.50 3.00 - 2.50 (g/day)
3,4
Energy 3 (kcal/kg) 120 (145 115 (145 110 (135 105 (135 - 95) - 95) - 80) - 80)
Fluid 5 (mL/kg) 160-125 160-130 145-125 135-120 (mL/day) 900 - 1,800 1,300 - 2,300 1,730 - 3,300
(kcal/day) 1,300 ( 900 - 1800) 1,700 (1300 - 2300) 2,400 (1650 - 3300)
700 - 900 620 - 820 620 - 820
> 50.0 > 55.0 > 60.0
2,200 (1500 - 3000) 2,100 (1200 - 3000) 2,100 (1400 - 2500)
1,500 - 3,000 1,200 - 3,000 1,400 - 2,500
Men 11 to < 15 yr 1,100 - 1500 > 55.0 2,700 (2000 - 3700) 2,000 - 3,700 15 to < 19 yr 1,100 - 1500 > 65.0 2,800 (2100 - 3900) 2,100 - 3,900 > 19 yr 1,000 - 1400 > 70.0 2,900 (2000 - 3300) 2,000 - 3,300 1 Modified from references 1 and 66. Initiate therapy with lowest value for age. Modify prescription based on frequently obtained blood and/or plasma values and growth in infants and children and frequently obtained plasma values and weight maintenance in adults. 2 Modified from reference 21. 3 During metabolic acidosis and/or infection following trauma, energy requirements may be 25-40% greater than those listed. Initiate therapy with energy value outside parentheses. 4 Modified from reference 10. Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL fluid to children and adults for each kcal ingested.
TABLE 6-2. Nutrient Composition of I-VALEX -1 1, 3, and I-VALEX -2 2, 3

Nutrient (per 100 g pwd) I-Valex-1 (per g protein equiv) 32 1.000 0.160 1.067 0.010 0.067 0.028 0.029 0.000 0.067 0.020 0.059 0.047 0.011 0.059 0.032 I-Valex-2 (per g protein equiv) 13.7 1.000 0.160 1.067 0.010 0.101 0.028 0.029 0.000 0.067 0.020 0.059 0.047 0.011 0.059 0.032 60 1.67 1.17 0.43 0.050 0.006 29 31.33/0.88 0.90 0.033 3.33 0.43 7.50 0.027 1.00 25 45.7/1.17 1.17 29.3/1.28 0.43 22 0.25 0.40 2.00 2.00 3.33 0.043 0.167 3.33 14.33 2.33 0.72 0.267 0.060 0.108
(per 100 g pwd)
Energy, kcal 480 410 Protein Equiv, g 15.00 30.00 2.40 4.80 Nitrogen, g 16.01 32.02 Amino Acids, g Cystine, g 0.15 0.30 Glycine, g 1.00 3.02 Histidine, g 0.42 0.84 Isoleucine, g 0.43 0.86 Leucine, g trace trace Lysine, g 1.00 2.00 Methionine, g 0.30 0.60 Phenylalanine, g 0.88 1.76 Threonine, g 0.70 1.40 Tryptophan, g 0.17 0.34 Tyrosine, g 0.89 1.78 Valine, g 0.48 0.96 Other Nitrogen-Containing Compounds Carnitine, mg 900 60 1,800 Taurine, mg 40 2.67 50 Carbohydrate, g 53.0 3.53 35 Fat, g 21.7 1.45 13 4 5 Linoleic acid, g 2.00 0.133 1.50 6 7 0.36 0.024 0.17 -Linolenic acid, g Minerals Calcium, mg 575 38 880 Chloride, mg/mEq 325/9.17 21.7/0.61 940/26.51 Chromium, g 11 0.73 27 Copper, mg 1.10 0.073 1.00 Iodine, g 65 4.33 100 Iron, mg 9.0 0.60 13 Magnesium, mg 50 3.33 225 Manganese, mg 0.50 0.033 0.80 Molybdenum, g 12 0.80 30 Phosphorus, mg 400 27 760 Potassium, mg/mEq 675/17.26 45/1.15 1,370/35.04 Selenium, g 20 1.33 35 Sodium, mg/mEq 190/8.26 12.7/0.55 880/38.28 Zinc, mg 8.0 0.53 13.0 Vitamins A, g RE 420 28 660 D, g 7.50 0.50 7.50 10.10 0.67 12.10 E, mg -TE K, g 50 3.33 60 Ascorbic acid, mg 50 3.33 60 Biotin, g 65 4.33 100 B6, mg 0.75 0.050 1.30 B12, g 4.90 0.327 5.00 Choline, mg 80 5.33 100 Folate, g 230 15 430 Inositol, mg 40 2.67 70 Niacin equiv, mg 12.80 0.850 21.7 Pantothenic acid, mg 6.90 0.460 8.00 Riboflavin, mg 0.90 0.060 1.80 Thiamin, mg 1.90 0.127 3.25 1 2 Designed for infants and toddlers. Designed for children, adolescents, and adults. 3 Approximate packed weights of I-Valex in level, dry US standard household measures: I-Valex-1 I-Valex-2 1 Tbsp = 7g 8g 1/4 cup = 26 g 32 g 1/3 cup = 35 g 41 g 1/2 cup = 53 g 61 g 1 cup = 105 g 117 g 4 5 Analytical data at manufacture = 4.32 g/100 g powder. Analytical data at manufacture = 2.66 g/100 g powder. 6 7 Analytical data at manufacture = 0.40 g/100 g powder. Analytical data at manufacture = 0.28 g/100 g powder.
TABLE 6-3. Serving Lists for LEU-Restricted Diets: Approximate LEU, Protein, Fat, and Energy Content per Serving1
Food List LEU (mg) Nutrient Fat (g) Protein (g) 0.50 0.10 0.60 0.60 0.10 0 00 1.86 1.66 1.40 3.53 3.39 Energy (kcal) 30 70 75 15 50 55 68 68 68 36 63
Breads/Cereals 35 0.00 Fats 10 8.00 Fruits 25 0.00 Vegetables 30 0.00 Free Foods A 5 varies Free Foods B 0 varies Alimentum Protein Hydrolysate Formula With Iron, Ready to Feed, 100 mL 2 173 3.74 Isomil Soy Formula With Iron, Ready to Feed, 100 mL 2 135 3.70 Similac With Iron Infant Formula, Ready to Feed, 100 mL 2 144 3.65 Skim milk, 100 mL 3 346 0.19 3 Whole cows milk, 100 mL 332 3.46 1 From reference 20. 2 See Appendices 4 through 7, pp A-4 to A-7, for complete nutrient composition of infant formulas. 3 From reference 52. See Appendix 8, p A-8, for complete nutrient composition.
TABLE 6-4. Nutrient Composition of ProViMin and Skim Milk

Nutrient ProViMin (per 100 g powder) 36 3.53 3.58 33 75 95 213 346 280 89 171 159 50 171 236 NA NA 5.02 0.19 0.005 0.002 127 104/2.93 0.01 7 0.04 11 0.002 105 172/4.4 2.17 54/2.35 0.41 63 1.06 0.04 NA 1.01 2.00 0.04 0.39 NA 5.18 NA 0.92 0.34 0.14 0.04
1
Skim Milk (per 100 mL)
Energy, kcal 312 Protein Equiv, g 73.0 79.59 Amino Acids, g Cystine, mg 410 Glycine, mg 1,380 Histidine, mg 1,950 Isoleucine, mg 3,400 Leucine, mg 6,750 Lysine, mg 5,760 Methionine, mg 2,200 Phenylalanine, mg 3,630 Threonine, mg 3,130 Tryptophan, mg 1,000 Tyrosine, mg 4,150 Valine, mg 4,250 Other Nitrogen-Containing Compounds Carnitine, mg 40 Taurine, mg 110 Carbohydrate, g 2.00 Fat, g 1.4 Linoleic acid, g 0 0 -Linolenic acid, g Minerals Calcium, mg 2,400 Chloride, mg/mEq 2,300/65 Copper, mg 2.10 Iodine, g 335 Iron, mg 40 Magnesium, mg 200 Manganese, mg 0.20 Phosphorus, mg 1,700 Potassium, mg/mEq 3,300/84 Selenium, g 70 Sodium, mg/mEq 1,200/52 Zinc, mg 17 Vitamins A, g RE 2,020 D, g 25 45 E, mg -TE K, g 90 Ascorbic acid, mg 200 Biotin, g 100 B6, mg 1.35 B12, g 5.6 Choline, mg 335 Folate, g 320 Inositol, mg 105 Niacin equiv, mg 40.6 Pantothenic acid, mg 10.1 Riboflavin, mg 2.02 Thiamin, mg 2.24 1 Approximate weight in grams of level, dry, US standard household measures: 1 Tbsp = 2.9 g 1/4 cup = 11 g 2/3 cup = 30 g 1 cup = 44 g 2 From reference 52. NA = Not available.
TABLE 6-5. Isovaleric Acidemia Clinical Summary Sheet Name: Date of Birth: __________/__________/__________ Mo Day Year
Date
(mo/d/yr)
Hospital Number:
Age
(yrs/mos)
Physical Data
Length/ Height (cm) Weight (kg) Head Circum (cm) Free Carnitine (mol/L) GLY IVA
1
Laboratory Data
LEU Hgb (g/dL) Hct (%) Ferritin (ng/mL) (mol/L) (mol/L) (mol/L) Transthyretin (mg/dL) Urine
IVA
1

LEU
2
GLY (mg)
Carnitine Protein (mg) (g)
Energy (kcal)
OHIVA
IVG
(mg)
1 2 3
Isovaleric acid. -hydroxyisovaleric acid. Isovalerylglycine
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Eur J Pediatr 1998;157:743-746. 35. Hyman SL, Porter CA, Page TJ, et al: Behavior management of feeding disturbances in urea cycle and organic acid disorders J Pediatr 1987;111:558-562. 36. Ito T, Kidouchi K, Sugiyama N, et al: Liquid chromatographic-atmospheric pressure chemical ionization mass spectrometric analysis of glycine conjugates and urinary isovalerylglycine in isovaleric acidemia. J Chromat 1995;B670:317-322. 37. Itoh T, Ito T, Ohba S, et al: Effect of carnitine administration on glycine metabolism in patients with isovaleric acidemia: Significance of acetylcarnitine determination to estimate the proper carnitine dose. Tohoku J Exp Med 1996;179:101-109. 38. Jones BJM, Lees R, Andrews J, et al: Comparison of an elemental and polymeric enteral diet in patients with normal gastrointestinal function. Gut 1983;24:78-84. 39. Kelleher JF, Yudkoff M, Hutchinson R, et al: The pancytopenia of isovaleric acidemia. Pediatrics 1980;65:1023-1027. 40. Ketel A, Ket JL, Schutgens RBH, et al: Clinical and biochemical observations on a child with a deficiency of 3-hydroxy-3-methylglutaryl coenzyme A lyase. J Inher Metab Dis 1980;3:89-90. 41. Krieger I, Tanaka K: Therapeutic effects of glycine in isovaleric acidemia. Pediatr Res 1976;10:25-29. 42. Lehnert W, Niederhoff H, Suormala T, Baumgartner ER: Isolated biotin-resistant 3-methylcrotonyl-CoA carboxylase deficiency: Long-term outcome in a case with neonatal onset. Eur J Pediatr 1996;155:568-572. 43. Leupold D, Bojasch M, Jakobs C: 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency in an infant with macrocephaly and mild metabolic acidosis. Eur J Pediatr 1982;183:73-76. 44. Lott IT, Erickson AM, Levy HL: Dietary treatment of an infant with isovaleric acidemia. Pediatrics 1972;49:616-618. 45. MacLean W, Graham G: Pediatric Nutrition in Clinical Practice. Menlo Park, Calif: Addison-Wesley Publishing Co, 1982. 46. Millington DS, Roe CR, Maltby DA, Inoue F: Endogenous catabolism is the major source of toxic metabolites in isovaleric acidemia. J Pediatr 1987;110:56-60. 47. Naglak M, Salvo R, Madsen K, et al: The treatment of isovaleric acidemia with glycine supplements. Pediatr Res 1988;24:9-13. 48. Narisawa K, Gibson KM, Sweetman L, et al: Deficiency of 3-methylglutaconyl- coenzyme A hydratase in two siblings with 3-methylglutaconic aciduria. J Clin Invest 1986;77:1148-1152. 49. Ohkohchi N, Andoh T, Ohi R, Mori S: Defined formula diets alter characteristics of the intestinal transport of amino acids and peptides in growing rats. J Pediatr Gastroenterol Nutr 1990;10:490-496. 50. Ostmann-Smith I, Brown G, Johnson A, Land JM: Dilated cardiomyopathy due to type II X-linked 3-methylglutaconic aciduria: successful treatment with pantothenic acid. Br Heart J 1994;72:349-53. 51. Pearson MA, Aleck KA, Heidenreich RA: Benign clinical presentation of 3-methylcrotonylglycinuria. J Inher Metab Dis 1995;18:640-641. 52. Posati LP, Orr ML: Composition of Foods: Dairy and Egg Products, Agriculture Handbook No. 8-1. Washington, DC: US Dept of Agriculture, Agricultural Research Service, 1976. 53. Pratt EL, Snyderman SE, Cheung MW, et al: The threonine requirement of the normal infant. J Nutr 1955;56:231-251. 54. Riubier D, Parvy P, Bardet J, et al: Alloisoleucine in isovaleric acidemia. J Inher Metab Dis 1992;15:154-155. 55. Roe CR, Millington DS, Maltby DA: Identification of 3-methylglutaryl-carnitine. J Clin Invest 1984;77:1391-1394. 56. Roe CR, Millington DS, Maltby DA, et al: L-carnitine therapy in isovaleric acidemia. J Clin Invest 1984;74:2290-2295. 57. Rolland MD, Divry P, Zabot MT, et al: Isolated 3-methylcrotonyl-CoA carboxylase deficiency in a 16-month-old child. J Inher Metab Dis 1991;14:838-839. 58. Rousson R, Guidbaud P: Long term outcome of organic acidurias: Survey of 105 French cases (1967-1983). J Inher Metab Dis 1984;7 (Suppl 1):10-12. 59. Rutledge SL, Berry GT, Stanley CA, et al: Glycine and L-carnitine therapy in 3-methylcrotonyl-CoA carboxylase deficiency. J Inher Metab Dis 1995;18:229-305. 60. Salamino F, DiLisa F, Burlina AB, et al: Involvement of erythrocyte calpain in glycine- and carnitine-treated isovaleric acidemia. Pediatr Res 1994;36:182-186.
61. Schoeffer A, Herrmann ME, Broesicke HG, Moench E: Effect of dosage and timing of amino acid mixtures on nitrogen retention in patients with phenylketonuria. J Nutr Med 1994;4:415-418. 62. Shilkin R, Wilson G, Owles E: 3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency. Acta Paediatr Scand 1981;70:265-268. 63. Smith CA, Nelson NM (eds): The Physiology of the Newborn Infant, ed 4. Springfield, IL: Charles C Thomas Publisher, 1976. 64. Smith JL, Arteaga C, Heymsfield SB: Increased ureagenesis and impaired nitrogen use during infusion of a synthetic amino acid formula - A controlled trial. N Engl J Med 1982;306:1013-1018. 65. Smith JL, Heymsfield SB: Enteral nutrition support: Formula preparation from modular ingredients. JPEN 1983;7:280-288. 66. Snyderman SE, Roitman EL, Boyer A, et al: The essential amino acid requirements of infants: Leucine. Am J Dis Child 1961;102:157-162. 67. Stacey TE, de Sousa C, Tracey BM, et al: Dizygotic twins with 3-hydroxy- 3-methylglutaric aciduria: Unusual presentation, family studies, and dietary management. Eur J Pediatr 1985;1444:177-181. 68. Sweetman L, Williams JC: Branched chain organic acidurias. In Scriver CR, et al (eds): The Metabolic and Molecular Bases of Inherited Disease, ed 8. New York: McGraw-Hill Medical Publishing Division, 2001, pp 2125-2164. 69. Thompson GN, Chalmers RA, Holliday D: The contribution of protein catabolism to metabolic decompensation in 3-hydroxy-3-methylglutaric aciduria. Eur J Pediatr 1990;149:346-350. 70. van Hove JLK, Kahler G, Millington DS, et al: Intravenous L-carnitine and acetyl-L-carnitine in medium-chain-acylcoenzyme A dehydrogenase deficiency and isovaleric acidemia. Pediatr Res 1994;35:96-101. 71. van Hove JLK, Rutledge SL, Nada MA, et al: 3-Hydroxyisovalerylcarnitine in 3-methylcrotonyl-CoA carboxylase deficiency. J Inher Metab Dis 1995;18:592-601. 72. Wilson WG, Audenaert SM, Squillaro EJ: Hyperammonemia in a preterm infant with isovaleric acidemia. J Inher Metab Dis 1984;7:71. 73. Winokur PA, Vashistha K, Seshamani R: Isovaleric acidemia: A case report. Pediatrics 1978;61:902-903. 74. Yudkoff M, Cohn RM, Puschak R, et al: Glycine therapy in isovaleric acidemia. J Pediatr 1978;92:813-817.
PROTOCOL 7 Mitochondrial Acetoacetyl-CoA Thiolase Deficiency (-Ketothiolase Deficiency) Nutrition Support of Infants, Children, and Adults With KETONEX -1 and KETONEX -2 Amino Acid-Modified Medical Foods
I. Introduction
Beta-ketothiolases catalyze the reversible cleavage of -ketoacyl-CoA with a-CoA to form an acyl-CoA with two fewer carbons and acetyl-CoA. Mitochondrial acetoacetyl-CoA thiolase interconverts -methylacetoacetyl-CoA to propionyl-CoA plus acetyl-CoA in essential isoleucine (ILE) catabolism and acetoacetyl-CoA to two acetyl-CoAs in fatty acid oxidation (Figure F) (46).
Figure F. Isoleucine metabolism in mitochondrial acetoacetyl-CoA thiolase deficiency The clinical features of mitochondrial acetoacetyl-CoA thiolase deficiency range from frequent severe catabolic crises in infants to asymptomatic adults (46). The most common features are failure to thrive, intermittent severe metabolic acidosis, and ketosis (9, 10) with hematemesis (6), melena (6, 46), and coma (21, 34) following upper respiratory or gastrointestinal infections or increased protein intake. The episodes usually begin between 1 and 2 years of age and may occur every few months. One patient expired with congestive cardiomyopathy at 8 years of age (18). Several siblings of probands who were presumably affected died during acute episodes. Acute episodes usually resolve with intravenous glucose and no permanent damage may result, although two patients had developmental retardation and another is mentally retarded. Most patients are treated with moderate restriction of ILE intake, avoidance of fasting, and L-carnitine administration, which greatly reduce or eliminate severe episodes. Several patients have reported severe headaches beginning at 6 to 7 years of age (17) and 2 patients had ataxia (17). The father of 1 patient was shown to have the same severe deficiency of enzyme activity and never had symptoms (46). In one case, the initial diagnosis was of salicylate toxicity because of similar symptoms and a positive test for salicylates (35).

With prompt correction of severe metabolic acidosis and ketosis and treatment with moderate restriction of essential ILE and L-carnitine administration (7), prognosis and subsequent growth and development are excellent for patients with mitochondrial acetoacetyl-CoA thiolase deficiency.
124 -Ketothiolase Deficiency 2001 Ross Products Division

A. The Defect 1. Results from deficiency of mitochondrial acetoacetyl-CoA thiolase (3, 10, 11, 20, 21, 26-28, 34, 35). B. The Disorder 1. Diagnostic studies should be conducted in any infant or child with recurring episodes of severe ketosis, metabolic acidosis (6), hyperglycinemia (20, 23), hematemesis (6), and melena (6). 2. Studies should be conducted during acute illness. C. Laboratory Studies 1. Analysis of urinary organic acids. a. Elevations of the following metabolites are diagnostic: 1) -methyl--hyroxybutyric acid (3, 10, 11, 14, 31). 2) -methylacetoacetic acid (3, 10, 11, 14). 3) Butanone. 4) Tiglylglycine (3, 10, 11). 2. Assay of acetoacetyl-CoA thiolase in fibroblasts (6, 38) or leukocytes (3, 11, 14, 21, 28, 38). D. Prenatal Diagnosis 1. Measure activity of mitochondrial acetoacetyl-CoA thiolase in cultured amniocytes or chorionic villus cells (46).

A. Correct Primary Imbalance in Metabolic Relationships 1. Restrict dietary ILE to amount that maintains normal urinary excretion of organic acids. B. Provide Conditionally Essential Nutrient 1. Administer L-carnitine to maintain normal plasma free carnitine concentration > 30 mol/L.
V. Nutrition Support During Acute Illness or at Diagnosis

A. Initiation of Nutrition Support 1. Initiate nutrition support immediately on confirmation of diagnosis and control of metabolic acidosis and ketosis. 2. Evaluate plasma concentrations of ILE, leucine (LEU), and valine (VAL) daily initially to prevent deficiency. B. Patients Without Severe Neurologic Involvement 1. Begin high-energy feeds (120-150 kcal/kg for infants, 80-100 kcal/kg for children, and 40-50 kcal/kg for adults) that supply adequate water (Table 7-1, p 113). a. Depending on age and clinical status, feed patient by nipple, nasogastric tube, intravenous infusion, or combine these methods. 1) For nipple or nasogastric feeds, use Ketonex (Table 7-2, p 133). 2) For intravenous feeds via central line, use hypertonic D-glucose and Liposyn II (Appendix 26, p A-28). 3) For intravenous feeds via peripheral line, use isotonic glucose and Liposyn II (Appendix 26, p A-28). 2. Introduce nutrition support with Ketonex (Table 7-2, p 133) with added source of L-LEU and L-VAL as rapidly as possible. See Table 7-1, p 133, for Recommended LEU, VAL, Protein, Energy, and Fluid Intakes. 3. Add ILE (Table 7-1, p 133) to Ketonex feeds when plasma ILE concentration reaches lower limit of normal (50 mol/L). a. Calculate amount of infant formula, beikost, whole cow's milk, or table foods (Table 7-3, p 133) required to fill ILE prescription. b. Measure into Ketonex medical food mixture with disposable syringe if liquid infant formula or cow's milk is used. Weigh powder on scale that reads in grams.
2001 Ross Products Division -Ketothiolase Deficiency 125
C. Comatose Patients 1. See Reference 34 for medical management. 2. Begin ILE-free parenteral or nasogastric feeding of amino acids and energy within 36 to 48 hours of initiation of dialysis using nitrogen-free (amino acid-free) dialysate. a. See Table 7-1, p 133, for Recommended LEU, VAL, Protein, and Energy Intakes. b. See Table7-2, p 133, for Ketonex composition. 3. Begin intravenous infusion of Liposyn II (Appendix 26, p A-28) and 10% D-glucose during nasogastric feeding, continuing until major neurologic signs subside. 4. When plasma ILE reaches lower limit of normal (50 mol/L), add L-ILE to Ketonex feeds. a. See Section VB3, p 124. 5. If parenteral amino acid solutions are indicated, see Appendix 26, p A-28.

A. Plasma Amino Acid Concentrations (30) 1. Maintain 2- to 4-hour postprandial plasma BCAA concentrations in ranges noted below when measured by quantitative methods (modified from reference 30), or near lower limit of normal range for age established by laboratory used.
Amino Acid ILE LEU VAL mol/L 50 - 105 50 - 185 130 - 318 mg/dL 0.6 - 1.4 0.6 - 2.4 1.5 - 3.7
2. In practice, obtaining blood 2 to 4 hours postprandially is not always possible. Acceptable local standards should be developed if plasma amino acids are evaluated at other times (Practical Aspects of Nutrition Support, p viii). B. Growth, Development, and Nutrition Status 1. Support normal growth rate in infants and children and maintain appropriate weight for height in adults. 2. Support normal development. 3. Maintain normal nutrition status (8). 4. Prevent catabolism. 5. Avoid prolonged fasting. 6. Maintain urine free of organic acids and ketones. 7. Prevent osteopenia (18).

A. ILE 1. Prescribe ILE intake that promotes goals of nutrition support (1-3, 7, 10, 11, 18, 26, 27, 36). 2. ILE requirements vary widely: a. From patient to patient, depending on activity of acetoacetyl-CoA thiolase (26, 28). b. In same patient, depending on: 1) Age. 2) Growth rate. 3) Adequacy of energy and protein intakes. 4) State of health. 3. Lowest values for age for ILE listed in Table 7-1, p 133, are suggested for initiating therapy. 4. Changing requirements of patient are determined by frequent monitoring of: a. Plasma ILE concentration. b. Urine concentrations of organic acids. c. See Section X, Suggested Evaluation of Nutrition Support, p 128. d. With ILE, LEU, and VAL in normal range, plasma amino acids must be measured frequently to prevent deficiency. Warning: ILE, LEU, and VAL deficiencies result in adverse effects: ILE deficiency: Weight loss or no weight gain; redness of buccal mucosa; fissures at corners of mouth; tremors of extremities; decreased plasma cholesterol and ILE concentrations; increased plasma lysine,
phenylalanine, serine, tyrosine, and VAL concentrations; and skin desquamation if deficiency is prolonged (42). LEU deficiency: Loss of appetite, apathy, irritability; weight loss or poor weight gain; decreased plasma LEU concentration; and increased plasma ILE, methionine, serine, threonine, and VAL concentrations (44). VAL deficiency: Poor appetite, drowsiness; excess irritability and crying in infants; weight loss or decrease in weight gain; and decreased plasma albumin concentration (43).
B. Carnitine 1. Prescribe adequate carnitine to maintain plasma free carnitine concentrations in normal range (> 30 mol/L). 2. Between 150 and 300 mg L-carnitine/kg may be required (3). C. Protein 1. Prescribe, initially, amount greater than Recommended Dietary Allowances (RDAs) (2, 13) (Table 7-1, p 133). 2. Requirements are greater than RDAs when L-amino acids supply majority of protein equivalent as a result of: a. Rapid amino acid absorption (15, 16). b. Early and high peak of plasma amino acids after ingestion of meals where large part of protein is supplied by L-amino acids (15, 16). c. Rapid catabolism of amino acids (19, 22, 37, 40). d. Possible decreased total amino acid absorption (29). Warning: Long-term inadequate protein intake will result in failure to thrive in infants, poor growth in children, weight loss in adults, low plasma transthyretin concentrations, osteopenia, and hair loss. D. Energy 1. Prescribe amount that should support normal weight gain in infants and children and maintain appropriate weight for height in adults (Table 7-1, p 133). 2. Requirements vary widely and may be greater than normal when L-amino acids supply majority of protein equivalent (33). 3. At diagnosis and during metabolic acidosis resulting from infection, energy needs may be 25% to 40% higher than values listed in Table 7-1, p 133. Warning: Inadequate energy intake will result in failure to thrive in infants, poor growth in children, weight loss in adults, depressed tolerance of ILE, and increased plasma ILE concentration. E. Fluid 1. Prescribe amount that will supply water requirements (Table 7-1, p 133) (5). Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL fluid to children and adults for each kcal ingested (5). F. Sodium Bicarbonate 1. Administer sodium bicarbonate hourly when Acetest is 3+. 2. Administer 1 g hourly until Acetest is negative.

A. ILE 1. Calculate amount of infant formula with iron, beikost, whole cow' milk, or table foods (Table 7-2, p 133) required to fill ILE prescription. a. Low-iron infant formula, whole cow's milk, or evaporated milk should not be used as ILE source for infants because of low iron content. 2. Measure liquid infant formula with disposable syringe. Weigh powdered infant formula on scale that reads in grams. 3. Add beikost or table foods to gradually displace ILE provided by infant formula after infant is 3 to 4 months old or is developmentally ready.
-Ketothiolase Deficiency 127
4. Parents or patients may select any foods in prescribed Servings Lists for BCAA-Restricted Diets (Protocol 5, pp 88-99) in specified amounts to fill diet prescription. B. LEU and VAL 1. Calculate approximate amounts of LEU and VAL provided by infant formula with iron, beikost, whole cow's milk, or table foods (Table 7-2, p 133). 2. Subtract amount determined above from total LEU and VAL prescription. 3. Supply any remaining prescribed LEU and VAL as individual pure solutions. Add supplemental LEU and VAL (Appendix 26, p A-28) only if plasma concentrations are below normal. a. Mix weighed amounts of L-LEU and L-VAL powders with boiled, cooled water to make volume of each that yields 10 mg/mL (eg, 1 g with enough water to yield 100 mL). b. Refrigerate solutions in separate, sterilized, closed containers until used. Discard unused suspensions after 1 week, if not frozen. c. Measure solutions into medical food mixture with disposable syringes. C. Protein 1. Calculate amount of infant formula with iron, beikost, whole cow's milk, or table foods (Table 7-2, p 133) required to fill the ILE prescription. 2. Subtract amount determined above from protein prescription 3. Supply remaining prescribed protein with Ketonex (Table 7-2, p 133). a. Ketonex-1 is for infants and toddlers and Ketonex-2 is for children, adolescents, and adults. b. Weigh Ketonex powder on scale that reads in grams because of variability of household measuring equipment (Practical Aspects of Nutrition Support, p vii) and changes in density during shipping. c. See Table 5-2 (p 86, footnote 3) for approximate packed weight of Ketonex powder in level, dry US standard household measures. D. Carnitine 1. Calculate amount of carnitine provided by Ketonex (Table 5-2, p 86) and infant formula with iron (Appendices 4 through 7, pp A-4 to A-7). 2. Supply remaining carnitine prescribed with L-carnitine (Appendix 26, p A-28). E. Energy 1. Calculate energy provided by infant formula with iron, beikost, whole cow's milk, or table foods (Table 7-2, p 133) required to fill ILE prescription plus energy provided by Ketonex (Table 7-2, p 133) required to fill protein prescription. 2. Subtract amount of energy supplied by these sources from energy prescription. 3. Provide remaining prescribed energy with Polycose Glucose Polymers powder (23 kcal/Tbsp, 3.8 kcal/g) or liquid (2 kcal/mL) (Appendix 9, p A-9); Pro-Phree Protein-Free Energy Module With Iron, Vitamins & Minerals (Appendix 11, p A-10); sugar (48 kcal/Tbsp); or Free Foods B (Table 7-2, p 133). a. Do not use corn syrup or table sugar for infants because of osmolarity they yield. b. Do not use honey for infants because it may contain botulinum toxin (45). F. Fluid and Mixing Instructions 1. Add sufficient boiled, cooled water to infant formula, Ketonex, L-carnitine, and carbohydrate (if needed) to yield prescribed volume. 2. Mix with sterilized blender at lowest speed for no longer than 3 to 4 seconds. Excess mixing may destabilize emulsion. May also be mixed in tightly closed container by shaking vigorously for 10 to 12 seconds. 3. Refrigerate in sterilized, closed containers until used. Discard unused portion 24 hours after mixing because of nutrient loss. 4. Do not use terminal sterilization because of Maillard reaction (Practical Aspects of Nutrition Support, p viii). 5. Warm or cool medical food mixture to room temperature before feeding to infants. Shake well before feeding. 6. Do not warm medical food mixture for infants in microwave oven. Unevenly heated formula can burn infants, and steam can make bottles explode.
7. Notify parents or caretakers when they may discontinue using aseptic technique in preparing medical food mixture for infants. 8. For children and adults, chill Ketonex medical food mixture to improve taste. G. Diet Guide 1. Provide parents, caretakers, or patient with completed Diet Guide (Appendix 22, p A-24) with each diet change. 2. Feed young infants 6 to 8 times daily (15, 16, 19, 37). 3. Feed children and adults 4 to 6 times daily (15, 16, 19, 37). 4. Avoid prolonged fasting.

A. Nutrient Adequacy 1. Determine if diet provides nutrients in amounts prescribed in Section VII, Establish Prescription, p 125. a. See Table 7-2, p 133, for composition of Ketonex, infant formulas, and whole cow's milk. 2. Check diet to determine if it supplies Recommended Dietary Intakes (RDIs) for minerals and vitamins (Table 5-2, p 86, and Appendices 13 and 14, pp A-14 and A-15). a. See Table 5-2, p 86, and Appendices 4 through 7, pp A-4 to A-7, for complete nutrient composition of Ketonex and infant formulas. b. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. c. If Ketonex mixture provides < 100% of RDIs for infants and < 75% for children and adults, supplement diet with needed minerals and vitamins if not provided by beikost or table foods and laboratory tests indicate need. 1) See Appendix 11, p A-10, for composition of supplements. B. Osmolarity 1. If concentration of prescribed medical food mixture is > 24 kcal/fl oz, determine if osmolarity is in acceptable range. a. Determine osmolarity by laboratory analysis or use mathematical formula given in Appendix 18, p A-20. b. Osmolarity per gram of Ketonex is listed in Appendix 19, p A-21. 2. If osmolarity is > 450 mosm /kg H2O for neonates, > 750 mosm/L for children, > 1,000 mosm/L for adults, or is greater than tolerated by patient, increase water content of prescribed medical food mixture and recalculate its osmolarity (25, 41). C. Potential Renal Solute Load 1. Dehydration will result if renal solute load is greater than renal-concentrating ability of patient. 2. If concentration of medical food mixture prescribed is > 24 kcal/fl oz, estimate its potential renal solute load. a. This step is important to prevent dehydration of infants who may have renal-concentrating capacity as low as 600 mosm/L. b. Upper limit of renal solute load for neonates is approximately 1,100 mosm/L (39). 3. A method for estimating potential renal solute load is given in Appendix 20, p A-22. 4. If potential renal solute load is excessive, increase water content of medical food mixture and recalculate.

A. Plasma BCAA Concentrations 1. Initial: a. Evaluate daily by quantitative methods to make sure that concentrations stabilize in low normal range. 2. Ongoing: a. Frequent evaluations help ensure adherence to nutrition support plan. b. Evaluate twice monthly by quantitative methods until patient is 6 months old and monthly thereafter.
3. Unacceptable amino acid concentrations. a. If plasma ILE, LEU, or VAL concentration is not detected and patient has ingested full prescription: 1) Increase prescribed amount of undetected amino acid(s) by 25% and reevaluate plasma concentrations in 3 days. 2) If plasma ILE, LEU, or VAL concentration continues undetected, repeat above process until value is in treatment range. b. If plasma ILE concentration is < 50 mol/L, plasma LEU concentration is < 50 mol/L, or plasma VAL concentration is < 130 mol/L, and the patient has ingested full prescription: 1) Increase prescribed amount of amino acid that is low by 5% to 10% and reevaluate plasma concentration in 1 week. 2) If plasma ILE, LEU, or VAL concentration continues to be low, repeat above process until value is in treatment range. c. If plasma ILE concentration is > 105 mol/L, plasma LEU concentration is > 185 mol/L, or plasma VAL concentration is > 318 mol/L, and patient is not ill and has not ingested more or less protein and energy than prescribed: 1) Decrease prescribed amount of elevated amino acid by 5% to 10% and reevaluate plasma concentration in 1 week. 2) If plasma ILE, LEU, or VAL concentration continues high, repeat above process until value is in treatment range. B. Urine Ketoacids by Ketostix (17) 1. Evaluate daily to 6 months of age and twice weekly thereafter. 2. If patient is ill, evaluate daily. 3. Urine should be free of ketoacids at all times (negative Ketostix). 4. If urine contains ketoacids (positive Ketostix): a. Immediately obtain blood sample for evaluation of ILE concentration by quantitative methods. b. Brief metabolic physician immediately on patient's illness. C. Plasma Carnitine Concentration 1. Analyze plasma free carnitine concentration monthly during first 6 months of life and every 3 months thereafter. 2. If plasma free carnitine concentration is < 30 mol/L, increase L-carnitine administered by 5% to 10% and reevaluate in 1 week. 3. If plasma free carnitine concentration remains low, repeat above process until value is in normal range. D. Protein Status 1. Evaluate plasma transthyretin every 3 months until patient is 1 year of age and every 6 months thereafter (Appendix 17, p A-18, for standards). a. Plasma transthyretin concentrations provide a more reliable and rapid indication of protein status than plasma albumin concentrations. b. Plasma albumin concentrations may be in the normal range when plasma transthyretin concentrations show a clear deficiency (4). 2. If plasma transthyretin concentration is below standard: a. Increase prescribed protein by 5% to 10% and reevaluate plasma transthyretin concentration in 1 month. If ILE concentration is in treatment range, use Ketonex to increase protein. b. If plasma transthyretin concentration remains low, repeat above process until value is in normal range. E. Iron Status 1. Plasma ferritin concentration. a. Evaluate at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17, p A-18, for standards). b. If plasma ferritin concentration is below standard: 1) Increase iron intake to 4 mg/kg body weight with supplements (ferrous sulfate).
2) Evaluate plasma ferritin concentration monthly on increased iron intake. 3) Continue iron supplements until plasma ferritin concentration is in normal range. 2. Complete blood count. a. Hemoglobin and hematocrit concentrations should be evaluated every 3 months in infants and every 6 months in toddlers (Appendix 17, p A-18, for standards). F. Growth Status 1. Length/height and weight. a. Measure monthly to 1 year and every 3 months thereafter. Plot measurements on NCHS growth charts. b. Maintain length/height and weight between 10th and 90th percentiles. Some normal infants, children, and adults will fall above or below these percentiles. 2. If length/height or weight falls below usual growth channel: a. Increase protein and energy prescriptions by 5% to 10% and remeasure in 1 month. b. If length/height or weight remains low, repeat above process until usual growth channel is achieved. G. Nutrient Intake 1. Maintain records of food intake for 3 days immediately before each blood test (Appendices 24 and 25, pp A-26 and A-27). 2. Evaluate intakes of BCAAs, protein, and energy before each blood test. 3. Evaluate mineral and vitamin intakes after each diet change. a. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. b. See Appendix 28, p A-29, for information about ordering software for diet evaluation. H. Clinical Summary 1. A summary record of growth, laboratory, and nutrient intake data is useful for patient management (Table 7-3, p 134).

A. Example 1 Establish and fill prescription for newborn weighing 3.0 kg using Recommended Daily Nutrient Intakes from Table 7-1, p 133 and nutrient contents from Table 7-2, p 133. 1. Establish prescription.
ILE LEU VAL Protein Energy Fluid 100 mg/kg 180 mg/kg 100 mg/kg 3.5 g/kg 140 kcal/kg 150 mL/kg x x x x x x 3.0 kg 3.0 kg 3.0 kg 3.0 kg 3.0 kg 3.0 kg Measure = = = = = = 300 mg > 540 mg > 300 mg 10.5 g 420 kcal 450 mL LEU (mg) 0 583 VAL (mg) 0 336 Protein (g) 4.8 5.7 Energy (kcal) 154 275
Medical Food Mixture ILE (mg) 0 304
Ketonex-1 32 g Similac With Iron RTF 405 mL Add water to make 450 mL (15 fl oz).
304 583 336 10.5 429 Total per day 101 194 112 3.5 143 Total per kg Approximate osmolarity of medical food mixture is < 450 mosm/L. Estimated potential renal solute load is 100 mosm.
B. Example 2 Establish and fill prescription for 2-year-old child weighing 13 kg using Recommended Daily Nutrient Intakes from Table 7-1, p 133 and nutrient contents from Table 7-2, p 133. 1. Establish prescription.
ILE LEU VAL Protein Energy Fluid 750 mg/day > 1,000 mg > 750 mg 30 g 1,300 kcal 1,300 mL Measure ILE (mg) LEU (mg) VAL (mg) Protein (g) 12.6 4.9 Energy (kcal) 172 91
Ketonex-2 42 g 0 0 0 Whole cow's milk 144 mL 295 478 327 Add water to make 710 mL (24 fl oz). Offer additional fluid ad libitum daily. Food List Breads/Cereals Fats Fruits Vegetables Servings 14 4 4 5 252 28 68 110 490 40 100 150 350 28 88 120 913
7.0 0.4 2.4 3.0 30.3
420 280 300 75 1,338
753 1,258 Total per day Approximate osmolarity of medical food mixture is < 400 mosm/L.
C. Example 3 Establish and fill prescription for 15-year-old boy weighing 60 kg using Recommended Daily Nutrients Intakes from Table 7-1, p 133 and nutrient contents from Table 7-2, p 133. 1. Establish prescription.
ILE LEU < VAL < Protein Energy Fluid 1,300 mg/day > 1,650 mg > 1,300 mg 65 g 2,800 kcal 2,800 mL Measure 122 g 314 mL ILE (mg) 0 644 LEU (mg) 0 1,042 VAL (mg) 0 713 Protein (g) 36.6 10.6 Energy (kcal) 500 198
Medical Food Mixture Ketonex-2 Whole cow's milk
Add water to make 1,000 mL (34 fl oz). Offer additional fluid ad libitum daily. Food List Breads/Cereals Fats Fruits Vegetables Free Foods B Servings 20 12 6 5 3 360 84 102 110 0 700 120 150 150 0 500 84 132 120 0 1,549 10.0 1.2 3.6 3.0 0.0 65.1 600 840 450 75 165 2,828
1,300 2,162 Total per day Approximate osmolarity of medical food mixture is < 750 mosm/L.
132 -Ketothiolase Deficiency

A. Rationale 1. Febrile illness and trauma are life-threatening if not diagnosed and treated promptly (47). B. Management of Nutrition Support 1. See Section V, Nutrition Support During Acute Illness or at Diagnosis, p 124.
TABLE 7-1. Recommended Daily Nutrient Intakes (Ranges) for Infants, Children, and Adults With -Ketothiolase Deficiency
Age Nutrient ILE1 (mg/kg) 90 - 140 85 - 135 80 - 135 75 - 125 (mg/day) Girls and Boys 1 to < 4 yr 4 to < 7 yr 7 to < 11 yr Women 11 to < 15 yr 15 to < 19 yr > 19 yr 750 - 1,000 850 - 1,100 1,000 - 1,300 LEU1 (mg/kg) > 180 > 160 > 150 > 140 (mg/day) > 1,000 > 1,150 > 1,300 VAL1 (mg/kg) > 100 > 90 > 80 > 70 (mg/day) > 750 > 850 > 1,000 Protein2 (g/kg) 3.50 3.50 3.00 3.00 - 3.00 - 3.00 - 2.50 - 2.50 Energy2 (kcal/kg) 120 (145 115 (145 110 (135 105 (135 - 95) - 95) - 80) - 80) Fluid3 (mL/kg) 150 - 125 160 - 130 145 - 125 135 - 120 (mL/day) 900 - 1,800 1,300 - 2,300 1,650 - 3,300
Infants 0 to < 3 mo 3 to < 6 mo 6 to < 9 mo 9 to < 12 mo
(g/day) > 30 > 35 > 40
(kcal/day) 1,300 ( 900 - 1800) 1,700 (1300 - 2300) 2,400 (1650 - 3300)
1,200 - 1,500 1,000 - 1,300 1,000 - 1,300
>1,900 > 1,300 > 1,330
> 1,800 > 1,000 > 1,000
> 50 > 55 > 60
2,200 (1500 - 3000) 2,100 (1200 - 3000) 2,100 (1400 - 2500)
1,500 - 3,000 1,200 - 3,000 1,400 - 2,500
Men 11 to < 15 yr 1,000 - 1,300 > 1,900 > 1,150 > 55 2,700 (2000 - 3700) 2,000 - 3,700 15 to < 19 yr 1,300 - 1,650 > 1,650 > 1,300 > 65 2,800 (2100 - 3900) 2,100 - 3,900 > 19 yr 1,300 - 1,650 > 1,650 > 1,300 > 70 2,900 (2000 - 3300) 2,000 - 3,300 1 From references 1, 12, and 24. Initiate prescription with lowest recommended intake for age. Modify prescription based on frequently obtained plasma values and growth in infants and children and frequently obtained plasma values and weight maintenance in adults. 2 Modified from reference 13. 3 From reference 5. Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL fluid to children and adults for each kcal ingested. Fluid intake should be higher during illness to enhance urinary ketoacid excretion.
TABLE 7-2. Serving Lists for ILE-Restricted Diets: Average Nutrient Content per Serving
Food List ILE (mg) 18 7 17 22 3 0 108 74 0 0 75 205 LEU (mg) 35 10 25 30 5 0 173 135 0 0 144 332
Breads/Cereals Fats Fruits Vegetables Free Foods A Free Foods B 2 Alimentum Protein Hydrolysate Formula With Iron, Ready to Feed, 100 mL 2 Isomil Soy Formula With Iron, Ready to Feed, 100 mL Ketonex-1 powder, 100 g Ketonex-2 powder, 100 g 2 Similac With Iron Infant Formula, Ready to Feed, 100 mL 3 Whole cow's milk, 100 mL 1 Reference 12 2 See Appendices 4 through 7, pp A-4 to A-7, for complete nutrient composition of infant formulas. 3 From reference 32. See Appendix 8, p A-8, for complete nutrient composition.
Nutrient VAL Protein (mg) (g) 25 0.5 7 0.1 22 0.6 24 0.6 4 0.1 0 0.0 140 1.86 76 1.66 0 15.00 0 30.00 83 1.40 227 3.39
Energy (kcal) 30 70 75 15 50 55 68 68 480 410 68 63
TABLE 7-3. - Ketothiolase Deficiency Clinical Summary Sheet Name: Date of Birth: __________/__________/__________ Mo Day Year
Date
(mo/d/yr)
Hospital Number:
Age
(yrs/mos)
Physical Data
Length/ Height (cm) Weight (kg) Head Circum (cm) ILE
1
Laboratory Data
LEU
1

ILE (mg) LEU (mg) VAL (mg) CARN (mg) Protein (g) Energy (kcal)
VAL
Free Carn (mol/L)
Hgb (g/dL)
Hct (%)
Ferritin Transthyretin Ketostix or Acetest (mg/dL) (ng/mL)
Indicate if mol/L or mg/dL.
REFERENCES
1. Acosta PB: The contribution of therapy of inherited amino acid disorders to knowledge of amino acid requirements. In Wapnir RA (ed): Congenital Metabolic Diseases: Diagnosis and Treatment. New York: Marcel Dekker Inc, 1985, 115-135. Acosta PB, Yannicelli S: Protein intake affects phenylalanine requirements and growth of infants with phenylketonuria. Acta Paediatr 1994;407 (Suppl):66-67. Aramaki S, Lehotay D, Sweetman L, et al: Urinary excretion of 2-methylacetoacetate, 2-methyl-3-hydroxybutyrate and tiglyglycine after isoleucine loading in the diagnosis of 2-methylacetyl-CoA thiolase deficiency. J Inher Metab Dis 1991;14:63-74. Arnold GL, Vladutiu CJ, Kirby RS: Protein insufficiency and impaired growth in children with PKU. J Inher Metab Dis 2000;23 (Suppl 1):A29. Behrman RE, Kliegman RM, Arvin AA (eds): Nelson Textbook of Pediatrics, ed 15. Philadelphia: WB Saunders Co, 1996.Bennett MJ, Littlewood JM, MacDonald A, et al: A case of -ketothiolase deficiency. J Inher Metab Dis 1983;6:157. Brown GK, Hunt SM, Mitchell DK, Danks DM: Profound neurological illness, relieved by protein restriction, in a baby with a transient disturbance in the metabolism of ingested isoleucine. Eur J Pediatr 1987;146:363-369. Calomme MR, Vanderpas JB, Francois B, et al: Thyroid function parameters during a selenium repletion/depletion study in phenylketonuric subjects. Experientia 1995;51:1208-1215. Cromby CH, Manning NJ, Pollitt, et al: 6-Methyluracil excretion in 2-methylacetoacetyl-CoA thiolase deficiency and in two children with an unexplained recurrent ketoacidaemia. J Inher Metab Dis 1994;17:81-84. Daum RS, Lamm PH, Mamer OA, Scriver CR: A "new" disorder of isoleucine catabolism. Lancet 1971;2:1289-1290. Daum RS, Scriver CR, Mamer OA, et al: An inherited disorder of isoleucine catabolism causing accumulation of -methylacetoacetate and -methyl--hydroxybutyrate, and intermittent metabolic acidosis. Pediatr Res 1973;7:149-160. Elsas LJ, Acosta PB: Nutrition support of inherited metabolic diseases. In Shils ME, et al (eds): Modern Nutrition in Health and Disease, ed 9. Baltimore: Williams & Wilkins, 1999, pp 1003-1056. Food and Nutrition Board, Committee on Dietary Allowances: Recommended Dietary Allowances, eds 9 and 10. Washington, DC: National Academy of Sciences, 1980 and 1989. Gompertz D, Saudubray JM, Charpentier C, et al: A defect in L-isoleucine metabolism associated with -methyl-hydroxybutyric acid and -methylacetoacetic aciduria: Quantitative in vivo and in vitro studies. Clin Chim Acta 1974;57:269-281. Gropper S, Acosta PB: Effect of simultaneous ingestion of L-amino acids and whole protein on plasma amino acid concentrations and urea nitrogen in humans. JPEN 1991;15:48-53. Gropper SS, Gropper DM, Acosta PB: Plasma amino acid response to ingestion of L-amino acids and whole protein. J Pediatr Gastroenterol Nutr 1993;16:143-150. Halvorsen S, Stokke O, Jellum E: A variant form of 2-methyl-3-hydroxybutyric and 2-methylacetoacetic aciduria. Acta Paediatr Scand 1979;68:123-128. Henry CG, Strauss AW, Keating JP, Hillman RE: Congestive cardiomyopathy associated with -ketothiolase deficiency. J Pediatr 1981;99:754-757. Herrmann ME, Broesicke HG, Keller M, et al: Dependence of the utilization of a phenylalanine-free amino acid mixture on different amounts of single dose ingested. A case report. Eur J Pediatr 1994;153:501-503. Hillman RE, Keating JP: Beta-ketothiolase deficiency as a cause of the "ketotic hyperglycinemia syndrome." Pediatrics 1974;53:221-225. Hiyama K, Sakura N, Matsumoto T, Kuhara T: Deficient beta-ketothiolase activity in leukocytes from a patient with 2-methylacetoacetic aciduria. Clin Chim Acta 1986;155:189-194. Jones BJM, Lees R, Andrews J, et al: Comparison of an elemental and polymeric enteral diet in patients with normal gastrointestinal function. Gut 1983;24:78-84. Keating JP, Fergin RD, Tenenbaum SM, Hillman RE: Hyperglycinemia with ketosis due to a defect in isoleucine metabolism: A preliminary report. Pediatrics 1972;50:890-895. Leverton RM, Johnson N, Dazur J, Ellison J: Amino acid requirements of young adults. In Albanese AA (ed): Protein and Amino Acid Nutrition. New York: Academic Press, 1959. MacLean W, Graham G: Pediatric Nutrition in Clinical Practice. Menlo Park, Calif: Addison-Wesley Publishing Co, 1982. Merinero B, Perez-Cerda C, Garcia MJ, et al: -ketothiolase deficiency: Two siblings with different clinical conditions. J Inher Metab Dis 1987;10 (Suppl 2):276-278. Middleton B, Bartlett K, Romanos A, et al: 3-Ketothiolase deficiency. Eur J Pediatr 1986;144:586-589. Middleton B, Gray RGF, Bennett MJ: Two cases of -ketothiolase deficiency: A comparison. J Inher Metab Dis 1984;7 (Suppl 2):131-132. Ohkohchi N, Andoh T, Ohi R, Mori S: Defined formula diets alter characteristics of the intestinal transport of amino acids and peptides in growing rats. J Pediatr Gastroenterol Nutr 1990;10:490-496.
2. 3.
4. 5. 6. 7. 8. 9. 10. 11.
12. 13. 14.
15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29.
30. Picone TA, Benson JD, Moro G, et al: Growth, serum biochemistries, and amino acids of term infants fed formulas with amino acid and protein concentrations similar to human milk. J Pediatr Gastroenterol Nutr 1989;9:351-360. 31. Pollitt RJ: The occurrence of substituted 3-methyl-3-hydroxyglutaric acids in urine in propionic acidemia and in -ketothiolase deficiency. Biomed Mass Spec 1983;10:253-257. 32. Posati LP, Orr ML: Composition of Foods: Dairy and Egg Products, Agriculture Handbook No. 8-1. Washington, DC: US Dept of Agriculture, Agricultural Research Service, 1976. 33. Pratt EL, Snyderman SE, Cheung MW, et al: The threonine requirement of the normal infant. J Nutr 1955;56:231-251. 34. Riudor E, Ribes A, Perez-Cerda C, et al: Metabolic coma with ketoacidosis and hyperglycaemia in 2-methylacetoacetyl-CoA thiolase deficiency. J Inher Metab Dis 1995;18:748-749. 35. Robinson BH, Sherwood WG, Taylor J, et al: Acetoacetyl-CoA thiolase deficiency: A cause of severe ketoacidosis in infancy simulating salicylism. J Pediatr 1979;95:228-233. 36. Sabetta G, Bachmann C, Giardini O, et al: -ketothiolase deficiency with favourable evolution. J Inher Metab Dis 1987;10:405-406. 37. Schoeffer A, Herrmann ME, Broesicke HG, Moench E: Effect of dosage and timing of amino acid mixtures on nitrogen retention in patients with phenylketonuria. J Nutr Med 1994;4:415-418. 38. Schutgens RBH, Middleton B, Blij JFvd, et al: -ketothiolase deficiency in a family confirmed by in vitro enzymatic assay in fibroblasts. Eur J Pediatr 1982;139:39-42. 39. Smith CA, Nelson NM (eds): The Physiology of the Newborn Infant, ed 4. Springfield, IL: Charles C Thomas Publisher, 1976. 40. Smith JL, Arteaga C, Heymsfield SB: Increased ureagenesis and impaired nitrogen use during infusion of a synthetic amino acid formula - A controlled trial. N Engl J Med 1982;306:1013-1018. 41. Smith JL, Heymsfield SB: Enteral nutrition support: Formula preparation from modular ingredients. JPEN 1983;7:280-288. 42. Snyderman SE, Boyer A, Norton PM, et al: The essential amino acid requirements of infants: IX. Isoleucine. Am J Clin Nutr 1964;15:313-321. 43. Snyderman SE, Holt LE, Smellie F, et al: The essential amino acid requirements of infants: Valine. Am J Dis Child 1959;97:186-191. 44. Snyderman SE, Roitman EL, Boyer A, et al: The essential amino acid requirements of infants: Leucine. Am J Dis Child 1961;102:157-162. 45. Spika JS, Shaffer N, Hargrett-Bean N, et al: Risk factors for infant botulism in the United States. Am J Dis Child 1989;143:828-832. 46. Sweetman L, Williams JC: Branched-chain-organic acidurias. In Scriver CR, et al (eds): The Metabolic and Molecular Bases of Inherited Disease, ed 8. New York: McGraw-Hill Medical Publishing Division, 2001, pp 2125-2164. 47. Wannemacher RW: Key role of various individual amino acids in host response to infection. Am J Clin Nutr 1977;30:1269-1280.
PROTOCOL 8 Homocystinuria Nutrition Support of Infants, Children, and Adults With HOMINEX -1 and HOMINEX -2 Amino Acid-Modified Medical Foods
I. Introduction (14, 27)
Intact protein contains from 0.3% to 5.0% of the essential amino acid methionine (MET) (33). Some dietary MET is used by the body for tissue protein synthesis, but most is utilized through the transsulfuration pathway (Figure G). The first step in the transsulfuration pathway is synthesis of S-adenosylmethionine (SAM), a reaction catalyzed by methionine-S-adenosyltransferase (MAT). Impaired MAT activity results in hypermethioninemia and variable clinical expression from sulfurous breath odor to mental retardation. Biologically important compounds that obtain their methyl group from SAM include creatine, choline and phosphatidylcholine, methylated DNA and RNA, and epinephrine. S-adenosylhomocysteine is an intermediary product in the transsulfuration pathway and is hydrolyzed to homocysteine (27).
Tissue protein catabolism Dietary protein
Glycine
Serine
Methionine
Tissue protein synthesis
Tetrahydrofolate 5,10-Methylene tetrahydrofolate

5,10-Methylene tetrahydrofolate reductase 5-Methyltetrahydrofolate homocysteine methyltransferase CH3-B 12
ATP
Dimethylglycine
Methionine-S-adenosyltransferase (MAT)
5-Methyltetrahydrofolate
Betaine-homocysteine methyltransferase
Betaine S-Adenosylmethionine
Choline Homocystine
Homocysteine
Cystathionine -synthase (CBS), B 6
Serine
Adenosylhomocysteine Cystathionine
Cystathionase, B 6
Accumulates in MAT deficiency, if untreated. Accumulates in CBS deficiency, if untreated (n) = several steps = site of enzyme malfunction
Cystine SO4
Cysteine (n) Taurine
+ -Ketobutyrate
Propionyl CoA
(n)
Succinyl CoA
Figure G. Methionine metabolism in homocystinuria Four possible pathways are open to homocysteine. It can be remethylated to form MET through two different enzymatic reactions. In one reaction, the methyl group is derived from betaine and is catalyzed by betaine-homocysteine methyltransferase. The second reaction requires 5 N -methyltetrahydrofolate as a methyl donor and methylcobalamin (CH3-B12) as coenzyme (Figure G) (47). The enzyme catalyzing this reaction is 5-methyltetrahydrofolate-homocysteine methyltransferase. The third pathway open to homocysteine is spontaneous oxidation to homocystine
138 Homocystinuria 2001 Ross Products Division
(Figure G). This reaction occurs only when homocysteine is present in tissue in abnormal amounts. Homocystine is not
Homocystinuria 139
further metabolized. Most homocysteine is metabolized by cystathionine -synthase (CS) to cystathionine using serine as co-substrate and pyridoxal phosphate as coenzyme. Cystathionine is then hydrolyzed to cysteine and ketobutyrate. The enzyme cystathionase, for which pyridoxal phosphate is coenzyme, is required for this reaction (Figure G). A deficiency of cystathionase results in cystathioninuria, which has no pathologic consequence. Alpha-ketobutyrate is converted to propionyl-CoA, which is carboxylated to methylmalonyl-CoA and isomerized to succinyl-CoA, a Krebscycle intermediate. L-Cysteine is catabolized to pyruvate, NH3, and H2S. Defects in the function of CS or 5-methyltetrahydrofolate-homocysteine methyltransferase result in classical homocystinuria. Impaired activity of the latter enzyme may be caused by failure to synthesize methylcobalamin from vitamin B12 or by a deficiency in 5, 10 methylenetetrahydrofolate reductase, as well as by mutations in the apoenzyme. Several different defects impair the uptake, transfer, and conversion of dietary vitamin B12 to methylcobalamin. The most common form of homocystinuria is caused by a deficiency of CS. Some forms are responsive to vitamin B6 while others are not. Severely impaired enzyme function produces accumulation of plasma homocyst(e)ine and MET and decreased cyst(e)ine in cells and physiologic fluids. If this disorder is not treated early in life, skeletal changes, dislocated lenses, intravascular throboses (8), osteoporosis (31), malar flushing, and, in some patients, mental retardation will occur. In a large survey of patients with homocystinuria due to CS deficiency, only 13% were vitamin B6 responsive (28). The mechanism involves stabilizing CS to biological degradation. The more residual enzyme activity present, the more dramatic the response to vitamin B6. Hypermethioninemia may not be present in the newborn if the activity of CS is greater than 15%. Management of CH3-B12 deficiency or impaired methyl transfer with homocystinuria does not require MET-restricted diets. Rather, pharmacologic amounts of vitamin B12 (47), folate, choline, or betaine are added, depending on the primary defect. Pharmacologic doses of pyridoxine should be tried in all patients with hypermethioninemia and homocystinemia. In newborns and early childhood, 25 to 100 mg per day should be tried for a 4-week interval before MET restriction. In older children and adults, oral pyridoxine (1 g daily) should be tried. Weeks may be required for a biochemical response to occur. If the plasma MET and homocysteine concentrations are reduced, the amount of pyridoxine should be gradually lowered until the minimum dose required to maintain biochemical normality is reached. Doses of 25 to 750 mg day have been required for some patients. Excess vitamin B6 for prolonged periods of time may cause peripheral neuropathy (5, 36) or rhabdomyolysis (38); consequently, if it is not helpful, vitamin B6 should be discontinued. Betaine supplements will assist in maintaining postprandial plasma homocysteine concentrations in the near-normal range in individuals (42, 48). Patients who do not respond completely to pyridoxine will require a MET-restricted diet supplemented with L-cysteine. L-cysteine becomes an essential amino acid in homocystinuria (Figure G). If plasma folate concentrations are below normal owing to excess consumption in remethylating homocysteine to MET, folate should be added as a supplement. Prenatal diagnosis may be provided by direct enzyme assay of amniotic fluid cells or by DNA analysis if the mutations are known.

In a retrospective study of 629 patients with CS deficiency, MET restriction initiated neonatally prevented mental retardation, decreased the frequency of lens dislocation, and reduced the incidence of seizures (28). Newborn screening and treatment of 25 cases in Ireland also supports the efficacy of nutrition management (49). Pyridoxine treatment of vitamin B6-responsive patients decreased the rate of thromboembolic events (28). Weight and height in a girl with homocystinuria treated from the 9th day of life was at the 90th percentile (3). Hispanic male twins born at 38 weeks gestation with homocystinuria grew well during the entire 1st year of life while on nutrition support. Protein intake of these two subjects averaged 3.7 g/kg/day during the 1st 6 months of life and 2.6 g/kg/day during the 2nd 6-months of life. Energy intake during the 1st 6 months averaged 131 kcal/kg and 100 kcal/kg during the 2nd 6 months (2). Cysteine deficiency manifested as abnormally low plasma cysteine concentrations, elevated plasma MET concentrations, and weight loss in homocystinuria has been reported (35). Up to 150 mg L-cysteine/kg/day may be required to maintain normal plasma cysteine concentrations. Elevated plasma copper and ceruloplasmin concentrations were found in patients with homocystinuria (13, 50). No relationship to plasma homocysteine could be found. The twins described
above had elevated serum copper concentrations of 151 and 144 g/dL at about 3 months of age (2). Low plasma selenium concentration and erythrocyte glutathione peroxidase activity were found in a child with homocystinuria treated with a medical food free of selenium (45). Vitamin A absorption tests were carried out in untreated patients with homocystinuria by measuring the elevation in serum retinol concentration after administration of vitamin A alcohol. The explanation proposed for the resulting subnormal serum retinol elevation was that retinol was oxidized by -SH groups excreted into the gut (3). Of the 8 plasma retinol values obtained on the twins studied, 1 was < 20 g/dL and 5 were between 20 and 30 g/dL. According to parental report, vitamin A intake was always more than adequate (1.20-5.58 times RDA for age). Serum transthyretin concentrations were all below 20 mg/dL (marginal) and 2 values obtained were below 15 mg/dL (deficient) (2). Fasting serum folate concentrations in untreated patients with homocystinuria were abnormally low. Two of these subjects were treated with 20 mg folate daily, which led to a decrease in urinary homocystine excretion (11). Severe folate deficiency was found in an untreated infant with homocystinuria who was receiving diluted boiled cow's milk for an episode of gastroenteritis (3). Excessive utilization of 5-methyltetrahydrofolate in remethylation of homocysteine to form MET is proposed as a reason for folate deficiency in untreated patients (14). The twins reported had adequate hemoglobin concentrations after 4 months of age, and mean corpuscular volume was normal (2). Most clinicians who treat individuals with homocystinuria believe that patients should be kept on diet indefinitely. Termination of diet after growth is achieved may lead to thromboembolisms and ciliary muscle laxity with lens dislocation. Where initiation or maintenance of nutrition support is not possible, acetylsalicylic acid (1 g daily), betaine and dipyridamole (100 mg daily) increase platelet survival time and decrease thrombotic events. Vitamin B6 in pharmacological doses should be tried and folate should be given (14).

A. The Defect 1. Homocystinuria without methylmalonic aciduria may result from defect in any of at least 3 enzymes (14, 27). a. Methylenetetrahydrofolate reductase. b. 5-Methyltetrahydrofolate-homocysteine methyltransferase. c. CS. 1) Abnormalities in this enzyme may respond to pharmacologic doses of vitamin B6 (25-100 mg/day for 1-month trial in neonates). 2) Administer smallest amount of vitamin B6 daily that maintains normal concentrations of plasma MET and homocyst(e)ine (5, 26, 38). 3) Patients who respond to vitamin B6 therapy usually do not require nutrition support. B. Clinical Screening 1. MET concentration > 1 mg/dL by bacterial inhibition assay or positive urine nitroprussidecyanide test requires differential diagnosis.
C. Differential Diagnosis (14, 27). 1. Differential diagnosis will reveal false-positives and identify specific enzyme defects. 2. Therapy depends on enzyme defect present. 3. This protocol addresses nutrition support of patients with vitamin B6 non-responsive CS deficiency.

A. Correct Primary Imbalance in Metabolic Relationships 1. Restrict dietary MET to amount tolerated by patient to maintain treatment plasma MET concentration (1, 14). B. Supply Product of Blocked Primary Pathway 1. Supplement dietary cystine (CYS) as necessary to maintain normal plasma CYS concentration (35)
Homocystinuria 141
V. Establish Goals of Long Term Nutrition Support (14)

A. Plasma MET Concentration 1. Maintain 2- to 4-hour postprandial plasma MET concentration between 18 and 45 mol/L when measured by quantitative methods or within range of normal for age in laboratory used (14) a. In practice, obtaining blood 2 to 4 hours postprandially is not always possible. Acceptable local standards should be developed if plasma amino acids are evaluated at other times (Practical Aspects of Nutrition Support, p viii). 2. Opinions vary as to best concentration of plasma MET and CYS to support normal growth and development in infants and children. a. In this protocol, concentrations as close to normal as possible are recommended. B. Plasma CYS Concentration 1. Maintain 2- to 4-hour postprandial plasma CYS concentration between 25 and 50 mol/L, or in normal range for age as established by laboratory used. C. Blood Homocystine Concentration 1. Maintain concentration of homocystine in blood at < 12 mol/L. D. Growth, Development, and Nutrition Status 1. Support normal growth rate in infants and children; maintain appropriate weight for height in adults. 2. Support normal development. 3. Maintain normal nutrition status (4, 10, 11). 4. Prevent catabolism. E. Other Manifestations 1. Prevent dystonia (7, 21), thromboembolic disease (8, 12), gastrointestinal disease (20), bleeding tendency (29), and pancreatitis (32).

A. MET 1. Prescribe MET intake that promotes goals of nutrition support (1, 14, 23). 2. MET requirements vary widely: a. From patient to patient, depending on activity of CS. b. In same patient, depending on: 1) Age. 2) Growth rate. 3) Adequacy of energy and protein intakes. 4) State of health. 3. Lowest values for age listed in Table 8-1, p 148, are suggested for initiating therapy. 4. Frequent monitoring of plasma MET concentration is essential to assess patient's changing requirements (Section IX, Suggested Evaluation of Nutrition Support, p 144). Warning: MET deficiency results in adverse effects (43): Decreased plasma MET concentration. Increased concentrations of plasma phenylalanine, proline, serine, threonine, and tyrosine. Decreased plasma cholesterol concentration. Failure to thrive in infants and children and weight loss in adults. B. CYS 1. Prescribe CYS intake that maintains treatment plasma CYS concentration (35). 2. Lowest value for CYS for each age group listed in Table 8-1, p 148, is suggested to start therapy. 3. Changing requirements of patient are determined by frequent monitoring of plasma CYS concentration. a. Prescribe CYS above amount supplied by Hominex and beikost or table foods only if plasma CYS concentration is below normal.
Warning:
CYS deficiency will result in adverse effects (35): Elevated plasma MET and homocystine concentrations. Decreased plasma CYS concentration. Failure to thrive in infants and children and weight loss in adults.
C. Folate 1. Prescribe amount that maintains plasma or erythrocyte folate concentration in normal range (11, 18) (Appendix 17, p A-18). 2. Daily supplement of 500 to 1000 g may be required (11). D. Protein 1. Prescribe, initially, amount greater than Recommended Dietary Allowances (RDAs) (15) (Table 8-1, p 148). 2. Requirements may be greater than RDAs when L-amino acids supply majority of protein equivalent as result of: a. Rapid amino acid absorption (16, 17). b. Early and high peak of plasma amino acids after ingestion of meals where large part of protein is supplied by L-amino acids (16, 17). c. Rapid catabolism of amino acids (19, 22, 37, 40). d. Possible decreased total amino acid absorption (30). Warning: Inadequate protein intake will result in failure to thrive in infants, poor growth in children, weight loss in adults, low plasma transthyretin concentrations, osteopenia, hair loss, and decreased MET tolerance. E. Energy 1. Prescribe amount that should support normal weight gain in infants and children and maintain appropriate weight for height in adults (Table 8-1, p 148). 2. Requirements vary and may be greater than normal when L-amino acids supply majority of protein equivalent (34). Warning: Inadequate energy intake will result in failure to thrive in infants, poor growth in children, and weight loss in children and adults. Weight loss will result in elevated plasma MET concentration as result of protein catabolism. Poor growth will result in lower than expected tolerance of MET. F. Betaine (Appendix 26, p A-28 Cystadane) 1. Prescribe amount that will blunt plasma homocyst(e)ine response to meals (42, 48). 2. 3 g betaine 2 to 3 times daily with meals resulted in significant decline in plasma homocystine concentration and increase in plasma MET concentrations (48). G. Fluid 1. Prescribe amount that will supply water requirements (Table 8-1, p 148). Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL fluid to children and adults for each kcal ingested (9).

A. MET 1. Calculate amount of infant formula with iron, human milk, beikost, whole cow's milk, or table foods (Table 8-2, p 148) required to fill MET prescription. a. Low-iron infant formula, whole cow's milk, or evaporated milk should not be used as MET source for infants because of low iron content. 2. Measure liquid infant formula, human milk, or whole cow's milk with disposable syringe. Weigh powdered infant formula on scale that reads in grams. 3. Add beikost or table foods (Table 8-2, p 148) to gradually displace MET provided by infant formula or human milk after infant is 3 to 4 months old or is developmentally ready. 4. Parents or patients may select any food in prescribed food lists (Table 8-3, pp 149-161) in specified amounts to fill diet prescription.
Homocystinuria 143
B. Protein 1. Calculate amount of protein provided by infant formula with iron, human milk, beikost, whole cow's milk, or table foods (Table 8-2, p 148) required to fill MET prescription. 2. Subtract amount determined above from protein prescription. 3. Supply remaining prescribed protein with Hominex (Table 8-2, p 148). a. Hominex-1 is for infants and toddlers and Hominex-2 is for children, adolescents, and adults. b. Weigh Hominex powder on scale that reads in grams because of variability of household measuring equipment (Practical Aspects of Nutrition Support, p vii) and changes in density during shipping. c. See Table 8-4 (p 162, footnote 3) for approximate packed weight of Hominex powder in level, dry US standard household measures. C. CYS 1. Calculate approximate amount of CYS provided by infant formula with iron, human milk, beikost, whole cow's milk, or table foods (Table 8-2, p 148) required to fill MET prescription. 2. Calculate amount of CYS supplied by Hominex (Table 8-2, p 148) required to fill protein prescription. 3. Added together, values calculated in C1 and C2 should fall within range of CYS intake recommended in Table 8-1, p 148. 4. Add supplemental L-CYS (Appendix 26, p A-28) only if plasma CYS concentration is below normal a. Mix weighed amount of L-CYS with boiled, cooled water to yield 10 mg/100 mL (eg, 1.0 mg L-CYS with enough water to yield 100 mL). b. Refrigerate suspension in sterilized, closed container until used. Discard unused suspension after 1 week, if not frozen. c. Shake well before using. Measure L-CYS suspension into medical food mixture with disposable syringe. 1) L-cystine is not very soluble in water (11 mg/100 mL). D. Folate 1. Administer in 3 equal doses daily. a. A prescription is required for folic acid when given in excess of 400 g/day. 2. Crush folic acid tablet and mix prescribed dose with applesauce or other fruit pures. E. Energy 1. Calculate energy provided by infant formula with iron, human milk, beikost, or table foods and Hominex (Table 8-2, p 148) required to fill MET and protein prescriptions. 2. Subtract amount determined above from energy prescription. 3. Provide any remaining prescribed energy with Polycose Glucose Polymers powder (23 kcal/Tbsp, 3.8 kcal/g) or liquid (2 kcal/mL) (Appendix 9, p A-9); Pro-Phree Protein-Free Energy Module With Iron, Vitamins & Minerals (Appendix 11, p A-10); sugar (48 kcal/Tbsp); or Free Foods B (Table 8-2, p 148), depending on age of patient. a. Do not use corn syrup or table sugar for infants because of osmolarity they yield (25). b. Do not use honey for infants because it may contain botulinum toxin (44). F. Betaine (Appendix 26, p A-28) 1. Mix with medical food mixture to administer. G. Fluid and Mixing Instructions 1. Add sufficient boiled, cooled water to infant formula or human milk, Hominex, carbohydrate (if needed), and L-CYS suspension (if needed) to yield prescribed volume. Tap water may replace boiled, cooled water when preparing Hominex for older infants, children, and adults. 2. Mix with sterilized blender at lowest speed for no longer than 3 to 4 seconds. Excess mixing may destabilize emulsion. May also be mixed in sterilized, tightly closed container by shaking vigorously for 10 to 12 seconds. 3. Refrigerate in sterilized, closed containers until used. Discard unused portion 24 hours after mixing because of nutrient loss.
4. Do not use terminal sterilization or boil because of Maillard reaction (Practical Aspects of Nutrition Support, p viii). 5. Warm or cool medical food mixture to room temperature before feeding to infants. Shake mixture well before feeding. 6. Do not warm medical food mixture for infants in microwave oven. Unevenly heated formula can burn infants, and steam can make bottles explode. 7. Notify parents or caretakers when they may discontinue using aseptic technique in preparing medical food mixture for infants. 8. For children and adults, chill Hominex medical food mixture to improve taste. H. Diet Guide 1. Provide parents, caretakers, or patient with completed Diet Guide (Appendix 22, p A-24) with each diet change. 2. Feed young infants 6 to 8 times daily (16, 17, 19, 37). 3. Feed older infants, children, and adults 4 to 6 times daily (16, 17, 19, 37).

A. Nutrient Adequacy 1. Determine if diet provides nutrients in amounts prescribed in Section VI, Establish Prescription, p 140. a. See Table 8-2, p 148, for composition of infant formulas, human milk, whole cow's milk and Hominex. b. See Appendix 9, p A-9, for composition of Polycose and Appendix 11, p A-10, for composition of Pro-Phree. 2. Check diet to determine if it supplies Recommended Dietary Intakes (RDIs) of minerals and vitamins (Appendices 13 and 14, pp A-14 and A-15). a. See Table 8-4, p 162, for composition of Hominex and Appendices 4 through 7, pp A-4 to A-7, for complete nutrient composition of infant formulas. b. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. c. If Hominex mixture provides < 100% of RDIs for infants and < 75% for children and adults, supplement diet with needed minerals and vitamins if not provided by beikost or table foods and laboratory tests indicate need (Appendix 11, p A-10, for composition of supplements). B. Osmolarity 1. If concentration of prescribed medical food mixture is > 24 kcal/fl oz, determine if osmolarity is in acceptable range. a. Determine osmolarity by laboratory analysis or use mathematical formula given in Appendix 18, p A-20. b. Osmolarity per gram of Hominex is listed in Appendix 19, p A-21. 2. If osmolarity is > 450 mosm/L for infants, > 750 mosm/L for children, > 1,000 mosm/L for adults, or greater than tolerated by patient, increase water content of prescribed medical food mixture and recalculate its osmolarity (24, 25, 41). C. Potential Renal Solute Load 1. Dehydration will result if renal solute load is greater than renal-concentrating ability of patient. 2. If concentration of medical food mixture prescribed is > 24 kcal/fl oz, estimate its potential renal solute load. a. This step is important to prevent dehydration of infants who may have renal-concentrating capacity as low as 600 mosm/L. b. Upper limit of renal solute load for neonates is approximately 1,100 mosm/L (39). 3. A method for estimating potential renal solute load is given in Appendix 20, p A-22. 4. If potential renal solute load is excessive, increase water content of medical food mixture and recalculate.
Homocystinuria 145

A. Plasma MET, CYS, and Homocystine Concentrations 1. Initial: a. Evaluate twice weekly by quantitative methods until plasma concentrations stabilize and approximate dietary MET and CYS requirements are known (14). b. Unless plasma samples are immediately deproteinized after drawing, CYS will form disulfide bridges with protein and be precipitated with protein, resulting in plasma CYS concentration that appears below normal. 2. Ongoing: a. Frequent evaluations help ensure adherence to nutrition support plan. b. Evaluate plasma MET, CYS, and homocystine concentrations by quantitative methods weekly until 6 months of age and monthly when concentrations are in treatment range (14). 3. Unacceptable MET concentrations: a. If plasma MET concentration is not detected and patient has ingested full prescription: 1) Add 20 mg to prescribed MET and reevaluate plasma MET concentration in 7 days. 2) If plasma MET concentration continues undetected, repeat above process until value is in treatment range. b. If plasma MET concentration is > 45 mol/L and patient has ingested full prescription: 1) Subtract 5% to 10% from prescribed MET and reevaluate plasma MET concentration in 7 days. 2) If plasma MET concentration continues > 45 mol/L, repeat above process until value is in treatment range. B. Protein Status 1. Evaluate plasma transthyretin concentration every 3 months until patient is 1 year of age and every 6 months thereafter (Appendix 17, p A-18, for standards). a. Plasma transthyretin concentrations provide a more reliable and rapid indication of protein status than plasma albumin concentrations. b. Plasma albumin concentrations may be in the normal range when plasma transthyretin concentrations show a clear deficiency (6). 2. If plasma transthyretin concentration is below standard: a. Increase prescribed protein by 5% to 10% and reevaluate plasma transthyretin concentration in 1 month. If plasma MET, CYS, and homocysteine concentrations are in treatment range, use Hominex to increase protein. b. If plasma transthyretin concentration continues below standard, repeat above process until value is in normal range. C. Iron Status 1. Plasma ferritin concentration. a. Evaluate at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17, p A-18, for standards). b. If plasma ferritin concentration is below standard: 1) Increase iron intake to 4 mg/kg with supplements (ferrous sulfate). 2) Evaluate plasma ferritin concentration monthly on increased iron intake. 3) Continue iron supplements until plasma ferritin concentration is in normal range. 2. Complete blood count. a. Hemoglobin and hematocrit concentrations should be evaluated at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17, p A-18, for standards). D. Erythrocyte Folate Status 1. Evaluate every 3 months in infants and twice yearly thereafter. a. Maintain concentration in normal range of 200 ng/mL (18). b. If erythrocyte folate concentration falls to < 200 ng/mL: 1) Supplement with 500 g folate/day. 2) Evaluate erythrocyte folate concentration in 1 month.
146 Homocystinuria
E. Growth Status 1. Length/height and weight. a. Measure monthly to 1 year, every 3 months to 4 years, and every 6 months thereafter. Plot measurements on NCHS growth charts. b. Maintain length/height and weight between 10th and 90th percentiles. Some normal infants, children, and adults will fall above or below these percentiles. 2. If length/height or weight falls below usual growth channel: a. Increase prescribed protein and energy by 5% to 10% and remeasure in 1 month. b. If length/height or weight remains low, repeat above process until usual growth channel is achieved. F. Nutrient Intake 1. Maintain records of food intake for 3 days immediately before each blood test (Appendices 24 and 25, pp A-26 and A-27). 2. Evaluate intakes of MET, CYS, protein, and energy before each blood test. 3. Evaluate mineral and vitamin intakes after each diet change. a. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. b. See Appendix 28, p A-29, for information about ordering software for diet evaluation. G. Clinical Summary 1. A summary record of growth, laboratory, and nutrient intake data is useful for patient management (Table 8-5, p 163).
A. Example 1 Establish and fill prescription for 1-month-old infant weighing 4 kg using Recommended Daily Nutrient Intakes from Table 8-1, p 148 and nutrient contents from Table 8-2, p 148. 1. Establish prescription.
MET CYS1 Folate Protein Energy Fluid Betaine
1
15 mg/kg 300 mg/kg 3.5 g/kg 120 kcal/kg 150 mL/kg 1g
x x x x x x
4 kg 4 kg 4 kg 4 kg 4 kg 4 kg
= = = = = = =
60 mg/day 1,200 mg 500 g 14 g 480 kcal 600 mL 4g
Add only if plasma CYS concentration is below normal. Measure 78 g 171 mL 2 82 mL 0 60 0 MET (mg) CYS (mg) 351 32 820 Protein (g) 11.7 2.4 0.0 Energy (kcal) 374 116 0
Medical Food Mixture Hominex-1 Similac With Iron Ready to Feed 1 L-Cystine Add water to make 600 mL (20 fl oz). Total per day Total per kg 60 15 1,203 300 14.1 3.5 490 122
Approximate osmolarity of medical food mixture is < 450 mosm/L. Estimated potential renal solute load is 100 mosm. 1 Suspension is 10 mg/mL (1 g L-cystine with water added to make 100 mL). 2 Add only if plasma CYS concentration is below normal.
Homocystinuria 147
B. Example 2 Establish and fill prescription for 2-year-old child weighing 13 kg using Recommended Daily Nutrient Intakes from Table 8-1, p 148 and nutrient contents from Table 8-2, p 148. 1. Establish prescription.
1
130 mg/day 1,300 mg 1 mg 30 g 1,300 kcal 1,300 mL 6g
Add only if plasma CYS concentration is below normal. Measure MET (mg) CYS (mg) Protein (g) 22.5 0.0 Energy (kcal) 720 0
Hominex-1 150 g 0 675 L-Cystine1 50 mL2 0 500 Add water to make 710 mL (24 fl oz). Offer additional fluid ad libitum daily. Food List Breads/Cereals Fats Fruits Vegetables Total per day 4 3 3 3 Servings 80 6 15 30 131 80 0 15 24 1,294
4.8 0.3 1.5 3.0 32.1
220 150 180 40 1,310
Approximate osmolarity of medical food mixture is < 600 mosm/L. 1 Add only if plasma CYS concentration is below normal. 2 Suspension is 10 mg/mL (1 g L-cystine with water added to make 100 mL).
C. Example 3 Establish and fill prescription for 9-year-old child weighing 25 kg using Recommended Daily Nutrient Intakes from Table 8-1, p 148, and nutrient contents from Table 8-2, p 148. 1. Establish prescription.
1
150 mg/day 2,500 mg (2.5 g) 1 mg 40 g 2,400 kcal 2,400 mL 8g
Add only if plasma CYS concentration is below normal.
148 Homocystinuria
Medical Food Mixture Measure MET (mg) CYS (mg) Protein (g) 27.9 0.0 0.0 Energy (kcal) 381 0 576
Hominex-2 93 g 0 837 1 2 L-Cystine 152 mL 0 1,520 Sugar 144 g (3/4 cup) 0 0 Add water to make 1000 mL (33 fl oz). Offer additional fluid ad libitum daily. Food List Breads/Cereals Fats Fruits Vegetables Free Foods A Free Foods B Total per day
1
Servings 4 4 7 2 7 4 80 8 35 20 7 0 150 80 0 35 16 7 0 2,495 4.8 0.4 3.5 2.0 1.4 0.0 40.0
220 200 420 40 350 220 2,407
Approximate osmolarity of medical food mixture is < 1,000 mosm/L. Add only if plasma CYS concentration is below normal. 2 Suspension is 10 mg/mL (1 g L-cystine with water added to make 100 mL).

A. Rationale 1. In normal persons, febrile illness and trauma are accompanied by catabolism of body protein (46). 2. Well-nourished patients with homocystinuria respond to infection and trauma as do normal persons. 3. Extent of protein catabolism determines subsequent elevation in blood MET concentration. B. Objectives of Nutrition Support 1. Maintain hydration and electrolyte balance. a. Offer infants and toddlers Pedialyte Oral Electrolyte Maintenance Solution ad libitum (Appendix 9, p A-9). 2. Depress catabolism. a. Enhance energy intake when possible by offering fruit juices ad libitum as tolerated; liquid Jell-O ; Polycose powder or liquid (Appendix 9, p A-9) or Pro-Phree (Appendix 11, p A-10); and caffeine-free soft drinks (not diet drinks). b. Add 1/3 cup Polycose powder may be added to liquid Pedialyte to yield 8 fl oz. c. Return patient to Hominex medical food mixture and pre-illness diet as rapidly as possible. 1) Begin with 1/2 original strength Hominex medical food mixture. 2) Increase to original strength as tolerated. C. Parenteral Nutrition 1. If parenteral amino acid solutions are indicated, see Appendix 26, p A-28.
Homocystinuria 149
TABLE 8-1. Recommended Daily Nutrient Intakes (Ranges) for Infants, Children, and Adults With Homocystinuria
Age MET1,2 (mg/kg) Infants 0 to < 3 mo 3 to < 6 mo 6 to < 9 mo 9 to < 12 mo 15 - 30 10 - 25 10 - 25 10 - 20 (mg/kg) Girls and Boys 1 to < 4 yr 4 to < 7 yr 7 to < 11 yr Women 11 to < 15 yr 15 to < 19 yr > 19 yr 10 - 20 8 - 16 6 - 12 300 250 200 200 (mg/kg) 100 - 200 100 - 200 100 - 200 CYS2 (mg/kg) Nutrient Protein3,4 (g/kg) 3.50 - 3.00 3.50 - 3.00 3.00 - 2.50 3.00 - 2.50 (g/day) > 30.0 > 35.0 > 40.0 Energy3,4 (kcal/kg) - 95) - 95) - 80) - 80) Fluid5 (mL/kg) 150 - 125 160 - 130 145 - 125 135 - 120 (mL/day) 900 - 1,800 1,300 - 2,300 1,650 - 3,300
120 (145 115 (145 110 (135 105 (135
(kcal/day) 1,300 ( 900 - 1800) 1,700 (1300 - 2300) 2,400 (1650 -3300)
6 - 14 6 - 12 4 - 10
50 - 150 25 - 125 25 - 100
> 50.0 > 55.0 > 60.0
2,200 (1500 - 3000) 2,100 (1200 - 3000) 2,100 (1400 - 2500)
1,500 - 3,000 1,200 - 3,000 1,400 - 2,500
Men 11 to < 15 yr 6 - 14 50 - 150 > 55.0 2,700 (2000 - 3700) 2,000 - 3,700 15 to < 19 yr 6 - 16 25 - 125 > 65.0 2,800 (2100 - 3900) 2,100 - 3,900 > 19 yr 6 - 15 25 - 100 > 70.0 2,900 (2000 - 3300) 2,000 - 3,300 1 Initiate prescription with lowest value for patient's age. Modify prescription based on frequently obtained plasma values and growth in infants and children and frequently obtained plasma values and weight maintenance in adults. 2 From references 1, 14, 23. 3 From reference 15. 4 Based on ideal body weight in kilograms. 5 From reference 9. Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL fluid to children and adults for each kcal ingested.
TABLE 8-2. Serving Lists For MET-Restricted Diets: Average Nutrient Content Per Serving1
Food List Nutrient CYS Protein (mg) (g) 20 1.2 0 0.1 5 0.5 8 1.0 1 0.2 0 0.0 32 1.86 450 15.00 900 30.00 20 1.05 18 1.66 19 1.40 31 3.39
MET (mg) Breads/Cereals 20 Fats 2 Fruits 5 Vegetables 10 Free Foods A 1 Free Foods B 0 2 Alimentum Protein-Hydrolysate Formula With Iron, Ready to Feed, 100 mL 54 Hominex-1, powder, 100 g 0 Hominex-2, powder, 100 g 0 Human Milk, 100 mL 2 22 Isomil Soy Formula With Iron, Ready to Feed, 100 mL 2 42 2 Similac With Iron Infant Formula, Ready to Feed, 100 mL 35 3 Whole cow's milk , 100 mL 86 1 From reference 14. 2 See Appendices 4 through 7, pp A-4 to A-7, for complete nutrient composition of infant formulas. 3 From reference 33. See Appendix 8, p A-8, for complete nutrient composition.
Energy (kcal) 55 50 60 20 50 55 68 480 410 72 68 68 63
150 Homocystinuria
TABLE 8-3. Serving Lists for MET-Restricted Diets: Gerber Baby Foods (Beikost)
Weight Approximate MET (g) Measure (mg) For greatest accuracy, weigh food on scale that reads in grams. All measures are level. BREADS AND CEREALS Baked Finger Snacks Animal crackers, cinnamon graham Apple cinnamon cookies Arrowroot cookies Banana cookies Pretzels Strawberry fruit bars Veggie crackers Cereals, Dry Barley Mixed Oatmeal Oatmeal/banana Oateal/mixed fruit Rice Rice/apple Rice/apple bits Rice/banana Rice/mixed fruit Cereals, Jarred 1st Foods Oatmeal 2nd & 3rd Foods Banana/oatmeal/peach Mixed/apples/bananas Mixed/applesauce/banana Oatmeal/apples/cinnamon Oatmeal/applesauce/banana Rice/applesauce/banana Vegetables 1st Foods Peas Potatoes Sweet potatoes 2nd and 3rd Foods Creamed corn Creamed spinach Garden vegetables Mixed vegetables Peas Sweet potatoes, 2nd Foods Sweet potatoes, 3rd Foods FRUITS/JUICES Banana/pineapple Banana/strawberry Fruit salad Mixed fruit juice Orange juice 42 42 83 100 100 3 Tbsp 3 Tbsp 5 Tbsp + 2 tsp 3.2 fl oz 3.2 fl oz 5 5 5 4 7 6 7 7 6 4 0.4 0.4 0.3 0.2 0.6 32 39 52 48 42 Food CYS (mg) Protein (g) Energy (kcal)
24 20 18 16 12 16 21
6 crackers 2 cookies 3-2/3 cookies 2 cookies 4 pretzels 1-3/4 bar 30 crackers
19 24 24 21 24 20 20
45 40 53 39 47 32 42
1.4 1.6 1.5 1.1 1.5 0.9 1.8
107 85 82 69 47 65 100
9 9 7 12 10 8 12 11 10 8
2 Tbsp + 1 tsp 2 Tbsp + 1 tsp 1 Tbsp + 2 tsp 3 Tbsp 2 Tbsp + 2 tsp 2 Tbsp 3 Tbsp 2 Tbsp + 2-3/4 tsp 2 Tbsp + 2 tsp 2 Tbsp
20 19 20 20 20 19 20 20 21 19
31 28 40 35 38 19 20 20 23 19
1.1 0.9 1.1 1.4 1.1 0.7 0.7 0.8 0.7 0.6
34 35 28 48 42 30 47 43 39 32
57 106 100 100 90 91 80
1/4 cup 7 1/2 Tbsp 7 Tbsp 7 Tbsp 6 Tbsp + 1 tsp 6 Tbsp + 1 tsp 5 Tbsp + 1-1/2 tsp
20 20 20 20 20 20 20
33 28 36 36 38 38 21
1.0 1.2 1.2 1.0 1.0 1.2 0.6
31 78 76 86 60 76 73
48 133 105 43 26 58 90 52 96 84
3 Tbsp + 1-1/2 tsp 9 Tbsp + 1 tsp 7 Tbsp + 1 tsp 3 Tbsp 2 Tbsp 1/4 cup 6 Tbsp + 1 tsp 3 Tbsp + 1-1/2 tsp 6 Tbsp + 2 tsp 7 Tbsp + 1 tsp
20 20 20 20 20 20 20 20 20 20
18 17 23 13 12 18 18 20 20 16
1.4 1.3 1.2 0.8 0.8 1.2 1.2 1.6 1.0 0.8
24 63 68 27 12 22 32 25 60 50
Homocystinuria 151
Food
Weight Approximate MET (g) Measure (mg) For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Orange/banana/pineapple juice 50 1 1/5 fl oz 5 Pear juice 100 3.2 fl oz 5 Tropical blend 100 3.2 fl oz 5 1st Foods Applesauce 86 1/4 cup + 2 Tbsp 5 Bananas 26 1 Tbsp + 2 tsp 5 Peaches 62 4 Tbsp + 2 tsp 5 Pears 62 4 Tbsp + 1 tsp 5 Prunes 100 7 Tbsp 5 2nd & 3rd Foods Apple/blueberry 125 1/2 cup + 2 tsp 5 Apricot/mixed fruit 83 5 Tbsp + 2 tsp 5 Bananas 26 1 Tbsp + 2 tsp 5 Bananas/apples/pears 36 2 Tbsp + 1-1/2 tsp 5 Peaches 62 1/4 cup + 1 tsp 5 Pears 62 1/4 cup + 1 tsp 5 Pear/pineapple 62 1/4 cup + 1 tsp 5 Plums/apples 100 7 Tbsp 5 Prunes/apples 83 5 Tbsp + 2 tsp 5 Fruit Desserts Guava Mango Papaya Peach cobbler dessert, 2nd Foods Peach cobbler dessert, 3rd Foods Fruit Dices, Graduates Mixed fruit Peaches Fruit/Vegetable Juices Apple/carrot Apple/sweet potato White grape juice Tender Harvest Pear/wild blueberry Tropical fruit blend Apple/sweet potato Pears/winter squash VEGETABLES 1st Foods Carrots Green beans Squash 2nd Foods Carrots Green beans Squash 3rd Foods Carrots Green beans/rice Peas/rice Squash
CYS (mg) 4 4 5 2 5 6 4 5 6 7 5 6 6 5 4 6 7
Protein (g) 0.1 0.2 0.6 0.2 0.3 0.4 0.2 1.0 0.3 0.5 0.3 0.3 0.4 0.4 0.2 0.4 0.5
Energy (kcal) 32 48 56 48 26 27 35 101 62 50 23 30 40 61 34 70 64
125 100 125 50 56 125 83
8 Tbsp + 2 tsp 7 Tbsp 8 Tbsp + 2 tsp 3 Tbsp + 1-1/2 tsp 1/4 cup ND ND
5 5 5 5 5 5 5
3 3 3 3 5 6 7
0.4 0.4 0.4 0.2 0.3 0.4 0.4
88 74 80 38 43 61 41
167 100 100 167 62 125 31
5-1/3 fl oz 3-1/4 fl oz 3.2 fl oz 11 Tbsp + 2 tsp 4 Tbsp + 1 tsp 8 Tbsp + 2 tsp 2 Tbsp + 1-1/2 tsp
5 5 5 5 5 5 5
3 5 5 8 5 4 3
0.3 0.3 0.3 0.7 0.4 0.4 0.3
72 52 65 102 46 79 16
100 33 59 100 50 53 56 42 26 100
7 Tbsp 2 Tbsp + 1 tsp 1/4 cup 7 Tbsp 3 Tbsp + 1-1/2 tsp 3 Tbsp + 2 tsp 1/4 cup 3 Tbsp 1 Tbsp + 2 tsp 7 Tbsp
10 10 10 10 10 10 10 10 10 10
10 8 10 10 20 11 6 10 10 11
0.9 0.4 0.5 0.8 0.6 0.4 0.4 0.5 0.6 0.8
35 10 20 30 15 17 16 18 14 33
152 Homocystinuria
Weight Approximate MET (g) Measure (mg) For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Tender Harvest Butternut squash/corn 32 2 Tbsp + 3/4 tsp 10 Garden carrots/brown rice 83 5 Tbsp + 2 tsp 10 Green beans/potatoes 19 1 Tbsp + 1 tsp 10 Spring garden vegetables 59 4 Tbsp + 1 tsp 10 Vegetable Dices, Graduates ND Carrots 77 10 ND Green beans 48 10 ND Mixed vegetables 31 10 FREE FOODS A Fruit Dices Apples Pears Fruit Juices Apple juice Apple/cranberry juice Apple/cherry juice Apple/grape juice Apple/prune juice Banana strawberry juice medley
Food
CYS (mg)
Protein (g)
Energy (kcal)
6 7 5 9 6 7 9
0.6 0.7 0.4 0.9 0.5 0.6 0.6
16 35 12 21 18 12 14
50 33
ND ND
1 1
2 1
0.1 0.1
24 18
248 100 124 124 124 100
8 fl oz 3.2 fl oz 4 fl oz 4 fl oz 4 fl oz 3.2 fl oz
1 1 1 1 1 1
1 1 1 1 1 1
0.1 0.1 0.3 0.1 0.1 0.1
124 44 62 64 32 58
ND = no data. Weights and Measures Except for Dry Cereals and Food Dices, the following weights apply: Level 1 tsp 1 Tbsp 1/4 cup 1/3 cup 1/2 cup 2/3 cup 3/4 cup 1 cup Level 1/3rd Tbsp 1/16th cup 4 Tbsp 5-1/3rd Tbsp 8 Tbsp 10 2/3rd Tbsp 12 Tbsp 16 Tbsp
= = = = = = = =
= = = = = = = =
4.8 g 14.3 g 57.2 g 76.2 g 114.3 g 152.5 g 171.5 g 228.6 g
Homocystinuria 153
TABLE 8-3. Serving Lists for MET-Restricted Diets: Table Foods

Food
1, 2
Weight Approximate (g) Measure For greatest accuracy, weigh food on scale that reads in grams. All measures are level. BREADS AND CEREALS Cereals, Cooked. Level measure after cooking Corn Grits instant cheese flavor plain regular, quick (plain) Cream of Rice Cream of Wheat instant Mix'n Eat flavored plain quick regular Farina Maltex Malt-o-Meal Oats, regular, quick, and instant Ralston Wheatena Whole Wheat Hot Natural Cereals, Ready To Eat All Bran Alpha-Bits Apple Jacks 100% Bran Bran Buds Bran Chex 40% Bran Flakes (Post ) Cap'n Crunch Cap'n Crunch's Crunch Berries Cap'n Crunch's Peanut Butter Cheerios Cinnamon Toast Crunch Cocoa Krispies Cocoa Pebbles Cocoa Puffs Cookie Crisp Corn Bran Corn Chex Corn Flakes Crispy Rice Crispy Wheat'n Raisins C.W. Post plain w/ raisins Froot Loops Frosted Mini-Wheats Frosted Rice Krinkles Frosted Rice Krispies Fruit Wheat Squares Fruity Pebbles
MET (mg)
CYS (mg)
Protein (g)
Energy (kcal)
47 46 60 81 60 36 38 80 84 60 47 80 44 47 51 60
1/3 packet 1/3 packet 1/4 cup 1/3 cup 1/4 cup 1/4 packet 1/4 packet 1/3 cup 1/3 cup 1/4 cup 3 Tbsp 1/3 cup 3 Tbsp 3 Tbsp 3 Tbsp + 1 tsp 1/4 cup
22 17 20 21 20 23 17 22 23 20 20 22 19 20 19 20
21 16 19 12 25 28 21 27 28 19 24 26 28 23 23 33
0.9 0.7 0.9 0.7 1.1 1.2 0.9 1.2 1.3 0.8 1.1 1.2 1.1 1.0 1.0 1.2
36 27 36 42 38 66 34 43 45 36 34 41 27 25 28 38
11 14 21 12 11 9 12 18 18 18 7 38 12 16 28 19 13 11 11 9 19 12 13 18 11 14 14 17 16
2 Tbsp 1/2 cup 3/4 cup 3 Tbsp 2 Tbsp 3 Tbsp 1/4 cup 1/2 cup 1/2 cup 1/2 cup 1/3 cup 1 cup 1/3 cup 1/2 cup 1 cup 1/2 cup + 2 Tbsp 1/4 cup + 2 Tbsp 1/4 cup + 2 Tbsp 1/2 cup 1/3 cup 1/4 cup + 3 Tbsp 2 Tbsp 2 Tbsp 1/2 cup + 2 Tbsp 1-1/2 pieces 7 Tbsp 1/2 cup 3 Tbsp + 1 tsp 1/2 cup
22 20 22 21 21 18 21 21 20 22 18 22 19 22 19 19 20 18 22 18 20 21 21 21 19 20 20 19 19
30 26 26 30 29 20 27 22 20 24 27 26 11 13 19 21 21 17 21 10 25 26 26 24 21 12 11 23 11
1.5 1.1 1.1 1.5 1.5 1.0 1.3 1.0 0.9 1.2 1.1 1.3 0.6 0.7 1.0 0.9 0.9 0.8 0.9 0.6 1.3 1.1 1.1 1.1 1.1 0.7 0.6 1.2 0.6
26 56 82 32 27 30 38 78 73 77 28 60 46 66 110 74 74 42 44 37 65 54 56 69 38 55 55 59 66
154 Homocystinuria
Weight Approximate (g) Measure For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Golden Grahams 15 1/4 cup + 2 Tbsp Grape Nut Flakes 10 1/3 cup Honey Nut Cheerios 9 1/4 cup Honey Nut Corn Flakes 19 1/2 cup Honeycomb 16 3/4 cup King Vitaman 16 3/4 cup Kix 9 1/2 cup Life 5 2 Tbsp Lucky Charms 14 1/4 cup + 3 Tbsp Nature Valley Granola , Toasted Oat Mixture 14 2 Tbsp Nutri-Grain barley 10 1/4 cup corn 10 1/4 cup rye 13 1/3 cup wheat 15 1/3 cup Oat Flakes 6 2 Tbsp Product 19 10 1/3 cup Quisp 20 2/3 cup Raisin Bran (Post ) 14 1/4 cup Rice Chex 13 1/2 cup Rice Krispies 9 1/3 cup Rice, Puffed 10 3/4 cup Special K 4 2 Tbsp Sugar Frosted Flakes 18 1/2 cup Sugar Pops 16 1/2 cup + 1 Tbsp Sugar Smacks 17 1/4 cup + 3 Tbsp Super Sugar Crisp 16 1/2 cup Team 14 1/3 cup Toasties 11 1/2 cup Total 11 1/3 cup Trix 14 1/2 cup Wheat Chex 12 1/4 cup Wheat puffed 8 2/3 cup shredded 12 1/2 large biscuit Wheaties 11 1/4 cup + 2 Tbsp Grains Corn cooked (cream style) meal on the cob (medium ear) Rice, prepared brown fried pilaf Rice-A-Roni Spanish white instant Pasta, cooked Macaroni Noodles Ramen Noodles Spaghetti
Food
MET (mg) 18 18 18 22 20 18 18 19 21 24 19 20 20 22 21 22 22 18 20 19 20 19 22 19 20 18 22 22 19 17 20 21 22 18 17 21 25 21 22 18 19 21 32 36 26 20 33 25 28 22 23 23 11 11 11 12 20 18 23 21 18 20 21 18 23 23 25 20
CYS (mg)
Protein (g) 0.8 1.1 1.0 1.2 0.9 0.8 0.8 1.0 1.3 1.4 1.1 0.8 1.2 1.3 1.1 1.0 1.0 1.3 0.7 0.6 0.7 0.7 0.9 0.8 1.2 1.0 0.9 0.9 1.1 0.8 1.1 1.2 1.3 1.0
Energy (kcal) 56 36 36 75 63 64 37 21 54 63 38 40 48 53 22 39 83 44 50 37 42 14 66 61 62 62 55 44 39 54 42 29 42 38
53 13 32 33 28 25 36 51 39 40
3 Tbsp + 1 tsp 1 Tbsp + 1 tsp 1/2 ear 3 Tbsp 2 Tbsp 1 Tbsp + 2 tsp 2 Tbsp + 1 tsp 3 Tbsp + 1 tsp 3 Tbsp 1 Tbsp + 2 tsp
19 21 21 18 18 19 21 19 18 20
8 23 8 17 14 20 20 16 15 17
0.9 1.0 1.0 0.8 0.7 1.0 1.1 0.9 0.8 0.9
38 46 29 39 36 38 47 44 42 43
24 30 20 21
3 Tbsp 3 Tbsp 2 Tbsp 2 Tbsp + 1 tsp
22 21 18 19
26 24 22 23
1.2 1.2 1.1 1.1
36 37 45 32
Homocystinuria 155
Food
Weight Approximate (g) Measure For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Tubers Potatoes, sweet baked, in skin (mashed) 50 1/4 cup boiled, no skin (mashed) 41 2 Tbsp canned, drained 98 1/2 cup Potatoes, white baked no skin 61 1/2 cup w/ skin 61 1/2 cup boiled no skin 78 1/2 cup w/ skin 68 1/4 cup + 3 Tbsp French fries, frozen (baked) (1/2" x 1/2" x 2") 50 10 pieces hash browns, frozen (cooked) 52 1/3 cup Tater Tots 84 9 pieces Yams, baked or boiled (mashed) 102 3/4 cup Miscellaneous Chow mein noodles Croutons Flour all purpose cake whole wheat Succotash Snack Foods Barnum's Animal Crackers Breadsticks Cookies chocolate chip fig bar gingersnap oatmeal raisin Oreo sugar butter Sugar Wafer (Nabisco ) vanilla wafer Crackers Goldfish , original graham (2" x 2") Melba toast Ritz Ritz Bits , cheese Rykrisp saltine Triscuits Waverly Wheat Thins Ding Dongs Doodads, original Doritos Fritos Ho Ho's Marshmallow Puff
MET (mg)
CYS (mg)
Protein (g)
Energy (kcal)
21 17 16
7 5 5
0.9 0.7 0.6
52 43 53
19 22 23 21 20 18 19 21
15 18 19 16 12 10 11 18
1.2 1.4 1.5 1.3 1.8 1.6 1.7 1.5
46 66 68 59 163 112 138 71
11 8 11 14 10 28
3 Tbsp 1 Tbsp + 1/2 tsp 1 Tbsp + 1-1/2 tsp 3 Tbsp + 1 tsp 1 Tbsp + 1 tsp 2 Tbsp + 1 tsp
19 19 20 19 22 19
22 23 24 23 29 15
1.1 1.2 1.1 1.1 1.3 1.4
56 41 39 53 33 32
16 9 24 40 21 14 27 20 28 20 17 14 9 17 11 11 12 14 14 16 48 12 18 18 28 38
6 crackers 1-1/2 breadsticks 2 cookies 2-1/2 cookies 3 cookies 1 cookie 2-1/2 cookies 1-1/2 cookies 5 wafers 5 wafers 28 crackers 2 crackers 1-1/2 pieces 5 crackers 15 crackers 1-3/4 pieces 4 crackers 3 crackers 2 crackers 9 crackers 1 piece 3 Tbsp + 1 tsp 10 chips 9 chips 1 piece 2 pieces
18 19 19 20 20 19 19 21 18 19 20 20 20 19 20 20 19 20 17 20 20 19 19 20 21 20
22 23 22 31 24 20 24 25 22 23 21 24 24 23 19 23 23 24 21 24 24 22 22 18 22 22
1.0 1.1 1.3 1.6 1.2 0.9 1.4 1.2 1.1 1.1 1.2 1.1 1.2 1.2 1.0 1.1 1.1 1.2 1.1 1.2 1.4 1.3 1.3 1.2 1.1 1.3
67 35 124 143 88 64 133 83 133 92 82 54 31 83 52 39 52 63 69 78 219 58 88 98 119 162
156 Homocystinuria
Weight Approximate (g) Measure For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Popcorn buttered 9 1 cup caramel 13 1/4 cup + 2 Tbsp plain 6 1 cup Potato chips, regular (2" diameter) 20 10 chips Pringles potato crisps 22 12 chips Pretzels 12 2 pretzels Sno Balls 43 1 piece Social Tea Biscuits 21 4 biscuits Twinkies 32 3/4 piece FATS Butter, stick Gravy, mushroom, canned Margarine liquid soft stick or brick Nondairy creamer w/ sodium caseinate liquid powder Rich's Coffee Rich Olives green black Salad dressings, commercial French Italian mayonnaise ranch Russian Thousand Island Toppings, commercial Cool Whip extra creamy regular Dessert topping w/ sodium caseinate frozen pressurized powder, amount to prepare Richwhip pressurized prewhipped Whipped cream, pressurized 10 10 5 10 10 5 2 49 9 9 11 11 5 5 5 11 2 tsp 2 tsp 1 tsp 2 tsp 2 tsp 1 tsp 1 tsp 1-3/4 fl oz 2 large 2 large 2 tsp 2 tsp 1 tsp 1 tsp 1 tsp 2 tsp
Food
MET (mg)
CYS (mg)
Protein (g)
Energy (kcal)
22 19 18 20 19 20 22 21 18
20 18 17 16 15 25 22 24 19
0.9 0.8 0.8 1.3 1.2 1.2 1.3 1.2 1.0
41 50 23 105 124 47 149 96 115
2 2 2 2 2 2 3 2 2 1 2 2 2 3 2 2
0 3 1 0 0 0 0 2 1 1 1 1 1 2 1 2
0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1
72 5 34 68 68 7 11 74 11 17 47 51 33 26 25 41
5 4 4 8 1 28 12 3
1 Tbsp 1 Tbsp 1 Tbsp 2 Tbsp 1 Tbsp 1 fl oz 3 Tbsp 1 Tbsp
3 1 2 2 2 2 2 2
1 0 0 0 0 2 2 1
0.1 0.1 0.1 0.1 0.1 0.1 0.2 0.1
16 11 13 22 8 78 37 8
FRUITS
Fruits are raw unless otherwise noted. Weight of raw fruits is only for parts that can be eaten. Drain canned, cooked, and frozen fruits before measuring or weighing. Apricots canned, heavy syrup diced dried cooked, diced halves
129 78 83 35
1/2 cup halves 1/2 cup 1/3 cup 10
4 5 5 6
3 3 3 4
0.7 1.1 1.1 1.3
107 37 70 83
Homocystinuria 157
Food
Weight Approximate (g) Measure For greatest accuracy, weigh food on scale that reads in grams. All measures are level. frozen, sweetened 121 1/2 cup nectar, canned 251 8 fl oz Avocados, all varieties, mashed 14 1 Tbsp Bananas, sliced 42 3 Tbsp 1 Blackberries canned, heavy syrup 32 2 Tbsp frozen, sweetened 77 1/3 cup raw 48 1/3 cup 1 Blueberries canned, heavy syrup 64 1/4 cup frozen, sweetened 77 1/3 cup raw 45 1/3 cup 1 Boysenberries canned, heavy syrup 32 2 Tbsp frozen, unsweetened 33 1/4 cup 1 Cherries sour, red, canned, heavy syrup 77 1/3 cup sweet canned, heavy syrup 48 1/3 cup frozen, sweetened 48 3 Tbsp raw 48 1/3 cup Dates 25 3 fruits Figs canned, heavy syrup 130 1/2 cup dried cooked 65 1/2 + 2 Tbsp uncooked 19 1 fruit whole, medium 75 1-1/2 fruits Fruit cocktail, canned, heavy syrup 64 1/2 cup Fruit salad, canned, heavy syrup 80 1/3 cup Gooseberries, canned, light syrup 47 3 Tbsp Grapefruit canned or raw, sections 230 1 cup juice, canned 247 8 fl oz Grapes adherent skin 30 3 Tbsp Thompson, seedless, canned, heavy syrup 31 2 Tbsp slipskin 23 1/4 cup juice, canned 253 8 fl oz Guava raw, diced 110 2/3 cup sauce 238 1 cup Kiwi fruit 19 1/4 piece Mangoes, diced 110 2/3 cup 3 Melons , cubed cantaloupe 40 1/4 cup casaba 42 1/4 cup honeydew 85 1/2 cup Mixed fruit, canned, heavy syrup 64 1/4 cup 3 Nectarines , sliced 26 3 Tbsp Oranges, all varieties juice fresh 248 8 fl oz canned 249 8 fl oz frozen, diluted 249 8 fl oz sections 22 2 Tbsp
MET (mg) 4 4 5 5 6 5 5 6 5 5 4 5 5 5 5 5 6 4 7 5 5 6 5 5 5 4 7 5 5 3 6 5 5 6 5 5 5 5 6 3 2 3 7 5 3 4 4 3 3 4 4 3 3 3 3 11 8 14 9 9 2 2 3 5 6 3 2 2 2 3 3 2 3 4 5 5 2 2
CYS (mg)
Protein (g) 0.8 0.9 0.3 0.4 0.4 0.3 0.3 0.4 0.3 0.3 0.3 0.4 0.6 0.6 0.6 0.6 0.5 0.5 0.8 0.6 0.6 0.2 0.3 0.3 1.3 1.3 0.2 0.2 0.1 1.4 0.9 0.8 0.2 0.6 0.4 0.4 0.4 0.2 0.2
Energy (kcal) 119 141 23 39 32 62 25 56 62 25 28 16 70 70 44 34 68 114 70 48 56 142 58 34 69 93 21 23 14 155 56 87 12 72 14 11 30 46 13
7 7 7 5
12 10 12 2
1.7 1.5 1.7 0.2
111 104 112 11
158 Homocystinuria
Weight Approximate (g) Measure For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Papayas, diced 140 1 cup Peaches canned, heavy syrup, sliced 64 1/4 cup frozen, sweetened, sliced 47 3 Tbsp nectar, canned 62 2 fl oz sliced 42 1/4 cup spiced, canned, heavy syrup 60 1/4 cup Pears canned, heavy syrup, halves 255 1 cup dried cooked, diced 64 1/4 cup uncooked halves 18 1 nectar, canned 250 8 fl oz sliced 124 3/4 cup Persimmons, Japanese, raw 126 3/4 fruit Pineapple canned, heavy syrup, chunks or crushed 64 1/4 cup frozen, sweetened, chunks 61 1/4 cup diced 39 1/4 cup juice canned 62 2 fl oz frozen, diluted 62 2 fl oz Plantain, cooked, sliced 51 1/3 cup Plums purple, canned, heavy syrup 129 1/2 cup sliced 82 1/2 cup Prunes dried cooked 53 1/4 cup uncooked 25 3 fruits juice, canned 128 4 fl oz Raisins, seedless 5 1-1/2 tsp 1 Raspberries canned, heavy syrup 64 1/4 cup frozen, sweetened 62 1/4 cup raw 41 1/3 cup 1 Rhubarb , cooked, sweetened 120 1/2 cup Tangerines canned, light syrup 47 3 Tbsp juice canned 249 8 fl oz fresh 247 8 fl oz frozen, diluted 241 8 fl oz sections 37 3 Tbsp Watermelon, diced 80 1/2 cup
Food
MET (mg) 3 7 7 4 7 6 5 7 4 4 6 6 6 7 4 6 7 5 4 5 1 2 2 2 2 2 5 6 3 3 5 16 1 1 1 1 1 6 3 4
CYS (mg)
Protein (g) 0.9 0.3 0.3 0.2 0.3 0.2 0.5 0.6 0.3 0.3 0.5 0.7 0.2 0.2 0.2 0.2 0.2 0.4 0.5 0.6
Energy (kcal) 54 48 44 34 18 45 188 81 46 149 73 88 50 52 19 35 32 60 115 46
5 5 6 5 7 6 5 7 6 5 5 5 5 5
3 3 4 2 6 5 4 6 3 10 10 7 3 2
0.6 0.7 0.8 0.1 0.5 0.4 0.4 0.5 0.3 1.2 1.2 1.0 0.2 0.5
57 60 90 14 58 64 20 139 17 125 106 110 16 25
VEGETABLES Vegetables are raw unless otherwise noted. Weight of raw vegetables is only for parts that can be eaten. Drain canned, cooked, and frozen fruits before measuring or weighing. Asparagus, cooked Bamboo shoots, cooked Beans snap, green, cooked sprouts, mung (seed attached to sprout) yellow wax, cooked 45 60 41 26 65 1/2 cup 1/2 cup 1/3 cup 1/4 cup 1/4 cup 11 10 10 9 9 14 8 7 4 7 1.2 0.9 0.8 0.8 0.7 11 7 14 8 13
Homocystinuria 159
Food
Weight Approximate (g) Measure For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Beets, cooked greens, chopped 48 1/3 cup root 85 1/2 cup Broccoli, fresh or frozen, cooked 24 2 Tbsp + 1-1/2 tsp Brussels sprouts, fresh or frozen, cooked 42 2 sprouts Cabbage, shredded Chinese (Pak-choi) cooked, 112 2/3 cup raw 116 1-2/3 cup red cooked 94 10 Tbsp raw 70 1 cup white coleslaw 60 1/2 cup cooked 112 3/4 cup Carrots cooked 137 3/4 cup + 2 Tbsp raw, shredded 137 1-1/4 cups Cauliflower cooked 41 1/3 cup raw 33 1/3 cup Celery, diced cooked 225 1-1/2 cups raw 180 1-1/2 cups Chives 36 3/4 cup Collards, cooked, chopped 63 1/3 cup Cucumbers, pared, sliced 208 2 cups Eggplant, cubed cooked 120 1-1/4 cups raw 82 1 cup Endive, shredded 75 1-1/2 cups Kale, cooked 49 1/4 cup + 2 Tbsp Kohlrabi, cooked, sliced 72 1/4 cup + 3 Tbsp Leeks, diced cooked 91 3/4 cup + 2 Tbsp raw 52 1/2 cup Lettuce, shredded bibb 56 1 cup iceberg 70 1-1/4 cups leaf 56 1 cup Romaine 49 3/4 cup + 2 Tbsp Mushroom, Agaricus bisporus, sliced cooked 26 1/3 cup raw 22 1/3 cup Mustard greens, chopped cooked 46 1/3 cup raw 42 3/4 cup Okra, cooked 53 1/3 cup Onions cooked 158 3/4 cup diced 106 2/3 cup rings 13 1-1/4 rings Parsnips, cooked 59 1/4 cup + 2 Tbsp Peas, green cooked 13 1 Tbsp + 1 tsp
MET (mg)
CYS (mg)
Protein (g)
Energy (kcal)
10 10 9 10
11 11 5 7
1.2 0.9 0.7 1.1
13 26 7 16
10 11 10 10 11 11 10 10 11 9 9 9 11 9 8 11 10 11 9 10 9 9 9 10 9 10 10 9 10 11 11 11 11 10 10 11
19 20 9 8 9 9 12 11 9 8 7 7 18 7 6 5 5 8 12 5 13 13 8 10 9 9 1 1 16 17 10 25 22 14 4 4
1.8 1.7 1.0 1.0 0.8 1.1 1.5 1.4 0.8 0.7 1.1 1.2 1.0 0.7 1.1 1.0 0.9 0.9 0.9 1.3 0.7 0.8 0.7 0.7 0.7 0.8 0.5 0.5 1.0 1.1 1.0 1.4 1.2 0.7 0.8 0.7
13 15 20 19 41 24 61 59 10 8 34 29 9 9 27 34 21 13 16 21 28 32 7 9 10 8 6 6 7 11 17 44 36 51 47 11
160 Homocystinuria
Weight Approximate (g) Measure For greatest accuracy, weigh food on scale that reads in grams. All measures are level. pods (edible) cooked 80 1/2 cup raw 95 2/3 cup w/ carrots, cooked 20 2 Tbsp Pickles, cucumber dill relish 19 1 Tbsp + 1 tsp whole 180 3 pickles sweet relish 251 1 cup sliced 180 6 pickles Pumpkin cooked 81 1/3 cup pie mix (no eggs) 89 1/3 cup Radishes, red, sliced 145 1-1/4 cup Rutabagas cooked, mashed 112 2/3 cup raw, cubed 105 3/4 cup Sauerkraut 118 1/2 cup Shallots, chopped 40 1/4 cup Spinach, chopped cooked 19 1 Tbsp + 2 tsp raw 18 1/3 cup Squash, summer, all varieties summer, all varieties cooked 67 1/4 cup + 2 Tbsp sliced 65 1/2 cup winter acorn, baked 68 1/3 cup butternut, baked 103 1/2 cup Hubbard, baked 58 1/2 cup spaghetti, boiled 135 3/4 cup + 2 Tbsp Tomatoes catsup 16 1 Tbsp juice 128 4 fl oz paste 66 1/4 cup pure 49 3 Tbsp raw, diced 125 1/2 cup sauce 122 1/2 cup spaghetti sauce, no meat 124 1/2 cup stewed, canned 135 3/4 cup Turnips greens, cooked chopped 36 1/4 cup w/ turnips 24 2 Tbsp + 1 tsp root cooked 117 3/4 cup diced 98 3/4 cup Vegetables, mixed, cooked 28 2 Tbsp + 1-1/2 tsp
Food
MET (mg)
CYS (mg)
Protein (g)
Energy (kcal)
10 11 9
30 31 4
2.6 2.7 0.6
34 40 10
10 9 10 9 10 11 10 10 11 11 11 10 10
1 7 8 7 2 3 7 11 12 9 22 6 7
0.1 1.3 1.3 1.3 0.9 1.0 0.9 1.2 1.3 1.1 1.0 0.5 0.5
4 20 346 263 28 93 25 38 38 22 29 4 4
9 11 10 11 10 9 11 10 12 9 11 9 11 11
7 8 7 8 8 7 3 15 15 11 13 10 14 16
0.6 0.8 0.8 0.9 1.4 0.9 0.3 1.2 2.5 1.9 2.1 1.6 2.3 1.2
13 13 38 41 29 39 16 33 55 41 51 37 135 26
9 10 11 11 10
5 5 5 5 7
0.4 0.5 0.8 0.9 0.8
7 4 21 26 17
Soups, Campbell's , Condensed. Weigh or measure before diluting and dilute with water only. Asparagus, Cream of 31 2 Tbsp 10 Beef Broth 15 1 Tbsp 9 Celery, Cream of 39 2 Tbsp + 1-1/2 tsp 9 Chicken Cream of 16 1 Tbsp 10 Gumbo 31 2 Tbsp 11
8 4 6 6 4
0.6 0.3 0.5 0.4 0.7
22 2 28 15 14
Homocystinuria 161
Food
Weight Approximate (g) Measure For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Noodle 15 1 Tbsp Vegetable 20 1 Tbsp + 1 tsp Minestrone 31 2 Tbsp Mushroom, Cream of 31 2 Tbsp Onion 38 2 Tbsp + 1-1/2 tsp Potato, Cream of 39 2 Tbsp + 1-1/2 tsp Scotch Broth 15 1 Tbsp Tomato 63 1/4 cup Tomato Bisque 39 2 Tbsp + 1-1/2 tsp Tomato Rice 48 3 Tbsp Vegetable, Chunky, Ready To Serve 90 1/4 cup + 2 Tbsp Vegetable, Old Fashioned 46 3 Tbsp Vegetarian Vegetable 46 3 Tbsp
MET (mg) 9 10 11 10 9 9 11 11 9 9 10 9 9 6 4 8 6 21 9 4 14 7 11 10 9 9
CYS (mg)
Protein (g) 0.5 0.6 1.1 0.5 1.2 0.5 0.6 1.0 0.7 0.8 1.3 0.8 0.8
Energy (kcal) 9 13 21 32 18 23 10 43 38 45 46 24 27
FREE FOODS A
Limit to prescribed number of servings. Desserts Apple butter Fruit ices Fruit juice bars Fruit Roll-Ups Fun Fruits Gelatin dessert, prepared M&M plain candy Marshmallow, large Mocha Mix, frozen vanilla Fruits/Juices Apples canned w/ sugar dried, diced cooked uncooked whole Applesauce w/ sugar Cranberry sauce w/ sugar Lemon juice Lime juice Marmalade Pie filling apple cherry peach strawberry Papaya nectar Pear nectar Tangerine juice w/ sugar Miscellaneous Chocolate drink powder (Quik )
20 12 14 26 16 11 1 8 8
1 Tbsp 1 Tbsp 1 bar 1 piece 1 Tbsp 1/4 cup 1 piece 1 1 Tbsp
1 1 1 1 2 1 1 1 1
1 1 1 1 2 0 1 0 2
0.1 0.0 0.2 0.1 0.2 0.1 0.1 0.2 0.1
37 16 55 100 65 8 4 26 17
67 64 11 69 64 35 31 92 13 81 26 17 83 94 94 62
1/3 cup 1/4 cup 2 Tbsp 1/2 fruit 1/4 cup 2 Tbsp 1 fl oz 3 fl oz 2 tsp 1/3 cup 1 Tbsp + 2 tsp 1 Tbsp 1/3 cup 3 fl oz 3 fl oz 2 fl oz
1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1
1 2 1 2 1 1 1 2 1 2 1 1 3 1 1 3
0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.2 0.1 0.1 0.1 0.1 0.4 0.2 0.1 0.3
45 36 26 41 48 52 6 19 33 89 27 18 90 54 56 31
1 tsp
0.1
11
FREE FOODS B These foods contain little or no MET or CYS. They may be used as desired if patient is not overweight and if they do not depress appetite for prescribed foods. Beverages Apple juice
62
2 fl oz
0.0
29
162 Homocystinuria
Weight Approximate (g) Measure For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Carbonated beverages cola 123 4 fl oz cream soda 124 4 fl oz Dr Pepper 123 4 fl oz ginger ale 122 4 fl oz grape soda 124 4 fl oz lemon lime soda 123 4 fl oz orange soda 124 4 fl oz root beer 123 4 fl oz Cranberry juice cocktail 127 4 fl oz Exceed Energy Drink 124 4 fl oz Fruit Drink (Hi-C ) 124 4 fl oz Gatorade Thirst Quencher 121 4 fl oz Kool-Aid sweetened w/ sugar 123 4 fl oz Lemonade sweetemed w/ sugar 123 4 fl oz Orange drink powder (Tang ) 12 1 Tbsp Strawberry Quik drink powder 8 1 Tbsp Desserts/Sweets Candies candy corn gumdrops hard candy jelly beans Frosting, strawberry and vanilla Fruit bars, frozen raspberry strawberry Fruit juice bars Jams/preserves Jelly Lemon pudding, canned (Hunt's ) Molasses Popsicle , twin Sugar brown powdered table Syrup corn maple table Miscellaneous Oil olive vegetable Richwhip liquid Vinegar/oil salad dressing
1 2
Food
MET (mg)
CYS (mg)
Protein (g)
Energy (kcal)
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.0 0.0
50 63 50 41 53 49 60 50 72 35 58 30 49 49 47 33
16 16 15 14 16 74 74 52 20 20 121 21 128 14 8 12 20 20 20
10 pieces 8 pieces 3 pieces 5 pieces 1 Tbsp 1 bar 1 bar 1 bar 1 Tbsp 1 Tbsp 1 can 1 Tbsp 1 popsicle 1 Tbsp 1 Tbsp 1 Tbsp 1 Tbsp 1 Tbsp 1 Tbsp
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 4 0 4 1 0 0 0 0 0 0 0 0 0 0
0.0 0.0 0.0 0.0 0.0 0.6 0.0 0.6 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
58 56 58 51 69 60 60 43 54 54 151 48 95 52 31 48 58 50 50
13 14 14 16
1 Tbsp 1 Tbsp 1 Tbsp 1 Tbsp
0 0 0 0
0 0 0 0
0.0 0.0 0.0 0.0
119 120 40 70
MET calculated as 1.4% of protein and CYS as 1.2% of protein. See Appendix 12, p A-11, for nutrient composition of very-low-protein foods.
Homocystinuria 163
TABLE 8-4. Nutrient Composition of HOMINEX -1 1,3 and HOMINEX -2 2,3

Hominex-1 Hominex-2 (per 100 g pwd) (per g protein equiv) (per 100 g pwd) (per g protein equiv) Energy, kcal 480 32 410 13.7 Protein equiv, g 15.00 1.000 30.00 1.000 Nitrogen, g 2.40 0.160 4.80 0.160 17.67 1.178 35.34 1.178 Amino acids, g Cystine, g 0.45 0.030 0.90 0.030 Histidine, g 0.42 0.028 0.84 0.028 Isoleucine, g 1.08 0.072 2.16 0.072 Leucine, g 1.68 0.112 3.36 0.112 Lysine, g 1.00 0.067 2.00 0.067 Methionine, g trace 0 trace 0 Phenylalanine, g 0.88 0.059 1.76 0.059 Threonine, g 0.70 0.047 1.40 0.047 Tryptophan, g 0.17 0.011 0.34 0.011 Tyrosine, g 0.89 0.059 1.78 0.059 Valine, g 1.22 0.081 2.44 0.081 Other Nitrogen-Containing Compounds Carnitine, mg 20 1.33 40 1.33 Taurine, mg 40 2.67 50 1.67 Carbohydrate, g 53.0 3.53 35 1.17 Fat, g 21.7 1.45 14 0.47 4 5 Linoleic acid, g 2.00 0.133 1.50 0.050 6 7 0.36 0.024 0.17 0.006 -Linolenic acid, g Minerals Calcium, mg 575 38 880 29 Chloride, mg/mEq 435/12.27 29.0/0.82 1,160/32.72 38.7/1.09 Chromium, g 11 0.73 27 0.90 Copper, mg 1.10 0.073 1.00 0.033 Iodine, g 65 4.33 100 3.33 Iron, mg 9.0 0.60 13 0.43 Magnesium, mg 50 3.33 225 7.50 Manganese, mg 0.50 0.033 0.80 0.027 Molybdenum, g 12 0.80 30 1.00 Phosphorus, mg 400 27 760 25 Potassium, mg/mEq 675/17.26 45./1.15 1,370/35.04 45.7/1.17 Selenium, g 20 1.33 35 1.17 Sodium, mg/mEq 190/8.26 12.7/0.55 880/38.28 29.3/1.28 Zinc, mg 8.0 0.53 13 0.43 Vitamins A, g RE 420 28 660 22 D, g 7.50 0.50 7.50 0.25 10.10 0.67 12.10 0.40 E, mg -TE K, g 50 3.33 60 2.00 Ascorbic acid, mg 50 3.33 60 2.00 Biotin, g 65 4.33 100 3.33 B6, mg 0.75 0.050 1.30 0.043 B12, g 4.90 0.327 5.00 0.167 Choline, mg 80 5.33 100 3.33 Folate, g 230 15 450 15 Inositol, mg 40 2.67 70 2.33 Niacin equiv, mg 12.80 0.850 21.7 0.72 Pantothenic acid, mg 6.90 0.460 8.00 0.267 Riboflavin, mg 0.90 0.060 1.80 0.060 Thiamin, mg 1.90 0.127 3.25 0.108 1 2 Designed for infants and toddlers. Designed for children, adolescents, and adults. 3 Approximate packed weight of Hominex in level, dry US standard household measures: Hominex-1 Hominex-2 1 Tbsp = 7g 8g 1/4 cup = 26 g 32 g 1/3 cup = 35 g 41 g 1/2 cup = 53 g 61 g 1 cup = 105 g 117 g 4 5 Analytical data at manufacture = 4.32 g/100 g powder. Analytical data at manufacture = 2.66 g/100 g powder. 6 7 Analytical data at manufacture = 0.40 g/100 g powder. Analytical data at manufacture = 0.28 g/100 g powder. Nutrient
4
164 Homocystinuria
2001 Ross Products Division Homocystinuria 163
TABLE 8-5. Homocystinuria Clinical Summary Sheet Name: Date of Birth: __________/__________/__________
Mo Day Year
Hospital Number:
Date
(mo/d/yr)
Age
(yrs/mo)
Physical Data
Length/ Height (cm) Weight (kg) Head Circum (cm) MET
1
Laboratory Data
CYS
1

Ferritin (ng/mL) Transthyretin (mg/dL) Folate
2
Homo1 cystine
Hgb (g/dL)
Hct (%)
MET (mg)
CYS (mg)
Protein (g)
Energy (kcal)
(ng/mL)
1 2
Indicate if mg/dL or mol/L. Indicate if serum or erythrocyte.
REFERENCES
1. Acosta PB: The contribution of therapy of inherited amino acid disorders to knowledge of amino acid requirements. In Wapnir RA (ed): Congenital Metabolic Diseases: Diagnosis and Treatment. New York: Marcel Dekker Inc, 1985, 115-135. Acosta PB: Growth, tolerance, plasma amino acids, and plasma biochemistries of infants with cystathionine-synthase deficiency (B-6 nonresponsive) or phenylalanine hydroxylase deficiency. Columbus OH: Ross Laboratories, 1992. Acosta PB, Yannicelli S: Nutrition support of inherited disorders of amino acid metabolism. Part 2. Top Clin Nut 1995;10:48-72 (Review). Acosta PB, Yannicelli S: Protein intake affects phenylalanine requirements and growth of infants with phenylketonuria. Acta Paediatr 1994;407 (Suppl):66-67. Albin RL, Albers JW, Greenberg HS, et al: Acute sensory neuropathy-neuronopathy from pyridoxine overdose. Neurology 1987;37:1729-1732. Arnold GL, Vladutiu CJ, Kirby RS: Protein insufficiency and impaired growth in children with PKU. J Inher Metab Dis 2000;23 (Suppl 1):29A. Berardelli A, Thompson PD, Zaccaqnini M, et al: Two sisters with generalized dystonia associated with homocystinuria. Mov Disord 1991;6:163-165. Berg WVd, Verbrook FD, Bos PJM: Homocystinuria presenting as longstanding thromboembolic disease. Br J Ophthalmol 1990;74:696-697. Behrman RE, Kliegman RM, Arvin AA: Nelson Textbook of Pediatrics, ed 15. Philadelphia: WB Saunders Co, 1996. Calomme MR, Vanderpas JB, Francois B, et al: Thyroid function parameters during a selenium repletion/depletion study in phenylketonuric subjects. Experientia 1995;51:1208-1215. Carey MC, Fennelly JJ, Fitzgerald O: Homocystinuria II. Subnormal serum folate levels, increased folate clearance and effects of folic acid therapy. Am J Med 1968;45:26-31. Celermayer DS, Sorensen, K, Ryalls M, et al: Impaired endothelial function occurs in the systemic arteries of children with homozygous homocystinuria but not in their heterozygous parents. J Am Coll Cardiol 1993;22:854-858. Dudman NPB, Wilcken DEL: Increased plasma copper in patients with homocystinuria due to cystathionine--synthase deficiency. Clin Chim Acta 1983;127:105-113. Elsas LJ, Acosta PB: Nutrition support of inherited metabolic diseases. In Shils ME, et al (eds): Modern Nutrition in Health and Disease, ed 9. Baltimore: Williams & Wilkins, 1999, pp 1003-1056. Food and Nutrition Board, Committee on Dietary Allowances: Recommended Dietary Allowances, eds 9 and 10. Washington, DC: National Academy of Sciences, 1980 and 1989. Gropper S, Acosta PB: Effect of simultaneous ingestion of L-amino acids and whole protein on plasma amino acid and urea nitrogen concentrations in humans. JPEN 1991;15:48-53. Gropper SS, Gropper DM, Acosta PB: Plasma amino acid response to ingestion of L-amino acids and whole protein. J Pediatr Gastroent Nutr 1993;16:143-150. Herbert VD, Das KC: Folic acid. In Shils ME, et al (eds): Modern Nutrition in Health and Disease, ed 9. Philadelphia: Williams & Wilkins, 1999, pp 433-448. Herrmann ME, Broesicke HG, Keller M, et al: Dependence of the utilization of a phenylalanine-free amino acid mixture on different amounts of single dose ingested. A case report. Eur J Pediatr 1994;153:501-503. Ilan Y, Eid A, Rivkind AI, et al: Gastrointestinal involvement in homocystinuria. J Gastroent Hepat 1993;8:60-62. Kempster PA, Brenton DP, Gale AN, Stern GM: Dystonia in homocystinuria. J Neurol Neurosurg Psychiatry 1988;51:859-862. Jones BJM, Lees R, Andrews J, et al: Comparison of an elemental and polymeric enteral diet in patients with normal gastrointestinal function. Gut 1983;24:78-84. Leverton RM, Johnson N, Dazur J, Ellison J: Amino acid requirements of young adults. In Albanese AA (ed): Protein and Amino Acid Nutrition. New York: Academic Press, 1959. MacLean W, Graham G: Pediatric Nutrition in Clinical Practice. Menlo Park, Calif: Addison-Wesley Publishing Co, 1982. Martin SB, Acosta PB: Osmotic behaviors of components of chemically-defined formulas. J Pediatr Perinat Nutr 1987;1:1-17. Mpofu C, Whitehouse C, Fowler B, Wraith JE: No sensory neuropathy during pyridoxine treatment in homocystinuria. Arch Dis Child 1991;66:1081-1082. Mudd SH, Levy HL, Kraus J: Disorders of transsulfuration. In Scriver CR, et al (eds): The Metabolic and Molecular Bases of Inherited Metabolic Disease, ed 8. New York: McGraw-Hill Medical Publishing Division, 2001, pp 2007-2056. Mudd SH, Skovby F, Levy H, et al: The natural history of homocystinuria due to cystathionine--synthase deficiency. Am J Hum Genet 1985;37:1-31.
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13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27.
28.
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29. Munnich A, Saudubray JM, Dautzenberg MD, et al: Diet-responsive proconvertin (factor VII) deficiency in homocystinuria. J Pediatr 1983;102:730-734. 30. Ohkohchi N, Andoh T, Ohi R, Mori S: Defined formula diets alter characteristics of the intestinal transport of amino acidsand peptides in growing rats. J Pediatr Gastroenterol Nutr 1990;10:490-496. 31. Parrot F, Redonnet-Verhet I, Lacombe D, Gin H: Osteoporosis in late-diagnosed adult homocystinuric patients. J Inher Metab Dis 2000;23:338-340. 32. Patil RV, Kulthe SG, John Boby KF, et al: Chronic pancreatitis in homocystinuria. Indian Pediatr 1995;32:469-470. 33. Posati LP, Orr ML: Composition of Foods: Dairy and Egg Products, Agriculture Handbook No. 8-1. Washington, DC: US Dept of Agriculture, Agricultural Research Service, 1976. 34. Pratt EL, Snyderman SE, Cheung MW, et al: The threonine requirement of the normal infant. J Nutr 1955;56:231-251. 35. Sansaricq C, Garg S, Norton PM, et al: Cystine deficiency during dietotherapy of homocystinemia. Acta Paediatr Scand 1975;64:215-218. 36. Schaumburg H, Kaplan J, Windebank A, et al: Sensory neuropathy from pyridoxine abuse. N Engl J Med 1983;309:445-448. 37. Schoeffer A, Herrmann ME, Broesicke HG, Moench E: Effect of dosage and timing of amino acid mixtures on nitrogen retention in patients with phenylketonuria. J Nutr Med 1994;4:415-418. 38. Shoji Y, Takahashi T, Sato W, et al: Acute life-threatening event with rhabdomyolysis after starting on high-dose pyridoxine therapy in an infant with homocystinuria. J Inher Metab Dis 1998;21:439-440. 39. Smith CA, Nelson NM: The Physiology of the Newborn Infant, ed 4. Springfield, Ill: Charles C Thomas Publisher, 1976. 40. Smith JL, Arteaga C, Heymsfield SB: Increased ureagenesis and impaired nitrogen use during infusion of a synthetic amino acid formula - A controlled trial. N Engl J Med 1982;306:1013-1018. 41. Smith JL, Heymsfield SB: Enteral nutrition support: Formula preparation from modular ingredients. JPEN 1983;7:280-288. 42. Smolin LA, Benevenga NJ, Berlow S: The use of betaine for the treatment of homocystinuria. J Pediatr 1981;99:467-472. 43. Snyderman SE, Boyer A, Norton PM, et al: The essential amino acid requirements of infants. X. Methionine. Am J Clin Nutr 1964;15:322-330. 44. Spika JS, Shaffer N, Hargrett-Bean N, et al: Risk factors for infant botulism in the United States. Am J Dis Child 1989;143:828-832. 45. Spooner RJ, Fell GS, Halls DJ, et al: Selenium depletion and its correction in a child with homocystinuria. Clin Nutr 1986;5:29-32. 46. Wannemacher RW: Key role of various individual amino acids in host response to infection. Am J Clin Nutr 1977;30:1269-1280. 47. Weir DG, Scott JM: Vitamin B12 "Cobalamin". In Shils ME, et al (eds): Modern Nutrition in Health and Disease, ed 9. Philadelphia: Williams & Wilkins, 1999, pp 447-458. 48. Wilcken DEL, Wilcken B, Dudman NPB, et al: Homocystinuria The effects of betaine in the treatment of patients not responsive to pyridoxine. N Engl J Med 1983;309:448-453. 49. Yap S, Naughten E: Homocystinuria due to cystathionine -synthase deficiency in Ireland: 25 years experience of a newborn screened and treated population with reference to clinical outcome and biochemical control. J Inher Metab Dis 1998;21:738-747. 50. Yoshida Y, Nakano A, Hamada R, et al: Patients with homocystinuria: High metal concentrations in hair, blood and urine. Acta Neurol Scand 1992;86:490-495.
Homocystinuria 167
PROTOCOL 9 Glutaric Aciduria Type I or 2-Ketoadipic Aciduria Nutrition Support of Infants, Children, and Adults With GLUTAREX -1 and GLUTAREX -2 Amino Acid-Modified Medical Foods
I. Introduction
A. Glutaric Aciduria Glutaric aciduria type I (GA-I) is an autosomal recessive disorder caused by a defect in activity of glutaryl-CoA dehydrogenase (GDH) (Figure H), a mitochondrial flavin-dependent enzyme required for catabolism of essential lysine (LYS) and tryptophan (TRP) (24, 32). A defect in GDH results in accumulation of glutaric acid, 3-hydroxy (OH)-glutaric and glutaconic acids in physiologic fluids. Pharmacologic doses of oral riboflavin (100-200 mg/day), a coenzyme for the GDH complex, are given to increase half-life of any residual enzyme. GA-I is heterogeneous in its clinical and biochemical presentations (24, 26, 31). Patients with GA-I appear normal at birth and develop normally until a viral-like illness results in overwhelming clinical crisis and neurologic deterioration. Symptoms often include macrocephaly, myoclonic seizures, ataxia, choreoathetosis, episodic vomiting, intermittent metabolic acidosis or a Reye-like syndrome (5, 24, 29, 30). Neuro-imaging shows characteristic frontotemporal atrophy and delayed myelination (2, 5, 7). Plasma glutaric acid concentrations during acute crises vary and may even be normal (5, 29). Abnormal urinary organic acids and acylcarnitine concentration is diagnostic in most cases (29, 31, 42). Nearly 100 mutations have been identified in the gene encoding GDH. No clear correlation has been found between genotype and clinical phenotype (31). The exact cause of the pathophysiology of GA-I is not known, but may be due to toxic effects of glutaric acid, quinolinic acid, or 3-OH-glutaric acid (24, 28, 67) or an abnormality in aminobutyric acid metabolism (24). Incidence of GA-I is not known, but may be as high as one in 30,000 live births (35) with an increased prevalence in an old-order Amish community (43).
Figure H. Lysine and tryptophan metabolism in 2-ketoadipic aciduria and glutaric aciduria type I B. 2-Ketoadipic Aciduria 2-Ketoadipic aciduria (KAA) results from defect in activity of 2-ketoadipic acid dehydrogenase (KAD), which is required for metabolism of essential LYS and TRP. Defect in KAD results in
168 Glutaric Aciduria Type I or 2-Ketoadipic Aciduria 2001 Ross Products Division
accumulation of plasma LYS and TRP and 2-aminoadipic, 2-ketoadipic, and 2-OH-adipic acids in biologic fluids. Symptoms include hypotonia, intermittent metabolic acidosis, and motor and
Glutaric Aciduria Type I or 2-Ketoadipic Aciduria 169
developmental delay (50). One patient has been described with psychomotor retardation and seizures with abnormal electroencephalograms (15). Actual incidence of KAA is not known, and few patients have been reported. No clear correlation has been found between the metabolic defect and clinical symptoms in patients with KAA (24, 50). Large phenotypic heterogeneity in this disorder and findings of asymptomatic patients suggest that KAA may be a benign defect (45). However, one patient showed clinical improvement after diet intervention (24).

Early identification and appropriate medical and nutrition management of patients with GA-I during acute crises affect outcome. Researchers have reported near-normal development in most patients treated prior to initial neurologic crises (5, 31, 42, 68). Patients who are diagnosed after acute encephalopathy suffer permanent loss in motor skills, but preserve cognitive functions. In neurologically impaired patients, treatment results in limited or no clinical improvement, but may prevent further neurologic deterioration. Treatment should be directed towards normalization of plasma glutaric acid, and maintaining low normal LYS and TRP concentrations.

A. The Defects 1. GA-I results from defect in GDH. 2. KAA results from defect in KAD. B. Screening 1. Neonatal screening for the presence of elevated plasma glutarylcarnitine concentrations using tandem mass spectrometry can be used to identify patients with GA-I. C. Clinical Evaluation 1. Glutaric aciduria type I. a. Diagnostic studies should be conducted in any child who has following signs within first 18 months of life (24, 29): 1) Macrocephaly (5, 30). 2) Abnormal CT scan or magnetic resonance imaging (MRI) (5, 7, 24). 3) Abnormal movement disorder including spasticity and choreoathetosis. 4) Ketosis, vomiting, hepatomegaly, coma, and convulsions. 5) Metabolic acidosis. 6) Hypoglycemia (14). 7) Renal cysts. 2. 2-Ketoadipic aciduria. a. Diagnostic studies should be conducted in any child who has following signs within first 2 years of life (24). 1) Hypotonia. 2) Motor and developmental delay (49, 50). 3) Psychomotor retardation and seizures (15). 4) Metabolic acidosis.

A. Correct Primary Imbalance in Metabolic Relationships (16) 1. Restrict dietary LYS and TRP to amounts tolerated by patient to maintain treatment plasma concentrations. B. Stabilize Altered Enzyme Protein 1. Administer trial of pharmacologic oral riboflavin if any GDH activity is present (29).
V. Nutrition Support During Acute Illness

A. Initiation of Nutrition Support 1. Initiate nutrition support immediately. Do not wait for confirmation of diagnosis.
170 Glutaric Aciduria Type I or 2-Ketoadipic Aciduria
B. Medical Care 1. Implement standard medical management. 2. Intravenous L-carnitine (100 to 300 mg/kg), glucose infusion, and bicarbonate therapy have been suggested to treat acute crises (5, 29). C. Patients With Acute Metabolic Acidosis and Neurologic Depression 1. Begin oral or nasogastric feeds free of LYS and TRP with sufficient protein and energy to promote anabolism. a. Provide recommended protein (Table 9-1, p 176) with Glutarex (Table 9-2, p 177). b. Provide remaining prescribed energy with Pro-Phree Protein-Free Energy Module With Iron, Vitamins & Minerals (Appendix 11, p A-10) or Polycose Glucose Polymers (3.8 kcal/g) (Appendix 9, p A-9). c. When plasma concentrations of LYS and TRP approach lower limit of normal and urine contains no glutaric, 3-OH-glutaric, glutaconic, 2-ketoadipic, 2-hydroxyadipic, or 2-aminoadipic acids, begin adding LYS and TRP using Similac With Iron Infant Formula, beikost, or table foods (Table 9-3, p 178). Note: Some patients do not excrete glutaric acid during acute crises (5, 24, 29). 2. L-carnitine therapy is essential during acute illness. Administration should be considered if insufficient Glutarex is provided to supply prescribed oral carnitine. a. Recommended L-carnitine intake is between 100 and 300 mg/kg (Appendix 26, p A-28). 3. If parenteral amino acid solutions are indicated, see Appendix 26, p A-28. 4. See references 5 and 42 for more information on treatment during acute intermittent illness.

A. Plasma LYS and TRP Concentrations 1. Maintain 2- to 4-hour postprandial plasma LYS and TRP concentrations in low-normal ranges given below, or on low side of normal for age in laboratory used. a. LYS: 45-90 mol/L (38, 41). b. TRP: 15-65 mol/L (3). c. In practice, obtaining blood 2 to 4 hours postprandially is not always possible. Acceptable local standards should be developed if plasma amino acids are evaluated at other times (Practical Aspects of Nutrition Support, p viii). B. Plasma Glutaric Acid Concentration 1. Maintain plasma concentration of glutaric acid < 250 ng/mL. 2. See Table 9-4, p 178, for laboratory that quantifies plasma glutaric acid. C. Urine Metabolites 1. Maintain normal excretion of glutaric, 3-HO-glutaric, glutaconic, 2-ketoadipic, or 2-hydroxyadipic acids. Organic acids may not be present in urine even during acute illness (9, 10, 24, 29). D. Growth, Development, and Nutrition Status 1. Support normal growth rate in infants and children and maintain appropriate weight for height in adults. 2. Support normal development. 3. Maintain normal nutrition status. a. Avoid prolonged fasting. 4. Maintain adequate hydration. 5. Prevent catabolism and neurologic deterioration. E. Plasma Free Carnitine Concentration 1. Maintain normal plasma free carnitine concentration ( 30 mol/L).

A. LYS and TRP 1. Prescribe LYS and TRP intakes that promote goals of long-term nutrition support (Table 9-1, p 176).
2001 Ross Products Division Glutaric Aciduria Type I or 2-Ketoadipic Aciduria 171
2. LYS and TRP requirements. a. Are not well-established because of limited clinical experience with these disorders. b. Vary based on genotype and enzyme activity, which ranges from 0% to 10% of normal (24, 32) in GA-I. c. Vary in same patient, depending on: 1) Age. 2) Growth rate. 3) Adequacy of energy and protein intakes. 4) State of health. 3. Lowest values for age for LYS and TRP (Table 9-1, p 176) are suggested for initiating longterm nutrition support. 4. Changing requirements of patients are determined by frequent monitoring of plasma LYS, TRP, and glutaric acid concentrations and growth in infants and children, and plasma LYS, TRP, and glutaric acid concentrations and weight in adults. a. See Section X, Suggested Evaluation of Nutrition Support, p 172. Warning: LYS and TRP deficiencies result in the following adverse effects: LYS (60): Impaired weight gain and excessive urinary nitrogen excretion. TRP: Impaired weight gain; increased plasma urea nitrogen; increased plasma -amino nitrogen; decreased plasma cholesterol concentration (59), irritability, sleeplessness, and anorexia (5). B. Protein 1. Prescribe, initially, amount greater than Recommended Dietary Allowances (RDAs) (22) (Table 9-1, p 176). 2. Requirements may be greater than RDAs when L-amino acids supply majority of protein equivalent as result of: a. Rapid amino acid absorption (25). b. Early and high peak of plasma amino acid concentrations after ingestion of meals where large part of protein is supplied by L-amino acids (25). c. Rapid catabolism of amino acids (27, 34, 57). d. Possible decreased total amino acid absorption (44). Warning: Long-term inadequate protein intake will result in failure to thrive in infants, poor growth in children, weight loss in adults, low plasma transthyretin concentrations, osteopenia, hair loss, and decreased LYS and TRP tolerance. C. Energy 1. Prescribe amount that should support normal weight gain in infants and children and maintain appropriate weight for height in adults (Table 9-1, p 176). 2. Requirements vary widely and may be greater than normal when L-amino acids supply majority of protein equivalent (48). 3. Choreoathetosis, seizures, and intermittent febrile illness (5, 24, 31) may significantly increase energy needs. Warning: Inadequate energy intake may precipitate metabolic and neurologic crises; failure to thrive in infants and weight loss in children and adults and decreased LYS and TRP tolerance. D. Fluid 1. Prescribe amount that will supply water requirements (Table 9-1, p 176). Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL fluid to children and adults for each kcal ingested (6). 2. Requirements may be higher than recommended secondary to accompanying fever, excessive perspiration, or presence of choreoathetosis or seizures (24, 29). E. Oral L-Carnitine (29, 54, 62) 1. Prescribe amount that maintains normal plasma free carnitine concentrations. 2. The usual dose is 100 mg/kg/day during long-term care (29, 62). a. Excessive carnitine may cause gastrointestinal distress and fishy odor.
F. Riboflavin (GA-I only) 1. A small percentage of patients may respond to pharmacologic doses of riboflavin (10). 2. Prescribe a trial of 100 mg oral riboflavin daily (5). G. Preformed Niacin 1. Restriction of TRP intake may require administration of 100% of RDA for age for niacin equivalents (Appendices 13 and 14, pp A-14 and A-15), since restricted TRP may be inadequate for de novo niacin synthesis.

A. LYS 1. Calculate amount of infant formula with iron, beikost, whole cow's milk, or table foods (Table 9-3, p 178) required to fill LYS prescription. a. Low-iron infant formula, whole cow's milk, or evaporated milk should not be used as LYS source for infants because of low iron content. 2. Measure liquid infant formula and whole cow's milk with disposable syringe or graduated cylinder. Weigh powdered infant formula on scale that reads in grams. 3. Add beikost or table foods to gradually displace LYS provided by infant formula when infant is 3 to 4 months of age or is developmentally ready. This may not be possible with a neurologically impaired patient. 4. Parents or patients may select any food in prescribed food lists (Table 9-5, pp 179-191) in specified amounts to fill diet plan. B. TRP 1. Calculate approximate amount of TRP provided by infant formula with iron, beikost, whole cow's milk, or table foods (Table 9-3, p 178) required to fill LYS prescription. 2. Subtract amount determined above from TRP prescription. a. TRP provided by infant formula, beikost, whole cow's milk, or table foods will be close to amount prescribed. C. Protein 1. Calculate amount of protein provided by infant formula with iron, beikost, whole cow's milk, or table foods (Table 9-3 p 178) required to fill LYS and TRP prescriptions. 2. Subtract amount determined above from protein prescription. 3. Supply any remaining prescribed protein with Glutarex (Table 9-2, p 177). a. Glutarex-1 is for infants and toddlers and Glutarex-2 is for children, adolescents, and adults. b. Weigh Glutarex powder on scale that reads in grams because of variability of household measuring equipment (Practical Aspects of Nutrition Support, p vii) and changes in density during shipping. c. See Table 9-2 (p 177, footnote 3) for approximate packed weight of Glutarex powder in level, dry US standard household measures. D. Energy 1. Calculate energy provided by Glutarex (Table 9-2, p 177) and infant formula with iron, beikost, whole cow's milk, or table foods (Table 9-3, p 178) required to fill LYS and protein prescriptions. 2. Subtract amount of energy supplied by these sources from total energy prescription. 3. Provide remaining prescribed energy with Polycose Glucose Polymers powder (23 kcal/Tbsp, 3.8 kcal/g) or liquid (2 kcal/mL) (Appendix 9, p A-9); Pro-Phree Protein-Free Energy Module With Iron, Vitamins & Minerals (Appendix 11, p A-10); sugar (48 kcal/Tbsp); or Free Foods B (Table 9-3, p 178), depending on age of patient. a. Do not use corn syrup or table sugar for infants because of osmolarity they yield (40). b. Do not use honey for infants because it may contain botulinum toxin (61). E. L-Carnitine (Appendix 26, p A-28) 1. If L-carnitine in prescribed Glutarex is insufficient to maintain normal plasma concentration of free carnitine, add oral L-carnitine to medical food mixture. 2. L-carnitine may also be added to beikost or table foods and fruit juices.
3. If not mixed with medical food mixture, administer TID or QID with meals. 4. L-carnitine tablets may be used if patient is old enough to swallow them. F. Riboflavin (Appendix 26, p A-28) 1. Supplement with 100 mg oral riboflavin, administer 15-25 mg with each feed (73). 2. Do not give intravenously because of low solubility. G. Fluid and Mixing Instructions 1. Add sufficient boiled, cooled water to infant formula, Glutarex, carbohydrate (if needed), and L-carnitine (if needed) to yield prescribed volume. Tap water may replace boiled, cooled water when preparing Glutarex for older infants, children, and adults. 2. Mix with sterilized blender at lowest speed for no longer than 3 to 4 seconds. Excess mixing may destabilize emulsion. May also be mixed in sterilized, tightly closed container by shaking vigorously for 10 to 12 seconds. 3. Refrigerate in sterilized, closed containers until used. Discard unused portion 24 hours after mixing because of nutrient loss. 4. Do not use terminal sterilization or boil because of Maillard reaction (Practical Aspects of Nutrition Support, p viii). 5. Warm or cool medical food mixture to room temperature before feeding to infants. Shake stored medical food mixture prior to each feeding. 6. Do not warm medical food mixture for infants in microwave oven. Unevenly heated formula can burn infants, and steam can make bottles explode. 7. Notify parents or caretakers when they may discontinue using aseptic technique in preparing medical food mixture for infants. 8. For children and adults, chill Glutarex medical food mixture to improve taste. G. Diet Guide 1. Provide parents, caretakers, or patient with completed Diet Guide (Appendix 22, p A-24) with each diet change. 2. Feed young infants 6 to 8 times daily (27, 53). 3. Feed older infants, children and adults 4 to 6 times daily (27, 53).

A. Nutrient Adequacy 1. Determine if diet provides nutrients in amounts prescribed in Section VII, Establish Prescription, p 168. a. See Table 9-2, p 177, for composition of Glutarex and Table 9-3, p 178, for nutrient composition of infant formulas and whole cow's milk. b. See Appendix 9, p A-9, for composition of Polycose and Appendix 11, p A-10, for composition of Pro-Phree. 2. Check diet to determine if it supplies Recommended Dietary Intakes (RDIs) (22) for minerals and vitamins (Appendices 13 and 14, pp A-14 and A-15). a. See Table 9-2, p 177, for composition of Glutarex and Appendices 4 through 7, pp A-4 to A-7, for complete nutrient composition of infant formulas and Appendix 8, p A-8, for composition of whole cow's milk. b. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. c. If Glutarex mixture provides < 100% of RDIs for infants and < 75% for children and adults, supplement diet with needed minerals and vitamins, if laboratory tests indicate need (Appendix 11, p A-10, for composition of supplements). B. Osmolarity 1. If concentration of prescribed medical food mixture is > 24 kcal/fl oz, determine if osmolarity is in acceptable range. a. Determine osmolarity by laboratory analysis or use mathematical formula given in Appendix 18, p A-20. b. Osmolarity per gram of Glutarex is listed in Appendix 19, p A-21.
2. If osmolarity is > 450 mosm/L for infants (37), > 750 mosm/kg H2O for children, > 1,000 mosm/L for adults (58), or greater than that tolerated by patient, increase water content of prescribed medical food mixture and recalculate its osmolarity. C. Potential Renal Solute Load 1. Dehydration will result if renal solute load is greater than renal-concentrating ability of patient. 2. If concentration of medical food mixture prescribed is > 24 kcal/fl oz, estimate its potential renal solute load. a. This step is important to prevent dehydration of infants who may have renal-concentrating capacity as low as 600 mosm/L. b. Upper limit of renal solute load for neonates is approximately 1,100 mosm/L (56). 3. A method for estimating potential renal solute load is given in Appendix 20, p A-22. 4. If potential renal solute load is excessive, increase water content of medical food mixture and recalculate. D. Drug and Nutrient Interactions 1. Monitor all possible drug and nutrient interactions. 2. Anticonvulsant therapy with Depakene (valproic acid) may result in gastrointestinal distress, secondary carnitine deficiency (55), and hyperglycinemia (62).

A. Plasma LYS and TRP Concentrations 1. Initial. a. Evaluate daily by quantitative methods until plasma concentrations stabilize and approximate dietary LYS and TRP requirements are known. 2. Ongoing. a. Frequent evaluations help ensure adherence to nutrition support plan. b. Evaluate plasma concentrations of LYS and TRP by quantitative methods twice monthly until the patient is 12 months of age and monthly thereafter. 3. Unacceptable Plasma LYS or TRP Concentration. a. If LYS or TRP is not detected and patient has ingested full prescription: 1) Increase prescribed amount of LYS or TRP by 25% and reevaluate in 3 days. 2) If either plasma LYS or TRP concentration continues undetected, repeat above process until value is in treatment range. b. If plasma LYS concentration is < 45 mol/L or TRP is < 15 mol/L and patient has ingested full prescription: 1) Increase prescribed amount of LYS or TRP by 5% to 10% and reevaluate plasma concentration in 1 week. 2) If plasma LYS or TRP concentration remains low, repeat above process until value is in treatment range. c. If plasma LYS concentration is > 90 mol/L or TRP concentration is > 65 mol/L and patient is not ill and has not ingested more LYS or TRP or significantly less protein and energy than prescribed: 1) Decrease prescribed amount of LYS or TRP by 5% to 10% and reevaluate plasma concentration in 1 week. 2) If plasma LYS or TRP concentration continues elevated, repeat above process until value is in treatment range. Warning: Not all laboratories quantitate plasma TRP concentrations. It is essential that plasma TRP concentrations be assessed to prevent deficiency. 4. If plasma albumin concentration is below normal (Appendix 17, p A-18, free plasma TRP may be greater than normal (13, 39). 5. If equipment for determining plasma TRP concentration or other plasma amino acid concentrations is unavailable, see Table 9-4, p 178, for provider of this service. 6. Anticonvulsants such as valproic acid may cause elevated plasma glycine concentration (62). 7. Low plasma concentrations of branched-chain amino acids (BCAAs) indicate inadequate protein intake. a. If plasma BCAA concentrations are below normal, increase prescribed Glutarex by 5% to 10% and reevaluate plasma concentrations in 1 week.
B. Plasma Glutaric Acid Concentration 1. At presentation, measure daily until concentration is stabilized in treatment range. 2. Ongoing, measure twice monthly until patient is 12 months of age and monthly thereafter. 3. If equipment for determining plasma glutaric acid concentration is unavailable, see Table 9-4, p 178, for provider of this service. C. Urine Organic Acids 1. Initially, measure at presentation; then reevaluate 1 week after nutrition support is begun. a. Urine organic acid levels are initially useful for diagnosis but do not reflect adequacy of nutrition support as accurately as plasma concentrations of LYS, TRP, and glutaric acid. D. Protein Status 1. Evaluate plasma albumin and transthyretin concentrations every 3 months until patient is 1 year of age and 6 months thereafter (Appendix 17, p A-18, for standards). 2. If plasma albumin or transthyretin concentration is below standard: a. Increase prescribed protein by 5% to 10% and reevaluate plasma albumin or transthyretin concentration in 1 month. If plasma LYS and TRP concentrations are in treatment range, use Glutarex to increase protein. b. Plasma albumin concentration may be in the normal range when plasma transthyretin shows a clear deficiency (4). c. If plasma albumin or transthyretin concentration continues below standard, repeat above process until value is in normal range. Warning: Hypoalbuminemia (< 3.5 g/dL) may increase effects of some skeletal muscle relaxants and anticonvulsants (23). E. Iron Status 1. Plasma ferritin concentration (8). a. Evaluate at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17, p A-18, for standards). b. If plasma ferritin concentration is below standard: 1) Increase iron intake to 4 mg/kg with supplements (ferrous sulfate). 2) Evaluate plasma ferritin concentration monthly on increased iron intake. 3) Continue iron supplements until plasma ferritin concentration is in normal range. 2. Complete blood count. a. Evaluate hemoglobin and hematocrit concentrations at diagnosis and at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17, p A-18, for standards). F. Plasma Free Carnitine Concentration 1. Plasma free carnitine should be evaluated as necessary to maintain normal concentration ( 30 mol/L). G. Riboflavin 1. Effectiveness of riboflavin supplementation may be assessed by quantitating urinary glutaric acid concentrations on same dietary intake of LYS and TRP pre- and post-riboflavin supplementation (5, 29). H. Growth Status 1. Length/height and weight. a. Measure monthly to 1 year, every 3 months to 4 years, and every 6 months thereafter. Plot measurements on NCHS growth charts. b. Maintain length/height and weight between 10th and 90th percentiles. Some normal infants, children, and adults will fall above or below these percentiles. 2. If length/height or weight falls below usual growth channel: a. Increase prescribed protein and energy by 5% to 10% and remeasure after 1 month. b. If length/height or weight remains low, repeat above until usual growth channel is achieved. c. Neurologically compromised patients may have difficulty maintaining weight gain equal to height or linear gain and require frequent monitoring to prevent failure to thrive. Nutrition
intervention may include prescribing an energy intake greater than RDA for age and use of gastrostomy tube. I. Nutrient Intake 1. Maintain records of food intake for 3 days immediately before each blood test (Appendices 24 and 25, pp A-26 and A-27). 2. Evaluate intakes of LYS, TRP, protein, and energy before each blood test. 3. Evaluate mineral and vitamin intakes after each diet change. a. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. b. See Appendix 28, p A-29, for information about ordering software for diet evaluation.
XI. Special Concerns

A. Hydration 1. Request parents or caretakers to monitor hydration status at home if neurologic impairment results in dysarthria or dysphagia. a. Teach family members clinical signs of impending dehydration (17), including dry mouth, decreased urine output, lack of tears, sunken eyes, lethargy, poor skin elasticity, and depressed fontanel in young infants. b. Use Ketostix to monitor hydration status. Normal random urine specific gravity ranges between 1.002 and 1.006 in infants (65). B. Dysphagia 1. Severely neurologically impaired patients require nasogastric or gastrostomy tube feedings. C. Constipation 1. Chronic constipation may be present in nonambulatory patients. Use appropriate methods to prevent constipation: a. Increase fluid intake. b. Increase either fiber-containing foods such as raw fruits, vegetables, dried fruits, and cooked vegetables or commercially available soluble fiber products. c. Recommend prune juice (may be mixed with 7-Up ). d. Avoid long-term use of laxatives or mineral oil.
XII. Sample Prescriptions

A. Example 1 Establish and fill prescription for 4-month-old girl weighing 6.0 kg (50th percentile) using Recommended Daily Nutrient Intakes from Table 9-1, p 176, and nutrient contents from Tables 9-2 and 9-3, pp 177 and 178. 1. Establish prescription.
LYS TRP L-Carnitine Protein Energy Fluid Riboflavin (GA-I) 70 mg/kg 14 mg/kg 145 mg 3.3 g/kg 120 kcal/kg 150 mL/kg x x x x x x 6.0 kg 6.0 kg 6.0 kg 6.0 kg 6.0 kg 6.0 kg = = = = = = = 420 mg/day 84 mg 870 mg 19.8 g 720 kcal 900 mL 100 mg
Medical Food Mixture Measure LYS (mg) 0 420 TRP (mg) 0 82 L-Carnitine Protein Energy (mg) (g) (kcal) 873 14.6 466 0 5.2 253
Glutarex-1 97 g Similac With Iron Ready to Feed 372 mL Add water to make 946 mL (32 fl oz).
420 82 873 19.8 719 Total per day 70 14 145 3.3 126 Total per kg Approximate osmolarity of medical food mixture is < 400 mosm/L. Estimated potential renal solute load is 187 mosm.
B. Example 2 Establish and fill prescription for 7-year-old girl weighing 20 kg using Recommended Daily Nutrient Intakes from Table 9-1, p 176, and nutrient contents from Tables 9-2 and 9-3, pp 177and 178. 1. Establish prescription.
LYS TRP L-Carnitine Protein Energy Fluid Riboflavin (GA-I) 35 mg/kg 10 mg/kg 100 mg/kg x x x 20 kg 20 kg 20 kg = = = 700 mg/day 200 mg 2,000 mg 40 g 2,400 kcal 2,400 mL 100 mg Protein Energy (g) (kcal) 21.0 287 0.0 0 0.0 216
LYS TRP L-Carnitine (mg) (mg) (mg) Glutarex-2 70 g 0 0 1,260 L-Carnitine 7.4 mL 0 0 740 Sugar 54 g (4.5 Tbsp) 0 0 0 Add water to make 840 mL (28 fl oz). Offer additional water ad libitum. Food List Servings Breads/Cereals 12 360 120 Fats 12 72 24 Fruits 6 120 30 Vegetables 6 120 30 Free Foods A 5 25 5 Free Foods B 1 0 0 697 209 Total per day Approximate osmolarity of medical food mixture is < 700 mosm/L. 1 Add only if plasma free carnitine is below normal. Medical Food Mixture Measure
0 0 0 0 0 0 2,000
10.8 1.2 3.6 3.0 0.5 0.0 40.1
480 720 270 90 275 60 2,398
XIII. Nutrition Support During Febrile Illness or Following Trauma

A. Rationale 1. In normal persons, febrile illness and trauma are accompanied by catabolism of body protein. 2. Well-nourished patients respond to infection and trauma as do normal persons. B. See Section V, Nutrition Support During Acute Illness, p 167.
TABLE 9-1. Recommended Daily Nutrient Intakes (Ranges) for Infants, Children, and Adults With Glutaric Aciduria Type I or 2-Ketoadipic Aciduria
Age LYS (mg/kg) Infants 0 to < 3 mo 3 to < 6 mo 6 to < 9 mo 9 to < 12 mo 80 - 100 70 - 90 60 - 80 50 - 70 (mg/kg) Girls and Boys 1 to < 4 yr 4 to < 7 yr 7 to < 11 yr Women 11 to < 15 yr 15 to < 19 yr 19 yr Men 11 to < 15 yr 15 to < 19 yr
1 2 1,2
Nutrient TRP (mg/kg) 10 - 20 10 - 15 10 - 12 10 - 12 (mg/kg) 8 - 12 7 - 11 4 - 10

2,3
Protein4 (g/kg) 3.50 - 3.00 3.50 - 3.00 3.00 - 2.50 3.00 - 2.50 (g/day) 30.0 35.0 40.0
Energy4 (kcal/kg) 120 (145 115 (145 110 (135 105 (135 - 95) - 95) - 80) - 80)
Fluid5 (mL/kg) 150 - 125 160 - 130 145 - 125 135 - 120 (mL/day) 1,300 ( 900 - 1800) 1,700 (1300 - 2300) 2,400 (1650 - 3300)
(kcal/day) 1,300 ( 900 - 1800) 1,700 (1300 - 2300) 2,400 (1650 - 3300)
55 - 65 45 - 55 35 - 45
30 - 40 20 - 30 10 - 20
4-6 3-5 3-4
50.0 55.0 60.0
2,200 (1500 - 3000) 2,100 (1200 - 3000) 2,100 (1400 - 2500)
2,200 (1500 - 3000) 2,100 (1200 - 3000) 2,100 (1400 - 2500)
30 - 40 35 - 45
4-6 6-8
60.0 65.0
2,700 (2000 - 3700) 2,800 (2100 - 3900)
2,700 (2000 - 3700) 2,800 (2100 - 3900)
3 4 5
> 19 yr 35 - 45 3-5 2,900 (2000 - 3300) 2,900 (2000 - 3300) 65.0 Modified from references 1, 11, 12, 18, 21, 36, 44, 51, 60, 66, 68, 70. Initiate therapy with lowest value for age range. Modify prescription based on frequently obtained blood and/or plasma values and growth in infants and children and frequently obtained plasma values and weight maintenance in adults. Modified from references 19, 20, 21, 52, 59, 69. Modified from reference 22. Modified from reference 6. Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL fluid to children and adults for each kcal ingested.
TABLE 9-2. Nutrient Composition of GLUTAREX -1 1, 3 and GLUTAREX -2 2, 3

Nutrient (per 100 g pwd) Glutarex-1 (per g protein equiv) 32 1.000 0.160 1.032 0.010 0.028 0.072 0.112 0 0.020 0.059 0.047 0 0.059 0.081 Glutarex-2 (per g protein equiv) 13.7 1.000 0.160 1.032 0.010 0.028 0.072 0.112 0 0.020 0.059 0.047 0 0.059 0.081 60 1.67 1.17 0.43 0.050 0.006 29 31.33/0.88 0.033 0.90 3.33 0.43 7.50 0.027 1.00 25 45.7/1.17 1.17 29.3/1.28 0.43 22 0.25 0.40 2.00 2.00 3.33 0.043 0.167 3.33 14.33 2.33 0.53 0.267 0.060 0.108
(per 100 g pwd)
Energy, kcal 480 410 Protein equiv, g 15.00 30.00 Nitrogen, g 2.40 4.80 15.49 30.98 Amino acids Cystine, g 0.15 0.30 Histidine, g 0.42 0.84 Isoleucine, g 1.08 2.16 Leucine, g 1.68 3.36 Lysine, g trace trace Methionine, g 0.30 0.60 Phenylalanine, g 0.88 1.76 Threonine, g 0.70 1.40 Tryptophan, g trace trace Tyrosine, g 0.89 1.78 Valine, g 1.22 2.44 Other Nitrogen-Containing Compounds L-Carnitine, mg 900 60 1800 Taurine, mg 40 2.66 50 Carbohydrate, g 53.0 3.53 35 Fat, g 21.7 1.45 13 4 5 Linoleic acid, g 2.00 1.333 1.50 6 7 0.36 0.024 0.17 -Linolenic acid, g Minerals Calcium, mg 575 38 880 Chloride, mg/mEq 325/9.17 21/0.61 940/26.51 Copper, mg 1.1 0.073 1.00 Chromium, g 11 0.73 27 Iodine, g 65 4.3 100 Iron, mg 9.0 0.6 13 Magnesium, mg 50 3.33 225 Manganese, mg 0.50 0.033 0.80 Molybdenum, g 12 0.80 30 Phosphorus, mg 400 27 760 Potassium, mg/mEq 675/17.26 45/1.15 1,370/35.04 Selenium, g 20 1.3 35 Sodium, mg/mEq 190/8.26 12.7/0.55 880/38.28 Zinc, mg 8.0 0.53 13 Vitamins A, g RE 420 28 660 D, g 7.50 0.50 7.50 10.10 0.67 12.10 E, mg -TE K, g 50 3.33 60 Ascorbic acid, mg 50 3.33 60 Biotin, g 65 4.33 100 B6, mg 0.75 0.050 1.30 B12, g 4.90 0.327 5.00 Choline, mg 80 5.3 100 Folate, g 230 15 430 Inositol, mg 40 2.67 70 Niacin, mg 10.0 0.667 16.0 Pantothenic acid, mg 6.90 0.460 8.00 Riboflavin, mg 0.90 0.06 1.80 Thiamin, mg 1.90 0.127 3.25 1 2 Designed for infants and toddlers. Designed for children, adolescents, and adults. 3 Approximate packed weight of Glutarex-1 and Glutarex-2 in level, dry US standard household measures: Glutarex-2 Glutarex-1 1 Tbsp = 7g 8g 1/4 cup = 26 g 32 g 1/3 cup = 30 g 41 g 1/2 cup = 53 g 61 g 1 cup = 105 g 117 g 4 5 Analytical data at manufacture = 4.32 g/100 g powder. Analytical data at manufacture = 2.66 g/100 g powder. 6 7 Analytical data at manufacture = 0.40 g/100 g powder. Analytical data at manufacture = 0.28 g/100 g powder.
TABLE 9-3. Serving Lists for LYS- and TRP-Restricted Diets: Average Nutrient Content per Serving
Food List LYS (mg) Breads/Cereals Fats Fruits Vegetables Free Foods A Free Foods B Alimentum Protein Hydrolysate Formula With Iron, Ready to Feed, 100 mL
1
Nutrient TRP (mg) 10 2 5 5 1 0 25 Protein (g) 0.9 0.1 0.6 0.5 0.1 0.0 1.86 Energy (kcal) 40 60 45 15 55 60 68
30 6 20 20 5 0 163
Isomil Soy Formula With Iron, Ready to Feed, 100 mL 1 100 21 1 Similac With Iron Infant Formula, Ready to Feed, 100 mL 113 22 Whole cow's milk, 100 mL 2 269 47 1 See Appendices 4 through 7, pp A-4 to A-7, for complete nutrient composition of infant formulas. 2 From reference 47. See Appendix 8, p A-8, for complete nutrient composition.
1.66 68 1.40 68 3.39 63
TABLE 9-4. Suppliers of Products and Services for Nutrition Support of Glutaric Aciduria Type I and 2-Ketoadipic Aciduria
Product/Service Oral riboflavin and thiamine Provider Nature's Bounty, Inc. 90 Orville Drive Bohemia, NY 117816 (800) 645-5412 (516) 567-9500 NeoGen Abele Business Park 90 Emerson Lane Suite 1403 Bridgeville, PA 15017 (412) 220-2300; FAX (412) 220-0784 Stephen I. Goodman, MD Biochemical Genetics Laboratory Dept of Pediatrics University of Colorado Health Sciences Center Box C-233 4200 E 9th Ave Denver, CO 80262 (303) 315-7301
Plasma amino acids and urine organic acids1
(Ask for instructions on how to treat, store, and ship sample.) Plasma glutaric acid1
(Ask for instructions on how to treat, store, and ship sample.)

1
The local University School of Medicine medical genetics or metabolic laboratories may also be able to quantify these analytes.
TABLE 9-5. Serving Lists for LYS- and TRP-Restricted Diets: Gerber Baby Foods (Beikost)
Food Weight Approximate (g) Measure For greatest accuracy, weigh food on scale that reads in grams. All measures are level. BREADS AND CEREALS Baked Finger Snacks Animal crackers, cinnamon graham Apple cinnamon cookies Arrowroot cookies Banana cookies Pretzels Strawberry fruit bars Veggie crackers Cereals, Dry Barley Mixed Oatmeal Oatmeal/banana Oateal/mixed fruit Rice Rice/apple Rice/apple bits Rice/banana Rice/mixed fruit Cereals, Jarred 1st Foods Oatmeal 2nd & 3rd Foods Mixed/applesauce/banana Oatmeal/applesauce/banana Rice/applesauce Tender Harvest Banana/oatmeal/peach Butternut squash/corn Garden carrots/brown rice Green beans/potatoes Spring garden vegetables Vegetables 1st Foods Peas Potatoes Sweet potatoes 2nd Foods Creamed corn Creamed spinach Garden vegetables Mixed vegetables Peas Sweet potatoes 3rd Foods Green beans/rice Peas/rice Sweet potatoes LYS (mg) TRP (mg) Protein (g) Energy (kcal)
34 20 24 20 14 18 21
8-1/2 cookies 2 cookies 5 cookies 2-1/2 cookies 5 pretzels 2 bars 30 crackers
30 30 30 29 30 27 31
27 15 27 17 26 16 16
2.0 1.6 1.9 1.4 1.8 1.0 1.7
152 85 109 86 54 73 100
7 11 5 7 8 10 13 14 12 8
1-3/4 Tbsp 3 Tbsp 1 Tbsp + 1 tsp 1-3/4 Tbsp 2 Tbsp 2 Tbsp + 2 tsp 3 Tbsp + 1-1/2 tsp 3-3/4 Tbsp 3 Tbsp 2 Tbsp
29 29 29 29 30 32 30 31 29 30
11 10 9 9 9 12 12 12 12 9
0.9 1.1 0.8 0.8 0.9 0.8 0.8 1.0 0.8 0.9
27 42 20 28 33 38 51 55 46 33
50 77 70 130 60 61 143 22 47
3 Tbsp + 1-1/2 tsp 5 Tbsp + 1 tsp 4-3/4 Tbsp 9 Tbsp 4 Tbsp 4-1/4 Tbsp 10 Tbsp 1 Tbsp + 1-1/2 tsp 3-1/4 Tbsp
30 30 30 30 30 30 30 30 30
11 8 8 9 3 10 13 7 7
0.9 0.8 0.9 1.0 0.7 1.2 1.3 0.5 0.7
28 66 58 118 44 31 26 14 16
15 60 100 43 18 23 42 14 91 67 19 77
1 Tbsp 2 Tbsp 7 Tbsp 3 Tbsp 1 Tbsp + 1/4 tsp 1 Tbsp + 1 tsp 3 Tbsp 1 Tbsp 6 Tbsp + 1 tsp 4 Tbsp + 1-1/2 tsp 1 Tbsp + 1 tsp 5 Tbsp + 1 tsp
30 30 30 30 30 29 30 29 30 30 30 30
5 11 16 13 7 6 5 5 14 11 5 18
0.5 0.6 1.1 0.8 0.6 0.5 0.5 0.4 0.9 0.8 0.4 0.8
7 28 65 27 8 9 15 7 56 28 10 46
Food
Weight Approximate (g) Measure For greatest accuracy, weigh food on scale that reads in grams. All measures are level. FRUITS/JUICES 1st Foods Bananas Peaches Pears Prunes 2nd Foods Apricot/mixed fruit Bananas/apples/pears Peaches Peach cobbler dessert 3rd Foods Hawaiian delight dessert Fruit Juices Mixed juice Orange juice Orange/banana/pineapple juice
LYS (mg)
TRP (mg)
Protein (g)
Energy (kcal)
45 83 133 133 107 56 83 125 26
3 Tbsp 5-3/4 Tbsp 9 Tbsp + 1 tsp 9 Tbsp + 1 tsp 7 Tbsp + 1 tsp 4 Tbsp 5-3/4 Tbsp 8-3/4 Tbsp 1 Tbsp + 2 tsp
20 20 20 20 20 20 20 20 20
2 5 8 8 2 2 5 10 3
0.5 0.6 1.3 1.3 0.6 0.5 0.6 0.6 0.3
45 36 134 134 63 46 53 95 23
100 218 10
3.2 fl oz 7 fl oz 3-1/3 fl oz
20 21 21
3 5 2
0.3 1.6 0.5
48 100 58
Fruit/Vegetable Juices Apple/sweet potato Tender Harvest Pear/wild blueberry Pears/winter squash Tropical fruit blend VEGETABLES 1st Foods Carrots Green beans Squash 2nd Foods Carrots Green beans Squash 3rd Foods Carrots Squash Vegetable Dices, Graduates Carrots Green beans FREE FOODS A Dessert, Tropical Fruit Fruit medley Guava Mango Papaya Finger Foods, Graduates Apples Mixed fruit Peaches Pears 2001 Ross Products Division
154 154 53 77
5 fl oz 10 3/4 Tbsp 3-3/4 Tbsp 5 Tbsp + 1 tsp
20 20 20 20
5 3 5 2
0.5 0.6 0.6 0.5
80 94 27 57
105 30 49 105 38 59 83 80
7 Tbsp + 1 tsp 2 Tbsp 3 Tbsp + 1-1/2 tsp 7 Tbsp + 1 tsp 2-3/4 Tbsp 4 Tbsp 5-3/4 Tbsp 5-1/2 Tbsp
20 20 20 20 20 20 20 20
6 7 6 6 10 9 7 7
0.9 0.4 0.4 0.8 0.5 0.5 0.7 0.6
37 9 17 32 11 19 24 26
56 24
ND ND
20 20
4 4
0.3 0.3
13 6
56 56 36 45
4 Tbsp 4 Tbsp 2 Tbsp + 1-1/2 tsp 3 Tbsp
5 5 5 5
2 2 1 1
0.1 0.1 0.1 0.1
36 36 25 33
100 62 38 56
ND ND ND ND
5 5 5 5
5 4 1 5
0.1 0.2 0.2 0.2
48 30 19 30
Food
Weight Approximate (g) Measure For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Fruits 1st Foods Applesauce Pears Prunes 2nd & 3rd Foods Apple/blueberry Bananas Pears Pear/pineapple Plums Prunes Tender Harvest Apple/sweet potato Fruit Juices Apple/carrot juice Apple/cherry juice Apple/cranberry juice Apple/grape juice Apple juice Pear juice Tender Harvest Apple/sweet potato
LYS (mg)
TRP (mg)
Protein (g)
Energy (kcal)
43 33 33 50 33 33 33 100 50 50
3 Tbsp 2 Tbsp + 1 tsp 2 Tbsp + 1 tsp 3 Tbsp + 1-1/2 tsp 2 Tbsp + 1 tsp 2 Tbsp + 1 tsp 2 Tbsp + 1 tsp 7 Tbsp 3 Tbsp + 1-1/2 tsp ND
5 5 5 5 5 5 5 5 5 5
1 2 2 1 2 2 1 3 4 2
0.1 0.1 0.3 0.1 0.2 0.1 0.1 0.3 0.4 0.2
23 19 33 25 26 18 18 74 38 32
71 100 100 100 100 100 50
2-1/4 fl oz 3.2 fl oz 3.2 fl oz 3.2 fl oz 3.2 fl oz 3.2 fl oz ND
5 5 5 5 5 5 5
1 1 1 1 1 1 2
0.1 0.1 0.1 0.1 0.1 0.1 0.2
31 48 44 48 46 47 32
ND = No data. Prepared from 1998 and 1999 data from Gerber Products, Co., Fremont, MI, 49413. Weights and Measures Except for Dry Cereals and Food Dices, the following weights apply: Level Level Weight 1 tsp = 1/3rd Tbsp = 4.8 g 1 Tbsp = 1/16th cup = 14.3 g 1/4 cup = 4 Tbsp = 57.2 g 1/3 cup = 5-1/3rd Tbsp = 76.2 g 1/2 cup = 8 Tbsp = 114.3 g 2/3 cup = 10 2/3rd Tbsp = 152.5 g 3/4 cup = 12 Tbsp = 171.5 g 1 cup = 16 Tbsp = 228.6 g
TABLE 9-5. Serving Lists for LYS- and TRP-Restricted Diets: Table Foods
Weight Approximate (g) Measure For greatest accuracy, weigh food on scale that reads in grams. All measures are level. BREADS AND CEREALS Cereals, Cooked. Measure after cooking Cream of Rice Cream of Wheat instant Mix'n Eat plain flavored quick regular Farina Oats, regular, quick, and instant Wheatena Cereals, Ready To Eat All Bran Alpha-Bits Apple Jacks Bran Buds Bran Chex 40% Bran Flakes (Post) Cap'n Crunch Cap'n Crunch's Crunch Berries Cap'n Crunch's Peanut Butter Cheerios Cinnamon Toast Crunch Cocoa Krispies Cocoa Pebbles Cocoa Puffs Cookie Crisp Corn Bran Corn Chex Corn Flakes Crispy Wheat'n Raisins Froot Loops Frosted Mini-Wheats Frosted Rice Krinkles Fruit Wheat Squares Fruity Pebbles Golden Grahams Grape Nut Flakes Honey Nut Cheerios Honeycomb King Vitaman Kix Life Lucky Charms Nutri-Grain corn rye wheat Quisp Raisin Bran (Post) Food
LYS (mg)
TRP (mg)
Protein (g)
Energy (kcal)
81 61 70 75 80 83 87 29 61
1/3 cup 1/4 cup 1/2 packet 1/2 packet 1/3 cup 1/3 cup 6 Tbsp 2 Tbsp 1/4 cup
30 29 35 32 31 32 29 31 29
11 15 19 17 17 18 18 10 18
0.7 1.1 1.4 1.3 0.9 1.3 0.7 0.8 1.2
42 39 50 54 43 44 44 18 34
5 9 19 5 9 9 24 18 12 5 38 13 16 38 20 18 21 17 16 19 9 16 20 16 20 8 6 22 21 12 3 8 21 8 14 23 11
1 Tbsp 1/3 cup 2/3 cup 1 Tbsp 3 Tbsp 3 Tbsp 2/3 cup 1/2 cup 1/3 cup 3 Tbsp + 1 tsp 1 cup 1/4 cup + 2 Tbsp 1/2 cup 1-2/3 cup 2/3 cup 1/2 cup 3/4 cup 3/4 cup 1/4 cup + 2 Tbsp 2/3 cup 1-1/3 pieces 1/2 cup 1/4 cup 1/2 cup 1/2 cup 1/4 cup 2 Tbsp + 1 tsp 1 cup 1 cup 2/3 cup 1 Tbsp 1/4 cup 1/2 cup 3 Tbsp + 1 tsp 1/4 cup + 1 Tbsp 3/4 cup 3 Tbsp
30 26 27 29 28 33 33 27 27 29 27 30 32 32 30 32 30 27 30 30 30 33 29 28 32 27 30 33 29 29 29 30 33 30 33 30 29
12 9 11 11 10 17 11 8 8 10 15 10 10 10 11 10 9 8 18 11 19 12 16 10 12 16 16 11 9 9 7 10 10 8 20 10 15
0.8 0.7 1.0 0.7 1.0 1.0 1.2 0.9 0.8 0.7 1.3 0.7 0.8 1.3 1.0 1.2 1.5 1.4 1.1 1.1 1.0 0.8 1.4 0.6 1.1 0.9 0.7 1.3 1.1 1.1 0.5 0.7 1.7 0.7 1.2 1.1 1.0
13 37 72 14 30 29 103 74 51 18 160 52 66 146 79 62 83 66 56 73 34 62 71 66 75 29 22 86 85 49 10 31 80 30 4 93 33
Food
Weight Approximate (g) Measure For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Rice Chex 13 1/2 cup Rice Krispies 9 1/3 cup Rice, puffed 10 3/4 cup Special K 4 2 Tbsp + 1 tsp Sugar Frosted Flakes 31 3/4 cup + 2 Tbsp Sugar Smacks 17 7 Tbsp Super Sugar Crisp 17 1/2 cup Team 13 1/4 cup + 1 Tbsp Total 10 1/4 cup + 1 Tbsp Trix 21 3/4 cup Wheat puffed 8 2/3 cup shredded 9 1/3 oz Wheat Chex 12 1/4 cup Wheaties 10 1/3 cup Grains Corn, cooked cream style whole kernel Rice, cooked brown fried pilaf Rice-A-Roni Spanish white instant regular Pasta, cooked Macaroni Noodles, egg Ramen noodles Spaghetti Tubers Potatoes, sweet baked no skin, mashed w/ skin, mashed canned, packed in syrup Potatoes, white baked, no skin boiled no skin w/ skin canned French fries (1/2" x 1/2" x 2"), fresh frozen, baked microwaved, w/ skin hash browns, frozen, cooked Tater Tots Yams, baked or boiled
LYS (mg) 29 27 28 30 30 32 30 32 32 27 32 31 32 28 10 36 10 11 10 18 17 12 20 8 18 29 18 17
TRP (mg)
Protein (g) 0.7 0.6 0.7 0.8 1.5 1.2 1.1 0.8 1.0 1.1 1.1 1.0 1.1 0.9
Energy (kcal) 50 37 42 16 117 62 62 51 36 81 28 32 42 34
40 20 33 28 29 36 45 36 39
2-1/2 Tbsp 2 Tbsp 3 Tbsp 2 Tbsp 2 Tbsp 2 Tbsp + 1 tsp 3 Tbsp 3 Tbsp + 1 tsp 3 Tbsp
30 29 31 33 31 32 30 29 28
5 5 12 8 14 10 9 9 8
0.7 0.7 0.8 0.7 1.2 1.0 0.8 0.8 0.8
29 22 39 32 44 41 39 39 42
24 20 29 27
3 Tbsp 2 Tbsp 3 Tbsp 3 Tbsp
27 28 33 31
15 9 18 17
1.2 0.8 1.6 1.4
36 25 65 41
41 38 61 23 29 29 34 15 15 26 20 28 51
2 Tbsp 3 Tbsp 1/4 cup + 1 Tbsp 3 Tbsp 3 Tbsp 3 Tbsp 3 Tbsp 3 pieces 3 pieces 2 Tbsp + 2 tsp 2 Tbsp 3 pieces 1/4 cup + 2 Tbsp
33 32 27 27 30 33 29 32 28 33 33 30 30
8 8 7 7 8 9 8 8 7 9 8 8 6
0.7 0.6 0.5 0.4 0.5 0.5 0.5 0.6 0.5 0.5 0.6 0.6 0.8
43 39 84 21 25 26 20 47 49 26 43 46 59
Food
Weight Approximate (g) Measure For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Miscellaneous Chocolate sauce (Hershey's ) 38 2 Tbsp Chow Mein noodles 11 3 Tbsp Ice cream cone, wafer type 4 1 (cone only) Jell-O , prepared w/ sugar 45 3 Tbsp Snack Foods Barnum's Animal Crackers Breadsticks Cookies chocolate chip fig bar gingersnap Oreo sandwich Sno Balls Social Tea Biscuits Sugar Wafers (Nabisco) vanilla wafer Crackers Goldfish , original graham (2" x 2") Melba toast Ritz Ritz Bits , cheese Rykrisp saltines Triscuits Waverly Wheat Thins Doodads , original Doritos Fritos Popcorn buttered caramel plain Pringles potato crisps Pretzels Tortilla (6" diameter) corn flour FATS Butter stick whipped Gravy mushroom, canned onion mix, dry Margarine imitation soft stick or brick
LYS (mg)
TRP (mg)
Protein (g)
Energy (kcal)
31 26 10 30
10 13 5 0
0.7 1.1 0.4 0.7
82 56 17 26
21 12 12 32 25 22 28 32 21 33 24 15 18 12 20 9 6 15 16 21 18 12 18 22 16 23 12 8 18 21 15
8 crackers 2 pieces 1 cookie 2 cookies 3-1/2 cookies 2 cookies 2-1/2 cookies 3/4 cookie 4 cookies 6 cookies 6 cookies 25 crackers 2-1/2 crackers 2 pieces 6 crackers 13 crackers 1 triple cracker 5 crackers 3-1/2 crackers 3 crackers 10 crackers 3 Tbsp + 1 tsp 10 chips 11 chips 1-3/4 cups 2/3 cup 2 cups 4 chips 3 pretzels 1 tortilla 1/2 tortilla
31 32 18 30 30 26 29 30 30 27 29 29 31 33 29 28 26 30 29 33 28 29 28 30 33 28 30 31 30 27 26
17 18 7 16 16 12 16 11 14 15 16 12 17 18 16 11 7 17 16 18 15 13 19 18 9 8 9 8 30 6 14
1.4 1.4 0.6 1.2 1.3 1.1 1.3 1.0 1.2 1.3 1.3 1.1 1.4 1.6 1.4 0.9 0.6 1.4 1.4 1.6 1.4 1.3 1.3 1.5 1.6 1.4 1.5 0.5 1.8 1.0 1.2
89 46 62 115 103 107 136 112 96 160 111 74 67 41 99 45 23 65 73 104 86 58 88 120 72 88 46 42 70 30 48
9 9 20 3 14 9 9
2 tsp 1 Tbsp 1 Tbsp + 1 tsp 2 Tbsp 1 Tbsp 2 tsp 2 tsp
6 6 6 6 6 6 6
1 1 3 3 1 1 1
0.1 0.1 0.3 0.3 0.1 0.1 0.1
68 68 10 10 50 68 67
Food
Weight Approximate (g) Measure For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Nondairy creamer w/ sodium caseinate liquid 10 2 tsp Polyrich 29 2 Tbsp powder 2 1 tsp Rich's Coffee Rich 29 2 Tbsp Olives black 10 2 olives green 10 2 olives Salad dressings, commercial Catalina 51 3 Tbsp French 16 1 Tbsp Italian 15 1 Tbsp mayonnaise 9 2 tsp Miracle Whip 14 1 Tbsp Thousand Island 10 2 tsp Tartar sauce 7 1-1/2 tsp Toppings, commercial Cool Whip , extra creamy 3 2 tsp regular 5 1 Tbsp + 1 tsp Dessert topping w/ sodium caseinate, pressurized 9 2 Tbsp Whipped cream, pressurized 2 2 tsp
LYS (mg)
TRP (mg)
Protein (g)
Energy (kcal)
7 5 8 5 6 7 6 6 7 7 4 6 7
2 1 1 1 1 2 2 1 2 2 1 1 2
0.1 0.1 0.1 0.1 0.1 0.1 0.2 0.1 0.1 0.1 0.1 0.1 0.1
174 44 11 44 18 12 217 67 69 66 70 39 37
6 6 7 6
1 1 1 1
0.1 0.1 0.1 0.1
10 15 23 6
FRUITS Fruits are raw unless otherwise noted. Weight of raw fruits is only for parts that can be eaten. Drain canned, cooked, and frozen fruits before measuring or weighing. Apples butter canned, sweetened, sliced dried sauce, canned, sweetened whole, medium Apricots canned, heavy syrup dried cooked, mashed halves nectar, canned whole Avocadoes, all varieties, mashed Banana, sliced Blackberries canned, heavy syrup frozen, sweetened raw Blueberries frozen, sweetened raw Cherries, canned, heavy syrup sour, red sweet Coconut, shredded dried dried, sweetened w/ sugar Currants, black Dates Elderberries, raw
80 204 23 168 138 48 21 7 79 18 20 42 37 38 72 287 163 117 72 7 15 84 33 76
1/4 cup 1 cup 1/3 cup 1 cup 1 fruit 3 Tbsp 1 Tbsp + 1 tsp 2 2-1/2 fl oz 1/2 fruit 1 Tbsp + 1-1/4 tsp 3 Tbsp 2 Tbsp + 1 tsp 1/4 cup 1/2 cup 1-1/4 cups 1 cup + 2 Tbsp 1/2 cup 1/2 cup 1 Tbsp + 1 tsp 3 Tbsp 3/4 cup 4 fruits 1/2 cup
19 22 16 19 17 18 19 18 20 17 19 20 20 18 21 20 20 19 20 21 21 21 20 19
3 4 3 3 3 4 5 5 6 3 4 5 6 5 6 6 5 9 9 5 6 5 17 10
0.3 0.4 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.2 0.4 0.4 0.5 0.4 0.5 1.1 1.1 0.9 0.9 0.5 0.6 1.2 0.7 0.5
148 137 69 128 81 40 18 17 44 8 33 39 34 24 38 233 91 106 52 47 69 53 91 55
Food
Weight Approximate (g) Measure For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Figs canned, heavy syrup 129 1/2 cup dried cooked, mashed 33 2 Tbsp uncooked, chopped 17 1 Tbsp + 1 tsp whole, large 64 1 fruit Fruit cocktail, canned, heavy syrup 127 1/2 cup Fruit salad, canned, heavy syrup 127 1/2 cup Grapefruit canned in juice 124 1/2 cup juice, canned, unsweetened 278 9 fl oz sections red and pink 115 1/2 cup white 118 1/2 fruit Grapes European, green 120 3/4 cup Thompson, seedless, canned, heavy syrup 169 2/3 cup Guavas 90 1 fruit Kiwi fruit 57 3/4 fruit Lemons 33 1/2 fruit Mangoes, sliced 54 1/3 cup Melons, cubed cantaloupe 53 1/3 cup casaba 56 1/3 cup honeydew 112 2/3 fruit Mixed fruit, canned, heavy syrup 127 1/2 cup Nectarines 67 1/2 fruit Oranges juice fresh 248 8 fl oz canned 249 8 fl oz frozen, diluted 249 8 fl oz sections 45 1/4 cup Papayas nectar, canned 282 9 fl oz cubed 70 1/2 cup Peaches canned, heavy syrup, sliced 128 1/2 cup dried, halves 13 1 frozen, sweetened 82 1/3 cup nectar, canned 218 7 fl oz sliced 85 1/2 cup Pears canned, heavy syrup 255 1 cup dried cooked 64 1/4 cup halves 35 2 sliced 124 3/4 cup Persimmons, Japanese 55 1/3 fruit Pineapple canned, heavy syrup 127 1/2 cup diced 77 1/2 cup frozen, sweetened, chunks 81 1/3 cup juice bar, frozen 74 1 bar juice, canned 125 4 fl oz canned, heavy syrup, tidbits or crushed 128 1/2 cup Plantains, cooked, sliced 51 1/3 cup 2001 Ross Products Division
LYS (mg)
TRP (mg)
Protein (g)
Energy (kcal)
19 17 20 19 19 22 22 19 18 19 18 19 21 19 18 22 19 21 21 20 21
4 4 4 4 5 5 2 6 2 2 4 3 6 15 3 4 3 4 3 4 2
0.5 0.4 0.5 0.5 0.5 0.4 0.9 1.4 0.7 0.7 0.8 0.8 0.7 0.6 0.4 0.3 0.5 0.5 0.5 0.5 0.6
113 36 42 47 93 93 46 106 37 38 85 123 46 35 9 35 18 15 39 92 33
22 20 22 21 20 18 19 15 17 20 20 18 20 23 17 18 20 19 21 19 19 21 18
5 5 5 4 5 6 1 0 2 2 2 18 17 17 11 6 6 4 4 4 5 7 5
1.7 1.5 1.7 0.4 0.5 0.4 0.6 0.5 0.5 0.6 0.6 0.5 0.6 0.7 0.5 0.3 0.4 0.3 0.3 0.3 0.4 0.5 0.4
111 104 112 21 161 27 95 31 78 118 37 189 81 91 73 39 99 38 69 70 70 100 59
Food
Weight Approximate (g) Measure For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Plums purple, canned, heavy syrup 258 1 cup sliced 109 2/3 cup Prunes canned, heavy syrup 117 1/2 cup dried cooked 70 1/3 cup uncooked 34 4 pieces juice, canned 128 4 fl oz Raisins golden 27 3 Tbsp regular, seedless 27 3 Tbsp Raspberries canned, heavy syrup 64 1/4 cup frozen, red, sweetened 63 1/4 cup raw 61 1/2 cup Rhubarb, cooked, sweetened 119 1/2 cup Strawberries frozen, sweetened, sliced 84 1/3 cup sliced 74 1/2 cup Tangerines juice, canned 249 8 fl oz whole 63 3/4 fruit Watermelon, cubed 30 3 Tbsp
LYS (mg)
TRP (mg)
Protein (g)
Energy (kcal)
21 19 22 18 20 18 20 19 22 18 23 18 19 19 17 20 19
21 2 2 2 2 2 4 4 6 5 6 6 5 5 3 4 2
0.9 0.9 1.0 0.8 0.9 0.8 0.9 0.9 0.5 0.4 0.6 0.6 0.4 0.5 1.2 0.4 0.2
230 60 123 75 80 91 82 82 58 65 30 139 81 22 124 28 10
VEGETABLES Vegetables are raw unless otherwise noted. Weight of raw vegetables is only for parts that can be eaten. Drain canned, cooked, and frozen fruits before measuring or weighing. Asparagus fresh or frozen, cooked raw Bamboo shoots, canned, sliced Beans snap green canned fresh, cooked frozen, cooked sprouts, mung (seed attached to sprout) cooked raw yellow wax, canned Beets greens, cooked, chopped red, sliced fresh, canned, cooked pickled Broccoli, fresh or frozen cooked raw Brussels sprouts, fresh or frozen, cooked Cabbage, shredded Chinese (Pak-choi) cooked raw
15 15 22
1 spear 1 spear 3 Tbsp
19 19 18
4 4 4
0.4 0.4 0.3
6 4 3
34 23 34 16 13 33 27 53 75 13 13 16
1/4 cup 3 Tbsp 1/4 cup 2 Tbsp 2 Tbsp 2 Tbsp 3 Tbsp 1/4 cup + 1 Tbsp 1/3 cup 1 Tbsp + 1 tsp 1 Tbsp + 1 tsp 1 Tbsp + 2 tsp
19 21 22 20 22 18 20 20 22 19 20 19
4 5 5 4 5 4 11 7 7 4 4 5
0.4 0.4 0.5 0.3 0.4 0.4 0.7 0.6 0.6 0.4 0.4 0.4
7 8 9 3 4 7 7 16 50 4 4 6
21 23
2 Tbsp 1/3 cup
20 21
3 4
0.3 0.3
3 3
Food
Weight Approximate (g) Measure For greatest accuracy, weigh food on scale that reads in grams. All measures are level. red cooked 37 1/4 cup raw 35 1/2 cup Carrots canned, sliced 73 1/2 cup cooked 49 1/4 cup + 1 Tbsp sliced 55 1/2 cup Cauliflower diced, cooked fresh 20 2 Tbsp + 2 tsp frozen 13 1 Tbsp + 2 tsp raw 19 3 Tbsp Celery, diced cooked 99 2/3 cup raw 79 2/3 cup Chard, Swiss, cooked 22 2 Tbsp Collards, cooked, chopped fresh 36 3 Tbsp frozen 14 1 Tbsp + 1 tsp Eggplant, cubed cooked 48 1/2 cup raw 41 1/2 cup Endive, shredded 33 2/3 cup Horseradish 7 2-1/2 Tbsp Kale, cooked fresh 16 2 Tbsp frozen 11 1 Tbsp + 1 tsp Kohlrabi, sliced cooked 31 3 Tbsp raw 35 1/4 cup Leeks, diced cooked 52 1/2 cup raw 26 1/4 cup Lettuce, shredded iceberg 28 1/2 cup Romaine 18 1/3 cup Mushrooms Agaricus bisporus, sliced cooked or canned 9 2 Tbsp raw 9 2 Tbsp Shitake cooked, pieces 48 1/3 cup dried 5 1-1/2 mushrooms Mustard greens, chopped cooked 19 2 Tbsp + 1/2 tsp raw 18 1/4 cup + 1 Tbsp Okra, cooked, sliced 27 2 Tbsp + 2 tsp Onions cooked 53 1/4 cup flakes 5 1 Tbsp raw, diced 40 1/4 cup rings, canned 23 1 cup Parsnips, cooked 39 1/4 cup Peas, green, cooked, canned, frozen 10 1 Tbsp Peppers green, sweet, diced cooked 68 1/2 cup 2001 Ross Products Division
LYS (mg)
TRP (mg)
Protein (g)
Energy (kcal)
19 20 18 21 22
4 4 5 6 6
0.4 0.4 0.5 0.5 0.6
8 8 17 22 24
20 13 20 20 21 23 19 20 19 21 21 20 19 19 18 20 22 20 21 19
5 3 5 7 7 4 5 5 4 4 2 5 4 4 3 4 3 3 2 2
0.4 0.2 0.4 0.5 0.5 0.4 0.4 0.4 0.4 0.5 0.4 0.3 0.3 0.3 0.6 0.6 0.4 0.4 0.3 0.3
5 3 5 15 13 4 5 5 13 11 6 4 5 3 9 10 16 16 4 3
19 19 22 18 20 22 20 23 21 22 10 20 18
4 4 1 2 5 5 4 7 6 7 5 5 2
0.2 0.2 0.7 0.5 0.4 0.5 0.5 0.5 0.5 0.5 0.4 0.5 0.3
2 2 27 17 3 5 8 15 16 14 82 32 5
19
0.4
12
Food
Weight Approximate (g) Measure For greatest accuracy, weigh food on scale that reads in grams. All measures are level. raw 50 1/2 cup jalapeo, canned, cooked 51 1/4 cup + 2 Tbsp Pickle, cucumber dill relish 14 1 Tbsp whole, small 60 1 pickle sweet relish 16 1 Tbsp sliced 60 2 slices Pumpkin canned 31 2 Tbsp cooked 34 3 Tbsp Radishes, red, sliced 58 1/2 cup Rutabaga cooked, mashed 56 1/3 cup raw, cubed 46 1/3 cup Sauerkraut 44 3 Tbsp Shallots, chopped 17 1 Tbsp + 2 tsp Spinach, chopped fresh or frozen, cooked 11 1 Tbsp raw 11 3 Tbsp Squash, summer, all varieties summer, all varieties fresh or frozen, cooked 37 3 Tbsp + 1 tsp sliced 33 1/4 cup winter acorn, baked, cubed 51 1/4 cup butternut, baked, cubed 68 1/3 cup Hubbard, baked, cubed 38 1/3 cup spaghetti, boiled 101 2/3 cup Taro, cooked leaves 15 1 Tbsp + 2 tsp root, sliced 75 1/2 cup Tomato catsup 26 1 Tbsp + 1 tsp fresh, canned, cooked 45 3 Tbsp juice 92 3 fl oz paste 19 1 Tbsp + 1/2 tsp pure 39 2-1/2 Tbsp sauce marinara 45 3 tbsp w/ onions, green peppers, and celery 46 3 Tbsp stewed, canned 64 1/4 cup whole, chopped 59 1/3 cup Turnips greens, cooked, chopped 27 3 Tbsp root, diced cooked 78 1/2 cup raw 60 1/2 cup Vegetable cocktail juice (V8 ) 39 2-1/2 Tbsp
LYS (mg) 19 18 6 5
TRP (mg)
Protein (g) 0.4 0.4
Energy (kcal) 13 12
4 17 3 17 18 20 20 20 18 19 21 19 19
1 3 1 3 4 5 2 7 6 4 5 4 4
0.1 0.4 0.1 0.4 0.3 0.4 0.3 0.6 0.6 0.4 0.4 0.3 0.3
3 7 22 88 10 35 10 19 17 8 12 3 2
19 21 21 22 21 22 20 17 21 19 20 21 19 20 17 22 20 20 22 21 19
3 4 5 9 8 9 4 6 5 4 5 5 4 5 4 5 4 5 5 5 4
0.3 0.4 0.6 0.6 0.9 0.7 0.4 0.4 0.5 0.5 0.7 0.7 0.7 0.7 0.6 0.6 0.5 0.3 0.6 0.5 0.7
7 7 29 27 19 29 4 107 27 11 16 16 16 31 14 17 11 5 14 17 16
Soups, Campbell's , Condensed. Weigh or measure before diluting and dilute with water only. Asparagus, Cream of 21 1 Tbsp + 1 tsp 19 Celery, Cream of 31 2 Tbsp 19 Mushroom, Cream of 24 1-1/2 Tbsp 20 Onion 15 1 Tbsp 22
5 5 5 7
0.4 0.4 0.4 0.5
14 23 24 7
Food
Weight Approximate (g) Measure For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Potato, Cream of 31 2 Tbsp Tomato 47 3 Tbsp Tomato Bisque 31 2 Tbsp Tomato Rice 48 3 Tbsp Vegetable, Chunky, Ready To Serve 25 1 Tbsp + 2 tsp Vegetable, Old Fashioned 26 1 Tbsp + 2 tsp Vegetarian Vegetable 26 1 Tbsp + 2 tsp
LYS (mg) 21 19 22 19 20 21 21 6 8 6 8 3 3 3
TRP (mg)
Protein (g) 0.4 0.8 0.6 0.8 0.4 0.5 0.4
Energy (kcal) 19 32 30 45 13 14 15
FREE FOODS A Limit to prescribed number of servings. Beverages Apple juice Chocolate drink powder (Quik ) Grape juice, canned Lemon juice Orange juice canned frozen, diluted Orange-grapefruit juice, canned Papaya nectar Pear nectar Tangerine juice, frozen, diluted Fruits/Fruit Products Apples, dried, cooked Apple pie filling Blueberries, raw Cranberry sauce sweetened w/ sugar Fruit ices Fruit Roll-Ups Grapes, slipskin Guava sauce Jams and preserves Marmalade Loquats Miscellaneous Licorice M&M Candy, plain Raisins, chocolate covered Sorbet peach pineapple strawberry Tapioca, dry Vegetables Chives Cucumbers, pared, sliced Radishes, white icicle, sliced
155 3 63 92 62 62 62 93 125 90
5 fl oz 1 tsp 2 fl oz 3 fl oz 2 fl oz 2 fl oz 2 fl oz 3 fl oz 4 fl oz 3 fl oz
5 4 6 5 5 6 5 7 5 6
0 1 10 1 1 1 1 2 3 1
0.1 0.1 0.4 0.4 0.4 0.4 0.4 0.2 0.1 0.4
73 11 38 19 26 28 27 53 75 42
42 61 36 132 24 14 48 59 20 19 20
3 Tbsp 1/4 cup 1/4 cup 1/2 cup 2 Tbsp 1 piece 20 grapes 1/4 cup 1 Tbsp 1 Tbsp 2 fruits
6 4 4 6 5 6 6 5 5 5 6
1 1 1 1 1 3 2 2 1 1 1
0.1 0.1 0.2 0.3 0.1 0.2 0.3 0.2 0.1 0.1 0.1
24 68 52 209 3 55 30 21 54 50 10
5 1 1 24 15 30 31 3 26 21
1/2 piece 1 piece 1 raisin 2 Tbsp 1 Tbsp 2 Tbsp 3 Tbsp 1 Tbsp 1/4 cup 1/4 cup
4 3 4 5 4 5 6 4 6 6
2 1 1 0 1 1 3 1 1 0
0.2 0.1 0.1 0.1 0.1 0.1 0.2 0.1 0.1 0.1
17 4 6 30 14 29 109 1 4 4
FREE FOODS B These foods contain little or no LYS or TRP. They may be used as desired if patient is not overweight and if they do not depress appetite for prescribed foods. Beverages Carbonated drinks cola 2001 Ross Products Division
123
4 fl oz
0.0
50
Food
Weight Approximate (g) Measure For greatest accuracy, weigh food on scale that reads in grams. All measures are level. cream soda 124 4 fl oz Dr Pepper 31 1 fl oz ginger ale 122 4 fl oz grape soda 124 4 fl oz lemon-lime soda 123 4 fl oz orange soda 124 4 fl oz root beer 123 4 fl oz Cranberry juice cocktail 190 6 fl oz Exceed Energy Drink 124 4 fl oz Fruit drink (Hi-C ) 124 4 fl oz Fruit juice drink 124 4 fl oz Gatorade Thirst Quencher 121 4 fl oz Kool-Aid , prepared w/ sugar 123 4 fl oz Lemonade 123 4 fl oz Lime juice 31 1 fl oz Orange drink powder (Tang ) 12 1 Tbsp Strawberry drink powder (Quik ) 8 1 Tbsp Desserts/Sweeteners Candies candy corn gumdrops hard candy jelly beans Frosting, strawberry and vanilla Jellies Lemon pudding, canned (Hunt's ) Popsicle , twin Miscellaneous Butterscotch chips Fruit juice bars Fun fruits Honey Lard Molasses Oil olive vegetable Richwhip liquid Sugar brown powdered table Syrup maple table Tallow, beef
1
LYS (mg) 0 0 0 0 0 0 0 2 0 0 2 0 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
TRP (mg)
Protein (g) 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.0 0.0 0.1 0.1 0.0 0.0
Energy (kcal) 63 13 41 53 49 60 50 108 23 58 62 30 49 49 6 47 33
8 20 10 28 16 20 121 128
5 pieces 4 pieces 2 pieces 10 pieces 1 Tbsp 1 Tbsp 1 container 1/2 popsicle
1 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
29 28 39 103 69 54 151 95
1 52 26 21 13 21 13 14 14 14 8 12 20 20 13
1 piece 1 bar 1 piece 1 Tbsp 1 Tbsp 1 Tbsp 1 Tbsp 1 Tbsp 1 Tbsp 1 Tbsp 1 Tbsp 1 Tbsp 1 Tbsp 1 Tbsp 1 Tbsp
2 2 2 2 0 0 0 0 0 0 0 0 0 0 0
0 1 1 1 0 0 0 0 0 0 0 0 0 0 0
0.0 0.1 0.1 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
3 43 100 64 115 48 119 120 40 52 31 48 50 50 115
For composition of very-low-protein foods, see Appendix 12, p A-11.
TABLE 9-6. Glutaric Aciduria Type I or 2-Ketoadipic Aciduria Clinical Summary Sheet Name: Date of Birth: __________/__________/__________
Mo Day Year Mo
Hospital Number: Date of Diagnosis: ___________/__________/__________

Day Year
Medications:
Date
(mo/d/yr)
Supplements:
Physical Data Laboratory Data
Free Carnitine (mol/L) Glutaric Acid (ng/mL) LYS (mol/L) TRP (mol/L) Hgb (g/dL) Hct (%) Ferritin (ng/mL) Albumin/ Transthyretin (g/dL / mg/dL) Urinary Organic Acids LYS (mg)

TRP (mg) Protein (g) Energy (kcal)
Length/ Height (cm)
Weight (kg)
Head Circum (cm)
REFERENCES
1. 2. 3. Abernathy RP, Speirs M, Engel RW, Moore ME: Effects of several levels of dietary protein and amino acids on nitrogen balance of preadolescent girls. Am J Clin Nutr 1968;19:407-414. Amir N, Elpeleg ON, Shalev RS, Christensen E: Glutaric aciduria type I. Enzymatic and neuroradiologic investigations of two kindreds. J Pediatr 1989;114:983-989. Applegarth DA, Edelstein AD, Wong LTK, Morrison BJ: Observed range of assay values for plasma and cerebrospinal fluid amino acid levels in infants and children aged 3 months to 10 years. Clin Biochem 1979;5:173-178. Arnold GL, Vladutiu CJ, Kirby RS: Protein insufficiency and impaired growth in children with PKU. J Inher Metab Dis 2000;23 Suppl 1:29A. Baric I, Zchocke J, Christensen E, et al: Diagnosis and management of glutaric aciduria type I. J Inher Metab Dis 1998;21:326-340. Behrman RE, Kleigman RM, Arvin AA (eds): Nelson Textbook of Pediatrics, ed 15. Philadelphia: WB Saunders Co, 1996. Bergman I, Finegold D, Gartner JC: Acute profound dystonia in infants with glutaric acidemia. Pediatrics 1989;83:228-234. Bohles H, Ullrich K, Endres W, et al: Inadequate iron availability as a possible cause of low serum carnitine concentrations in patients with phenylketonuria. Eur J Pediatr 1991;150:425-428. Brandt NJ, Brandt S, Christensen E, et al: Glutaric aciduria in progressive choreoathetosis. Clin Genet 1978;13:7780. Brandt NJ, Gregersen N, Christensen E, et al: Treatment of glutaryl-CoA dehydrogenase deficiency (glutaric aciduria). J Pediatr 1979;94:669-673. Clark HE, Kenney MA, Goodwin AF, et al: Effect of certain factors on nitrogen retention and lysine requirements of adult human subjects. IV. Total nitrogen intake. J Nutr 1963;81:223-229. Clark HE, Mertz ET, Kwong EH, et al: Amino acid requirements of men and women. I. Lysine. J Nutr 1957;62:71-82. Curzon G, Kantamaneni BD, Winch J, et al: Plasma and brain tryptophan changes in experimental acute hepatic failure. J Neurochem 1973;21:137-145. Dunger DB, Snodgrass GJAI: Glutaric aciduria type I presenting with hypoglycaemia. J Inher Metab Dis 1984;7:122-124. Duran M, Beemer FA, Wadman SK, et al: A patient with -ketoadipic and -aminoadipic aciduria. J Inher Metab Dis 1984;7:61. Elsas LJ, Acosta PB: Nutrition support of inherited metabolic diseases. In Shils ME, et al (eds): Modern Nutrition in Health and Disease, ed 9. Baltimore: Williams & Wilkins, 1999, pp 1003-1059. Finberg L: Assessing the clinical clues to dehydration. Contemp Pediatr 1990;7:45-57. Fisher H, Brush MK, Griminger P: Reassessment of amino acid requirements of young women on low nitrogen diets. I. Lysine and tryptophan. Am J Clin Nutr 1969;22:1190-1196. Fisher H, Brush MK, Shapiro R, et al: Amino acid balance in the adult: High-nitrogen low-tryptophan diets. J Nutr 1963;81:230-234. Fomon SJ, May CD: Metabolic studies of normal full-term infants fed pasteurized human milk. Pediatrics 1958;22:101-114. Fomon SJ, Thomas LN, Filer LJ Jr, et al: Requirements for protein and essential amino acids in early infancy. Acta Paediatr Scand 1973;62:33-45. Food and Nutrition Board, Committee on Dietary Allowances: Recommended Dietary Allowances, eds 9 and 10. Washington, DC: National Academy of Sciences, 1980 and 1989. Garabdian-Ruffalo S, Ruffalo RL: Drug and nutrient interactions. Am Fam Phys 1986;33:165-174. Goodman SI, Frerman FE: Organic acidemias due to defects in lysine oxidation: 2-ketoadipic acidemia and glutaric acidemia. In Scriver CR, et al (eds): The Metabolic and Molecular Bases of Inherited Disease, ed 8. New York: McGraw-Hill Medical Publishing Division, 2001, pp 2195-2204. Gropper S, Acosta PB: Effect of simultaneous ingestion of L-amino acids and whole protein on plasma amino acid and urea nitrogen concentrations in humans. JPEN 1991;15:48-53. Haworth JC, Booth PA, Chudley AE: Phenotype variability in glutaric aciduria type I. Report of fourteen cases in five Canadian Indian kindreds. J Pediatr 1991;118:52-58. Herrmann ME, Broesicke HG, Keller M, et al: Dependence of the utilization of a phenylalanine-free amino acid mixture and different amounts of single dose ingested. A case report. Eur J Pediatr 1994;153:502-503. Heyes MD: Hypothesis: A role for quinolinic acid in the neuropathy of glutaric aciduria type I. Can J Neurol Sci 1987;14:441-443. Hoffman GF: Disorders of lysine catabolism and related cerbral organic acid disorders. In Fernandes J, et al (eds): Inborn Metabolic Diseases: Diagnosis and Treatment, ed 3. New York: Springer-Verlag, 2000, pp 241-253. Hoffman GF, Tretz FK, Barth PG, et al: Macrocephaly: An important indication for organic acid analysis. J Inher Metab Dis 1991;14:329-332.
4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24.
25. 26. 27. 28. 29. 30.
31. Hoffman GF, Zschocke J: Glutaric aciduria type I: From clinical, biochemical, and molecular diversity to successful therapy. J Inher Metab Dis 1999;22:381-391. 32. Hyman DB, Tanaka K: Specific glutaryl-CoA dehydrogenase activity is deficient in cultured fibroblasts from glutaric aciduria patients. J Clin Invest 1984;73:778-784. 33. Jones EM, Baumann CA, Reynolds MS: Nitrogen balances of women maintained on various levels of lysine. J Nutr 1956;60:549-562. 34. Jones BJM, Lees R, Andrews J, et al: Comparison of an elemental and polymeric enteral diet in patients with normal gastrointestinal function. Gut 1983;24:78-84. 35. Kylerrman M, Steen G: Glutaric aciduria. A "common" metabolic disorder. Arch Fri Pediatr 1980;37:279-81. 36. Leverton RM, Johnson N, Dazur J, Ellison J: Amino acid requirements of young adults. In Albanese AA (ed): Protein and Amino Acid Nutrition. New York: Academic Press, 1959. 37. MacLean W, Graham G: Pediatric Nutrition in Clinical Practice. Menlo Park, Calif: Addison-Wesley Publishing Co, 1982. 38. MacLean WC, Placko RP, Graham GG: Fasting plasma free amino acids of infants and children consuming cow milk proteins. Johns Hopkins Med J 1978;142:147-151. 39. Madras BK, Cohen EL, Messing R, et al: Relevance of free tryptophan in serum to tissue tryptophan concentration. Metabolism 1974;23:1107-1116. 40. Martin SB, Acosta PB: Osmotic behaviors of components of chemically-defined formulas. J Pediatr Perinat Nutr 1987;1:1-17. 41. Meites S (ed): Pediatric Clinical Chemistry, ed 3. Washington, DC: AAAC Press, 1989. 42. Monavari AA, Naughten ER: Prevention of cerebral palsy in glutaric aciduria type I by dietary management. Arch Dis Child 2000;82:67-70. 43. Morton DH, Bennett MJ, Seargeant LE, et al: Glutaric aciduria type I: A common cause of episodic encephalopathy and spastic paralysis in the Amish of Lancaster County, Pennsylvania. Am J Med Genetics 1991;41:89-95. 44. Ohkohchi N, Andoh J, Ohi R, Mori S: Defined formula diets alter characteristics of the intestinal transport of amino acids and peptides in growing rats. J Pediatr Gastroenterol Nutr 1990;10:490-496. 45. Peng H, Shinka t, Inoue Y, et al: Asymptomatic alpha-ketoadipic aciduria detected during a pilot study of neonatal urine screenings. Acta Paediatr 1999;88:911-914. 46. Pineda O, Torun B, Viteri FE, Arroyave G: Protein quality in relation to estimates of essential amino acid requirements. In Bodwell CE, et al (eds): Protein Quality in Humans: Assessment and in Vitro Estimation. Westport, Conn: Avi Publishing Co Inc, 1981. 47. Posati LP, Orr ML: Composition of Foods: Dairy and Egg Products, Agriculture Handbook No. 8-1. Washington, DC: US Dept of Agriculture, Agricultural Research Services, 1976. 48. Pratt EL, Snyderman SE, Cheung MW, et al: The threonine requirement of the normal infant. J Nutr 1955;56:231-251. 49. Przyrembel H: Defects of lysine degradation. In Fernandes J, et al (eds): Inborn Metabolic Diseases: Diagnosis and Treatment. New York: Springer-Verlag, 1990, pp 301-310. 50. Przyrembel H, Bachmann D, Lombeck I, et al: Alpha-ketoadipic aciduria, a new inborn error of lysine metabolism: Biochemical studies. Clin Chim Acta 1975;58:257-269. 51. Rose WC: The amino acid requirements of adult man. Nutr Abstr Rev 1957;27:631-647. 52. Rose WC, Lambert GF, Coon MJ: The amino acid requirements of man. VII. General procedures: The tryptophan requirement. J Biol Chem 1954;211:817-827. 53. Schoeffer A, Herrmann ME, Broesicke HG, Moench E: Effect of dosage and timing of amino acid mixtures on nitrogen retention in patients with phenylketonuria. J Nutr Med 1994;4:415-418. 54. Seccombe DW, James L, Booth F: L-carnitine treatment in glutaric aciduria type I. Neurology 1986;36:264-267. 55. Shapira Y, Gutman A: Muscle carnitine deficiency in patients using valproic acid. J Pediatr 1991;118:646-649. 56. Smith CA, Nelson NM (eds): The Physiology of the Newborn Infant, ed 4. Springfield, IL: Charles C Thomas Publisher, 1976. 57. Smith JL, Arteaga C, Heymsfield SB: Increased ureagenesis and impaired nitrogen use during infusion of a synthetic amino acid formula - A controlled trial. N Engl J Med 1982;306:1013-1018. 58. Smith JL, Heymsfield SB: Enteral nutrition support: Formula preparation from modular ingredients. JPEN 1983;7:280-288. 59. Snyderman SE, Boyer A, Phansalkar SV, et al: Essential amino acid requirements of infants: Tryptophan. Am J Dis Child 1961;102:163-167. 60. Snyderman SE, Norton PM, Fowler DI, Holt LE: The essential amino acid requirements of infants: Lysine. Am J Dis Child 1959;97:175-185. 61. Spika JS, Shaffer N, Hargrett-Bean N, et al: Risk factors for infant botulism in the United States. Am J Dis Child 1989;143:828-832. 62. Stumpf DA, Parker WD, Angelini C: Carnitine deficiency, organic acidemias and Reye's syndrome. Neurology 1985;35:1041-1045. 63. Sturman JA, Applegarth DA: Automated amino acid analysis. In Boulton AA, et al (eds): Neuromethods: Amino Acids, vol 3. Totowa, NJ: Humana Press, 1985.
64. Superti-Fuerga A, Hoffman GF: Glutaric aciduria type I (glutaryl-GA-dehydrogenase deficiency): Advances and unanswered questions. Eur J Pediatr 1997;156:821-828. 65. Tietz NW (ed): Textbook of Clinical Chemistry. Philadelphia: WB Saunders Co, 1986. 66. Torun B, Pineda O, Vitera FE, Arroyave G: Use of amino acid composition data to predict protein nutritive value for children with specific reference to new estimates of their essential amino acid requirements. In Bodwell CE, et al (eds): Protein Quality in Humans. Assessment and in Vitro Estimation. Westport, Conn: Avi Publishing Co Inc, 1981. 67. Ullrich K, Flott-Rahmel B, Schluff P, et al : Glutaric aciduria type I: Pathomechanisms of neurodegeneration. J Inher Metab Dis 1999;22:392-403. 68. Yannicelli S, Rohr F, Warman ML: Nutrition support for glutaric acidemia type I. J Amer Diet Assoc 1994;94:183-191. 69. Young VR, Hussein MA, Murray E, Scrimshaw NS: Plasma tryptophan response curve and its relation to tryptophan requirements of young adult men. J Nutr 1971;101:45-60. 70. Young VR, Tontisirin K, Ozalp I, et al: Plasma amino acid response curve and amino acid requirements in young men: Valine and lysine. J Nutr 1972;102:1159-1170. 71. Zempleni J, Galloway JR, McCormick, DB: Pharmacokinetics of orally and intravenously administered riboflavin in healthy humans. Am J Clin Nutr 1996;63:54-66.
PROTOCOL 10 Glutaric Acidemia Type II (Multiple Acyl-CoA Dehydrogenase Deficiency) Nutrition Support of Infants, Children, and Adults With PROVIMIN Protein-Vitamin-Mineral Formula Component With Iron
I. Introduction (13, 44)
Glutaric acidemia type II (GA-II), or multiple acyl-CoA dehydrogenase deficiency, is an inherited disorder characterized by hypoketotic or nonketotic hypoglycemia and metabolic acidosis, pathologically by fatty degeneration of liver parenchymal cells, renal tubular epithelium, and myocardium, and biochemically by the accumulation of metabolites of compounds oxidized by enzymes that transfer electrons to electron transfer flavoprotein (ETF). In most cases the disorder is due to the deficiency of either ETF or electron transfer flavoprotein ubiquinone oxidoreductase (ETFQO) (Figure I), but in some cases the disorder may be due to an as yet undefined abnormality in flavin metabolism or transport. Complete deficiency of ETF-QO is often associated with congenital anomalies, the most frequent and characteristic being cysts, and dysplasia of the kidneys. All forms of the disease are transmitted as autosomal recessive traits. Most patients with severe disease do not survive the first few weeks of life (37). While different degrees of enzyme deficiency have been shown to cause all three clinical forms of the condition, ETF-QO deficiency appears to be more common in patients with congenital anomalies (43). Although there are no accurate figures of incidence, GA-II is probably one of the more common inborn errors.
Very-long chain acyl-CoA Medium-chain acyl-coA Fat (n) Long-chain acyl-CoA Short-chain acyl-CoA Isovaleryl-CoA Isoleucine, valine (n) 2-Methylbutyrl-CoA Glutaryl-CoA Dimethylglycine Sarcosine (n) (n) Lysine, tryptophan Leucine
Electron Transfer Flavoprotein (ETF)
ETF-Ubiquinone Oxidoreductase H+ + NADH Complex I NAD+ Complex II (n) Succinate

+
1/2 O2 + 2 H+ Q Cytochrome C Complex III Complex IV H2O = Several steps = Enzyme defect
Fumarate
Figure I. Metabolism in GA II. NAD , NADH = nicotinamide adenine dinucleotide, oxidized and reduced forms. Q = ubiquinone (coenzyme Q). Complexes I - IV of the respiratory chain (Modified from reference 9).
II. Outcome of Nutrition Support (13)

Patients who present within a few days of birth usually die within the first few months of life (16,17). Diets low in fat and protein with supplements of carnitine and riboflavin have not been successful. Nutrition support with riboflavin, carnitine, and diets low in protein and fat has been more successful for patients with milder or later-onset disease than for patients with early onset disease. Treatment with oral riboflavin (100 to 300 mg/day) has been effective in a few patients, including a woman whose organic aciduria and sarcosinuria developed only during pregnancy and intercurrent infections. With riboflavin administration during pregnancy, she delivered two normal offspring (23).
2001 Ross Products Division Glutaric Acidemia Type II 199

A. The Defect (13) 1. GA II may result from one of several defects: a. ETF-QO. b. ETF: 1) the -subunit. 2) the -subunit (49). 3) Excess lability of ETF (49). B. Differential Diagnosis (13, 15, 28, 46, 50) 1. Neonatal onset with congenital anomalies. a. Clinical manifestations (16, 17) include prematurity; presentation within first 24 to 48 hours of life; anomalies of external genitalia, including hypospadias and chordee; facial dysmorphism (high forehead, low-set ears, hypertelorism, hypoplastic midface) (5, 8), hepatomegaly; hypotonia; muscular defects of abdominal wall; "sweaty-feet" odor (8); palpably enlarged kidneys; and rocker bottom feet. b. Most of these infants die within 1st week of life; renal cysts may be observed on autopsy (5). 2. Neonatal onset without congenital anomalies. a. Clinical manifestations that develop within 1st few days of life; hepatomegaly, hypotonia, "sweaty feet" odor, and tachypnea. b. Patients who have survived beyond 1st week of life, because of prompt diagnosis and treatment, have died within a few months, usually with severe cardiomyopathy resulting from lipid storage (9, 11, 14). c. A few infants, hypoglycemic in newborn period, have later developed symptoms typical of Reye's syndrome. 3. Mild or later onset (ethylmalonic-adipic aciduria). a. Clinical manifestations include onset any time during 1st few years of life; proximal myopathy; vomiting; and hepatomegaly. 4. Laboratory evaluation (8, 11, 13, 15, 20, 28) a. Routine results include hyperammonemia (< 300 mol/L); hypoglycemia without ketonuria or ketonemia; metabolic acidosis, often with increased anion gap; elevated serum transaminases; prolonged prothrombin and partial thromboplastin times; and elevated plasma lactic acid concentration. b. Urine organic acid values may be abnormal for various combinations of following: adipic, dodecanedioic, ethylmalonic, glutaric, 2-hydroxyglutaric, 3-hydroxyisovaleric, 5-hydroxyhexanoic, isobutyric, isovaleric, 2-methylbutyric, sebacic, and suberic. Isobutrylglycine, isovalerylglycine, and 2-methylbutyrylglycine may also be present (3, 4, 13, 15, 20, 43) c. Serum sarcosine may be elevated. d. Pancytopenia (25). 5. Prenatal diagnosis is available (6, 24, 26, 39, 49).
IV. Rationale for Nutrition Support (13)

A. Correct Primary Imbalance in Metabolic Relationships (31, 34, 35). 1. Restrict dietary intake of fat to 20% to 25% of energy (9, 31). 2. Restrict dietary intake of intact protein to decrease excess essential isoleucine (ILE), leucine (LEU), lysine (LYS), tryptophan (TRP), and valine (VAL). 3. Some, but not all, investigators supplement with glycine (GLY) to enhance loss of acyl compounds (38, 45). 4. Provide adequate energy for normal growth, maintenance, and prevention of catabolism. B. Supply "Conditionally Essential" Nutrients 1. Supplement L-carnitine to maintain free plasma carnitine in normal range (9, 10, 11, 22, 30, 34, 35, 40, 45, 46, 49). 2. Possible deleterious effects of L-carnitine supplementation were reported by Green et al in 1991 (18).
200 Glutaric Acidemia Type II 2001 Ross Products Division
C. Stabilize Altered Enzyme Protein 1. Supplement with oral riboflavin (7, 19, 21, 23, 34, 35, 45, 49).

A. Blood Glucose and Plasma Carnitine 1. Maintain normal blood glucose concentrations. 2. Maintain normal plasma free carnitine concentration 30 mol/L (40, 48). B. Growth, Development, and Nutrition Status 1. Support normal growth rate in infants and children and maintain appropriate weight for height in adults. 2. Support normal development. 3. Maintain normal nutrition status. C. Avoid Lipid Storage in Liver and Muscles (33) D. Avoid Hyperammonemia and Metabolic Acidosis E. Prevent Presence of Organic Acids in Urine F. Prevent Catabolism

A. Energy (13) 1. Prescribe amount that should support normal weight gain for infants and children and maintain appropriate weight for height in adults (Table 10-1, p 203). 2. Requirements vary widely. Warning: Inadequate energy intake will result in growth failure (27). B. Fat 1. Prescribe amount of total fat that promotes goals of nutrition support. a. Supply 20% to 25% of total daily energy as fat. b. Prescribe 3% of total energy as linoleic acid and 1.0% as -linolenic acid (12). Warning: Essential fatty acid deficiency may occur if intakes of linoleic acid and linolenic acid are inadequate. C. Protein 1. Prescribe amount that promotes normal growth without exceeding tolerance for ILE, LEU, LYS, TRP, and VAL (Table 10-1, p 203). Warning: Inadequate protein will result in growth failure. D. Carbohydrate 1. Prescribe remaining energy as carbohydrate. E. Fluid 1. Prescribe amount that will supply water requirements (Table 10-1, p 203). Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL fluid to children and adults for each kcal ingested. F. L-Carnitine 1. Prescribe amount that maintains normal plasma free carnitine concentrations 30 mol/L. a. Amounts of 50 to 300 mg/kg have been suggested. G. GLY 1. Prescribe 100 to 150 mg/kg/day (43).
Glutaric Acidemia Type II 201
H. Riboflavin 1. Prescribe 100 to 300 mg/day oral riboflavin, depending on age. Prescribe 100 mg/day for infant, 200 mg/day for child, and 300 mg/day for adult. I. Fasting 1. Prevent infants from fasting > 4 hours, children > 6 hours, and adults > 8 hours.

A. Fat 1. Calculate grams of fat required to provide 20% to 25% of energy prescription (Table 10-1, p 203). 2. Determine amount of soy or canola oil (Appendix 10, p A-9) required to supply fat, linoleic acid and -linolenic acids. B. Protein 1. Calculate grams of protein required (Table 10-1, p 203). 2. Calculate amount of ProViMin Protein-Vitamin-Mineral Formula Component With Iron, beikost, or table foods (Tables 10-2 and 10-3, pp 203-204) required to fill the protein prescription. a. Use ProViMin until 2nd birthday due to iron it supplies. After 2nd birthday, use skim milk (Table 10-3, p 204). b. Weigh ProViMin powder on scale that reads in grams because of variability of household measuring equipment (Practical Approaches to Nutrition Support, p vii) and changes in density during shipping. c. See Table 6-4 (p 118, footnote 3) for approximate packed weight of ProViMin powder in level, dry US standard household measures. C. Energy 1. Calculate energy (kcal) provided by fat (Appendix 10, p A-9), beikost, or table foods (Tables 10-2 and 10-3, pp 203-204) and add to that supplied by ProViMin, skim milk, or other protein containing foods (Tables 10-2 and 10-3, pp 203-204). 2. Subtract amount of energy supplied by these sources from total energy requirement. 3. Supply any remaining prescribed energy with Polycose Glucose Polymers powder (23 kcal/Tbsp, 3.8 kcal/g) or liquid (2 kcal/mL) (Appendix 9, p A-9), sugar (48 kcal/Tbsp), beikost, or table foods containing little or no fat (Tables 10-2 and 10-3, pp 203-204). a. Do not use corn syrup or table sugar for infants because of osmolarity they yield (34). b. Do not use honey for infants because it may contain botulinum toxin (48). 4. Add baby foods after infant is 3 to 4 months old to provide variety in taste, color, and texture (Table 10-2, p 203) if developmentally ready. D. L-Carnitine (Appendix 28, p A-29) 1. Add liquid L-carnitine to ProViMin medical food mixture. 2. L-carnitine tablets may be used if patient is capable of swallowing them. E. GLY (Appendix 28, p A-29) 1. Add GLY powder to ProViMin medical food mixture. F. Fluid and Mixing Instructions 1. Boil bottles, nipples, rings and mixing utensils for 5 minutes and cool. Boil more water for 5 minutes and cool to room temperature. 2. Measure or weigh specified amounts of boiled, cooled water, ProViMin, fat, and carbohydrate into clean containers. 3. Pour 1/2 of specified amount of boiled, cooled water into clean blender. Running blender at slow speed, gradually add ProViMin and blend mixture for at least 15 seconds. 4. Slowly pour specified amount of fat into blender and continue blending for no longer than 1 to 3 seconds. 5. Dissolve powdered carbohydrate in some of remaining water and pour into ProViMin and fat mixture, mix well, add water to yield prescribed volume,
Refrigerate in sterilized, closed containers until used. Discard unused portion 24 hours after mixing because of nutrient loss. Shake well before feeding. 7. Do not use microwave oven to warm formula. Unevenly heated formula can burn infants and steam can make bottles explode. 8. Discard formula remaining in bottle or cup after feeding. 9. Notify parents or caretakers when they may discontinue aseptic technique in making formula. G. Riboflavin (Appendix 26, p A-28). 1. Should be administered orally with medical food mixture or meal. 2. Add finely crushed tablets to ProViMin medical food mixture. 3. Administer only 25 to 30 mg per time with food since more will not be absorbed (51). H. Diet Guide 1. Provide parents, caretakers, or patient with completed Diet Guide (Table 10-4, p 205) with each diet change. Warning: Never permit infant to fast > 4 hours, child > 6 hours, or adult > 8 hours; less time if patient is febrile, has diarrhea, or is vomiting.

A. Nutrient Adequacy 1. Determine if diet provides nutrients in amounts prescribed in Section VI, Establish Prescription, p 198. a. See Table 10-2, p 203, for nutrient composition of ProViMin and skim milk. b. See Appendix 9, p A-9, for composition of Polycose. 2. Check diet to determine if it supplies Recommended Daily Intakes (RDIs) for minerals and vitamins (Table 6-4, p 118, and Appendices 13 and 14, pp A-14 and A-15). a. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. b. If ProViMin mixture provides < 100% of RDIs for age, supplement diet with needed minerals and vitamins if not provided by beikost or table foods and laboratory tests indicate need (Appendix 11, p A-10, for composition of supplements). B. Osmolarity 1. If concentration of prescribed medical food mixture is > 27 kcal/fl oz, determine if osmolarity is in acceptable range. a. Determine osmolarity by laboratory analysis or use mathematical formula given in Appendix 18, p A-20. b. Osmolarity per gram of ProViMin powder is 2 mosm. 2. If osmolarity is > 450 mosm/L for neonate (30), > 750 mosm/L for children, > 1,000 mosm/L for adults, or greater than tolerated by patient, increase water content of prescribed medical food mixture and recalculate its osmolarity. C. Potential Renal Solute Load 1. Dehydration will result if renal solute load is greater than renal-concentrating ability of patient. 2. If concentration of medical food mixture prescribed is > 27 kcal/fl oz, estimate its potential renal solute load. a. This step is important to prevent dehydration of infants who may have renal-concentrating capacity as low as 600 mosm/L. b. Upper limit of renal solute load for neonates is approximately 1,100 mosm/L (41). 3. A method for estimating potential renal solute load is given in Appendix 20, p A-22. 4. If potential renal solute load is excessive, increase water content of medical food mixture and recalculate.

A. Blood Glucose Concentration 1. Measure during febrile episodes. If below normal, increase carbohydrate intake either by oral feeds or intravenous solutions.
B. Plasma L-Carnitine Concentration 1. Measure plasma free carnitine concentration monthly until patient is 6 months of age and every 3 to 6 months thereafter. 2. If free carnitine concentration is < 30 mol/L: a. Increase prescribed L-carnitine by 5% and reevaluate plasma concentration in 1 month. b. If concentration continues below normal, repeat above process until value is in normal range. C. Protein Status 1. Evaluate plasma transthyretin concentration every 3 months until patient is 1 year old and twice yearly thereafter (Appendix 17, p A-18, for standards). a. Plasma transthyretin concentrations provide a more reliable and rapid indication of protein status than plasma albumin concentrations. b. Plasma albumin concentrations may be in the normal range when plasma transthyretin concentrations show a clear deficiency (1). 2. If plasma transthyretin concentration is below normal for age: a. Increase prescribed amount of protein by 5% to 10% and reevaluate transthyretin concentration in 1 month. b. If plasma transthyretin concentration remains low, repeat above process until value is in normal range. D. Urine Organic Acids 1. Evaluate monthly in infancy and every 2 to 3 months in children and adults. 2. If present and patient is not ill, decrease fat in diet by 3% to 5% and protein by 1% to 2%. 3. If fat is decreased to < 15% of energy, supplying adequate linoleic and -linolenic acids may become difficult. E. Iron Status 1. Plasma ferritin concentration. a. Evaluate at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17, p A-18, for standards). b. If plasma ferritin concentration is below normal for age: 1) Increase iron intake to 2 mg/kg with supplements (ferrous sulfate). 2) Evaluate plasma ferritin concentration monthly. 3) Continue iron supplements until plasma ferritin concentration is in normal range. 2. Complete blood count. a. Hemoglobin and hematocrit concentrations should be evaluated at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17, p A-18, for standards). F. Growth Status 1. Length/height and weight. a. Measure monthly to 1 year, every 3 months to 4 years, and twice yearly thereafter. Plot measurements on NCHS growth charts. b. Maintain length/height and weight between 10th and 90th percentiles. Some normal infants and children will fall above or below these percentiles. Maintain appropriate weight for height in adults. 2. If infant's or child's length/height or weight falls below usual growth channel: a. Increase prescribed protein and energy by 5% to 10% and remeasure in 1 month. b. If length/height or weight remains low, repeat above process until usual growth channel is achieved. G. Nutrient Intake 1. Maintain records of food intake for 3 days immediately before each blood test (Appendices 24 and 25, pp A-26 and A-27). 2. Evaluate intakes of fat, linoleic and -linolenic acids, protein, energy, minerals, and vitamins after each diet change. a. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. b. See Appendix 28, p A-29, for information about ordering software for diet evaluation.
H. Clinical Summary 1. A summary record of growth, laboratory, and nutrient intake data is useful for patient management (Table 10-5, p 206).
A. Example Establish and fill prescription for newborn weighing 3.5 kg using Recommended Daily Nutrient Intakes from Table 10-1, p 203, and nutrient contents from Tables 10-2 and 10-3, pp 203 and 204, and Appendix 10, p A-9. 1. Establish prescription.
Energy Fat Protein Carbohydrate Fluid 120 kcal/kg 420 kcal 3.5 kg 420 kcal 150 mL/kg x x x x 3.5 kg 0.20 2.0 g/kg 112 kcal 3.5 kg Fat (g) 0.13 9.00 0.00 = = = = = 420 kcal 84 kcal 9 kcal = 9.3 g 7.0 g 308 kcal 4 kcal = 77 g 525 mL Protein (g) 7.00 0.00 0.00 Energy (kcal) 30 80 312
Medical Food Mixture Measure
ProViMin 9.6 g Soy Oil 10.0 mL Polycose powder 82 g Add water to make 525 mL (18 fl oz).
9.13 7.0 422 Total per day 20% Percentage of energy as fat Approximate osmolarity of medical food mixture is < 350 mosm/L. Estimated potential renal solute load is < 65 mosm. Linoleic acid is 4.60 g or 9.8% of energy; -linolenic acid is 0.70 g or 1.49% of energy.

A. Rationale 1. In normal persons, febrile illness and trauma are accompanied by catabolism of body fat and protein (47). 2. Well-nourished patients with GA-II respond to infection and trauma as do normal persons. B. Objectives of Nutrition Support 1. Maintain hydration and electrolyte balance. a. Offer infants and toddlers Pedialyte Oral Electrolyte Maintenance Solution ad libitum (Appendix 9, p A-9). 2. Depress catabolism a. Enhance energy intake when possible by offering fruit juices ad libitum as tolerated; liquid Jell-O ; Polycose powder or liquid (Appendix 9, p A-9) added to fruit juices or Pedialyte if tolerated; and caffeine-free soft drinks (not diet drinks). b. Add 1/3 cup Polycose powder to Pedialyte liquid to yield 8 fl oz. c. Return patient to ProViMin medical food mixture as rapidly as possible. 1) Begin with 1/2 original strength ProViMin medical food mixture. 2) Increase to original strength as tolerated. d. Feed Polycose solution (5 to 7 g carbohydrate/kg) or carbohydrate-containing foods every 2 to 3 hours. 1) If unable to feed every 2 to 3 hours, administer solution of raw cornstarch (2 to 3 g/kg) to children older than 9 months. e. Administer 10% glucose solution intravenously if oral intake cannot be maintained. 3. Prevent low blood glucose concentrations. 4. Prevent accumulation of toxic fatty acids. a. Add liquid L-carnitine to Pedialyte. Warning: Intravenous administration of lipids is contraindicated.
TABLE 10-1. Recommended Daily Nutrient Intakes (Ranges) for Infants, Children, and Adults With Glutaric Acidemia Type II
Age Protein (g/kg) Infants 0 to < 3 mo 3 to < 6 mo 6 to < 9 mo 9 to < 12 mo 2.0 1.7 1.4 1.4
1
Nutrient Fat (% of energy) 20 - 25 20 - 25 20 - 25 20 - 25 (% of energy) 20 - 25 20 - 25 20 - 25 20 - 25 20 - 25 20 - 25 20 - 25 20 - 25 20 - 25 Energy1 (kcal/kg) 120 (145 115 (145 110 (135 105 (135 - 95) - 95) - 80) - 80) Fluid2 (mL/kg) 150 - 125 160 - 130 145 - 125 135 - 120 (mL/day) 900 - 1,800 1,300 - 2,300 1,650 - 3,300 1,500 - 3,000 1,200 - 3,000 1,400 - 2,500 2,000 - 3,700 2,100 - 3,900 2,000 - 3,300
- 1.7 - 1.4 - 1.1 - 1.1
(g/day) Girls and Boys 1 to < 4 yr 4 to < 7 yr 7 to < 11 yr Women 11 to < 15 yr 15 to < 19 yr 19 yr Men 11 to < 15 yr 15 to < 19 yr 15 - 23 20 - 30 25 - 34 30 - 40 40 - 45 45 - 50 40 - 42 42 - 49 49 - 55
(kcal/day) 1,300 ( 900 - 1800) 1,700 (1300 - 2300) 2,400 (1650 - 3300) 2,200 (1500 - 3000) 2,100 (1200 - 3000) 2,100 (1400 - 2500) 2,700 (2000 - 3700) 2,800 (2100 - 3900) 2,900 (2000 - 3300)
19 yr 1 Modified from reference 12. 2 Modified from reference 2. Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL fluid to children and adults for each kcal ingested.
TABLE 10-2. Average Nutrient Contents of Gerber Baby Foods, ProViMin, and Skim Milk 1
Food Measure 0.17 0.07 0.04 0.00 0.00 0.00 0.00 0.67 0.04 0.00 0.19 1.40 Fat (g) Protein (g) 0.25 0.16 0.10 0.01 0.10 1.00 0.07 1.58 0.19 1.00 3.53 73.00 Energy (kcal) 15 11 12 10 10 62 16 14 6 25 36 312
Cereals, Dry, Ready To Serve 1 Tbsp2 Cereals with Fruit, 2nd and 3rd Foods , Jarred 1 Tbsp2 Desserts, 2nd and 3rd Foods 1 Tbsp2 Desserts, Tropical Fruit 1 Tbsp2 2 Fruits, 1st , 2nd , and 3rd Foods 1 Tbsp Dices 1 jar Juices 1 fl oz Meats 2nd and 3rd Foods 1 Tbsp2 2 Vegetables, 1st , 2nd , and 3rd Foods 1 Tbsp Vegetable Dices 1 jar 3 Milk, Skim 100 mL ProViMin 100 g 1 Nutrient Values. Fremont, Michigan: Gerber Products Co, 2000. 2 US standard level measure. 3 From reference 36.
206 Glutaric Acidemia Type II
TABLE 10-3. Exchange Lists for Nutrition Support of Children and Adults With Glutaric Acidemia Type II1
Food List Meat, lean Milk, skim Fat2 Fruit Measure Fat (g) Carbohydrate (g) Protein (g) Energy (kcal)
1 oz 3 0 7 55 1 cup trace 12 8 86 varies 5 0 0 45 1/2 cup canned or 1/2 cup fresh or juice 0 20 0 60 1/2 cup dried 0 15 0 80 Starch/Bread varies trace 15 3 25 Vegetable 1/2 cup cooked, or 1 cup raw 0 5 2 25 1 Exchange Lists for Weight Maintenance. Chicago: The American Dietetic Association, 1995. 2 Care must be taken to select fats that provide adequate linoleic and -linolenic acids, such as soy or canola oil.
TABLE 10-4. Glutaric Acidemia Type II Diet Guide

Date: ______ ___ _/______ ____/__________ Mo Day Year Hospital Number:
Name:_________________________________________________________________________________ Birth Date: ______ ___ _/______ ____/__________ Mo Day Year Age:
Length/Height: ____________________ (cm/in) Weight: ______________________ (kg/lb)
Medical Food ProViMin
Amount g g g mL mL
Protein (g)
Fat (g)
Energy (kcal)
Skim milk
cups
Add water to make ________________________ mL ________________ (fl oz)
Beikost or table foods Cereals/Starch/Bread Cereals: With Fruit Desserts Fruits/Juices Meats, lean Vegetables Total per day Total per kg Percentage of energy
Tbsp/Exchanges
Comments:
____________________________________________________ Nutritionist
TABLE 10-5. Glutaric Acidemia Type II Clinical Summary Sheet Name: Date of Birth: __________/__________/__________
Mo Day Year
Hospital Number:
Date
Physical Data
Length/ Height Weight Head Circum (cm) Plasma Carnitine Free Total (mol/L) (mol/L)
Laboratory Data
Blood Glucose (mg/dL) Ferritin Transthyretin Hgb Blood Ammonia (mol/L) (g) Fat Linoleic Acid (g) (%)

Linolenic Acid (g) (%) Protein LCarnitine (mg) Glycine Energy
(mo/d/yr)
(cm)
(kg)
(ng/mL)
(mg/dL) (g/dL)
(%)
(g)
(mg)
(kcal)
REFERENCES
1. 2. 3. 4. 5. Arnold GL, Vladutiu CJ, Kirby RS: Protein insufficiency and impaired growth in children with PKU. J Inher Metab Dis 2000;23 Suppl 1:29A. Behrman RE, Kliegman RM, Arvin AA (eds): Nelson Textbook of Pediatrics, ed 15. Philadelphia: WB Saunders Co, 1996. Bell RB, Brownell AKW, Roe CR, et al: Electron transfer flavoprotein: Ubiquinone oxidoreductase (ETF:QO) deficiency in an adult. Neurology 1990;40:1779-1782. Bennett MJ, Curnock DA, Engel PC, et al: Glutaric aciduria type II: Biochemical investigation and treatment of a child diagnosed prenatally. J Inher Metab Dis 1984;7:57-61. Bhm N, Vy J, Kiessling M, Lehnert W: Multiple acyl-CoA dehydrogenation deficiency (glutaric aciduria type II), congenital polycystic kidneys, and symmetric warty dysplasia of the cerebral cortex in two newborn brothers. II. Morphology and pathogenesis. Eur J Pediatr 1982;139:60-65. Bone J, Chalmers RA, Tracey BM, et al: Prenatal diagnosis of dysmorphic neonatal-lethal type II glutaric aciduria. Lancet 1984;1:846-847. Brivet M, Tardieu M, Khellaf A, et al: Riboflavin responsive ethylmalonic-adipic aciduria in a 9-month-old boy with liver cirrhosis, myopathy, and encephalopathy. J Inher Metab Dis 1991;14:333-337. Colevas AD, Edwards JL, Hruban RH, et al: Glutaric acidemia type II. Comparison of pathologic features in two infants. Arch Pathol Lab Med 1988;112:1133-1139. de Visser M, Scholte HR, Schutgens PA, et al: Riboflavin-responsive lipid-storage myopathy and glutaric aciduria type II of early adult onset. Neurology 1986;36:367-372. Di Donato, Frerman FE, Rimoldi M, et al: Systemic carnitine deficiency due to lack of electron transfer flavoprotein:ubiquinone oxidoreductase. Neurology 1986;957-963. Dusheiko G, Kew MC, Joffe BI, et al: Recurrent hypoglycemia associated with glutaric aciduria type II in an adult. New Engl J Med 1979;301:1405-1409. Food and Nutrition Board, Committee on Dietary Allowances: Recommended Dietary Allowances, eds 9 and 10. Washington DC: National Academy of Sciences, 1980 and 1989. Frerman FE, Goodman SI: Defects of electron transfer flavoprotein and electron transfer flavoprotein - ubiquinone oxidoreductase: Glutaric aciduria type II, ed 8. New York: McGraw-Hill Medical Publishing Division, 2001, pp 2357-2366. Galloway JH, Cartwright IJ, Bennett MJ: Abnormal myocardial lipid composition in an infant with type II glutaric aciduria. J Lipid Res 1987;28:279-284. Goodman SI, Frerman FE: Glutaric acidaemia type II (multiple acyl-CoA dehydrogenation deficiency). J Inher Metab Dis 1984;7(suppl 1):33-37. Goodman SI, Reale M, Berlow S: Glutaric acidemia type II: A form with deleterious intrauterine effects. J Pediatr 1983;102:411-413. Goodman SI, Stene DO, McCabe ERB, et al: Glutaric acidemia type II: Clinical, biochemical, and morphologic considerations. J Pediatr 1982;100:946-950. Green A, Preece MA, De Sousa C, Pollitt RJ: Possible deleterious effect of L-carnitine supplementation in a patient with mild multiple acyl-CoA dehydrogenation deficiency (ethylmalonic-adipic aciduria). J Inher Metab Dis 1991;14:691-697. Gregersen N, Christensen MF, Christensen E, Klvraa S: Riboflavin responsive multiple acyl-CoA dehydrogenation deficiency. Assessment of 3 years of riboflavin treatment. Acta Paediatr Scand 1986;75:676681. Gregersen N, Klvraa S, Rasmussen K, et al: Biochemical studies in a patient with defects in the metabolism of acyl-CoA and sarcosine: Another possible case of glutaric aciduria type II. J Inher Metab Dis 1980;3:67-72. Gregersen N, Rhead W, Christensen E: Riboflavin responsive glutaric aciduria type II. In Fatty Acid Oxidation Defects: Clincal, Biochemical, and Molecular Defects. New York: Alan R Liss, Inc, 1990, pp 477-494. Harpey JP, Charpentier C, Coude M: Methylene-blue for riboflavin-unresponsive glutaric aciduria type II. Lancet 1986;1:391. Harpey JP, Charpentier C, Goodman SI, et al: Multiple acyl-CoA dehydrogenase deficiency occurring in pregnancy and caused by a defect in riboflavin metabolism in the mother. J Pediatr 1983;103:394-398. Henderson HE, Balla R, De Jong G, et al: Postnatal and antenatal laboratory diagnosis of glutaric aciduria type II in a South African family. S Afr Med J 1987;71:589-591. Hoffman GF, Hunneman DH, Jakobs C, et al: Progressive fatal pancytopenia, psychomotor retardation, and muscle carnitine deficiency in a child with ethylmalonic aciduria and ethylmalonic acidaemia. J Inher Metab Dis 1990;13:337-340. Jakobs C, Sweetman L, Wadman SK, et al: Prenatal diagnosis of glutaric aciduria type II by direct chemical analysis of dicarboxylic acids in amniotic fluid. Eur J Pediatr 1984;141:153-157. Lipshitz F, Moses N: Growth failure: A complication of dietary treatment of hypercholesterolemia. Am J Dis Child 1989;143:537-542.
6. 7. 8. 9. 10. 11. 12. 13.
14. 15. 16. 17. 18.
19.
20. 21. 22. 23. 24. 25.
26. 27.
28. Loehr JP, Goodman SI, Frerman FE: Glutaric acidemia type II: Heterogeneity of clinical and biochemical phenotypes. Pediatr Res 1990;27:311-315. 29. MacLean W, Graham G: Pediatric Nutrition in Clinical Practice. Menlo Park, Calif: Addison-Wesley Publishing Co, 1982. 30. Mandel H, Africk D, Blitzer M, Shapira E: The importance of recognizing secondary carnitine deficiency in organic acidaemias: Case report in glutaric acidaemia type II. J Inher Metab Dis 1988;11:397-402. 31. Mantagos S, Genel M, Tanaka K: Ethyl-malonic-adipic aciduria. J Clin Invest 1979;64:1580-1589. 32. Martin SB, Acosta PB: Osmotic behaviors of components of chemically-defined formulas. J Pediatr Perinat Nutr 1987;1:1-17. 33. Mongini T, Doriguzzi C, Palmucci L, et al: Lipid storage myopathy in multiple acyl-CoA dehydrogenase deficiency: An adult case. Eur Neurol 1992;32:170-176. 34. Mooy PD, Giesberts MA, van Geldersen HH, et al: Glutaric aciduria type II: Multiple defects in isolated muscle mitochondria and deficient -oxidation in fibroblasts. J Inher Metab Dis 1984;7(Suppl 2):101-102. 35. Mooy PD, Przyrembel H, Giesberts MA, et al: Glutaric aciduria type II: Treatment with riboflavin, carnitine, and insulin. J Eur Pediatr 1984;143:92-95. 36. Posati LP, Orr ML: Composition of Foods: Dairy and Egg Products, Agriculture Handbook No. 8-1. Washington, DC: US Dept of Agriculture, Agricultural Research Service, 1976. 37. Przyrembel H, Wendel V, Becker K, et al: Glutaric aciduria type II: Report on a previously undescribed metabolic disorder. Clin Chim Acta 1976;66:227-239. 38. Rinaldo P, Welch RD, Previs SF, et al: Ethylmalonic/adipic aciduria: Effects of oral medium-chain-triglycerides, carnitine, and glycine on urinary excretion of organic acids, acylcarnitines, and acylglycines. Pediatr Res 1991;30:216-221. 39. Sakuma T, Sugiyama N, Ichiki T, et al: Analysis of acylcarnitines in maternal urine for prenatal diagnosis of glutaric aciduria type 2. Prenat Diagn 1991;11:77-82. 40. Schulpis KH, Nounopoulos C, Scarpalezou A, et al: Serum carnitine level in phenylketonuric children under dietary control in Greece. Acta Paediatr Scand 1990;79:930-934. 41. Smith CA, Nelson NM: The Physiology of the Newborn Infant, ed 4. Springfield, IL: Charles C Thomas Publisher, 1976. 42. Spika JS, Shaffer N, Hargrett-Bean N, et al: Risk factors for infant botulism in the United States. Am J Dis Child 1989;143:828-832. 43. Sweetman L, Nyhan WL, Trauner DA, et al: Glutaric aciduria type II. J Pediatr 1980;96:1020-1026. 44. Tanaka K, Mantagos S, Genel M, et al: New defect in fatty-acid metabolism with hypoglycaemia and organic aciduria. Lancet 1977;2:986-987. 45. Turnbull TM, Bartlett K, Eyre JA, et al: Lipid storage myopathy due to glutaric aciduria type II: Treatment of a potentially fatal myopathy. Dev Med Child Neurol 1988;30:667-672. 46. Uziel G, Garavaglia B, Ciceri E, et al: Riboflavin-responsive glutaric aciduria type II presenting as a leukodystrophy. Pediatr Neurol 1995;13:333-335. 47. Wannemacher RW: Key role of various individual amino acids in host response to infection. Am J Clin Nutr 1977;30:1269-1280. 48. Warshaw JB, Curry E: Comparison of serum carnitine and ketone body concentrations in breast- and in formulafed newborn infants. J Pediatr 1980;97:122-125. 49. Yamaguchi S, Orii T, Maeda K, et al: A new variant of glutaric aciduria type II: Deficiency of -subunit of electron transfer flavoprotein. J Inher Metab Dis 1991;13:783-786. 50. Yamaguchi S, Orii T, Suzuki Y, et al: Newly identified forms of electron transfer flavoprotein deficiency in two patients with glutaric aciduria type II. Pediatr Res 1992;29:60-63. 51. Zempleni J, Galloway JR, McCormick DB: Pharmokinetics of orally and intravenously administered riboflavin in healthy humans. Am J Clin Nutr 1996;63:54-66.
PROTOCOL 11 Lysinuric Protein Intolerance Nutrition Support of Infants, Children, and Adults With PRO-PHREE Protein-Free Energy Module With Iron, Vitamins & Minerals
I. Introduction
Lysinuric protein intolerance (LPI) results from an autosomal recessive defect in intestinal, hepatic, and renal transport of the dibasic (cationic) amino acids lysine (LYS), arginine (ARG), and ornithine (ORN). Decreased intestinal and renal tubular reabsorption of these amino acids results in depressed plasma concentrations (Figure J). The depleted pools of ARG and ORN impair hepatic urea cycle function causing hyperammonemia (7, 30). Hyperammonemia and growth retardation are the earliest manifestations of LPI (2, 29, 30). Patients with LPI present with failure to thrive, protein intolerance, osteoporosis, hepatomegaly, muscle hypotonia, and hematologic abnormalities (30). Seizures and mental retardation have also been reported (29); but most patients have normal cognitive abilities. Thymic hypoplasia has been described in one patient (9). Compromised humoral immune responses (14) and intermittent hematophagocytic lymphohistiocytosis has been reported in patients with LPI (4).
Genetic defect of epithelial LYS, ARG, and ORN transport
Decreased intestinal absorption
Decreased tubular reabsorption
Decreased transport into liver cells
Deficiency of LYS, ARG, and ORN
Protein malnutrition
Impaired urea cycle Postprandial hyperammonemia
Growth failure Osteoporosis Hepatomegaly
Nausea Protein aversion Seizures Stupor Coma
Figure J. Metabolic and clinical effects of decreased LYS, ARG, and ORN transport (modified from reference 30)

Long-term LYS deficiency may contribute to osteoporosis, and delayed skeletal maturation (2, 21, 33). The use of oral L-citrulline (CIT) and a protein-restricted diet resulted in improved protein tolerance, corrected hyperammonemia, accelerated growth, and increased bone mass (2, 7, 17). L-ARG supplements have also been used with moderate clinical success, but intestinal absorption is poor. Acute and chronic pulmonary involvement may progress to alveolar proteinosis (granular proteinaceous material in alveoli) or cholesterol granulomas resulting in poor outcome. Death secondary to pulmonary complications has been reported in several pediatric patients (11). Early diagnosis and aggressive nutrition support improve the outcome in patients with LPI. Successful reproductive outcome of a woman with LPI has been reported (34).
212 Lysinuric Protein Intolerance

A. The Defect 1. LPI results from defect in renal, intestinal, and hepatic membrane transport of dibasic amino acids, LYS, ARG, and ORN (30).
Lysinuric Protein Intolerance 213
B. Clinical Evaluation 1. Diagnostic studies should be considered for any infant or child who presents with following clinical symptoms: a. Vomiting, poor appetite, failure to thrive. b. Protein/energy malnutrition (2, 18, 20, 29) c. Hepatosplenomegaly. d. Hypotonia. e. Skeletal abnormalities (2, 7, 21, 33) f. Acute or chronic interstitial lung disease and pulmonary cholesterol granulomas (11, 20, 30). g. Renal tubular disease (3). 2. Biochemical findings (29, 30). a. Subnormal to low normal plasma concentrations of LYS, ARG, and ORN. b. Excessive urinary excretion of LYS, ARG, and orotic acid (23, 24, 25). c. Subnormal argininosuccinate synthetase activity (19). d. Homocitrullinuria and homoargininuria (10). e. Elevated plasma ferritin (27) and thyroxin-binding globulin (30). f. Hyperammonemia (100-560 mol/L postprandial) (8). g. Abnormal immune function (14, 36).

A. Correct Primary Imbalance in Metabolic Relationships 1. Restrict dietary protein to amount tolerated without hyperammonemia. B. Provide Alternate Metabolic Pathways 1. Prescribe L-CIT to correct deficiency of urea cycle intermediates (ARG and ORN), help normalize plasma ammonia concentration (17, 28), improve protein tolerance (30), and promote normal growth and development. C. Supplement Essential Nutrient 1. Long-term oral LYS supplements have not been successful in increasing plasma LYS concentrations (26, 29). Short-term oral and intravenous LYS supplementation has normalized plasma LYS concentration (12, 13). 2. N-acetyllysine, a readily absorbable form of LYS, has been used only in acute situations (26).

A. Plasma Amino Acid Concentrations 1. Maintain 2- to 4-hour postprandial plasma amino acid concentrations in following ranges or within normal range for age established by laboratory used:
Amino acid Alanine (ALA) (19) ARG (10, 24, 25) CIT (19, 28, 29) Glycine (GLY) (29) LYS (2, 26, 28) ORN (2, 24, 29) Serine (SER) (29) mol/L 148 - 485 57 - 142 20 - 55 117 - 223 85 - 218 26 - 96 79 - 112
2. In practice, obtaining blood 2 to 4 hours postprandially is not always possible. Acceptable local standards should be developed if plasma amino acids are evaluated at other times. B. Plasma Ammonia Concentration 1. Maintain plasma ammonia concentration < 35 mol/L (0.06 mg/dL) or in normal range for age as established in laboratory used. C. Growth, Development, and Nutrition Status 1. Support normal growth in infants and children and maintain appropriate weight for height in adults. 2. Support normal development.
214 Lysinuric Protein Intolerance 2001 Ross Products Division
3. Maintain normal nutrition status. a. Prevent catabolism. b. Prevent ARG and ORN deficiencies. c. Prevent prolonged fasting. D. Physical manifestations 1. Inhibit progressive osteoporosis.

A. Protein 1. Prescribe amount that promotes goals of nutrition support (Table 11-1, p 216). 2. Protein may need to be increased if sodium benzoate, sodium phenylacetate, or sodium phenylbutyrate is administered daily. Warning: Excessive protein intake will result in acute hyperammonemia. Inadequate protein intake will result in failure to thrive in infants, and weight loss in children and adults, low plasma transthyretin concentration, delayed skeletal maturation, and hair loss. B. Energy 1. Prescribe amount greater than Recommended Dietary Allowances (RDAs) (6) to prevent catabolism (Table 11-1, p 216). 2. Requirements vary widely and may be 5% to 10% greater than those listed in Table 11-1, p 216, when infection or hyperammonemia is present. Warning: Inadequate energy intake results in poor growth in infants and children; weight loss in children and adults; decreased dietary protein tolerance; and increased body protein catabolism, leading to hyperammonemia. C. L-CIT 1. May be used in place of L-ARG or L-ORN to correct deficient intermediates in urea cycle and prevent hyperammonemia. L-CIT is readily absorbed from intestine and partly converted to ARG and ORN (17, 25, 30). 2. Amount prescribed may differ based on age, weight, and tolerance to protein intake. 3. Recommended L-CIT supplementation is as follows:
Age Infants/Toddlers < 10 kg (3, 28) Children >10 kg and Adults (29, 30) Amount (g/day) 2.5 - 4.8 4.8 - 8.0
a. Must be divided into 3 to 5 doses per day and taken with protein-containing meals. b. Doses must be individually prescribed based on protein intake and extent of hyperammonemia. D. Fluid 1. Prescribe amount that will supply water requirements (Table 11-1, p 216). Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL fluid to children and adults for each kcal ingested (1).

A. Protein 1. Calculate amount of infant formula, beikost, whole cows milk, or table foods (Table 11-2, p 216) required to fill protein prescription. 2. See Servings Lists for PHE-Restricted Diets (Protocol 1, pp 13-26), for portion sizes. B. Energy 1. Calculate energy provided by infant formula, beikost, whole cow's milk, or table foods (Table 11-2, p 216) required to fill protein prescription. 2. Subtract amount determined above from total energy prescription.
3. Provide remaining prescribed energy with Pro-Phree Protein-Free Energy Module with Iron, Vitamins & Minerals (Appendix 11, p A-10), sugar (48 kcal/Tbsp), or Free Foods B (Table 11-2, p 216). a. For infants and toddlers, Pro-Phree is recommended choice for energy. b. Do not use corn syrup for infants because of osmolarity it yields (16). c. Do not use honey for infants because it may contain botulinum toxin (32). Note: Due to chronic elevated plasma ferritin concentrations in patients with LPI, it may be beneficial to use low-iron infant formula. C. L-CIT (Appendix 26, p A-28) 1. Solution of L-CIT. a. Mix weighed amount of L-CIT powder with boiled, cooled water to yield 100 mg/mL (eg, 100 g L-CIT with enough water to yield 1 liter). Make enough solution to last 1 week. b. Refrigerate in sterilized, closed container until used. Discard unused suspension after 1 week, if not frozen. c. Shake well before using. Measure L-CIT solution into medical food mixture using disposable syringe. 2. For children and adults, L-CIT may be added to beverages offered at each protein-containing meal. 3. L-CIT powder may be given in pre-weighed capsules (29). D. Fluid and Mixing Instructions 1. Add sufficient boiled, cooled water to infant formula, L-CIT solution and Pro-Phree to yield prescribed volume. Tap water may replace boiled, cooled water when preparing medical food mixture for older infants, children, and adults. 2. Mix with sterilized blender at lowest speed for no longer than 3 seconds. Excess mixing may destabilize emulsion. May also be mixed in sterilized, tightly closed container by shaking vigorously for 10 to 12 seconds. 3 Refrigerate in sterilized, closed containers until used. Discard unused portion 24 hours after mixing because of nutrient loss. 4. Do not use terminal sterilization or boil because of Maillard reaction (Practical Aspects of Nutrition Support, p viii). 5. Warm or cool medical food mixture to room temperature before feeding to infants. Shake mixture well before feeding. 6. Do not warm medical food mixture for infants in microwave oven. Unevenly heated formula can burn infants and steam can make bottles explode. 7. Notify parents or caretakers when they may discontinue using aseptic technique in preparing medical food mixture for infants. E. Diet Guide 1. Provide parents, caregivers, or patient with completed Diet Guide (Appendix 22, p A-24) with each diet change.

A. Nutrient Adequacy 1. Determine if diet provides nutrients in amounts prescribed in Section VI, Establish Prescription, p 211. 2. Check diet to determine if it supplies Recommended Dietary Intakes (RDIs) of minerals and vitamins (Appendices 13 and 14, pp A-14 and A-15). a. See Appendices 4 through 7, pp A-4 to A-7, for complete nutrient composition of infant formulas, Appendix 8, A-8, for composition of whole cow's milk, and Appendix 11, p A-10, for compostion of Pro-Phree. b. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. c. If infant formula plus Pro-Phree mixture provides < 100% of RDIs for age, supplement diet with needed minerals and vitamins if not provided by beikost or table foods and laboratory tests indicate need (Appendix 11, p A-10, for composition of supplements).
216 Lysinuric Protein Intolerance 2001 Ross Products Division
B. Osmolarity 1. If concentration of prescribed medical food mixture is > 27 kcal/fl oz, determine if osmolarity is in acceptable range. a. Determine osmolarity by laboratory analysis or use mathematical formula given in Appendix 18, p A-20. b. Osmolarity per gram of Pro-Phree, Similac, Isomil, and whole cow's milk is listed in Appendix 19, p A-21. 2. If osmolarity is > 450 mosm/L for infants (15), > 750 mosm/L for children, > 1,000 mosm/L for adults (31), or greater than tolerated by patient, increase water content of prescribed medical food mixture and recalculate its osmolarity. C. Potential Renal Solute Load 1. Dehydration will result if renal solute load is greater than renal-concentrating ability of patient. 2. If concentration of medical food mixture prescribed is > 27 kcal/fl oz, estimate its potential renal solute load. a. This step is important to prevent dehydration of infants who may have renal-concentrating capacity as low as 600 mosm/L. b. Upper limit of renal solute load for neonates is approximately 1,100 mosm/L. 3. A method for estimating potential renal solute load is given in Appendix 20, p A-22. 4. If potential renal solute load is excessive, increase water content of medical food mixture and recalculate.

A. Plasma ARG, LYS, AND ORN Concentrations 1. Initial. a. Evaluate twice weekly by quantitative methods until plasma concentrations stabilize. 2. Ongoing. a. Frequent evaluations help ensure adherence to nutrition support plan. b. Evaluate at least monthly when patient's condition is stable. For infants, evaluate every 2 weeks to 1 month. 3. Unacceptable plasma ARG, LYS, and ORN concentrations. a. Plasma LYS concentrations usually remain chronically low despite nutrition support (29). b. If plasma ARG or ORN concentrations are below lower limit of normal and patient has ingested and tolerated full protein prescription: 1) Either increase prescribed amount of protein or L-CIT supplementation by 5% to 10% and reevaluate plasma concentrations in 3 to 7 days. 2) If any amino acid continues below lower limit of normal, repeat above process until value is in treatment range listed. Warning: Plasma ARG or ORN deficiency will result in hyperammonemia (30, 37). B. Blood Ammonia Concentration 1. Initial. a. Evaluate daily until concentration is in normal range (< 35 mol/L). 2. Ongoing. a. Evaluate weekly until patient is 6 months old, twice monthly until 12 months of age, and monthly thereafter if patient is stable and well. 3. Elevated blood ammonia concentration. a. Obtain 3-day diet diary and evaluate protein intake. b. Evaluate patient for infection. c. If infection is ruled out, protein intake is not greater than prescribed, and energy intake is not less than prescribed: 1) Increase L-CIT supplement by 10% and reevaluate blood ammonia and plasma ARG and ORN concentrations in 2 to 3 days. Warning: Blood ammonia concentration is strongly correlated with protein ingestion and below-normal plasma ARG and ORN concentrations. 2) If blood ammonia concentration remains above upper limit of normal, repeat above process until normal concentration is attained.
2001 Ross Products Division Lysinuric Protein Intolerance 217
C. Protein Status 1. Evaluate plasma transthyretin concentration every 3 months throughout life (Appendix 17, p A-18, for standards). a. Plasma transthyretin concentrations provide a more reliable and rapid indication of protein status than plasma albumin concentrations. b. Plasma albumin concentrations may be in the normal range when plasma transthyretin concentrations show a clear deficiency. 2. If plasma transthyretin concentration is below normal: a. Increase prescribed protein by 5% to 10%, if tolerated, and reevaluate plasma transthyretin concentration in 1 month. b. If plasma transthyretin concentration continues below standard, repeat above process as tolerated until value is in normal range. c. Evaluate blood ammonia concentration with each increase in prescribed protein. D. Iron Status 1. Plasma ferritin concentration. a. Evaluate at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17, p A-18, for standards). b. Plasma ferritin concentrations are chronically elevated in patients with LPI secondary to LYS deficiency (27, 30). E. Complete blood count and differential 1. Hemoglobin and hematocrit concentrations and differential should be evaluated at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17, p A-18, for standards). F. Growth Status 1. Length/height and weight. a. Measure monthly to 1 year, every 3 months thereafter until physical growth is completed, and every 6 months thereafter. Plot measurements on NCHS growth charts. 2. If length/height or weight falls below usual growth channel: a. Evaluate plasma LYS, ARG, ORN, and blood ammonia concentrations. If blood ammonia concentration is normal and plasma LYS, ARG, and ORN concentrations are low or below normal, increase prescribed protein and energy by 5% and remeasure in 1 month. b. If length/height and weight remain low, repeat above process until usual growth channel is achieved. c. Evaluate blood ammonia and plasma LYS, ARG, and ORN concentrations within 4 days to 1 week after each increase in prescribed protein. G. Nutrient Intake 1. Maintain records of food intake for 3 days immediately before each blood test (Appendices 24 and 25, pp A-16 and A-27). 2. Evaluate intakes of protein and energy before each blood test. 3. Evaluate mineral and vitamin intakes after each diet change. a. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. b. See Appendix 28, p A-29, for information about ordering software for diet evaluation. H. Clinical Summary 1. A summary record of growth, laboratory, and nutrient intake data is useful for patient management (Table 11-3, p 217)
A. Establish and fill diet prescription for 4-month-old male weighing 6.2 kg using Recommended Daily Nutrient Intakes from Table 11-1, p 216, and nutrient contents from Table 11-2, p 216.
1. Establish prescription:
L-CIT Protein Energy Fluid 2.0 g/kg x 6.2 kg 130 kcal/kg x 6.2 kg 150 mL/kg x 6.2 kg = = = = Measure 886 mL 40.0 mL 40 g --4.0 --4.0 g 12.4 g/day 806 kcal/day 930 mL/day L-CIT (g) Protein (g) 12.4 --0.0 Energy (kcal) 602 --204
2. Fill prescription:
Medical Food Mixture Similac with Iron Ready to Feed L-CIT solution1 Pro-Phree Add water to make 930 mL (31 fl oz)
4.0 12.4 806 Total per day --2.0 130 Total per kg Approximate osmolarity of medical food mixture is 375 mosm/L. Estimated renal solute load is < 150 mosm. 1 L-CIT should be given in doses of 1.0 g/10 mL 4 times per day.
B. Establish and fill diet prescription for 6-year-old girl weighing 20 kg using Recommended Daily Nutrient Intakes from Table 11-1, p 216, and nutrient contents from Table 11-2, p 216. 1. Establish prescription:
L-CIT Protein Energy Fluid 6.0 g 20 g protein 2000 kcal 2000 mL Measure L-CIT (g) Protein (g) 149
0
Milk Substitute Mixture Energy (kcal)
Whole milk 236 mL --8.0 0.0 L-CIT solution1 60 mL 6.0 Pro-Phree 90 g --0.0 Add water to make 710 mL (24 fl oz). Offer additional fluid ad libitum daily Food List Servings Bread/cereal 10 Fats 4 Fruits 5 Vegetables 6 Free Foods A 5 Free Foods B 3 Total per day 1 L-CIT should be given as 1.5 g/ 15 mL 4 times daily.
459
-----------6.0
6.0 0.4 2.5 3.0 0.5 0.0 20.4
300 240 300 60 325 165 1,998
XI. Nutrition Support During Febrile Illness or Following Trauma Associated with Acute Hyperammonemia
A. Rationale 1. In normal persons, febrile illness and trauma are accompanied by catabolism of body protein (35). 2. Well-nourished patients with LPI respond to infection and trauma as do normal persons (29). Warning: Prolonged use of protein-free (> 2 days) or low-energy diet will lead to protein catabolism and rebound hyperammonemia. 3. Intravenous infusion of ORN, ARG, or CIT to correct for hyperammonemia has been suggested (30).
TABLE 11-1. Recommended Daily Nutrient Intakes (Ranges) for Infants, Children, and Adults with Lysinuric Protein Intolerance
Age Protein 1-3 (g/kg) Infants 0 to < 3 mo 3 to < 6 mo 6 to < 9 mo 9 to < 12 mo Girls and Boys 1 to < 4 yr 4 to < 7 yr 7 to < 11 yr Women 11 to < 15 yr 15 to < 19 yr > 19 yr 2.20 2.00 1.80 1.60 - 1.5 - 1.5 - 1.25 - 1.15 (g/day) 10 - 13 14 - 20 20 - 28 Nutrient Energy2 (kcal/kg) 140 - 125 130 - 120 130 - 115 120 - 110 (kcal/day) 945 - 1,890 1,365 - 2,415 1,730 - 3,465 Fluid4 (mL/kg) 160 - 130 160 - 130 150 - 125 130 - 120 (mL/day) 945 - 1,890 1,365 - 2,445 1,730 - 3,465
30 - 40 40 - 45 45 - 47
1,575 - 3,150 1,260 - 3,150 1,785 - 2,625
1,575 - 3,150 1,260 - 3,150 1,875 - 2,525
Men 11 to < 15 yr 30 - 42 2,100 - 3,885 2,100 - 3,885 15 to < 19 yr 42 - 49 2,200 - 4,095 2,200 - 4,095 > 19 yr 49 - 55 2,625 - 3,465 2,625 - 3,465 1 Modified from reference 5. 2 Modified from reference 6. 3 Protein intake may need to be increased if sodium benzoate, sodium phenylacetate, or sodium phenylbutyrate is prescribed. 4 Modified from reference 1. Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL fluid to children and adults for each kcal ingested.
TABLE 11- 2. Serving Lists for Protein-Restricted Diets: Approximate Protein And Energy Content Per Serving
Food List Nutrient Protein (g) Breads/cereals 0.6 Fats 0.1 Fruits 0.5 Vegetables 0.5 Free Foods A 0.1 Free Foods B 0.0 1 Alimentum Protein Hydrolysate Formula With Iron, Ready to Feed, 100 mL 1.86 1 Isomil Soy Formula With Iron, Ready to Feed, 100 mL 1.66 Pro-Phree Protein-Free Energy Module With Iron, Vitamins & Minerals Powder, 100 g 0.00 1 Similac With Iron Infant Formula, Ready to Feed, 100 mL 1.40 2 Whole cow's milk, 100 mL 3.39 1 See Appendices 4 through 7, pp A-4 to A-7, for complete nutrient composition of infant formulas. 2 From reference 22. See Appendix 8, A-8, for complete nutrient composition. Energy (kcal) 30 60 60 10 65 55 68 68 510 68 63
2001 Ross Products Division Lysinuric Protein Intolerance 217
TABLE 11-3. Lysinuric Protein Intolerance Clinical Summary Sheet Name: Date of Birth: __________/__________/__________
Mo Day Year
Hospital Number: Age at Diagnosis:

Laboratory Data
LYS (mol/L) ARG (mol/L) ORN (mol/L) L-CIT (mol/L) SGOT (U/L) SGPT (U/L) Ammonia (mol/L) HCT (%) Ferritin (ng/mL) Transthyretin (mg/dL)
Date
(mo/yr)
Age
(yr/mo)
Physical data
Length/ Height (cm) Weight (kg) Head Circum (cm)

CIT (mg) Protein (g) Energy (kcal)
REFERENCES
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. Behrman RE, Kleigman RM, Arvin AA (eds): Nelson Textbook of Pediatrics, ed 15. Philadelphia: WB Saunders Co, 1996. Carpenter TO, Levy HL, Holtrap ME, et al: Lysinuric protein intolerance presenting as childhood osteoporosis. N Engl J Med 1985;312:290-294 DiRocco M, Garibatto G, Rossi GA, et al: Role of haematological, pulmonary and renal complications in the longterm progress of patients with lysinuric protein intolerance. Eur J Pediatr 1992;152:437-440. Duval M, Fenneteau O, Doireau V, et al: Intermittent hematophagocytic lymphohistiocytosis is a regular feature of lysinuric protein intolerance. J Pediatr 1999;134:236-239. FAO/WHO/UNU Expert Consultation: Energy and Protein Requirements. Geneva: World Health Organization, 1985. Food and Nutrition Board, Committee on Dietary Allowances: Recommended Dietary Allowances, eds 9 and 10. Washington, DC: National Academy of Sciences, 1980 and 1989. Goto I, Yashimura T, Kuroiwa Y: Growth hormone studies in lysinuric protein intolerance. Eur J Pediatr 1984;141:240-242. Kato T, Mizutani N, Ban M: Hyperammonemia in lysinuric protein intolerance. Pediatrics 1984;73:489-492. Hasanoglu A, Dlek EO, Menis, L, Biberglu G: Lysinuric protein intolerance with thymic hypoplasia. J Inher Metab Dis 1996;19:372-373. Kato T, Sano M, Mizutani N: Homocitrullinuria and homoargininuria in lysinuric protein intolerance. J Inher Metab Dis 1989;12:157-161. Kerem E, Elpele ON, Shalev RS, et al: Lysinuric protein intolerance with chronic interstitial lung disease and pulmonary cholesterol granulomas at onset. J Pediatr 1993;123:275-278. Lukkarinen M, Nnt-Salonen K, Pulkki K, et al: Short-term lysine supplementation in lysinuric protein intolerance (LPI). J Inher Metab Dis 1996;19 (Suppl 1): P97 (abs). Lukkarinen M, Nnt-Salonen K, Pulkki K, et al: Effect of lysine infusion on urea cycle in lysinuric protein intolerance. Metabolism 2000;49;621-625. Lukkarinen M, Parto K, Ruuskanen O, et al: B and T cell immunity in patients with lysinuric protein intolerance. Clin Exp Immunol 1999;116;430:434. MacLean W, Graham G: Pediatric Nutrition in Clinical Practice. Menlo Park, Calif: Addison-Wesley Publishing Co, 1982. Martin SB, Acosta PB: Osmotic behaviors of components of chemically-defined formulas. J Pediatr Perinat Nutr 1987;1:1-17. Mizutani N, Kato T, Machara M, et al: Oral administration of arginine and citrulline in the treatment of lysinuric protein intolerance. Tohoku J Exp Med 1984;142;15-24. Nagata M, Suzuki M, Kawamura G, et al: Immunological abnormalities in a patient with lysinuric protein intolerance. Eur J Pediatr 1987;146:427-428. Ono N, Kishida K, Tokumoto K, et al: Lysinuric protein intolerance presenting deficiency of argininosuccinate synthetase. Intern Med 1992;31:55-59. Parto K, Maki J, Pelliniemi LJ, et al: Abnormal pulmonary macrophages in lysinuric protein intolerance. Ultrastructrural, morphometric and X-ray microanalytic study. Arch Pathol Lab Med 1994;118:536-541. Parto K, Pentliner R, Paronen I, et al: Osteoporosis in lysinuric protein intolerance. J Inher Metab Dis 1993;16:441450. Posati LP, Orr ML: Composition of Foods: Dairy and Egg Products, Agricultural Handbook No. 8-1. Washington, DC: US Dept of Agriculture, Agricultural Research Service, 1976. Rajantie J: Orotic aciduria in lysinuric protein intolerance: Dependence on the urea cycle intermediates. Pediatr Res 1981;75:115-119. Rajantie J, Simell O, Perheentupa J: Basolateral-membrane transport defect for lysinuric protein intolerance. Lancet 1980;June 7:1219-1221. Rajantie J, Simell O, Perheentupa J: Intestinal absorption in lysinuric protein intolerance: Impaired for diamino acids, normal for citrulline. Gut 1980;21:519-524. Rajantie J, Simell O, Perheentupa J: Oral administration of N-acetyl-lysine and homocitrulline in lysinuric protein intolerance. J Pediatr 1983;102:388-390. Rajantie J, Simell O, Perheentupa J, Siimes MA: Changes in peripheral blood cells and serum ferritin in lysinuric protein intolerance. Acta Paediatr Scand 1980;69:741-745. Rajantie J, Simell O, Rapola J, Perheentupa J: Lysinuric protein intolerance: A two-year trial of dietary supplementation therapy with citrulline and lysine. J Pediatr 1980;97:927-932. Simell O: Lysinuric protein intolerance and other cationic amino acidurias. In Scriver CR, et al (eds): The Metabolic and Molecular Bases of Inherited Disease, ed 8. New York: McGraw-Hill Medical Publishing Division, 2001, pp 4933-4956.
30. Simell O, Parto K, Nnt-Salonen K: Transport defects of amino acids of the cell membrane: Cystinuria, Hartnup disease, and lysinuric protein intolerance. In Fernandes J, et al (eds): Inborn Metabolic Diseases: Diagnosis and Treament, ed 3. New York: Springer, 2000, pp 266-273. 31. Smith JL, Heymsfield SB: Enteral nutrition support: Formula preparation from modular ingredients. JPEN 1983;7:280-288. 32. Spika JS, Shaffer N, Hargrett-Bean N, et al: Risk factors for infant botulism in the United States. Am J Dis Child 1989;143-828-832. 33. Svedstrom E, Parto K, Martinnen M, et al: Skeletal manifestations of lysinuric protein intolerances in a follow-up study of 29 patients. Skeletal Radiol 1993;22:11-16. 34. Takayama N, Hamada H, Kubo T: Lysinuric protein intolerance in pregnancy: Case report with successful outcome. Arch Gynecol-Obstet 1995;256(1):49-52. 35. Wannemacher RW: Key role of various individual amino acids in host response to infection. Am J Clin Nutr 1977;30;1269-1280. 36. Yoshida Y, Machigashira K, Suehara M, et al: Immunological abnormality in patients with lysinuric protein intolerance. J Neurol Sci 1995;134:178-182. 37. Zieve L: Conditional deficiencies of ornithine or arginine. J Amer Coll Nutr 1986;5:167-176.
PROTOCOL 12 Nonketotic Hyperglycinemia Nutrition Support of Infants, Children, and Adults With PRO-PHREE Protein-Free Energy Module With Iron, Vitamins & Minerals
I. Introduction
Glycine (GLY) is important in metabolism and functions as a methyl donor, a constituent of proteins, an oxidant, and conjugates with bile acids. Nonketotic hyperglycinemia (NKH) is an autosomal recessive inborn error of GLY catabolism in which GLY accumulates in all body tissues, most notably the central nervous system. Patients with NKH have little or no activity of the mitochondrial GLY cleavage system which catalyzes the major step in GLY catabolism (Figure K). Four genes that code for P-, H-, T-, and L-proteins, of this multienzyme complex can be affected. Several forms of NKH are described: neonatal, atypical (presenting later in life) (16), mild (12) and transient. Patients with the neonatal form of NKH have a defect in the P-protein gene. Patients with the neonatal phenotype present in the first days of life with vomiting, poor appetite, lethargy, muscle hypotonia, apnea, and intractable seizures (9), Some infants may present later in infancy with a milder clinical course. GLY accumulation in the cerebrospinal fluid (CSF) stimulates the cortex N-methyl--aspartate (NMDA)-type glutamate receptors, modulating their excitatory activity (9). The focus of therapy has been to inhibit GLY binding to NMDA receptors. Several NMDA antagonists including strychnine, imipramine, ketamine, diazepam, and dextromethorphan have been used with varied effects (11, 19, 28, 35, 40). Tryptophan (TRP) therapy has also been used with moderate success (14, 20). The current restriction on the use of TRP supplementation in the United States limits this therapeutic approach. One investigator tried peritoneal dialysis, without benefit (2). Another approach to treatment is to reduce plasma GLY concentrations via sodium benzoate administration (11, 38, 41) and a low protein diet (25, 37). Some investigators have supplemented the GLY-restricted diet with one-carbon donors such as methionine, folate, and choline because of the possible deficiency of one-carbon units in patients with NKH (9, 37). These carbon donors have not ameliored the clinical symptoms.
Heme
Oxalate
Porphyrin
Creatine Purines Nucleic acids
Phospholipids
Serine
Glycine NH2-CH2-COOH
Proteins (e.g., collagen, elastin) Glutathione
Pyruvate
GCS Bile acid conjugates; other conjugates
Oxaloacetate
Alanine
Kreb's Cycle
Acetyl-CoA
NH3 + CO2 + methylene tetrahydrofolate Site of defect in glycine cleavage system (GCS)
Figure K. Selected metabolic conversions of GLY (Modified from reference 9)

Whether early diagnosis and intervention affect outcome is not known. Thirty percent of patients with neonatal onset NKH die in the newborn period (9). Most patients who survive experience significant neurologic damage with intractable seizures (10, 21, 29). Assessing clinical response to treatment is difficult due to the variable phenotypes associated with this disorder (5). This protocol is designed to assist the clinician in prescribing an implementing a low protein diet to restrict intake of amino acids that are used to synthesize GLY. This protocol should be accompanied by pharmacologic therapy.
224 Nonketotic Hyperglycinemia 2001 Ross Products Division

A. The Defect 1. NKH results from defect in 1 of 4 protein components (ie, P-, H-, T-, or L-protein) of a multienzyme complex in mitochondrial GLY cleavage system (15, 34). Most patients with NKH have defect in P-protein (9, 15). B. Clinical Evaluation 1. Diagnostic studies should be performed on any neonates who present with neurologic deterioration, neonatal seizures (often myoclonic), flaccidity, lethargy, or coma, especially if accompanied by hiccups (9, 24). 2. Other clinical findings include: a. Vomiting, poor appetite. b. Pin-point pupils (9, 24, 26, 36). c. Respiratory insufficiency (9, 13). 3. Laboratory findings: a. Excessive urine, plasma, CSF GLY concentrations (9). b. CSF: plasma GLY ratio > 0.2 (7, 24, 33, 34). c. A CSF: plasma GLY ratio > 0.08 is considered diagnostic for NKH (9). d. Cortical atrophy, hypodensity of myelin when viewed with MRI. Note: Urine and plasma GLY concentrations are variable and may be normal. B. Differential diagnosis: 1. Unlike organic acidemias in which plasma GLY concentrations are elevated, patients with NKH have normal urinary organic acids and absence of ketosis. 2. Prenatal diagnosis is available for at-risk pregnancies (36).

A. Correct Primary Imbalance in Metabolic Relationships 1. Restrict dietary protein to amount required to reduce plasma GLY concentration and support normal growth. Warning: Nutrition support should accompany pharmacologic therapy (eg, dextromethorphan, imipramine, diazepam, sodium benzoate) as part of total treatment. See references 1, 11, 19, 22, 27, 28, 38, 40, and 41 for pharmacologic therapy. If medications are used, review possible drug:nutrient interactions to prevent nutrition-related clinical symptoms.

A. Plasma GLY Concentration 1. Maintain 2- to 4-hour postprandial plasma GLY concentrations between 56 and 323 mol/L (9, 11, 19, 25, 27) or within normal concentration for laboratory used. B. Growth, Development, and Nutrition Status 1. Support normal growth rates in infants and children and maintain appropriate weight for height in adults. 2. Support normal development. 3. Maintain normal nutrition status. 4. Prevent catabolism. a. Avoid prolonged fasting. 5. Maintain adequate hydration. C. Plasma Free Carnitine Concentration 1. Maintain concentration of plasma free carnitine 30 mol/L.

A. Protein 1. Prescribe intake that promotes goals of nutrition support (Table 12-1, p 226). 2. Amount of protein may need to be increased if sodium benzoate is administered daily.
2001 Ross Products Division Nonketotic Hyperglycinemia 225
Warning:
Inadequate protein intake results in failure to thrive in infants, weight loss, low plasma transthyretin concentration, and hair loss in children and adults.
B. Energy 1. Prescribe amount greater than Recommended Dietary Allowances (RDAs) to prevent catabolism (Table 12-1, p 226). 2. Requirements vary widely and may be 5% to 10% greater than those listed when infection is present. Warning: Inadequate energy intake will result in poor growth in infants and children, weight loss in children and adults, and increased body protein catabolism. 3. If patient is severely developmentally disabled, energy requirements may be less than RDAs. C. L-Carnitine (39) 1. Prescribe amount required to maintain normal plasma free or erythrocyte concentrations. a. Initiate intake at 50 mg/kg/day and titrate until plasma free carnitine concentration is 30 mol/L. D. Fluid 1. Prescribe amount that will supply water requirements (Table 12-1, p 226). Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL fluid to children and adults for each kcal ingested.

A. Protein 1. Calculate amount of infant formula with iron (use until 2nd birthday), beikost, whole cow's milk, or table foods (Table 12-2, p 226) required to fill protein prescription. 2. See Servings Lists for PHE-Restricted Diets (Protocol 1, pp 13-26), for portion sizes. 3. Parents or patients may select any food in prescribed food lists. B. Energy 1. Calculate energy provided by infant formula with iron, beikost, whole cow's milk, or table foods (Table 12-2, p 226) required to fill protein prescription. 2. Subtract amount determined above from total energy prescription. 3. Provide remaining prescribed energy with Pro-Phree Protein-Free Energy Module With Iron, Vitamins & Minerals (Appendix 11, p A-10), sugar (48 kcal/Tbsp), or Free Foods B (Table 122, p 226). a. Do not use corn syrup for infants because of osmolarity it yields (18). b. Do not use honey for infants because it may contain botulinum toxin (32). C. Fluid and Mixing Instructions 1. Add sufficient boiled, cooled water to infant formula or whole cow's milk (if child is > 2 years of age) and Pro-Phree to yield prescribed volume. Tap water may replace boiled, cooled water when preparing medical food mixture for older infants, children, and adults. 2. Mix in sterilized blender at lowest speed for no longer than 3 seconds. Excess mixing may destabilize emulsion and cause separation. May also be mixed in sterilized, tightly closed container by shaking vigorously for 10 to 12 seconds. 3. Refrigerate in sterilized, closed containers until used. Discard unused portion 24 hours after mixing because of nutrient loss. 4. Warm or cool medical food mixture to room temperature before feeding to infants. Shake well before feeding. 5. Do not warm medical food mixture in microwave oven. Unevenly heated formula can burn infants and steam can make bottles explode. 6. Notify parents or caretakers when they may discontinue using aseptic technique in preparing medical food mixture for infants. D. Diet Guide 1. Provide parents, caregivers or patient with completed Diet Guide (Appendix 22, p A-24) with each diet change.
226 Nonketotic Hyperglycinemia 2001 Ross Products Division

A. Nutrient Adequacy 1. Determine if diet provides nutrients in amounts prescribed in Section VI, Establish Prescription, p 221. 2. Check diet to determine if it supplies Recommended Dietary Intakes (RDIs) of minerals and vitamins (Appendices 13 and 14, pp A-14 and A-15). a. See Appendices 4 through 7, pp A-4 to A-7, for complete nutrient composition of infant formula and Appendix 11, p A-10, for composition of Pro-Phree. b. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. c. If medical food mixture provides < 100% of the RDIs for infants and < 75% for children and adults, supplement diet with needed minerals and vitamins if not provided by beikost or table foods and laboratory tests indicate need (Appendix 11, p A-10, for composition of supplements). d. Greater than 100% of RDI (Appendices 13 and 14, pp A-14 and A-15) is recommended for pyridoxine and folic acid, both coenzymes in GLY metabolism. B. Osmolarity 1. If concentration of prescribed medical food mixture is > 27 kcal/fl oz, determine if osmolarity is in acceptable range. a. Determine osmolarity by laboratory analysis or use mathematical formula given in Appendix 18, p A-20. b. Osmolarity per gram of Pro-Phree, Similac, Isomil, and whole cow's milk is listed in Appendix 19, p A-21. 2. If osmolarity is > 450 mosm/L for infants (17), > 750 mosm/L for children, > 1,000 mosm/L for adults (31), or greater than tolerated by patient, increase water content of prescribed medical food mixture and recalculate osmolarity. C. Potential Renal Solute Load 1. Dehydration will result if renal solute load is greater than renal-concentrating ability of patient. 2. If concentration of medical food mixture prescribed is > 27 kcal/fl oz, estimate its potential renal solute load. a. This step is important to prevent dehydration of infants who may have renal-concentrating capacity as low as 600 mosm/L. b. Upper limit of renal solute load for infants is approximately 1,100 mosm/L (30). 3. A method for estimating potential renal solute load is given in Appendix 20, p A-22. 4. If potential renal solute load is excessive, increase water content of medical food mixture and recalculate.

A. Plasma Amino Acid Concentrations 1. Initial. a. Evaluate twice weekly by quantitative methods until plasma concentrations stabilize in low normal range. 2. Ongoing. a. Frequent evaluations help ensure adherence to nutrition support plan. b Evaluate at least monthly when patient's condition is stable. 3. Unacceptable plasma GLY concentrations. a. If plasma GLY concentrations are above upper limit of treatment range and patient has ingested full protein prescription: 1) Decrease prescribed amount of protein by 5% to 10% and reevaluate plasma concentration in 3 to 7 days. 2) If plasma GLY concentration continues above upper limit of normal, repeat above process until value is in treatment range. Warning: Protein restriction alone will not reduce plasma GLY concentration to normal range. Do not over-restrict dietary protein, excessive restriction can result in protein malnutrition and growth failure.
3) Increase sodium benzoate prescription if not at maximal amount and if deemed safe. B. Protein Status 1. Evaluate plasma transthyretin concentration every 3 months throughout life (Appendix 17, p A-18, for standards). a. Plasma transthyretin concentrations provide a more reliable and rapid indication of protein status than plasma albumin concentrations. b. Plasma albumin concentrations may be in the normal range when plasma transthyretin concentrations show a clear deficiency (3). 2. If plasma transthyretin concentration is below normal: a. Increase prescribed protein by 5% to 10%, if tolerated, and reevaluate plasma transthyretin concentration in 1 month. b. If plasma transthyretin concentration continues below standard, repeat above process until value is in normal range. C. Iron Status 1. Plasma ferritin concentration. a. Evaluate at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17, p A-18, for standards). b. If plasma ferritin concentration is below standard: 1) Increase iron intake to 2 mg/kg with supplements (ferrous sulfate). 2) Evaluate plasma ferritin concentration monthly on increased iron intake. 3) Continue iron supplements until plasma ferritin concentration is in normal range. 2. Complete blood count. a. Hemoglobin and hematocrit concentrations should be evaluated at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17, p A-18, for standards). D. Plasma Free Carnitine Concentration 1. Plasma free carnitine concentration should be evaluated as necessary to maintain concentration 30 mol/L. E. Growth Status 1. Length/height and weight. a. Measure monthly to 1 year, every 3 months thereafter until physical growth is completed; obtain weight every 6 months thereafter. Plot measurements on NCHS growth charts. b. Maintain length/height and weight between 10th and 90th percentiles. Some normal infants and children will fall above or below these percentiles. 2. If length/height or weight falls below usual growth channel: a. Increase prescribed protein and energy by 5% and remeasure in 1 month. b. If length/height and weight remain low, repeat process until usual growth channel is achieved. F. Nutrient Intake 1. Maintain records of food intake for 3 days immediately before each blood test (Appendices 24 and 25, pp A-26 and A-27). 2. Evaluate intakes of protein and energy before each blood test. 3. Evaluate mineral and vitamin intakes after each diet change. a. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. b. See Appendix 28, p A-29, for information about ordering software for diet evaluation. G. Clinical Summary 1. A summary record of growth, laboratory, and nutrient intake data is useful for patient management (Table 12-3, p 227).
228 Nonketotic Hyperglycinemia
A. Establish and fill prescription for 4-month-old male weighing 6.2 kg using Recommended Daily Nutrient Intakes from Table 12-1, p 226, and nutrient composition from Table 12-2, p 226. 1. Establish prescription:
Protein Energy Fluid 2 g/kg 130 kcal/kg 150 mL/kg x x x 6.2 kg 6.2 kg 6.2 kg
Measure 886 mL 41 g 12.4 0.0
= = =
12.4 g/day 806 kcal/day 930 mL/day

Protein (g) 602 209 Energy (kcal)
Medical Food Mixture Similac with Iron Ready to Feed Pro-Phree Add water to make 930 mL (31 fl oz) Total per day Total per kg
12.4 2.0
811 131
Approximate osmolarity of medical food mixture is < 450 mosm/L. Estimated potential renal solute load is < 150 mosm.
B. Establish and fill diet prescription for 6-year old girl weighing 20 kg using Recommended Daily Nutrient Intakes from Table 12-1, p 226, and nutrient composition from Table 12-2, p 226, and Appendix 11, p A-10. 1. Establish prescription
Protein Energy Fluid = = = 20 g protein 2,000 kcal 2,000 mL
Measure Protein (g) Energy (kcal)
2. Fill prescription
Whole cow's milk 236 mL 8.0 Pro-Phree 91 g 0.0 Add water to make 710 mL (24 fl oz). Offer additional fluid ad libitum daily. Food List Bread/cereal Fats Fruits Vegetables Free Foods A Free Foods B 10 4 5 6 5 3 Servings 6.0 0.4 2.5 3.0 0.5 0.0
146 464
300 240 300 60 325 165 2,000
20.4 Total per day Approximate osmolarity of medical food mixture is < 300 mosm/L.
XI. Nutrition Support During Febrile Illness

A. Rationale 1. In normal persons and persons with NKH, febrile illness and trauma are accompanied by catabolism of body protein (39). 2. Remove protein from diet for 1 or 2 days during febrile illness. a. See references 9, 11, and 25 for management during acute crises. Warning: Prolonged use of a protein-free (> 2 days) or low-energy diet will lead to body protein catabolism.
Nonketotic Hyperglycinemia 229
TABLE 12-1. Recommended Daily Nutrient Intakes (Ranges) for Infants, Children, and Adults with Nonketotic Hyperglycinemia
Age Protein (g/kg) Infants 0 to < 3 mo 3 to < 6 mo 6 to < 9 mo 9 to < 12 mo 2.20 - 1.5 2.00 - 1.5 1.80 - 1.25 1.60 - 1.15 (g/day) Girls and Boys 1 to < 4 yr 4 to < 7 yr 7 to < 11 yr Women 11 to < 15 yr 15 to < 19 yr > 19 yr 10 - 13 14 - 20 20 - 28
1-3
Nutrient Energy2 (kcal/kg) 140 - 125 130 - 120 130 - 115 120 - 110 (kcal/day) 945 - 1,890 1,365 - 2,415 1,730 - 3,465 Fluid4 (mL/kg) 160 - 130 160 - 130 150 - 125 130 - 120 (mL/day) 945 - 1,890 1,365 - 2,445 1,730 - 3,465
30 - 40 40 - 45 45 - 47
1,575 - 3,150 1,260 - 3,150 1,785 - 2,625
1,575 - 3,150 1,260 - 3,150 1,875 - 2,525
Men 11 to < 15 yr 30 - 42 2,100 - 3,885 2,100 - 3,885 15 to < 19 yr 42 - 49 2,200 - 4,095 2,200 - 4,095 > 19 yr 49 - 55 2,625 - 3,465 2,625 - 3,465 1 Modified from reference 6. 2 Modified from reference 8. 3 Protein intake may need to be increased if sodium benzoate is prescribed. 4 Modified from reference 4. Under normal circumstances, offer minimum of 1.5 mL fluid and 1.0 mL fluid to children and adults to neonates for each kcal ingested.
Table 12-2. Servings Lists for Protein-Restricted Diets: Approximate Protein and Energy Content per Serving
Food List Protein (g) Breads/cereals Fats Fruits Vegetables Free Foods A Free Foods B Alimentum Protein Hydrolysate Formula With Iron, Ready to Feed, 100 mL Isomil Soy Formula With Iron, Ready to Feed, 100 mL Pro-Phree Protein-Free Energy Module With Iron, Vitamins & Minerals, 100 g Similac With Iron Infant Formula, Ready to Feed, 100 mL 1 Whole cow's milk, 100 mL 1 From reference 23.
Nutrient Energy (kcal) 30 60 60 10 65 55 68 68 510 68 63
0.6 0.1 0.5 0.5 0.1 0.0 1.86 1.66 0.00 1.40 3.39
TABLE 12-3. Nonketotic Hyperglycinemia Clinical Summary Sheet Name: Date of Birth: __________/__________/__________
Mo Day Year
Hospital Number:
Date
(mo/d/yr)
Age
(yrs/mos) Length/ Height (cm)
Physical Data
Weight (kg) Head Circum (cm) Plasma GLY (mol/L) Free Carnitine (mol/L)
Laboratory Data
Hgb (g/dL) Hct (%) Ferritin (ng/mL) Transthyretin (mg/dL)

Protein (g) Energy (kcal)
REFERENCES
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. Alemzadeh R, Gammeltoft K, Matteson K: Efficacy of low-dose dextromethorphan in the treatment of nonketotic hyperglycinemia. Pediatrics 1996;97:924-926. Apostolidou I, Papagaroufalis C, Michelakakis H, et al: Non-ketotic hyperglycinaemia: A therapeutic approach. J Inher Metab Dis 1991;14:835-836. Arnold GL, Vladutiu CJ, Kirby RS: Protein insufficiency and impaired growth in children with PKU. J Inher Metab Dis 2000;23 Suppl 1:29A. Behrman RE, Kleigman RM, Arvin AA (eds): Nelson Textbook of Pediatrics, ed 15. Philadelphia: WB Saunders Co, 1996. Boneh A, Degani Y, Harari M: Prognostic clues and outcome of early treatment of nonketotic hyperglycinemia. Pediatr Neurol 1996;15:137-141. FAO/WHO/UNU Expert Consultation: Energy and Protein Requirements. Geneva: World Health Organization, 1985. Flannery DB, Pellock J, Bousounis D, et al: Nonketotic hyperglycinemia in two retarded adults: A mild form of infantile nonketotic hyperglycinemia. Neurology 1983;33:1064-1066. Food and Nutrition Board, Committee on Dietary Allowances: Recommended Dietary Allowances, eds 9 and 10. Washington, DC: National Academy of Sciences, 1980 and 1989. Hamosh A, Johnston MV: Nonketotic hyperglycinemia. In Scriver CR, et al (eds): The Metabolic and Molecular Bases of Inherited Disease, ed 8. New York: McGraw-Hill Medical Publishing Division, 2001, pp 2065-2078. Hamosh A, Maher JF, Bellus GA, et al: Long-term use of high-dose benzoate and dextromethorphan for the treatment of nonketotic hyperglycinemia. J Pediatr 1998;132:709-713. Hamosh A, McDonald JW, Valle D, et al: Dextromethorphan and high-dose benzoate therapy for nonketotic hyperglycinemia in an infant. J Pediatr 1992;121:131-135. Holmgren G, Blomquist HK: Nonketotic hyperglycinemia in two sibs with mild psychoneurological symptoms. Neuropediatrie 1997;8:67-69. Holmquist P, Polberger S: Neonatal nonketotic hyperglycinemia (NKH): Diagnosis and management in two cases. Neuropediatrics 1985;16:191-193. Inoue F, Matsuo S, Yoshioka H, et al: Tryptophan therapy for non-ketotic hyperglycinaemia. J Inher Metab Dis 1992;15:399-401. Kure S, Narisawa K, Tada K: Enzymatic diagnosis of nonketotic hyperglycinemia with lymphoblasts. J Pediatr 1992;120:95-98. Leuzzi V, Morano S, Moretti F, et al: Nonketotic hyperglycinemia: A new case with late onset. J Inher Metab Dis 1990;13:238. MacLean W, Graham G: Pediatric Nutrition in Clinical Practice. Menlo Park, Calif: Addison-Wesley Publishing Co, 1982. Martin SB, Acosta PB: Osmotic behaviors of components of chemically-defined formulas. J Pediatr Perinat Nutr 1987;1:1-17. Matalon R, Naidu S, Hughes JR, Michals K: Nonketotic hyperglycinemia: Treatment with diazepam - A competitor for glycine receptors. Pediatrics 1983;71:581-584. Matsuo S, Inoue F, Takeuchi Y, et al: Efficacy of tryptophan for the treatment of nonketotic hyperglycinemia: A new therapeutic approach for modulating the N-methyl-D-aspartate receptor. Pediatrics 1995;95:142-146. Neuberger JM, Schweitzer S, Rolland MO, Burghard R: Effect of sodium benzoate in the treatment of atypical nonketotic hyperglycinaemia. J Inher Metab Dis 2000;23:22-26. Ohya Y, Ochi N, Mizutani N, et al: Nonketotic hyperglycinemia: Treatment with NMDA antagonist and consideration of neuropathogenesis. Pediatr Neurol 1991;7:65-68. Posati LP, Orr ML: Composition of Foods: Dairy and Egg Products, Agricultural Handbook No. 8 - 1. Washington, DC: US Dept of Agriculture, Agricultural Research Service, 1976. Press GA, Barshop BA, Haas RH, et al: Abnormalities of the brain in nonketotic hyperglycinemia: MR manifestations. AJNR 1989;10:315-321. Pueschel SM, Cha C-JM, Langon T: Therapeutic attempts in infants with nonketotic hyperglycinaemia. J Ment Defic Res 1981;25:61-69. Schiffman R, Borch A, Ergaz Z, Glick B: Nonketotic hyperglycinemia presenting with pin-point pupils and hyperammonemia. Isr J Med Sci 1992;28:91-93. Schmitt B, Steinmann B: Dextromethorphan in infantile nonketotic hyperglycinemia. J Pediatr 1993;122-324-325. Schmitt B, Steinmann B, Gitzelmann R, et al: Nonketotic hyperglycinemia: Clinical and electrophysiologic effects of dextromethorphan, an antagonist of the NMDA receptor. Neurol 1993;43:421-424. Schmitt B, Steinmann B: Dextromethorphan in a child with nonketotic hyperglycinaemia - A 6-year follow up. Eur J Pediatr 1998;157:349-350. Smith CA, Nelson NM: The Physiology of the Newborn Infant, ed 4. Springfield, IL: Charles C Thomas Publisher, 1976.
31. Smith JL, Heymsfield SB: Enteral nutrition support: Formula preparation from modular ingredients. JPEN 1983;7:280-288. 32. Spika JS, Shaffer N, Hargrett-Bean N, et al: Risk factors for infant botulism in the United States. Am J Dis Child 1989;143:828-832. 33. Tada K: Tada K: Nonketotic hyperglycinemia. In Fernandes J, et al (eds): Inborn Metabolic Disease, ed 3. New York: Springer, 2000, pp 255-258. 34. Tada K, Kure S, Takayanagi M: Non-ketotic hyperglycinemia: A life-threatening disorder in the neonate. Early Hum Dev 1992;29:75-81. 35. Tegtmeyer-Metzdorf H, Roth B, Gnther M, et al: Ketamine and strychnine treatment of an infant with nonketotic hyperglycinaemia. Eur J Pediatr 1995;54:649-653. 36. Toone JR, Applegarth DA, Levy HL: Prenatal diagnosis of non-ketotic hyperglycinaemia: Experience in 50 at-risk pregnancies. J Inher Metab Dis 1994;17:342-344. 37. Trijbels JF, Monnens LAH, van der Zee SPM, et al: A patient with nonketotic hyperglycinemia: Biochemical findings and therapeutic approaches. Pediatr Res 1974;8:598-605. 38. Van Hove JL, Kishnani P, Muenzer J, et al: Benzoate therapy and carnitine deficiency in non-ketotic hyperglycinemia. Am J Med Genet 1995;59:444-453. 39. Wannemacher RW: Key role of various individual amino acids in host response to infection. Am J Clin Nutr 1977;30:1269-1280. 40. Wiltshire EJ, Poplawski NK, Harrison JR, Fletcher JM: Treatment of late-onset nonketotic hyperglycinaemia: Effectiveness of imipramine and benzoate. J Inher Metab Dis 2000;23:15-21. 41. Wolff JA, Kulovich S, Yu AL, et al: The effectiveness of benzoate in the management of seizures in nonketotic hyperglycinemia. Am J Dis Child 1986;140:596-602.
PROTOCOL 13 Propionic or Methylmalonic Acidemia Nutrition Support of Infants, Children, and Adults With PROPIMEX -1 and PROPIMEX -2 Amino Acid-Modified Medical Foods
I. Introduction
Propionic acidemia (PA) and methylmalonic acidemia (MMA) are disorders of essential isoleucine (ILE), methionine (MET), threonine (THR), and valine (VAL) and odd-chain-fatty acid metabolism resulting from a defect in the genes that encode for propionyl-CoA carboxylase (PCC) and methylmalonyl-CoA mutase (MMM), respectively (Figure L). PCC requires biotin as a coenzyme while MMM requires adenosylcobalamin as coenzyme (13). Biotin-responsive PA has been described, but patients still require medical and nutrition intervention. Both PA and MMA are heterogeneous in their clinical presentation and outcome. In patients with PA, activity of PCC is not totally absent, but ranges from 1% to 5% of normal as shown in cultured skin fibroblasts (13). Mutations in MMM vary from no functional mutase (Muto) to structurally altered mutase with decreased affinity for adenosylcobalamin and reduced stability (Mut). Children with these mutations do not respond to cobalamin therapy and require a special diet. Several abnormalities in the reduction of cobalamin result in impaired MMM activity and some of these children respond to pharmacologic doses of hydroxycobalamin with enhancement of enzyme activity and increased tolerance of ILE, MET, THR, and VAL.
Isoleucine Methionine Threonine Valine Odd-chain fatty acids (OCFA) Excess polyunsaturated fatty acids (PUFA)
Biotin
Adenosylcobalamin
Propionyl-CoA*
L-Methylmalonyl-CoA**
Succinyl-CoA
Propionyl-CoA carboxylase
Methylmalonyl-CoA mutase
Propionic acid*
+ L-Carnitine
Methylmalonic acid**
* Accumulates in untreated MMA and PPA ** Accumulates in untreated MMA Indicates site of enzyme defect
Propionyl-carnitine
Figure L. Propionate and methylmalonate metabolism in propionic and methylmalonic acidemias Symptoms in patients with severe PA or MMA usually present within the 1st days of life and include acute or chronic vomiting (18), poor feeding, failure to thrive, dehydration, hypotonia, and severe metabolic acidosis (31). To a lesser extent, hypoglycemia and hyperammonemia may be present (45, 70). Hyperglycinemia occurs in both of these disorders. Some patients with PA or MMA present in late infancy or childhood with infection or after ingesting large amounts of protein. Symptoms in later presenting patients are usually milder than in early-presenting patients and they may tolerate more intact protein than patients who present as neonates.
2001 Ross Products Division Propionic Acidemia/Methylmalonic Acidemia 235
Laboratory findings for PA and MMA include accumulation of organic acids characteristic of each disorder in body fluids (eg, propionylcarnitine, methylcitrate, 3-OH-propionate, propionylglycine, tiglic acid, propionate, and methylmalonate). Vitamin B12 deficiency must be excluded when excessive urinary MMA is found (8). PA has an incidence of about 1/100,000 live births (31). More than 100 patients have been described with MMA (mutase deficiency) (13). Both disorders are autosomal recessive.

For patients with MMA, morbidity and mortality are based, in part, on the biochemical lesion. Patients with Muto have the poorest outcome and survival rate. Both mut and mut patients may have developmental delay, dystonia, and chronic renal failure (40), which may require renal transplantation (66). Patients with PA may suffer from pancreatitis (6, 23, 25) and recurrent infection (2). Poorly controlled patients with either MMA or PA may be immunocompromised (13, 20, 37, 55). Despite improved outcomes, patients suffer from growth retardation, chronic anorexia, neurologic impairment (17), pathophysiologic changes in the brain (16), and cardiomyopathy (4, 28). Early intervention and appropriate nutrition support can result in normal growth and outcome in these patients (4, 30, 44, 64). The use of parenteral nutrition support during acute crises has minimized catabolism and improved recovery in these patients (22, 24). Improvement in survival of patients reflects early diagnosis, rapid intervention during acute medical crisis, and improved treatment (4). Successful use of therapy has resulted in women surviving to the child-bearing years, offering new challenges to metabolic clinicians (63). Liver transplantation and combined liver-kidney transplantation (MMA) have been used with mixed results (41, 65, 66).

A. The Defect 1. PA results from deficient activity of PCC. a. Biotin-responsive PA has been described; patients still require nutrition support (58, 69). 2. Six types of MMA have been defined, based on enzyme complementation studies (13). a. Some patients may respond to pharmacologic doses of intramuscular hydroxycobalamin, and may not require other nutrition support. 3. Nutrition therapy for vitamin-nonresponsive forms of PA and MMA is the same. B. Clinical Evaluation 1. Infants or children who have any of following clinical and/or laboratory signs should be evaluated for PA and MMA (13, 31). a. Ketoacidosis, low blood pH, hyperlacticacidemia. b. Hypertonia, areflexia. c. Hyperventilation, apnea. d. Vomiting, dehydration, failure to thrive. e. Hyperammonemia, hyperglycinemia. f. Neutropenia, thrombocytopenia, pancytopenia, anemia. g. Lethargy and coma followed by death, if untreated. h. Blood glucose may be normal, reduced, or elevated.

A. Correct Primary Imbalance in Metabolic Relationships 1. Restrict dietary ILE, MET, THR, VAL, and odd-chain-fatty acids to maintain biochemical homeostasis. 2. Restrict dietary polyunsaturated fatty acids. B. Stabilize Altered Enzyme Protein 1. Administer pharmacologic doses of oral biotin if PCC activity is present in patients with PA. 2. Administer pharmacologic doses of intramuscular hydroxycobalamin if MMM activity is present in patients with MMA.
V. Nutrition Support During Acute Illness and at Diagnosis

A. Initiation of Nutrition Support 1. Initiate nutrition support immediately. Do not wait for confirmation of diagnosis.
236 Propionic Acidemia/Methylmalonic Acidemia 2001 Ross Products Division
B. Comatose or Neurologically Depressed Patients 1. For medical management during diagnosis and acute care, see references 13 and 31. 2. Begin MET- and VAL-free nasogastric feeding of protein, energy, and L-carnitine (Propimex) 36 to 48 hours after beginning dialysis with amino acid-free dialysate. Intravenous sodium phenylacetate and sodium benzoate reduce blood ammonia concentrations in PA (35). a. See Table 13-1, p 241, for Recommended Protein, Energy, and Fluid Intakes. b. See Table 13-2, p 242, for composition of Propimex. c. See Appendix 26, p A-28, for sources of L-carnitine (in addition to that in Propimex) and sodium phenylacetate 3. Begin intravenous infusion of Liposyn II (Appendix 26, p A-28) and 10% D-glucose during nasogastric feeding and continue until patient is medically stable. 4. Three approaches may be used to supply ILE, MET, THR, and VAL. a. Approach One. 1) After 24-48 hours of Propimex as the only protein source: i. Displace one-half the protein supplied by Propimex with intact protein (Table 13-3, p 243). b. Approach Two. 1) After 24-48 hours of Propimex as the only protein source: i. Supply the VAL (Table 13-1, p 241) prescription with infant formula with iron (Table 13-3, p 243). a) Use lowest recommended VAL intake (Table 13-1, p 241). b) Use disposable syringe to measure liquid infant formulas and gram scale to measure powdered infant formula. c) Decrease amount of protein supplied by Propimex by the amount of intact protein in infant formula required to supply VAL. ii. If ILE and THR prescriptions (lowest) (Table 13-1, p 241) are not met by Propimex and infant formula, supply with pure solutions (Appendix 26, p A-28) (10 mg/mL 1.0 g of L-amino acid with boiled, cooled water added to make 100 mL). a) Use disposable syringe to measure pure L-amino acid solutions. iii. MET intake will be within the prescribed range (Table 13-1, p 241) c. Approach Three. 1) Parenteral amino acid solutions, if indicated (Appendix 26, p A-28) (22, 24). Warning: Plasma amino acid concentrations must be assessed daily until ILE, MET, THR, and VAL prescriptions maintain plasma amino acid concentrations at the lower limit of reference ranges given in Section VI.A.I, below. 5. Energy. a. Use Polycose Glucose Polymers (3.8 kcal/g, 2 kcal/mL) and peanut oil (7.96 kcal/mL) to supply prescribed energy not provided by Propimex and infant formula with iron. 1) Use peanut oil as an energy source only if the osmolarity of the medical food mixture is > 450 mosm/L. i. See Appendices 18 and 19, pp A-20 and A-21 for mathematical formula and osmolarity of foods.

A. Plasma Amino Acid Concentrations 1. Maintain 2- to 4-hour postprandial plasma amino acid concentrations in ranges noted below, measured by quantitative methods, or near the lower limit of normal ranges established in laboratory used.
Amino Acid GLY ILE MET THR VAL mol/L 115 - 290 25 - 105 18 - 45 45 - 250 65 - 250 mg/dL 0.9 - 2.2 0.3 - 1.4 0.3 - 0.7 0.5 - 3.0 0.8 - 2.9
Propionic Acidemia/Methylmalonic Acidemia 237
2. In practice, obtaining blood 2 to 4 hours postprandially is not always possible. Acceptable local standards should be developed if plasma amino acids are evaluated at other times (Practical Aspects of Nutrition Support, p viii). B. Growth, Development, and Nutrition Status 1. Support normal growth rate in infants and children and maintain appropriate weight for height in adults. 2. Support normal development. 3. Maintain normal nutrition status. a. Prevent catabolism and ketosis (13, 31, 42, 68). b. Avoid prolonged fasting (60). 4. Maintain adequate hydration (31, 71). 5. Maintain blood ammonia in normal range: < 35 mol/L (enzymatic method) (61), < 33 mol/L (resin method), or in normal range established by laboratory used. C. Urine Metabolites 1. Maintain urine free of, or containing only trace abnormal metabolites (propionic acid, methylcitrate, 3-hydroxypropionate) and methylmalonic acid (found only in MMA) (31). Note: Urinary propionylcarnitine concentrations may be chronically elevated even with nutrition therapy.

A. Protein 1. Prescribe, initially, amount greater than Recommended Dietary Allowances (RDAs) (Table 13-1, p 241) (14). 2. Requirements may be greater than RDAs when L-amino acids supply majority of protein equivalent as a result of: a. Rapid amino acid absorption (15). b. Early and high peak of plasma amino acid concentrations after ingestion of meals where large part of protein is supplied by L-amino acids (15). c. Rapid catabolism of amino acids (7, 21, 48). d. Possible decreased total amino acid absorption (32). Warning: Inadequate protein intake will result in failure to thrive in infants; poor growth in children; weight loss in adults; low plasma transthyretin concentration, osteopenia, hair loss in children and adults; and decreased tolerance of ILE, MET, THR, and VAL. B. ILE, MET, THR, VAL 1. Prescribe intakes that promote goals of nutrition support (Table 13-1, p 241). 2. ILE, MET, THR, and VAL requirements vary widely: a. From patient to patient, depending on activity of catabolic enzymes and genotype. b. In same patient depending on: 1) Age. 2) Growth rate. 3) Adequacy of energy and protein intakes. 4) State of health. 3. Changing requirements of patient are determined by frequent monitoring of: a. Plasma GLY, ILE, MET, THR, VAL, and propionic or methylmalonic acid concentrations. b. Urine concentrations of propionic or methylmalonic acid and their catabolites. c. See Section X, Suggested Evaluation of Nutrition Support, p 236. d. With ILE, MET, THR, and VAL in low-normal range, plasma amino acid concentrations must be measured frequently to prevent deficiency. Warning: Inadequate intakes of ILE, MET, THR, and VAL result in adverse effects: ILE deficiency (50): Weight loss or no weight gain; redness of buccal mucosa; fissures at corners of mouth; tremors of extremities; decreased plasma cholesterol and ILE; increased concentrations of plasma lysine, phenylalanine (PHE), serine (SER), tyrosine (TYR), and VAL; skin desquamation (11), and corneal de-epithelialization (62).
MET deficiency (51): Decreased plasma MET and cholesterol and increased plasma PHE, proline, SER, THR, and TYR concentrations. THR deficiency (36): Arrested weight gain; glossitis and redness of buccal mucosa; and decreased plasma THR and globulin concentrations. VAL deficiency (52): Poor appetite, drowsiness; excessive irritability and crying in infants; weight loss or decrease in weight gain; and decreased plasma albumin concentration. C. Energy 1. Prescribe amount that should support normal weight gain in infants and children and maintain appropriate weight for height in adults (Table 13-1, p 241). 2. Requirements vary widely and may be greater than normal when L-amino acids supply majority of protein equivalent (32, 36). Warning: Inadequate energy intake may result in failure to thrive in infants, poor growth in children, weight loss in adults, and low tolerance of restricted amino acids. Catabolism increases ketone production and plasma concentrations of oddchain-fatty acids. D. L-Carnitine (56, 57) 1. Prescribe amount required to maintain normal plasma free carnitine concentration > 30 mol/L. a. Suggested intake is between 100 and 300 mg/kg body weight. 2. Ingestion of excess oral L-carnitine may cause gastrointestinal distress and fish odor (trimethylamines). E. Fluid 1. Prescribe amount that will supply water requirements (Table 13-1, p 241). 2. Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL fluid to children and adults for each kcal ingested. 3. Requirements may be higher than recommended secondary to accompanying fever and catabolic crises. F. D-Biotin 1. Patients with residual PCC activity may respond to pharmacologic doses of D-biotin, with increased tolerance of ILE, MET, THR, and VAL. 2. Prescribe 5 to 10 mg D-biotin daily for patients with PA (Appendix 26, p A-28). G. Odd-chain-Fatty Acids 1. Avoid dietary sources of odd-chain-fatty acids, including butter, cream, lard, olive oil, excess polyunsaturated fatty acids, and breads containing added sodium or calcium propionate. 2. Inhibit catabolism and loss of adipose tissue by maintaining adequate nutrition status and preventing weight loss.

A. Protein 1. Initiate protein prescription with highest recommended intake for age (Table 13-1, p 241). 2. Calculate amount of infant formula with iron, beikost, skim milk, or table foods (Tables 13-3, p 243) required to fill approximately 50% of protein prescription. a. See Serving Lists for ILE-, MET-, THR- and VAL-Restricted Diets (Table 13-3, p 243) for average nutrient content per serving. 3. Subtract amount determined above from total protein prescription. 4. Supply any remaining prescribed protein with Propimex (Table 13-2, p 242). a. Propimex-1 is for infants and toddlers and Propimex-2 is for children, adolescents, and adults. b. Weigh Propimex powder on scale that reads in grams because of variability of household measuring equipment (Practical Aspects of Nutrition Support, p vii) and changes in density during shipping. c. See Table 13-2 (p 242, footnote 3) for approximate packed weight of Propimex powder in level, dry US standard household measures.
B. ILE, MET, THR, and VAL 1. Calculate amounts of ILE and THR provided by Propimex (contains small amounts of ILE and THR) (Table 13-2, p 242) and infant formula, beikost, skim milk, or table foods (Table 13-3, p 243). 2. Compare sum of these amino acids to ranges found in Recommended Daily Nutrient Intakes (Table 13-1, p 241). Sum of these amino acids will vary based on type and amount of intact protein prescribed. 3. Either ILE or VAL in foods may be used as a marker to determine if more intact protein is required. a. If protein prescription provides total dietary ILE or VAL below minimum for age, increase intact protein to obtain at least minimum for age (Table 13-1, p 241). C. Energy 1. Calculate energy provided by Propimex (Table 13-2, p 242) and infant formula, beikost, skim milk, or table foods (Table 13-3, p 243) required to fill protein prescription. 2. Subtract amount determined above from total energy prescription. 3. Provide remaining prescribed energy with Polycose Glucose Polymers powder (23 kcal/Tbsp, 3.8 kcal/g) or liquid (2 kcal/mL) (Appendix 9, p A-9); Pro-Phree Protein-Free Energy Module with Iron, Vitamins & Minerals Powder (Appendix 11, p A-10); sugar (48 kcal/Tbsp); or Free Foods B (Table 13-3, p 243). a. Do not use corn syrup or table sugar for infants because of osmolarity they yield (27). b. Do not use honey for infants because it may contain botulinum toxin (54). D. L-Carnitine (Appendix 26, p A-28) 1. If L-carnitine in Propimex is inadequate to maintain normal concentration of plasma free carnitine, add liquid L-carnitine to medical food mixture. 2. Measure L-carnitine solution with disposable syringe if entire contents of container are not used. a. If L-carnitine is not added to medical food mixture, administer TID or QID with meals. 3. L-carnitine may be added to pured foods and fruit juices. 4. L-carnitine tablets may be used if patient is old enough to swallow them. E. Fluid and Mixing Instructions 1. Add sufficient boiled, cooled water to infant formula, Propimex, carbohydrate (if needed), and L-carnitine (if needed) to yield prescribed volume. Tap water may replace boiled, cooled water when preparing Propimex for older infants, children, and adults. 2. Mix with sterilized blender at lowest speed for no longer than 3 to 4 seconds. Excess mixing may destabilize emulsion. May also be mixed in sterilized, tightly closed container by shaking vigorously for 10 to 12 seconds. 3. Refrigerate in sterilized, closed containers until used. Discard unused portion 24 hours after mixing because of nutrient loss. 4. Do not use terminal sterilization because of Maillard reaction (Practical Aspects of Nutrition Support, p viii). 5. Warm or cool medical food mixture to room temperature before feeding to infants. Shake well before feeding. 6. Do not warm medical food mixture for infants in microwave oven. Unevenly heated formula can burn infants and steam can make bottles explode. 7. Notify parents or caretakers when they may discontinue using aseptic technique in preparing medical food mixture for infants. 8. For children and adults, chill Propimex medical food mixture to improve taste. F. Diet Guide 1. Provide parents, caretakers, or patient with completed Diet Guide (Appendix 22, p A-24) with each diet change. 2. Feed young infants 6 to 8 times daily (19, 43). 3. Feed older infants, children, and adults 4 to 6 times daily (19, 43).
240 Propionic Acidemia/Methylmalonic Acidemia

A. Nutrient Adequacy 1. Determine if diet provides nutrients in amounts prescribed in Section VII, Establish Prescription, p 233. a. See Table 13-2, p 242, for composition of Propimex and Table 13-3, p 243, for composition of infant formulas and skim milk. b. See Appendix 9, p A-9, for composition of Polycose and Appendix 11, p A-10, for composition of Pro-Phree. 2. Check diet to determine if it supplies Recommended Dietary Intakes (RDIs) of minerals and vitamins (Appendices 13 and 14, pp A-14 and A-15). a. See Appendices 4 through 7, pp A-4 to A-7, for complete nutrient composition of infant formulas. b. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. c. If Propimex-1 provides < 100% of RDIs for infants and < 75% for children and adults, supplement diet with minerals and vitamins if not provided by beikost or table foods and laboratory tests indicate need (Appendix 11, p A-10, for composition of supplements). B. Osmolarity 1. If concentration of prescribed medical food mixture is > 24 kcal/fl oz, determine if osmolarity is in acceptable range. a. Determine osmolarity by laboratory analysis or use mathematical formula given in Appendix 18, p A-20. b. Approximate osmolarity per gram of Propimex is listed in Appendix 19, p A-21. 2. If osmolarity is > 450 mosm/L for infants, > 750 mosm/L for children, > 1,000 mosm/L for adults or is greater than tolerated by patient, increase water content of prescribed medical food mixture and recalculate its osmolarity (26, 49). C. Potential Renal Solute Load 1. Dehydration will result if renal solute load is greater than renal-concentrating ability of patient. 2. If concentration of medical food mixture prescribed is > 24 kcal/fl oz, estimate its potential renal solute load. a. This step is important to prevent dehydration of infants who may have renal-concentrating capacity as low as 600 mosm/L. b. Upper limit of renal solute load for neonates is approximately 1,100 mosm/L (47). Warning: Patients with MMA diagnosed with end-stage renal disease will have reduced renal concentrating ability. 3. A method for estimating potential renal solute load is given in Appendix 20, p A-22. 4. If potential renal solute load is excessive, increase water content of medical food mixture and recalculate.

A. Plasma GLY, ILE, MET, THR, and VAL Concentrations 1. Initial. a. Measure daily by quantitative methods until plasma concentrations stabilize and approximate requirements for ILE, MET, THR, and VAL are known. b. Plasma GLY is often elevated in patients with PA or MMA (13, 31). Improvement in plasma GLY concentration suggests better metabolic control. 2. Ongoing. a. Frequent evaluations help ensure adherence to nutrition support plan. b. Evaluate 1 to 2 times weekly until patient is 6 months old and at least monthly thereafter. 3. Unacceptable ILE, MET, THR, and VAL concentrations. a. If either plasma ILE, MET, THR, or VAL concentration is not detected and patient has ingested the full prescription: 1) Increase prescribed amount of undetected amino acid(s) by 10% to 25% using intact protein and reevaluate plasma concentrations in 3 days. 2) If plasma ILE, MET, THR, or VAL concentration continues undetected, repeat above process until value is in treatment range.
b. If plasma ILE concentration is < 25 mol/L, plasma MET concentration is < 18 mol/L, plasma THR concentration is < 45 mol/L, or plasma VAL concentration is < 65 mol/L, and patient has ingested full prescription: 1) Increase intact protein intake by 5% to 10% if concentrations of more than two amino acids are low. 2) Repeat above process until value is in treatment range if plasma ILE, MET, THR, or VAL concentration continues to be low. 3) Individual supplementation of ILE and VAL may be required if tolerance to intact protein is limited. Supplements may be prepared using a sterile solution containing 10 mg amino acid/mL (ie, 1.0 g amino acid to make 100 mL total volume) (Appendix 26, p A-28). c. If plasma ILE concentration is > 105 mol/L, plasma MET concentration is > 45 mol/L, plasma THR concentration is > 250 mol/L, or plasma VAL concentration is > 250 mol/L and patient is not ill and has not ingested more or less protein and energy than prescribed: 1) Decrease prescribed amount of intact protein or L-amino acids by 5% to 10% and reevaluate plasma concentration in 1 week. 2) If plasma ILE, MET, THR, or VAL concentration continues to be high, repeat above process until value is in treatment range. B. Blood Ammonia Concentration 1. Initially, measure as clinically indicated until concentration is stabilized in normal range. a. Blood ammonia concentrations may indirectly reflect plasma methylmalonic and propionic acid concentrations (9, 46). 2. If blood ammonia concentration is > 35 mol/L or greater than normal as established in laboratory used: a. Decrease ILE, MET, THR, and/or VAL from intact protein by 5% to 10% and reevaluate blood concentration in 3 days. Be certain to maintain adequate energy and protein intakes from Propimex. b. Gradually increase restricted amino acids as tolerated to original prescription. C. Plasma or Urine Organic Acids 1. Measure monthly if plasma amino acid concentrations are greater than normal. a. Organic acids measured differ depending on disorder. 2. Measure urine ketoacids daily by Ketostix (71). a. Urine should be free of ketoacids at all times (negative Ketostix result). 3. If urine contains ketoacids (positive Ketostix result): a. Suggests catabolism and impending illness. Catabolism from insufficient protein and energy intakes requires nasogastric or gastrostomy tube feeding (25, 30, 64). b. Immediately obtain blood sample for evaluation of amino acid concentrations. c. Brief metabolic physician immediately on patient's illness. 4. Metronidazole, an antibiotic, can reduce urinary excretion of propionate from colonic gut flora (29). Dosages vary from 10 to 20 mg/kg/day over a 1- to 2-week period (59). Warning: Children with MMA and diagnosed renal failure may excrete reduced amounts of MMA (10). D. Protein Status 1. Evaluate plasma transthyretin concentration every 3 months until 1 year of age and twice yearly thereafter (Appendix 17, p A-18, for standards). a. Plasma transthyretin concentrations provide a more reliable and rapid indication of protein status than plasma albumin concentrations. b. Plasma albumin concentrations may be in the normal range when plasma transthyretin concentrations show a clear deficiency (3). 2. If plasma transthyretin concentration is below standard: a. Increase prescribed protein by 5% to 10% and reevaluate plasma transthyretin concentration in 1 month. If ILE, MET, THR, and VAL concentrations are in treatment range, use Propimex to increase protein. b. If plasma transthyretin concentration remains low, repeat above process until value is in normal range.
E. Iron Status 1. Plasma ferritin concentration. a. Evaluate at 6, 9, and 12 months of age and every 3 months thereafter (Appendix 17, p A-18, for standards). b. If plasma ferritin concentration is below standard: 1) Increase iron intake to 4 mg/kg with supplements (ferrous sulfate). 2) Evaluate plasma ferritin concentration monthly on increased iron intake. 3) Continue iron supplements until plasma ferritin concentration is in normal range. 2. Complete blood count and differential. a. Hemoglobin and hematocrit concentrations and differential should be evaluated at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17, p A-18, for standards). b. Evaluate more frequently if anemia persists. 1) Persistent anemia suggests chronic elevation in toxic metabolites that inhibit stem cell differentiation (20). F. Plasma Carnitine Concentration 1. Plasma free carnitine concentration should be evaluated as necessary to maintain normal concentration ( 30 mol/L). G. Growth Status 1. Length/height and weight. a. Measure monthly to 1 year, every 3 months to 4 years of age, and every 6 months thereafter. Plot measurements of infants and children on NCHS growth charts. b. Maintain length/height and weight between 10th and 90th percentiles. Some normal infants, children, and adults will fall above or below these percentiles. 2. If length/height or weight falls below usual growth channel: a. Increase protein and energy prescriptions by 5% to 10% and remeasure after 1 month. b. If length/height or weight remains low, repeat above process until usual growth channel is achieved. c. If patient remains below usual growth channel and does not respond to increase in protein and energy or cannot consume diet prescribed through oral feedings, nasogastric or gastrostomy tube feeding should be seriously considered (25, 30, 64). H. Nutrient Intake 1. Maintain records of food intake for 3 days immediately before each blood test (Appendices 24 and 25, pp A-26 and A-27). 2. Evaluate intakes of ILE, MET, THR, VAL, protein, and energy before each blood test. 3. Evaluate mineral and vitamin intakes after each diet change. a. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. b. See Appendix 28, p A- 29, for information about ordering software for diet evaluation. Warning: Anorectic patients require gastrostomy tube feedings which may limit intake if diets are not carefully planned. Gastrostomy tube feedings may improve morbidity (25, 30, 64) when the patient cannot meet energy and nutrient requirements by oral feeds. I. Clinical Summary 1. A summary record of growth, laboratory, and nutrient intake data is useful for patient management (Table 13-5, p 258).

A. Example 1 Establish and fill prescription for 1-month-old infant weighing 4.14 kg using Recommended Daily Nutrient Intakes from Table 13-1, p 241, and average nutrient contents from Tables 13-2 and 13-3, pp 242 and 243.
1. Establish prescription.
ILE MET THR VAL L-carnitine Protein Energy Fluid 108 mg/kg 45 mg/kg 108 mg/kg 104 mg/kg 100 mg/kg 3.5 g/kg 140 kcal/kg 164 mL/kg x x x x x x x x Measure 4.14 kg 4.14 kg 4.14 kg 4.14 kg 4.14 kg 4.14 kg 4.14 kg 4.14 kg = = = = = = = = 447 mg 186 mg 447 mg 431 mg 414 mg 14.5 g 580 kcal 680 mL L-Carn (mg) 432 0 Protein (g) 7.2 7.2 Energy (kcal) 230 352
Medical Food Mixture ILE MET THR VAL (mg) (mg) (mg) (mg) 58 388 0 181 48 399 0 430
Propimex-1 48 g Similac With Iron, Ready to 518 mL Feed Add water to make 680 mL (23 fl oz).
446 181 447 430 432 14.4 582 Total per day 108 44 108 104 104 3.5 141 Total per kg Approximate osmolarity of medical food mixture is < 375 mosm/L. Estimated potential renal solute load 150 mosm.
B. Example 2 Establish and fill prescription for 6-year-old child weighing 19 kg using Recommended Daily Nutrient Intakes from Table 13-1, p 241, and average nutrient contents from Tables 13-2 and 133, pp 242 and 243. 1. Establish prescription.
ILE MET THR VAL L-carnitine (100 mg/kg) Protein Energy Fluid 690 mg/day 255 mg 650 mg 720 mg 1,900 mg 35.0 g 2,000 kcal 2,000 mL
Medical Food Mixture Propimex-2 Skim milk Sugar L-carnitine 1 Measure 64 g 32 mL 96 g (1/2 cup) 7.5 mL ILE (mg) 154 68 0 0 MET (mg) 0 28 0 0 THR (mg) 128 51 0 0 VAL (mg) 0 76 0 0 L-Carn (mg) 1,152 0 0 750 Protein (g) 19.2 1.1 0.0 0.0 Energy (kcal) 262 12 384 0
Add water to make 1000 mL (34 fl oz). Offer additional fluid ad libitum daily. Food List Breads /Cereals Fats Fruits Vegetables Free Foods A Free Foods B
2
Servings 12 6 6 5 2 6 300 30 60 75 8 0 120 12 30 25 4 0 300 30 60 75 8 0 420 30 90 100 10 0 0 0 0 0 0 0 8.4 0.6 3.0 2.5 0.2 0.0 360 180 330 50 130 330
695 219 652 726 1,902 35.0 2,038 Total per day Approximate osmolarity of medical food mixture is < 1,000 mosm/L. 1 Add only if plasma free carnitine concentration is < 30 mol. 2 Many commercial breads contain propionic acid as an antimicrobial and flavoring agent. These breads should not be used.

A. Rationale 1. In normal persons, febrile illness and trauma are accompanied by catabolism of body protein (67). 2. Well-nourished infants, children, and adults with PA or MMA respond to infection and trauma as do normal persons. 3. Extent of protein catabolism determines subsequent elevation in concentrations of plasma and urine organic acids, odd-chain-fatty acids, and ketones. B. Objectives of Nutrition Support 1. Maintain hydration and electrolyte balance. 2. Depress catabolism. a. See Nutrition Support During Acute Illness and at Diagnosis, Section V, p 231.
TABLE 13-1. Recommended Daily Nutrient Intakes (Range) for Infants, Children, and Adults With Propionic or Methylmalonic Acidemia
Age ILE` (mg/kg) Infants 0 to < 3 mo 3 to < 6 mo 6 to < 9 mo 9 to < 12 mo 75 - 120 65 - 100 50 - 90 40 - 80 (mg/day) Girls and Boys 1 to < 4 yr 4 to <7 yr 7 to < 11 yr Women 11 to < 15 yr 15 to < 19 yr 19 yr Men 11 to < 15 yr 15 to <19 yr
1 2 1,2
Nutrient MET (mg/kg) 30 - 50 20 - 45 10 - 40 10 - 30 (mg/day) 180 - 390 255 - 510 290 - 580
1,2
THR (mg/kg) 75 - 135 60 - 100 40 - 75 20 - 40 (mg/day) 415 - 600 540 - 780 610 - 885
1,2
VAL (mg/kg) 75 - 105 65 - 90 35 - 75 30 - 60 (mg/day) 550 - 830 720 - 1,080 815 - 1,225
1,2
Protein (g/kg) 3.50 - 2.50 3.50 - 2.50 3.00 - 2.50 3.00 - 2.50 (g/day) 30.0 35.0 40.0
Energy (kcal/kg) (130) 95 - 145 (125) 95 - 145 (120) 80 - 135 (115) 80 - 135
Fluid (mL/kg) 125 - 200 130 - 160 125 - 145 120 - 135 (mL/day) 900 - 1,800 1,300 - 2,300 1,650 - 3,300
(kcal/day) 1,300 ( 900 - 1800) 1,700 (1300 - 2300) 2,400 (1650 - 3300)
485 - 735 630 - 960 715 - 1,090
965 - 1,470 965 - 1,470 925 - 1,410
390 - 780 275 - 780 265 - 750
830 - 1,195 830 - 1,195 790 - 1,145
1,105 - 1,655 1,105 - 1,655 790 - 1,585
55.0 55.0 50.0
2,200 (1500 - 3000) 2,100 (1200 - 3000) 2,100 (1400 - 2500)
1,500 - 3,000 1,200 - 3,000 1,400 - 2,500
540 - 765 670 - 950
290 - 765 475 - 950
810 - 1,170 1,010 - 1,455
1,080 - 1,515 1,345 - 2,015
50.0 65.0
2,700 (2000 - 3700) 2,800 (2100 - 3900)
2,000 - 3,700 2,100 - 3,900
1,175 - 1,190 475 - 950 1,010 - 1,455 1,345 - 2,015 2,900 (2000 - 3300) 2,000 - 3,300 19 yr 65.0 Modified from references 1, 12, 38, and 72. Initiate prescription with lowest recommended intake for age. Modify prescription based on frequently obtained plasma values and growth in infants and children and frequently obtained plasma values and weight maintenance in adults. Modified from references 14 and 53. When possible, initiate prescription with highest value. Modify prescription based on plasma transthyretin concentration and weight. From reference 5. Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL to children and adults for each kcal ingested.
TABLE 13-2. Nutrient Composition of PROPIMEX -1 1, 3, and PROPIMEX -2 2, 3

Propimex-1 Propimex-2 (per 100 g pwd) (per g protein equiv) (per 100 g pwd) (per g protein equiv) Energy, kcal 480 32 410 13.7 Nitrogen, g 2.40 0.160 4.80 0.160 Protein equiv, g 15.00 1.000 30.00 1.000 5 Amino acids , g 16.17 1.078 32.34 1.078 Cystine, g 0.45 0.030 0.90 0.030 Histidine, g 0.42 0.028 0.84 0.028 Isoleucine, g 0.12 0.008 0.24 0.008 Leucine, g 1.38 0.092 2.76 0.092 Lysine, g 1.00 0.067 2.00 0.067 Methionine, g trace 0 trace 0 Phenylalanine, g 0.88 0.059 1.76 0.059 Threonine, g 0.10 0.007 0.20 0.007 Tryptophan, g 0.17 0.011 0.34 0.011 Tyrosine, g 0.89 0.059 1.78 0.059 Valine, g trace trace 0 0 Other Nitrogen-Containing Compounds Carnitine, mg 900 60 1,800 60 Taurine, mg 40 2.66 50 1.67 Carbohydrate, g 53.0 3.53 35.0 1.17 Fat, g 21.7 1.45 13.0 0.43 4 5 Linoleic acid, g 2.00 0.133 2.00 0.07 6 7 0.36 0.024 0.17 0.006 -Linolenic acid, g Minerals Calcium, mg 575 38 880 29 Chloride, mg/mEq 410/11.56 27/0.77 1,160/32.72 38.7/1.09 Chromium, g 11 0.73 27 0.90 1.10 0.073 0.033 Copper, mg 1.00 Iodine, g 65 4.33 100 3.33 Iron, mg 9.0 0.6 13.0 0.43 Magnesium, mg 50 3.33 225 7.5 Manganese, mg 0.50 0.033 0.80 0.027 Molybdenum, g 12 0.80 30 1.00 Phosphorus, mg 400 27 760 25 Potassium, mg/mEq 675/17.26 45/1.15 1370/35.04 45.7/1.17 Selenium, g 20 1.33 35 1.17 Sodium, mg/mEq 190/8.26 12.7/0.55 880/38.28 29.3/1.28 Zinc, mg 8.0 0.53 13 0.43 Vitamins A, g RE 420 28 660 22 D, g 7.50 0.50 7.50 0.25 10.10 0.67 12.10 0.40 E, mg -TE K, g 50 3.33 60 2.00 50 3.33 60 2.00 Ascorbic acid, mg Biotin, g 65 4.3 100 3.33 B6, mg 0.75 0.05 1.30 0.043 B12, g 4.90 0.33 5.00 0.167 Choline, mg 80 5.3 100 3.33 Folate, g 230 15 430 14.33 Inositol, mg 40 2.7 70 2.33 Niacin equiv, mg 12.8 0.85 21.7 0.72 Pantothenic acid, mg 6.90 0.46 8.00 0.267 Riboflavin, mg 0.90 0.06 1.80 0.060 Thiamin, mg 0.108 1.90 0.127 3.25 1 2 Designed for infants and toddlers. Designed for children, adolescents, and adults. 3 Approximate packed weight of Propimex-1 and Propimex-2 in level, dry US standard household measures: Propimex-1 Propimex-2 1 Tbsp = 7g 8g 1/4 cup = 26 g 32 g 1/3 cup = 35 g 41 g 1/2 cup = 53 g 61 g 1 cup = 105 g 117 g 4 5 Analytical data at manufacture = 4.32 g/100 g powder. Analytical data at manufacture = 2.66 g/100 g powder. 6 7 Analytical data at manufacture = 0.40 g/100 g powder. Analytical data at manufacture = 0.28 g/100 g powder. Nutrient
TABLE 13-3. Serving Lists for ILE-, MET-, THR-, and VAL-Restricted Diets: Average Nutrient Content per Serving
Food List Nutrient ILE MET THR VAL Protein Energy (mg) (mg) (mg) (mg) (g) (kcal) Breads1/Cereals Fats Fruits Vegetables Free Foods A Free Foods B Alimentum Protein Hydrolysate Formula With Iron, Ready to Feed, 100 mL
2
25 5 10 15 4 0 109
10 2 5 5 2 0 54
25 5 10 15 4 0 88
35 5 15 20 5 0 141
0.70 0.10 0.50 0.50 0.10 0.00 1.86
30 30 55 10 65 55 68
Isomil Soy Formula With Iron, Ready to Feed, 100 mL 2 81 40 70 70 1.66 68 2 Similac With Iron Infant Formula, Ready to Feed, 100 mL 75 35 77 83 1.40 68 Skim milk, 100 mL 3 213 89 159 236 3.53 36 1 Many commercial breads contain propionic acid as antimicrobial and flavoring agent. These breads should not be used. Read labels carefully. 2 See Appendices 4 through 7, pp A-4 to A-7, for complete nutrient composition of infant formulas. 3 From reference 34. See Appendix 8, A-8, for complete nutrient composition.
TABLE 13-4. Serving Lists for ILE-, MET-, THR- and VAL-Restricted Diets: Gerber Baby Foods (Beikost)
1
Food
Weight Approximate (g) Measure
ILE (mg)
MET (mg)
THR (mg)
VAL (mg)
Protein Energy (g) (kcal)
For greatest accuracy, weigh food on scale that reads in grams. All measures are level. BREADS AND CEREALS Baked Finger Snacks, Graduates Animal crackers, cinnamon graham Apple cinnamon cookie Arrowroot cookie Banana cookie Pretzel Strawberry fruit bar Veggie crackers Cereals, Dry Barley Mixed Oatmeal Oatmeal/banana Oatmeal/mixed fruit Rice Rice/apples Rice/apple bits Rice/bananas Rice/mixed fruit Cereals, Jarred 1st Foods Oatmeal 2nd Foods Mixed/applesauce/bananas Oatmeal/applesauce/bananas Rice/applesauce 3rd Foods Mixed/apples/bananas Oatmeal/apples/cinnamon Tender Harvest Banana/oatmeal/peach Butternut squash/corn Green beans/potatoes Spring garden vegetables Vegetables 1st Foods Peas Sweet potatoes 2nd Foods Creamed corn Creamed spinach Garden vegetables Peas Sweet potatoes
14 10 10 12 6 13 12
3-1/2 crackers 1 cookie 2 cookies 1-1/2 cookies 2 pretzels 1-1/2 bars 17 crackers
29 26 26 28 28 28 29
11 12 13 16 12 17 12
17 20 20 18 17 21 22
36 31 31 34 32 34 34
0.8 0.8 0.8 0.8 0.8 0.7 0.6
36 43 46 52 23 53 57
6 8 4 5 6 7 12 10 7 9
1 Tbsp + 2 tsp 2 Tbsp 1 Tbsp + 1 tsp 1 Tbsp + 2 tsp 1 Tbsp + 2 tsp 1 Tbsp + 2 tsp 3 Tbsp 2 Tbsp + 2 tsp 2 Tbsp 2 Tbsp + 1-1/2 tsp
27 26 23 26 25 25 24 27 35 24
13 17 11 10 12 17 20 18 17 22
23 19 18 23 20 17 17 22 20 18
37 34 31 34 33 34 34 35 37 34
0.8 0.8 0.6 0.7 0.6 0.6 0.7 0.7 0.5 0.6
23 31 16 24 25 27 47 40 25 35
36 74 56 78 60 66 61 62 28 64
2 Tbsp + 1-1/2 tsp 5 Tbsp 4 Tbsp 5 Tbsp + 1-1/2 tsp 4 Tbsp 4 Tbsp + 2 tsp 4-1/4 Tbsp 4 Tbsp + 1 tsp 2 Tbsp 4 Tbsp + 1-1/2 tsp
23 26 27 26 23 26 21 29 27 28
13 15 12 20 15 15 12 19 15 11
21 17 12 15 20 19 20 20 23 31
35 35 35 35 35 35 35 35 35 35
0.6 0.7 0.7 0.6 0.7 0.7 0.7 1.2 0.6 1.0
20 64 46 71 46 44 45 31 18 22
22 70 40 22 35 23 70
1 Tbsp + 1-1/2 tsp 5 Tbsp 2-3/4 Tbsp 1 Tbsp + 1-1/2 tsp 2 Tbsp + 1-1/2 tsp 1 Tbsp + 1 tsp 5 Tbsp
29 22 28 31 28 29 25
9 13 18 16 12 9 15
31 30 22 26 29 31 30
35 39 35 35 35 35 35
0.7 0.8 0.7 0.7 0.8 0.7 0.7
11 46 25 10 13 11 43
Food
ILE (mg)
MET (mg)
THR (mg)
VAL (mg)
For greatest accuracy, weigh food on scale that reads in grams. All measures are level. 3rd Foods Peas/rice 29 2 Tbsp 29 Sweet potatoes 54 3-3/4 Tbsp 25 Graduates Mixed vegetables 42 ND 29 FRUITS/JUICES 1st Foods Bananas Peaches Pears Prunes 2nd Foods Apples/pears Apricots/mixed fruit Bananas Peach cobbler Peaches Pears Pear/pineapple Plums/apples Prunes/apples 3rd Foods Apricots/mixed fruit Bananas Banana/pineapple Banana/strawberry Fruit salad Hawaiian Delight dessert Peach cobbler Peaches Pears Plums/apples Fruit Juice Banana/strawberry juice medley Mixed Orange Tropical blend Fruit/Vegetable Juice Apple/carrot Apple/sweet potato Tender Harvest Apple/sweet potato Pear/wild blueberry Pears/winter squash Tropical fruit blend VEGETABLES 1st Foods Carrots 250 Propionic Acidemia/Methylmalonic Acidemia
11 13 13
27 28 32
35 35 35
0.7 0.5 0.8
16 32 19
25 79 115 88 36 79 25 150 79 94 115 125 115 79 25 34 32 115 23 136 94 94 73
1 Tbsp + 2 tsp 5 Tbsp + 1-1/2 tsp 8 Tbsp 6 Tbsp 2 Tbsp + 1-1/2 tsp 5 Tbsp + 1-1/2 tsp 1-3/4 Tbsp 10 Tbsp + 1-1/2 tsp 5 Tbsp + 1-1/2 tsp 6 Tbsp + 1-1/2 tsp 8 Tbsp 8 Tbsp + 2 tsp 8 Tbsp 5 Tbsp + 1-1/2 tsp 1 Tbsp + 2 tsp 2 Tbsp + 1 tsp 2 Tbsp 8 Tbsp 1 Tbsp + 2 tsp 9 Tbsp + 1-1/2 tsp 6 Tbsp + 1-1/2 tsp 6 Tbsp + 1-1/2 tsp 5 Tbsp
7 11 12 11 9 10 10 10 11 11 12 11 13 10 6 8 8 12 12 11 11 11 7
5 6 9 4 5 5 5 15 6 6 9 6 7 5 5 4 4 7 9 12 8 6 3
7 11 12 9 8 7 7 12 11 8 10 6 12 7 7 9 6 8 9 11 12 8 7
15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15
0.3 0.6 0.5 0.9 0.3 0.5 0.3 0.8 0.6 0.5 0.5 0.5 0.7 0.5 0.3 0.3 0.3 0.5 0.3 0.7 0.7 0.5 0.3
25 34 66 89 30 47 22 114 51 70 63 100 89 47 22 26 30 72 20 105 60 70 50
100 100 200 100
3-1/5 fl oz 3-1/5 fl oz 6-1/4 fl oz 3-1/5 fl oz
12 11 12 9
11 11 6 9
10 10 14 17
15 15 18 15
0.4 0.3 0.6 0.6
58 48 94 56
160 115 125 150 47 52
5 fl oz 3-2/3 fl oz ND ND ND ND
8 10 11 24 12 23
5 6 5 5 8 4
10 9 14 8 10 6
14 15 15 15 15 15
0.3 0.3 0.4 0.6 0.5 0.3
69 60 79 92 24 38
67
1/4 cup + 2 tsp
15
15
20
0.6
23
Food
ILE (mg)
MET (mg) 9 10 9 7 7 7 12 10 9 8
THR (mg) 16 14 15 15 15 16 15 15 14 14
VAL (mg) 20 35 20 20 20
Protein Energy (g) (kcal) 0.4 0.7 0.4 0.5 0.4 20 0.4 20 0.5 20 20 20 0.5 0.4 0.6 9 32 18 20 10 11 20 17 15 25
For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Green beans 30 2 Tbsp 15 Potatoes 69 4 Tbsp + 2 tsp 22 Squash 53 3 Tbsp + 1 tsp 22 2nd Foods Carrots 67 4 Tbsp + 2 tsp 15 Green beans 34 2 Tbsp + 1-1/2 tsp 15 Mixed vegetables 31 2 Tbsp 16 Squash 61 4-1/4 Tbsp 18 3rd Foods Carrots 57 15 4 Tbsp Green beans/rice 36 2 Tbsp + 1-1/2 tsp 15 Squash 77 5 Tbsp + 1 tsp 17 Vegetable Dices, Graduates Carrots Green beans FREE FOODS A Apple juice Apple/banana juice Apple/blueberry Apple/cherry juice Apple/cranberry juice Apple/grape juice Apple/prune juice Applesauce White grape juice Desserts, Tropical Fruit Fruit medley Guava Mango Papaya Fruit Dices, Graduates Apples Mixed fruit Peaches Pears
1
53 28
ND ND
15 16
7 6
15 14
20 20
0.3 0.3
12 7
163 65 62 81 100 98 81 57 50
5 fl oz 2 fl oz 4 Tbsp + 1-1/2 tsp 2-1/2 fl oz 3.2 fl oz 3 fl oz 2-1/2 fl oz 1/4 cup 1-2/3 fl oz
5 5 4 4 4 2 4 4 4
0 1 2 1 1 0 1 1 0
5 5 4 5 5 3 5 4 4
5 5 5 5 5 5 5 5 5
0.2 0.1 0.1 0.2 0.1 0.1 0.2 0.1 0.3
78 33 31 39 44 48 43 31 30
62 71 42 83
4 Tbsp + 1 tsp 1/3 cup 3 Tbsp 5 Tbsp + 2 tsp
3 4 4 4
1 3 2 3
2 3 3 4
5 5 5 5
0.1 0.1 0.1 0.1
40 45 29 61
100 62 50 56
ND ND ND ND
3 3 4 3
2 2 3 2
4 4 4 4
5 5 5 5
0.1 0.2 0.2 0.2
48 30 35 30
Prepared from 1998 and 1999 data from Gerber Products Co, Fremont, MI 49413. ND = No data. Weights and Measures Except for Dry Cereals and Food Dices, the following weights apply: Level Level 1 tsp = 1/3rd Tbsp = 4.8 g 1 Tbsp = 1/16th cup = 14.4 g 1/4 cup = 4 Tbsp = 57.3 g 1/3 cup = 5-1/3rd Tbsp = 76.3 g 1/2 cup = 8 Tbsp = 114.3 g 2/3 cup = 10 2/3rd Tbsp = 152.5 g 3/4 cup = 12 Tbsp = 171.5 g 1 cup = 16 Tbsp = 228.6 g
TABLE 13-4. Serving Lists for ILE-, MET-, THR- and VAL-Restricted Diets: Table Foods
Food Weight Approximate ILE (g) Measure (mg) For greatest accuracy, weigh food on scale that reads in grams. All measures are level. BREADS AND CEREALS Cereals, Cooked. Measure after cooking. Cream of Rice Cream of Wheat Mix'n Eat plain flavored regular Farina Grits Malt-o-Meal Oats, regular, quick, and instant Wheatena Cereals, Ready To Eat All Bran Alpha-Bits Apple Jacks Bran, 100% Bran Buds Bran Chex 40% Bran Flakes (Post ) Cap'n Crunch Cap'n Crunch's Crunch Berries Cap'n Crunch's Peanut Butter Cheerios Cinnamon Toast Crunch Cocoa Krispies Cocoa Pebbles Cocoa Puffs Cookie Crisp Corn Bran Corn Chex Corn Flakes Crispy Wheat'n Raisins C W Post plain w/ raisins Froot Loops Frosted Mini-Wheats Frosted Rice Krinkles Fruit Wheat Squares Fruity Pebbles Golden Grahams Granola (w/out nuts) Grape Nuts Grape Nut Flakes Heartland , plain Honey Nut Cheerios Honey Nut Corn Flakes Honeycomb King Vitaman Kix MET (mg) THR (mg)
VAL (mg)
20
1/4 cup
16
27
35
0.5
32
36 38 38 17 15 15 22 36
1/4 packet 1/4 packet 2 Tbsp + 1-1/2 tsp 3 Tbsp + 1-1/2 tsp 3 Tbsp 3 Tbsp 1 Tbsp + 1-1/2 tsp 2 Tbsp + 1 tsp
30 27 30 32 25 31 26 32
13 12 13 13 15 13 9 13
22 20 22 22 23 21 20 22
34 30 34 35 33 33 33 35
0.7 0.6 0.7 0.7 0.6 0.7 0.6 0.7
26 33 24 25 27 23 14 20
5 8 13 6 5 7 6 13 12 9 4 29 10 12 21 13 10 10 8 11 7 7 12 7 11 14 13 12 6 6 7 7 6 11 12 13 7
1 Tbsp 1/4 cup + 1-1/2 tsp 1/2 cup 1 Tbsp + 1-1/2 tsp 1 Tbsp 2 Tbsp + 3/4 tsp 2 Tbsp + 3/4 tsp 5 Tbsp + 1-1/2 tsp 5 Tbsp + 1-1/2 tsp 1/4 cup + 3/4 tsp 3 Tbsp 3/4 cup 1/4 cup + 1-1/2 tsp 1/4 cup + 2 Tbsp 3/4 cup 1/4 cup + 3 Tbsp 1/4 cup + 3/4 tsp 5 Tbsp + 1 tsp 1/4 cup + 2 Tbsp 1/4 cup 1 Tbsp 1 Tbsp 1/4 cup + 3 Tbsp 1 square 5 Tbsp + 1-1/2 tsp 2 Tbsp + 1-1/2 tsp 1/3 cup + 3-1/2 tsp 1/4 cup + 1 Tbsp 2-1/2 tsp 2-1/2 tsp 3 Tbsp + 1 tsp 1 Tbsp 2 Tbsp + 1 tsp 1/4 cup + 1 Tbsp 1/2 cup + 1 tsp 9 Tbsp + 1-1/2 tsp 1/3 cup + 1 Tbsp
24 27 27 25 24 26 25 27 27 26 30 32 28 29 25 27 27 27 27 28 29 27 29 29 29 31 28 29 28 28 30 29 27 28 27 27 27
11 11 13 11 10 14 10 14 14 11 11 14 15 16 13 13 14 16 16 12 11 10 14 13 16 15 16 15 10 12 12 12 11 14 14 14 14
25 21 22 25 24 25 22 23 22 21 22 23 26 28 23 22 23 25 24 22 23 22 24 24 27 24 27 24 21 22 23 22 22 26 23 23 23
36 35 35 36 35 36 35 35 34 35 38 35 34 35 35 35 35 35 35 34 35 35 37 36 35 35 34 36 35 35 36 36 34 35 35 35 35
0.8 0.6 0.7 0.8 0.7 0.7 0.7 0.6 0.6 0.6 0.6 1.0 0.5 0.6 0.7 0.7 0.7 0.7 0.7 0.7 0.6 0.6 0.7 0.7 0.5 1.0 0.5 0.7 0.6 0.7 0.7 0.7 0.6 0.8 0.7 0.6 0.7
13 31 50 17 14 22 19 53 51 40 17 123 39 50 76 52 34 39 33 37 31 28 49 25 43 49 53 47 26 21 24 31 21 47 45 51 29
Food
Weight Approximate ILE (g) Measure (mg) For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Life 3 1 Tbsp + 1/4 tsp 29 Lucky Charms 7 3 Tbsp + 3/4 tsp 29 Nutri-Grain corn 9 3 Tbsp + 3/4 tsp 28 rye 8 3 Tbsp 28 wheat 9 3 Tbsp 33 Oat Flakes 3 1 Tbsp 31 Product 19 8 3 Tbsp + 1-1/2 tsp 29 Quisp 13 1/4 cup + 3 Tbsp 28 Raisin Bran (Post ) 9 2 Tbsp + 1-1/2 tsp 27 Rice, puffed 8 1/2 cup + 2 Tbsp 29 Rice Chex 10 1/3 cup + 1 Tbsp 28 Rice Krispies 8 1/4 cup + 1-1/2 tsp 29 Special K 3 1 Tbsp + 2-1/4 tsp 29 Sugar Corn Pops 14 7 Tbsp + 1-1/2 tsp 26 Sugar Frosted Flakes 14 1/3 cup + 1 Tbsp 27 Sugar Smacks 11 1/4 cup + 1-1/2 tsp 32 Super Sugar Crisp 12 5 Tbsp + 1-1/2 tsp 32 Team 9 3 Tbsp + 1-1/2 tsp 27 Total 7 3 Tbsp + 1-1/2 tsp 27 Trix 12 1/4 cup + 3 Tbsp 26 Wheat germ plain 2 1 tsp 25 w/ sugar 3 1-1/4 tsp 24 puffed 5 1/3 cup 31 shredded 7 1 Tbsp + 2-1/2 tsp 28 Wheat Chex 7 2 Tbsp + 1-1/2 tsp 30 Wheaties 7 1/4 cup 27
MET (mg) 10 10 17 10 14 11 17 14 11 17 15 16 16 16 16 13 13 14 10 14
THR (mg) 22 22 25 24 23 27 25 23 23 28 26 28 27 23 24 23 23 24 25 23
VAL (mg) 33 35 35 34 35 35 35 35 35 35 35 35 36 35 35 35 35 35 35 35
Protein Energy (g) (kcal) 0.5 0.6 0.7 0.7 0.8 0.6 0.8 0.7 0.8 0.5 0.5 0.5 0.6 0.7 0.7 0.7 0.8 0.6 0.6 0.6 11 27 34 27 32 11 30 54 28 35 39 32 12 51 52 40 45 35 21 46
13 13 13 12 13 12
28 28 23 24 22 23
34 34 35 35 34 34
0.7 0.7 0.7 0.7 0.7 0.7
9 12 18 23 26 25
Grains Corn cob, medium cooked cream style whole kernel Rice, prepared brown fried pilaf Rice-A-Roni Spanish white instant regular Pasta, cooked Macaroni Noodles, egg Ramen Noodles Spaghetti Tubers Potatoes, sweet baked, in skin (mashed) boiled, no skin (mashed) canned, packed in syrup 2001 Ross Products Division
21 11 17 25 21 19 26 36 25 29
1/3 ear 2 Tbsp 1 Tbsp + 2 tsp 2 Tbsp + 3/4 tsp 1 Tbsp + 1-1/2 tsp 1 Tbsp + 3/4 tsp 1 Tbsp + 2 tsp 2 Tbsp + 1 tsp 2 Tbsp + 1 tsp 2 Tbsp + 3/4 tsp
26 22 23 24 25 28 28 25 24 25
14 12 12 14 14 15 15 13 13 14
26 22 23 23 21 22 23 22 20 21
37 32 33 36 33 35 35 35 34 36
0.6 0.6 0.6 0.6 0.5 0.7 0.8 0.6 0.6 0.6
19 23 18 29 27 28 33 31 27 32
18 15 17 18
2 Tbsp + 1/2 tsp 1 Tbsp + 1-1/2 tsp 1 Tbsp + 2 tsp 2 Tbsp
31 30 29 32
16 11 15 16
24 26 23 25
35 36 34 37
0.9 0.6 0.9 0.9
26 19 37 27
31 34 20
2 Tbsp + 1-1/2 tsp 1 Tbsp + 2 tsp 1/4 cup + 1 Tbsp
27 28 27
13 14 13
27 28 26
35 37 35
0.5 0.6 0.5
32 36 84
Food
Weight Approximate ILE (g) Measure (mg) For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Potatoes, white baked, no skin 27 1/4 cup 27 boiled no skin 36 3 Tbsp + 2 tsp 25 w/ skin 34 3 Tbsp + 1-1/2 tsp 26 French fries (1/2" x 1/2" x 2") fresh 15 3 fries 26 frozen, baked 20 4 fries 31 hash browns, frozen, cooked 23 2 Tbsp + 1 tsp 31 salad 21 1 Tbsp + 1 tsp 30 Tater Tots 33 3-1/2 pieces 29 Yams, baked or boiled 20 1/4 cup + 3 Tbsp 30
MET (mg)
THR (mg)
VAL (mg)
10 10 10 7 8 8 14 8 12
23 22 23 28 32 33 24 30 31
35 34 36 31 36 37 36 34 36
0.6 0.6 0.6 0.6 0.7 0.7 0.6 0.7 0.9
29 31 30 47 65 50 30 54 69
Miscellaneous Chow mein noodles Ice cream cone, wafer type Snack Foods Barnum's Animal Crackers Breadsticks Cookies chocolate chip fig bars gingersnaps oatmeal raisin Oreo sandwich Sno Balls Social Tea Biscuits sugar (buttery) Sugar Wafers (Nabisco ) vanilla wafers Crackers Goldfish , original graham crackers (2" x 2") Melba toast Ritz Ritz Bits , cheese Rykrisp saltines Triscuits Waverly Wheat Thins Ding Dongs Doodads , original Doritos Doughnut, cake Fritos Ho Ho's Marshmallow puffs Popcorn buttered caramel plain Potato chips Pringles chips,
10 9
1/4 cup 2, cone only
32 30
13 16
22 24
35 35
0.8 0.9
58 33
13 8 15 20 16 11 16 17 28 16 13 22 16 13 11 6 13 8 6 9 9 12 13 31 3 11 14 11 21 29 7 4 2 10 11
5 crackers 1-1/4 sticks 1-1/4 cookies 1-1/4 bars 2-1/4 cookies 3/4 cookie 1-1/2 cookies 1-1/2 cookies 2/3 cookie 3 biscuits 1 cookie 4 wafers 4 wafers 21 crackers 1-1/2 crackers 1 piece 4 crackers 11-1/2 crackers 1 piece 3 crackers 2 crackers 1-3/4 crackers 7 crackers 2/3 roll 2 Tbsp + 1-1/2 tsp 6 chips 1/3 doughnut 5-1/2 chips 3/4 roll 1-1/2 puffs 3/4 cup 1/4 cup + 1 Tbsp 14 Tbsp + 1-1/2 tsp 5 chips 6 chips
30 31 31 38 30 28 25 27 31 31 27 28 30 31 29 26 30 31 27 28 26 30 30 29 30 24 33 26 32 30 27 27 27 26 25
15 16 12 10 15 14 12 14 15 16 14 14 15 15 15 13 15 15 11 14 13 16 16 13 14 11 11 12 16 15 16 16 17 10 9
23 25 24 21 24 23 21 22 24 24 21 22 23 24 23 20 23 22 24 22 20 24 24 25 25 24 22 26 25 25 24 24 24 23 22
35 36 35 34 35 35 31 32 36 36 32 32 35 36 34 30 35 35 34 33 30 35 35 36 35 35 33 35 38 37 35 35 36 36 34
0.9 0.9 0.8 0.8 0.9 0.7 0.8 0.8 0.8 0.9 0.8 0.9 0.9 0.9 0.8 0.8 0.9 0.8 0.6 0.8 0.8 1.0 1.0 0.9 0.9 0.8 0.6 0.7 0.9 1.0 0.7 0.7 0.7 0.6 0.6
56 29 77 72 66 48 80 82 98 72 55 107 74 62 40 20 66 40 23 39 42 60 60 144 44 53 54 60 89 122 31 42 21 52 62
Food
Weight Approximate ILE MET THR VAL (g) Measure (mg) (mg) (mg) (mg) For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Pretzels 6 1-1/4 pretzel 28 16 26 34 Twinkies 28 2/3 cookie 31 16 25 36 FATS Gravy beef, canned brown, mix chicken canned mix, dried mushroom canned mix, dried onion mix, dried Margarine imitation soft stick or brick Nondairy creamer w/ sodium caseinate liquid powder Rich's Coffee Rich Polyrich Olives black green Salad dressings, commercial Catalina French Italian Mayonnaise Miracle Whip ranch Russian Thousand Island tartar sauce Toppings, commercial Cool Whip extra creamy regular Richwhip pressurized prewhipped
Protein Energy (g) (kcal) 0.5 0.8 23 101
2 1 5 1 10 1 1 5 9 9 10 1 36 36 10 10 22 13 16 7 21 3 5 8 5
1/2 tsp 2 tsp 1 tsp 2 tsp 2 tsp 1 Tbsp 1 Tbsp 1 Tbsp 2 tsp 2 tsp 2 tsp 3/4 tsp 2 Tbsp + 1-1/2 tsp 2 Tbsp + 1-1/2 tsp 2 olives 2 olives 1/4 cup 2-1/2 tsp 3 Tbsp 1-1/2 tsp 1 Tbsp + 1-1/2 tsp 1/2 tsp 1 tsp 1-1/2 tsp 1 tsp
4 4 4 4 4 5 5 5 4 5 6 4 5 5 4 5 5 4 4 5 5 4 5 4 4
2 2 2 2 2 2 2 2 2 2 2 2 1 1 2 2 1 2 2 2 2 2 2 2 2
4 3 3 3 3 4 4 3 3 4 4 3 4 4 4 4 6 4 4 4 5 3 4 4 3
4 5 4 5 5 6 5 5 5 5 6 5 5 5 5 6 5 5 5 5 5 5 5 4 5
0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.3 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1
1 3 4 5 5 4 5 50 68 67 14 8 55 55 18 12 290 56 65 50 105 17 25 29 25
3 5 7 3
2 tsp 1 Tbsp + 3/4 tsp 3 Tbsp 2 Tbsp
5 4 5 5
2 2 2 1
4 3 5 4
5 5 5 5
0.1 0.1 0.1 0.1
10 14 60 24
FRUITS Fruits are raw unless otherwise noted. Weight of raw fruits is only for parts that can be eaten. Drain canned, cooked, and frozen fruits before measuring or weighing. Apricots canned, heavy syrup dried cooked, mashed halves nectar, canned whole Avocados, all varieties, mashed
27 10 11 110 35 7
1/4 cup + 1 Tbsp 2 Tbsp 3 3-1/2 fl oz 1 fruit 1 Tbsp + 1-1/2 tsp
13 13 12 12 14 15
2 2 2 2 2 8
15 15 14 15 17 14
15 15 14 15 17 21
0.4 0.4 0.4 0.4 0.5 0.4
67 27 25 61 17 35
Food
Weight Approximate ILE (g) Measure (mg) For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Bananas, sliced 29 1/4 fruit 9 Blackberries canned, heavy syrup 8 2 Tbsp + 1-1/2 tsp 12 frozen, sweetened 16 1/4 cup + 1 Tbsp 13 raw 72 1/2 cup 12 Blueberries frozen, sweetened 29 1/4 cup + 2 Tbsp 10 raw 18 1/4 cup + 2 Tbsp 11 Cherries, canned, heavy syrup sour, red 29 1/4 cup + 2 Tbsp 12 sweet 17 5 Tbsp + 1-1/2 tsp 12 Currants, black 8 3 Tbsp + 1-1/2 tsp 11 Dates, chopped 7 2 Tbsp 10 Figs canned, heavy syrup 35 1/3 cup + 3-1/2 tsp 13 dried, uncooked, chopped 4 1 Tbsp 12 whole, large 50 1 fruit 12 Fruit cocktail, canned heavy syrup 33 1/3 cup + 1 Tbsp 10 light syrup 31 1/4 cup + 2 Tbsp 9 Fruit salad, canned, heavy syrup 37 1/4 cup + 3 Tbsp 11 Gooseberry, canned, light syrup 18 3 Tbsp + 1-1/2 tsp 11 Grapefruit, all varieties canned, light syrup 63 1/4 cup 10 juice, canned, unsweetened 185 6 fl oz 9 sections 57 1/4 cup 10 Grapes Concord 92 1 cup 5 European, green 80 1/2 cup 4 juice 158 5 fl oz 11 Thompson, seedless, canned, heavy syrup 128 1/2 cup 5 Guavas raw 59 2/3 fruit 18 sauce 17 1/4 cup + 1 Tbsp 16 Kiwi fruit 25 1/3 fruit 7 Mangoes, sliced 54 1/3 cup 10 Melons, cubed cantaloupe 53 1/3 cup 15 Casaba 18 1/4 cup + 1 Tbsp 15 honeydew 35 1/2 cup + 2 Tbsp 15 Mixed fruit, canned, heavy syrup 84 1/3 cup 9 Nectarines 34 1/4 fruit 9 Oranges juice canned 156 5 fl oz 9 frozen, diluted 140 4 1/2 fl oz 10 sections 33 1/4 fruit 8 Papayas, cubed 140 1 cup 11 Peaches canned, heavy syrup, sliced 64 1/4 cup 8 dried, chopped 8 1 Tbsp + 1-1/2 tsp 8 frozen, sweetened 16 3 Tbsp 8 nectar, canned 93 3 fl oz 8 sliced 42 1/4 cup 9 Pears canned, heavy syrup 69 3/4 cup + 1 Tbsp 13 dried 256 Propionic Acidemia/Methylmalonic Acidemia
MET (mg) 3 1 1 1 5 6 5 5 6 5 3 3 3 10 9 7 6 1 6 1 19 18 2 20 3 3 6 3 3 4 3 7 8
THR (mg) 10 16 17 16 10 10 14 14 9 12 13 12 12 12 11 12 10 6 11 6 16 14 25 17 18 16 10 10 13 13 14 9 12
VAL (mg) 13 15 16 15 15 15 16 15 14 15 15 14 14 15 15 16 15 15 15 16 16 14 16 17 17 14 14 14 15 15 15 14 17
Protein Energy (g) (kcal) 0.3 0.5 0.6 0.5 0.3 0.4 0.6 0.6 0.3 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 1.0 0.4 0.6 0.5 0.9 0.6 0.5 0.4 0.2 0.3 0.5 0.5 0.5 0.3 0.3 26 37 30 38 70 30 80 36 15 61 92 32 37 73 54 81 40 38 70 18 58 57 96 93 30 26 15 35 18 14 37 61 17
5 4 7 3 7 7 7 7 7 4
11 11 5 15 12 11 11 9 12 10
14 15 13 14 16 15 16 14 16 15
0.9 0.9 0.3 0.9 0.3 0.3 0.3 0.3 0.3 0.4
65 63 15 55 47 19 44 50 18 154
Food
Weight Approximate ILE (g) Measure (mg) For greatest accuracy, weigh food on scale that reads in grams. All measures are level. cooked 16 3 Tbsp 12 halves 22 1-1/4 halves 12 sliced 38 1/2 cup + 3 Tbsp 13 Persimmons, Japanese 55 1/3 fruit 14 Pineapple 32 1/2 cup + 2 Tbsp 13 canned, heavy syrup 127 1/2 cup 12 juice, canned 156 5 fl oz 13 Plantain, cooked, sliced 24 7 Tbsp + 1-1/2 tsp 16 Plums purple, canned, light syrup 166 2/3 cup 12 sliced 83 1/2 cup 13 Prunes canned, heavy syrup 22 1/4 cup + 1-1/2 tsp 11 dried cooked 53 1/4 cup 12 uncooked 21 2-1/2 fruits 11 juice, canned 96 3 fl oz 12 Raisins golden 16 1 Tbsp + 2-1/4 tsp 4 regular, seedless 6 2 Tbsp 5 Raspberries canned, heavy syrup 64 1/4 cup 12 frozen, red, sweetened 26 1/4 cup + 1 Tbsp 13 raw 61 1/2 cup 12 Rhubarb, cooked, sweetened 35 1/4 cup + 3 Tbsp 13 Strawberries frozen, sweetened, sliced 34 1/3 cup + 1 Tbsp 12 raw, sliced 28 1/2 cup + 1 Tbsp 12 Tangerines canned, light syrup 26 1/4 cup + 1 Tbsp 9 sections 55 2/3 fruit 9 Watermelon, cubed 32 9 Tbsp + 1-1/2 tsp 18
MET (mg) 5 5 6 3 11 12 13 7 5 5 5 5 5 5 18 19 1 1 1 3 1 1 8 7 6
THR (mg) 11 11 11 17 12 12 13 15 13 13 13 14 12 13 15 16 16 17 17 10 16 16 6 6 26
VAL (mg) 15 14 16 17 16 14 16 20 15 16 15 15 14 14 15 16 15 16 16 16 15 15 15 15 15
Protein Energy (g) (kcal) 0.4 0.4 0.4 0.3 0.4 0.4 0.5 0.6 0.6 0.7 0.6 0.6 0.5 0.6 0.5 0.6 0.5 0.5 0.6 0.4 0.5 0.5 0.4 0.3 0.6 61 57 67 39 47 99 87 84 105 45 69 57 50 68 48 54 58 81 30 121 97 25 48 24 30
VEGETABLES Vegetables are raw unless otherwise noted. Weight of raw vegetables is only for parts that can be eaten. Drain canned, cooked, and frozen fruits before measuring or weighing. Asparagus, fresh or frozen, cooked Bamboo shoots, canned, sliced Beans snap green, canned sprouts, mung, seed attached to sprout yellow wax, canned Beets, cooked greens, chopped red, fresh, canned, sliced Broccoli, fresh or frozen, cooked Brussels sprouts, fresh or frozen, cooked Cabbage Chinese (Pak-choi) cooked, cubed raw, shredded coleslaw red, shredded cooked raw 7 11 7 5 11 9 18 15 16 1-1/3 spears 1/4 cup + 1-1/2 tsp 2 Tbsp + 2 tsp 2 Tbsp + 1 tsp 2 Tbsp 3 Tbsp 1/4 cup + 1 Tbsp 1 Tbsp + 1-1/2 tsp 3/4 sprout 19 17 14 20 14 14 17 17 16 5 6 5 5 5 6 6 5 4 14 17 17 12 16 21 17 14 14 20 21 19 20 19 21 20 20 18 0.5 0.5 0.4 0.5 0.4 0.7 0.6 0.4 0.4 5 4 7 5 7 7 16 4 6
11 10 11 15 11
3 Tbsp 1/3 cup + 4 tsp 1/4 cup + 3/4 tsp 1/4 cup + 2 tsp 7 Tbsp + 1-1/2 tsp
28 25 20 23 23
3 3 6 5 5
16 14 16 16 16
22 19 20 20 19
0.5 0.4 0.4 0.5 0.5
4 4 22 9 9
Food
Weight Approximate ILE (g) Measure (mg) For greatest accuracy, weigh food on scale that reads in grams. All measures are level. white, shredded cooked 49 1/3 cup 24 raw 12 1/2 cup + 1-1/2 tsp 23 Carrots cooked 43 1/4 cup + 1-1/2 tsp 18 sliced 46 1/3 cup + 1-1/2 Tbsp 19 Cauliflower cooked 21 2 Tbsp + 2 tsp 15 raw 6 3 Tbsp 14 Celery, diced cooked 33 10 Tbsp + 1-1/2 tsp 16 raw 26 10 Tbsp + 1-1/2 tsp 16 Chard, Swiss, cooked 6 1 Tbsp + 2 tsp 28 Chives 6 5 Tbsp + 1-1/2 tsp 20 Collards, fresh, cooked, chopped 12 3 Tbsp 16 Cucumber, pared, sliced 39 1 cup + 2 Tbsp 20 Eggplant, cubed cooked 48 1/2 cup 17 raw 12 1/4 cup + 3 Tbsp 17 Endive, shredded 10 1/2 cup + 2 Tbsp 23 Kale, fresh, cooked 6 2 Tbsp + 1 tsp 22 Kohlrabi, cooked, sliced 12 3 Tbsp + 1-1/2 tsp 30 Leeks, diced cooked 22 1/2 cup + 2 Tbsp 18 raw 12 5 Tbsp + 1-1/2 tsp 19 Lettuce, shredded bibb 28 1/2 cup 33 iceberg 28 1/2 cup 21 leaf 28 1/2 cup 24 Romaine 8 1/3 cup + 3 tsp 25 Mushrooms, Agaricus bisporus, sliced cooked or canned 8 1/4 cup + 2 tsp 18 raw 7 1/4 cup + 2 tsp 17 Mustard greens, chopped cooked 7 2 Tbsp + 1-1/2 tsp 18 raw 18 1/3 cup 8 Okra, cooked 8 2 Tbsp + 1 tsp 15 Onions cooked 31 1/4 cup + 3 Tbsp 29 raw, diced 25 7 Tbsp + 1-1/2 tsp 32 rings, canned 30 1-1/3 cups 19 Parsnips, cooked 16 1/4 cup + 1 Tbsp 26 Peas, green green, canned or frozen, cooked 8 2-1/2 tsp 16 pods (edible) cooked 7 2 tsp 13 raw 8 2-1/2 tsp 12 w/ carrots 5 1 Tbsp + 1-1/2 tsp 17 Peppers diced cooked 25 1-1/2 cup + 1 Tbsp 15 raw 18 1/2 cup + 1-1/2 tsp 14 Jalapeo, canned, cooked 20 1/4 cup + 3 Tbsp 16 Pickles dill relish 30 1/3 cup + 3-1/2 tsp 20 whole, small 90 1-1/2 pickles 20 258 Propionic Acidemia/Methylmalonic Acidemia
MET (mg)
THR (mg)
VAL (mg)
5 5 3 3 5 5 4 4 4 5 5 5 4 4 4 3 5 7 6 5 4 5 5 8 8 5 5 5 6 8 7 8 7 1 1 7
16 16 17 17 14 14 14 15 16 18 14 18 14 14 16 16 19 22 23 17 15 17 17 20 19 13 13 14 20 21 13 18 17 8 7 17
20 19 20 20 19 19 20 21 21 21 19 20 21 21 20 20 19 20 20 19 17 20 20 20 20 19 19 20 19 20 19 21 19 21 21 20
0.5 0.5 0.5 0.5 0.4 0.4 0.5 0.5 0.3 0.5 0.4 0.6 0.4 0.4 0.4 0.4 0.6 0.5 0.5 0.4 0.3 0.4 0.4 0.4 0.4 0.5 0.5 0.4 0.8 0.9 0.5 0.6 0.4 0.2 0.2 0.5
10 9 20 20 5 5 15 13 4 4 5 15 13 9 5 6 10 50 22 4 4 5 4 5 5 3 5 7 26 26 109 40 7 3 3 7
6 5 6
18 17 17
20 19 20
0.5 0.5 0.5
14 13 14
50 5
17 17
20 20
0.6 0.6
17 10
Food
Weight Approximate ILE (g) Measure (mg) For greatest accuracy, weigh food on scale that reads in grams. All measures are level. sweet relish 125 1/2 cup 20 sliced 90 3 pieces 20 Pumpkin canned 18 3 Tbsp + 1-1/2 tsp 18 pie mix (no eggs) 17 3 Tbsp 17 Radishes, red, sliced 58 1/2 cup 17 Rutabaga cooked, mashed 15 1/4 cup + 3/4 tsp 21 raw, cubed 14 1/4 cup + 2 tsp 20 Sauerkraut 17 3 Tbsp + 1-1/2 tsp 24 Shallots, raw, chopped 7 2 Tbsp 21 Spinach, chopped fresh or frozen, cooked 4 1 Tbsp 16 raw 4 3 Tbsp + 1-1/2 tsp 18 Squash, summer, all varieties fresh or frozen, cooked 16 1/4 cup + 3/4 tsp 16 sliced 13 1/4 cup + 2 tsp 16 winter, cubed acorn, baked 14 3 Tbsp + 1 tsp 19 butternut, baked 51 1/4 cup 18 Hubbard, baked 10 1/4 cup + 3/4 tsp 18 spaghetti, boiled 77 1/2 cup 18 Tomatoes catsup 10 2 Tbsp 19 juice 137 4 1/2 fl oz 21 paste 8 1 Tbsp + 1-1/2 tsp 18 pure 19 3 Tbsp + 2 tsp 18 sauce w/ onions, green pepper,& celery 24 1/4 cup + 2 tsp 19 stewed, canned 28 5 Tbsp + 3/4 tsp 18 whole, chopped 28 7 Tbsp + 1-1/2 tsp 18 Turnips greens, cooked chopped 9 3 Tbsp 16 w/ turnips, 5 1 Tbsp + 1-1/2 tsp 16 root, diced cooked 29 1/2 cup + 1 Tbsp 26 raw 23 1/2 cup + 1 tsp 24 Vegetable Juice Cocktail (V-8 Juice) 167 5-1/2 fl oz 20 Vegetables, mixed 13 1 Tbsp + 1/2 tsp 19 Watercress, raw 5 1/3 cup + 4 tsp 13
MET (mg)
THR (mg)
VAL (mg)
5 5 7 6 4 4 4 5 5 6 7
18 17 17 16 17 20 19 16 20 14 15
20 20 20 19 19 20 20 20 22 18 20
0.6 0.6 0.6 0.6 0.3 0.5 0.5 0.5 0.5 0.3 0.4
173 131 18 53 10 15 15 10 14 3 3
6 6 6 6 6 5 22 6 5 5 5 7 7
11 11 14 14 14 14 21 23 21 22 21 19 19
20 20 21 20 20 20 19 21 19 19 19 20 19
0.4 0.4 0.5 0.5 0.8 0.5 0.6 1.0 0.9 1.0 0.9 0.8 0.8
10 8 24 21 16 22 33 23 21 23 21 22 16
7 6 8 7 5 5 3
17 15 18 17 23 15 19
21 18 20 20 20 20 19
0.3 0.3 0.6 0.6 1.0 0.4 0.3
5 3 16 18 32 8 2
Soups, Campbell's , Condensed. Weigh or measure before diluting and dilute with water only. Asparagus, Cream of 7 1 Tbsp + 1 tsp 16 7 Beef Broth 20 1 Tbsp + 1 tsp 20 12 Bouillon cubes beef 2 2/3 cube 18 10 chicken 2 1/2 cube 18 9 Celery, Cream of 26 1 Tbsp + 2 tsp 16 6 Chicken Broth 8 1-1/2 tsp 17 9 Cream of 16 1 Tbsp 21 10 Gumbo 21 1 Tbsp + 1 tsp 17 8 Noodle 5 1 Tbsp 19 9 Rice 10 2 tsp 15 8
13 20 17 15 12 14 16 14 16 12
19 22 20 17 19 17 22 19 21 16
0.4 0.5 0.4 0.4 0.3 0.3 0.4 0.4 0.5 0.3
14 3 4 5 19 2 15 9 9 5
Food
Weight Approximate ILE (g) Measure (mg) For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Vegetable 5 1 Tbsp 17 Minestrone 5 1 Tbsp 16 Mushroom, Cream of 24 1 Tbsp + 1-1/2 tsp 18 Onion 26 1 Tbsp + 2 tsp 28 Potato, Cream of 26 1 Tbsp + 2 tsp 16 Scotch Broth 13 2-1/2 tsp 20 Split Pea W/ Ham 6 1 tsp 18 Tomato 13 2 Tbsp + 1-1/2 tsp 18 Tomato Bisque 10 2 Tbsp 19 Tomato Rice 12 2 Tbsp + 1 tsp 18 Vegetable Beef 13 2 Tbsp + 1-1/2 tsp 18 Chunky, Ready To Serve 22 1 Tbsp + 1-1/2 tsp 15 Old Fashioned 23 1 Tbsp + 1-1/2 tsp 19 Vegetarian Vegetable 23 1 Tbsp + 1-1/2 tsp 19
MET (mg) 8 6 7 6 6 9 6 7 7 7 7 3 5 5
THR (mg) 14 13 15 19 13 16 15 16 16 15 16 10 14 14
VAL (mg) 20 22 20 18 19 23 21 21 21 20 21 18 19 19
Protein Energy (g) (kcal) 0.5 0.5 0.4 0.8 0.4 0.5 0.4 0.6 0.6 0.6 0.6 0.3 0.4 0.4 9 10 24 12 15 8 8 27 30 35 27 11 12 14
FREE FOODS A Limit to prescribed number of servings. Beverages Chocolate drink powder (Quik ) Juice apple lemon lime tangerine Lemonade Nectar papaya pear Desserts Apple butter Chocolate pudding mix syrup (Hershey's ) Fruit bars, frozen orange pineapple strawberry Fruit ice Fruit Roll-Ups Fun Fruits Gelatin dessert, prepared pop Marshmallow Marshmallow creme Mocha Mix, frozen chocolate vanilla M&M s, plain Raisins, chocolate covered Sherbet, orange
3 248 92 123 62 508 173 125
1 tsp 8 fl oz 3 fl oz 4 fl oz 2 fl oz 16-1/2 fl oz 5-1/2 fl oz 4 fl oz
3 5 4 4 3 5 3 4
1 0 2 1 1 0 2 1
3 5 5 4 4 5 5 4
5 5 6 5 5 5 5 5
0.1 0.1 0.4 0.3 0.3 0.5 0.3 0.1
11 116 19 26 31 203 98 75
9 5 5 24 37 74 9 14 51 15 22 8 21 6 8 1 1 6
1 Tbsp + 1 tsp 1-1/2 tsp 3/4 tsp 1/3 bar 1/2 bar 1 bar 2 Tbsp + 1 tsp 1 piece 2 pieces 1 Tbsp 1/2 pop 1 marshmallow 1/4 cup + 3 Tbsp 2 tsp 1 Tbsp 1 piece 1 raisin 1-1/2 tsp
4 3 3 2 5 4 3 4 4 3 4 2 4 4 5 3 3 4
1 1 1 2 4 0 2 1 2 2 2 1 3 1 1 1 2 2
4 3 3 2 4 7 2 5 2 4 4 3 3 4 4 2 3 3
5 5 5 4 6 6 5 5 5 6 6 4 5 5 5 3 4 5
0.1 0.1 0.1 0.1 0.1 0.2 0.1 0.2 0.2 0.2 0.3 0.2 0.6 0.1 0.1 0.1 0.1 0.1
49 17 10 23 35 60 36 55 200 9 16 26 198 11 17 4 6 8
Food
Weight Approximate ILE MET THR VAL (g) Measure (mg) (mg) (mg) (mg) For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Sorbet peach 20 1 Tbsp + 1 tsp 3 2 4 5 pineapple 10 2 Tbsp 4 3 4 5 strawberry 15 3 Tbsp 4 0 5 5 Fruits/Fruit Products Apples canned w/ sugar dried cooked, chopped uncooked sauce sweetened w/ sugar unsweetened whole Cranberry sauce w/ sugar Fruit juice bar Guava sauce Pie filling apple cherry peach strawberry
0.1 0.1 0.3
20 29 43
21 4 8 64 61 69 20 52 15 32 13 9 10
1/4 cup + 1 Tbsp 2 Tbsp 1/8 fruit 1/4 cup 1/4 cup 1/2 fruit 3 Tbsp + 1-1/2 tsp 1 bar 3 Tbsp 1/3 cup + 1 Tbsp 2 Tbsp + 1-1/2 tsp 1 Tbsp + 2 tsp 2 Tbsp
5 4 3 5 4 6 4 1 5 4 4 3 4
1 1 1 1 1 1 2 0 1 1 2 2 0
5 4 8 5 4 5 4 3 5 4 4 3 5
5 5 8 5 5 6 5 2 5 5 5 4 5
0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.2 0.1 0.2
43 26 19 48 26 41 91 43 16 107 41 30 34
Miscellaneous Barbecue sauce Butterscotch chips Chocolate frosting Coconut, dried sweetened w/ sugar unsweetened Cornstarch Honey Horseradish Jams and preserves Marmalade
5 2 8 2 1 11 14 1 30 8
1 Tbsp 3 chips 1-1/2 tsp 1-1/2 tsp 1/2 tsp 3 Tbsp + 1-1/2 tsp 2 Tbsp 1-1/2 tsp 1 Tbsp + 1-1/2 tsp 1 Tbsp + 3/4 tsp
6 4 3 3 2 4 4 4 4 3
1 2 1 2 1 2 0 1 0 3
6 3 3 3 2 4 2 3 5 2
6 4 5 5 4 5 4 5 5 5
0.3 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.2 0.1
12 9 32 12 6 114 128 1 81 62
FREE FOODS B These foods contain little or no ILE, MET, THR, or VAL. They may be used as desired if patient is not overweight and if they do not depress appetite for prescribed foods. Beverages Carbonated beverages cola cream soda diet soda, sweetened w/ saccharine Dr Pepper ginger ale grape soda lemon-lime soda orange soda root beer Cranberry juice cocktail Exceed Energy Drink Fruit drink (Hi-C ) Fruit juice drink Gatorade Thirst Quencher Kool-Aid , sweetened w/ sugar 2001 Ross Products Division
123 124 118 123 122 124 123 124 123 127 124 124 124 121 123
4 fl oz 4 fl oz 4 fl oz 4 fl oz 4 fl oz 4 fl oz 4 fl oz 4 fl oz 4 fl oz 4 fl oz 4 fl oz 4 fl oz 4 fl oz 4 fl oz 4 fl oz
0 0 0 0 0 0 0 0 0 1 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0 0 0 4 0 0
0 0 0 0 0 0 0 0 0 1 0 0 3 0 0
0 0 0 0 0 0 0 0 0 1 0 0 3 0 0
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.0 0.0
50 63 0 50 41 53 49 60 50 72 35 58 62 30 49
Food
Weight Approximate ILE MET THR VAL (g) Measure (mg) (mg) (mg) (mg) For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Orange drink powder (Tang ) 16 1/4 cup 1 0 1 1 Strawberry drink powder (Quik ) 3 1 Tbsp 0 0 0 0 Desserts/Sweeteners Candies candy corn gumdrops hard candy jelly beans Jellies Popsicle , twin Pudding lemon, canned (Hunt's ) vanilla mix, dried Tapioca, dry
Protein Energy (g) (kcal) 0.0 0.0 187 33
16 20 15 17 20 128 121 4 10
10 pieces 10 pieces 3 pieces 6 pieces 1 Tbsp 1/2 popsicle 1 container 1 Tbsp 1 Tbsp
0 0 0 0 0 0 0 0 1
0 0 0 0 0 0 0 0 1
0 0 0 0 0 0 0 0 1
0 0 0 0 0 0 0 0 2
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.1
58 69 58 62 54 95 151 40 36
Miscellaneous Frosting strawberry 15 1 Tbsp vanilla 16 1 Tbsp Molasses 7 1 Tbsp Oil, vegetable (except olive) 14 1 Tbsp Richwhip liquid 5 1 Tbsp Salad dressing, oil/vinegar 5 1 Tbsp Shortening 4 1 Tbsp Sugar brown 14 1 Tbsp powdered 3 1 Tbsp table 12 1 Tbsp Syrup corn 20 1 Tbsp maple 20 1 Tbsp table 7 1 Tbsp 1 See Appendix 12, p A-11, for Nutrient Composition of very low protein foods.
0 0 0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0 0 0 0
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
69 69 48 120 40 70 113 52 31 48 58 50 50
TABLE 13-5. Propionic Acidemia or Methylmalonic Acidemia Clinical Summary Sheet Name: Date of Birth: __________/__________/__________
Mo Day Year
Hospital Number: Age at Diagnosis: ____

Laboratory Data
ILE
1
Date
Age
Physical Data
Length/ Height (cm) Weight (kg) Head Circum (cm) MET
1

Hct Trans-thyretin ILE (mg/dL) (%) (mg) MET (mg) THR (mg) VAL (mg) Protein Energy (g) (kcal)
THR
VAL
GLY
(mo/d/yr) (yrs/mo)
Free Organic Ferritin Hgb Carnitine Acids (mol/L) (ng/mL) (g/dL)
1 Indicate if mol/L or mg/dL.
REFERENCES
1. Acosta PB: The contribution of therapy of inherited amino acid disorders to knowledge of amino acid requirements. In Wapnir RA (ed): Congenital Metabolic Diseases: Diagnosis and Treatment. New York: Marcel Dekker Inc, 1985, 115-135. Al-Essa M, Rahbeeni Z, Jumaah S, et al: Infectious complications of propionic acidemia in Saudi Arabia. Clin Genet 1998;54:90-94. Arnold GL, Vladutiu CJ, Kirby RS: Protein insufficiency and impaired growth in children with PKU. J Inher Metab Dis 2000;23 Suppl 1:29A. Baumgartner ER, Viardot C: Long-term follow up of 77 patients with isolated methylmalonic acidaemia. J Inher Metab Dis 1995;18:138-142. Behrman RE, Kleigman RM, Arvin AA (eds): Nelson Textbook of Pediatrics, ed 15. Philadelphia: WB Saunders Co, 1996. Burlina AB, Dionisi-Vici C, Piovan S, et al: Acute pancreatitis in propionic acidaemia. J Inher Metab Dis 1995;18:169-172. Chalmers RA, Stacey TE, Tracey BM, de Sousa D C: L-carnitine insufficiency in disorders of organic acid metabolism. Response to L-carnitine by patients with methylmalonic acidemia and 3-hydroxy-3-methylglutaric acidemia. J Inher Metab Dis 1984;7 (Suppl 2):109-110. Ciani F, Poggi GM, Pasquini E, et al: Prolonged exclusive breast-feeding from vegan mothers causing an acute onset of isolated methylmalonic aciduria due to mild mutase deficiency. Clin Nutr 2000;19:137-139. Coude FX, Ogier H, Grimber G, et al: Correlation between blood ammonia concentration and organic acid accumulation in isovaleric and propionic acidemia. Pediatrics 1982;69:115-117. Dechaux M, Touati G, Vargas-Poussou R, et al: Renal function and follow-up in children with methylmalonic acidemia. J Inher Metab Dis 2000;23 (Suppl 1):97 (Abs). DeRaeve L, De-Meirleir L, Ramet J, et al: Acrodermatitis enteropathica-like cutaneous lesions in organic acidemia. J Pediatr 1994;124:416-420. Elsas LJ, Acosta PB: Nutrition support of inherited metabolic diseases. In Shils ME, et al (eds): Modern Nutrition in Health and Disease, ed 9. Baltimore: Williams & Wilkins, 1999, pp 1003-1059. Fenton WA, Gravel RA, Rosenblatt DS: Disorders of propionate and methylmalonate metabolism. In Scriver CR, et al (eds): The Metabolic and Molecular Bases of Inherited Disease, ed 8. New York: McGraw-Hill Medical Publishing Division, 2001, pp 2165-2194. Food and Nutrition Board, Committee on Dietary Allowances: Recommended Dietary Allowances, eds 9 and 10. Washington, DC: National Academy of Sciences, 1980 and 1989. Gropper S, Acosta PB: Effect of simultaneous ingestion of L-amino acids and whole protein on plasma amino acid concentrations. JPEN 1991;15:48-53. Haas RH, Marsden DL, Capistrano-Estrada S, et al: Acute basal ganglia infarction in propionic acidemia. J Child Neurol 1995;10:18-22. Hamilton RL, Haas RH, Nyhan WL, et al: Neuropathy of propionic acidemia: A report of two patients with basal ganglia lesions. J Child Neurol 1995;10:25-30. Henriquez H, el-Din A, Ozand PT: Emerging presentations of patients with methylmalonic acidemia, propionic acidemia and branched-chain amino acidemia (MSUD). Brain Development 1994;16:86-93. Herrmann ME, Broesicke HG, Keller M, et al: Dependence of the utilization of a phenylalanine-free amino acid mixture and different amounts of single dose ingested. A case report. Eur Pediatr 1994;153:501-503. Inoue S, Kreiger I, Sarnaik A, et al: Inhibition of bone marrow stem cell growth in vitro by methylmalonic acid: A mechanism for pancytopenia in a patient with methylmalonic acidemia. Pediatr Res 1981;15:95-98. Jones BJM, Lees R, Andrews J, et al: Comparison of an elemental and polymeric enteral diet in patients with normal gastrointestinal function. Gut 1983;24:78-84. Kahler SG, Millington DS, Cederbaum SD, et al: Parenteral nutrition in propionic and methylmalonic acidemia. J Pediatr 1989;115:235-241. Kahler SG, Sherwood WG, Woolf D, et al: Pancreatitis in patients with organic acidemias. J Pediatr 1994;124:239-243. Kalloghlian A, Gleispach H, Ozand PT: A patient with propionic acidemia managed by continuous insulin infusion and total parenteral nutrition. J Child Neurol 1992;7 (Suppl):S88-S91. Leonard JV: The management and outcome of propionic and methylmalonic acidemia. J Inher Metab Dis 1995;18:430-434. MacLean W, Graham G: Pediatric Nutrition in Clinical Practice. Menlo Park, Calif: Addison-Wesley Publishing Co, 1982. Martin SB, Acosta PB: Osmotic behaviors of components of chemically-defined formulas. J Pediatr Perinat Nutr 1987;1:1-17. Massoud AF, Leonard JV: Cardiomyopathy in propionic acidaemia. Eur J Pediatr 1993;152:441-445. Mellon AP, Deshpande SA, Mathers JC, Bartlett K: Effect of oral antibiotics on intestinal production of propionic acid. Arch Dis Child 2000;82:169-172.
2. 3. 4. 5. 6. 7.
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30. North KN, Korson MS, Gopal YR, et al: Neonatal onset propionic acidemia: Neurologic and developmental profiles, and implications for management. J Pediatr 1995;126;916-922. 31. Ogier de Baulny H, Saudubray JM: Branched-chain-organic aciduria. In Fernandes J, et al (eds): Inborn Metabolic Diseases. Diagnosis and Treatment ed 3. New York: Springer-Verlag, 2000, pp 196-212. 32. Ohkohchi N, Andoh T, Ohi R, Mori S: Defined formula diets alter characteristics of the intestinal transport of amino acids and peptides in growing rats. J Pediatr Gastroenterol Nutr 1990;10:490-496. 33. Petrowski S, Nyhan WL, Reznik V, et al: Pharmacologic amino acid acylation in the acute hyperammonemia of propionic acidemia. J Neurogenet 1987;4:87-96. 34. Posati LP, Orr ML: Composition of Foods: Dairy and Egg Products, Agriculture Handbook No. 8-1. Washington, DC: US Dept of Agriculture, Agricultural Research Service, 1976. 35. Praphanphoj V, Brusilow S, Hamosh A, Geraghy MA: The use of intravenous sodium benzoate and sodium phenylacetate in propionic acidemia with hyperammonemia. J Inher Metab Dis 2000;23 (Suppl 1):91 (Abs). 36. Pratt EL, Snyderman SE, Cheung MW, et al: The threonine requirement of the normal infant. J Nutr 1955;56:231-251. 37. Raby RB, Ward JC, Herrod HG: Propionic acidaemia and immunodeficiency. J Inher Metab Dis 1994;17:250-251. 38. Rose WC, Wixon RL, Lockhart HB, Lambert GF: The amino acid requirements of man. XV. The valine requirements: Summary and final observations. J Biol Chem 1955;217:987-995. 39. Roth B, Younossi-Hartenstein A, Skopnik H, et al: Hemodialysis for metabolic decompensation in propionic acidaemia. J Inher Metab Dis 1987;10:147. 40. Rutledge SL, Geraghty M, Mroczek E, et al: Tubulointerstitial nephritis in methylmalonic acidemia. Pediatr Nephrol 1993;7:81-82. 41. Saudubray JM, Touati G, Delonlay P, et al: Liver transplantation in propionic acidemia. Eur J Pediatr 1999;158 (Suppl 2: S65-S69). 42. Sbai D, Narcy C, Thompson GN, et al: Contribution of odd-chain-fatty acid oxidation to propionate production in disorders of propionate metabolism. Am J Clin Nutr 1994;59:1332-1337. 43. Schoeffer A, Herrmann ME, Broesicke GH, Moench E: Effect of dosage and timing of amino acid mixtures on nitrogen retention in patients with phenylketonuria. J Nutr Med 1994;4:415-418. 44. Sequeira JSS, Dixon MA, Leonard JV: Growth in disorders of propionate metabolism. J Inher Metab Dis 1996;19 (Suppl):44 (Abs). 45. Shafai T, Sweetman L, Weyler W, et al: Propionic acidemia with severe hyperammonemia and defective glycine metabolism. J Pediatr 1978;92:84-86. 46. Shapiro LJ, Bocian ME, Raijam L, et al: Methylmalonyl-CoA mutase deficiency associated with severe neonatal hyperammonemia activity of urea cycle enzymes. J Pediatr 1978;92:986-988. 47. Smith CA, Nelson NM: The Physiology of the Newborn Infant, ed 4. Springfield, Ill: Charles C Thomas Publisher, 1976. 48. Smith JL, Arteaga C, Heymsfield SB: Increased ureagenesis and impaired nitrogen use during infusion of a synthetic amino acid formula - A controlled trial. N Engl J Med 1982;306:1013-1018. 49. Smith JL, Heymsfield SB: Enteral nutrition support: Formula preparation from modular ingredients. JPEN 1983;7:280-288. 50. Snyderman SE, Boyer A, Norton PM, et al: The essential amino acid requirements of infants: IX. Isoleucine. Am J Clin Nutr 1964;15:313-321. 51. Snyderman SE, Boyer A, Norton PM, et al: The essential amino acid requirements of infants. X. Methionine. Am J Clin Nutr 1964;15:322-330. 52. Snyderman SE, Holt LE, Smellie F, et al: The essential amino acid requirements of infants: Valine. Am J Dis Child 1959;97:186-191. 53. Snyderman SE, Holt LE, Norton PM, et al: The plasma aminogram. I. Influence of the level of protein intake and a comparison of whole protein and amino acid diets. Pediatr Res 1968;2:131-144. 54. Spika JS, Shaffer N, Hargrett-Bean N, et al: Risk factors for infant botulism in the United States. Am J Dis Child 1989;143:828-832. 55. Stork LC, Ambruso DR, Wallner SF, et al: Pancytopenia in propionic acidemia: Hematologic evaluation and studies of hematopoiesis in vitro. Pediatr Res 1986;20:783-788. 56. Stumpf DA, Parker WD, Engelini C: Carnitine deficiency, organic acidemias and Reye's syndrome. Neurology 1985;35:1041-1045. 57. Sugiyama N, Matsuda I, Wada Y, et al: Urinary propionylcarnitine analysis for monitoring carnitine supplementation in inherited disorders of propionate metabolism. J Inher Metab Dis 1994;17:611-615. 58. Thompson GN, Bresson JL, Bonnefont JP, et al: A simple isotopic technique for assessing vitamin responsiveness in vivo in propionic acidaemia. J Inher Metab Dis 1990;13:3413-351. 59. Thompson GN, Walter JH, Bresson JL: Sources of propionate in inborn errors of metabolism. Metabolism 1990;39:1133-1137. 60. Thompson GN, Chalmers RA: Increased urinary metabolic excretion during fasting in disorders of propionate metabolism. Pediatr Res 1990;27:413-416. 61. Tietz NW (ed): Textbook of Clinical Chemistry. Philadelphia: WB Saunders Company, 1986.
62. Tornqvist K, Tornqvist H: Corneal deepithelialization caused by acute deficiency of isoleucine during treatment of a patient with maple syrup urine disease. Acta Ophthalmol Scand 1996;74 (Suppl 219):48-49. 63. van Calcar SC, Harding CO, Davidson SR, et al: Case reports of successful pregnancy in women with maple syrup urine disease and propionic acidemia. Am J Med Genet 1992;44:641-646. 64. van der Meer SB, Poggi F, Spada M, et al: Clinical outcome and long term management of 17 patients with propionic acidemia. Eur J Pediatr 1996;155:205-210. 65. van't Hoff W, McKiernan PJ, Surtees RAH, Leonard JV: Liver transplantation for methylmalonic acidemia. Eur J Pediatr 1999;158 (Suppl 2):S70-S74. 66. van't Hoff WG, Dixon M, Taylor J, et al: Combined liver-kidney transplantation in methylmalonic acidemia. J Pediatr 1998;132;1043-1044. 67. Wannemacher RW: Key role of various individual amino acids in host response to infection. Am J Clin Nutr 1977;30:1269-1280. 68. Wendel U, Eibler A, Speir W, Schadewaldt P: On the differences between urinary metabolite excretion and oddnumbered fatty acid production in propionic and methylmalonic acidaemias. J Inher Metab Dis 1995;18:584-591. 69. Wolf B: Reassessment of biotin-responsiveness in "unresponsive" propionyl-CoA carboxylase deficiency. J Pediatr 1980;97:964-966. 70. Worthen HG, Ashwal AA, Ozand PT, et al: Comparative frequency and severity of hypoglycemia in selected organic acidemias, branched-chain amino acidemia, and disorders of fructose metabolism. Brain Dev 1994;16 (Suppl);81-85. 71. Yannicelli S: Nutrition support of methylmalonic acidemia. Metabolic Currents. 1988;1:10-13. 72. Young VR, Tontisirin K, Ozalp I, et al: Plasma amino acid response curve and amino acid requirements in young men: Valine and lysine. J Nutr 1972;102:1513-1170.
PROTOCOL 14 Galactosemia Nutrition Support of Infants, Children, and Adults With ISOMIL Soy Formula Powder With Iron
I. Introduction
Galactosemia is an inherited disorder of galactose (GAL) metabolism that results from a defect in one of three enzymes: galactokinase, GAL-1-phosphate uridyltransferase (GALT), and uridine diphosphate (UDP)-GAL-4-epimerase (Figure M). The most common form of galactosemia results from a defect in GALT activity. Its estimated incidence is 1/40,000 to 1/80,00 live births. Patients with GALT deficiency appear normal at birth, but soon develop severe hepatic, renal, and gastrointestinal manifestations which, if not treated, lead to death (36, 37, 71). Symptoms may include cataracts, diarrhea, E coli sepsis, failure to thrive, jaundice, vomiting, and increased intracranial pressure. Patients with galactokinase deficiency present with cataracts secondary to accumulation of galactitol in eye lenses (70). Galactonate accumulates in erythrocytes of patients with GALT deficiency and, if cellular redox potential is altered, may contribute to GAL toxicity (8, 80). Removal of dietary lactose and GAL is essential to prevent further metabolic crises in patients with GALT deficiency. Rapid screening, retrieval, diagnosis, and treatment are essential to prevent clinical manifestations. Galactosemia due to a deficiency in GALT leads to an accumulation of GAL-1-phosphate (GAL-1-P) and galactitol in erythrocytes, liver, kidney, brain, and other tissues (17, 70). Additional laboratory findings include albuminuria, hypophosphatemia, hypokalemia, and hyperaminoaciduria. Reasons for symptoms associated with GALT deficiency are not well defined but may be due to involvement of GAL-1-P in a futile phosphorylation cycle and reduced ATP, CTP, and GTP. Other proposed hypotheses include defective GAL incorporation into galactosylated compounds (14, 62, 66, 75).
Galactitol
Reductase
Galactose
Oxidase
Galactonate
ATP Galactokinase ADP P~P UDP - Galactose UTP Galactose-1-P* Pyrophosphorylase UDP - glucose Epimerase UDP - galactose GALT
Site of enzyme defects that lead to galactosemia * Accumulates in untreated galactosemia
Glucose-1-P
Glycolytic pathway
Figure M. Metabolism of GAL in galactosemia

If untreated, patients with GALT deficiency usually die of overwhelming sepsis (48). Early intervention with a GAL-restricted diet is successful in preventing death and reducing the risk for cataracts. For years, clinicians considered that patients who were diagnosed and treated early would develop normally.
2001 Ross Products Division Galactosemia 267
Komrower and Lee (44) in 1970 first reported neurologic impairment in early treated patients with galactosemia. Subsequent studies suggest that management has resulted in suboptimal clinical outcomes (22, 43). A report by Waggoner and coworkers based on survey data, presented the outcome of 350 children and adults with GALT deficiency (76). The patients showed a decline in IQ with age, delayed and deficient speech development (76), and stunted growth, especially in females. Surprisingly, no correlation was found between reduced IQ, age at onset of therapy or erythrocyte GAL-1-P concentrations. Hypogonadotropic hypogonadism and infertility have been reported in most females with galactosemia (40). Hypogonadism with reduced calcium intake results in reduced bone density in prepubertal and postpubertal patients. Calcium intake correlated positively with bone density (41). Multiple mutations in the GALT gene have been identified (21). Patients with the Q188R mutation, prevalent among Caucasians, have poorer outcomes than patients with the S135L mutation, which is common in African-American patients with galactosemia (45). Despite the apparent correlation between genotype and phenotype, genotype alone has not answered all the questions regarding outcome (15, 21, 42, 72). Several theories have been proposed to explain the poor outcomes in patients with galactosemia. These theories include fetal damage in utero, damage before nutrition intervention, over-restriction or inadequate restriction of dietary GAL, de novo GAL synthesis (7), and a deficiency of UDP-GAL (17, 51, 58). More questions than answers regarding optimal treatment to alleviate the clinical manifestations associated with GALT deficiency still abound. Further research may lead to modifications in nutrition support. Oral uridine therapy has not been beneficial despite normalization of erythrocyte UDP-GAL concentrations (51, 59).

A. The Defect 1. Galactosemia may result from defect in any 1 of 3 enzymes: a. Galactokinase. b. GALT. c. UDP-GAL-4-epimerase (37). B. Screening 1. A positive result on newborn galactosemia screening requires differential diagnosis. 2. Because not all states screen for galactosemia, infants with the following clinical findings should be evaluated for galactosemia (9, 19, 37, 71): a. Prolonged jaundice. b. Vomiting and/or diarrhea. c. Failure to thrive. d. Hepatomegaly. e. Sepsis caused by E coli. f. Cataracts. 3. Infants with abnormal results on newborn screening and/or above signs and symptoms should be switched to lactose-free infant formula such as Isomil powder. C. Differential Diagnosis 1. Differential diagnosis will reveal false-positives and identify specific enzyme defect. 2. Therapy depends on enzyme defect and residual enzyme activity present. 3. This protocol addresses nutrition support for patients with galactokinase and GALT deficiencies.

A. Correct Primary Imbalance in Metabolic Relationships 1. Remove or restrict dietary GAL to lowest amount compatible with nutritionally adequate diet. B. Chronic GAL Toxicity Theory 1. Of theories regarding poor outcomes in patients with GALT deficiency, chronic GAL toxicity has recently been supported by finding arabinogalactans, galactans (-1-4-linkages), galactolipids, and galactoproteins in cereals, fruits, legumes, nuts, and vegetables (1, 2, 5, 11,
268 Galactosemia 2001 Ross Products Division
12, 16, 18, 25-27, 47, 49, 52-54, 56, 64, 68, 69, 74, 79, 81) and free GAL in fruits, legumes, seeds, and vegetables (1, 13, 28-35, 39, 55, 61, 67). 2. Enzymes in intestinal juices and from the pancreas are capable of digesting several forms of GAL in -1-4 linkage (3, 4)

A. Growth, Development, and Nutrition Status 1. Support normal growth rate in infants and children and maintain appropriate weight for height in adults. 2. Support normal development (20, 37, 71, 72). 3. Maintain normal nutrition status. a. Prevent catabolism. 4. Maintain adequate hydration. B. Galactokinase Deficiency 1. Maintain blood and urine free of GAL and galactitol. 2. Prevent cataracts. C. GALT Deficiency and Variants With < 35% Enzyme Activity (65) 1. Maintain 2 to 4 hour postprandial erythrocyte (RBC) GAL-1-P concentration < 2 mg/dL (17) or < 20 g/g hemoglobin (65). 2. Attempt to reduce blood and urine galactitol to acceptable concentrations (63, 82). a. Urinary galactitol does not always correlate with RBC GAL-1-P concentration (70). 3. Prevent mental retardation and abnormal speech (76, 77). 4. Prevent neurologic deterioration (10, 24, 50, 57, 70). 5. Reduce risk of ovarian failure in women (40).

A. GAL 1. Remove foods and do not use drugs (45) containing free GAL, lactose, and bound GAL that may be released by - and -galactosidases. B. Protein 1. Recommended protein intakes are same as for normal infants, children, and adults (Table 14-1, p 269). C. Energy 1. Recommended energy intakes are same as for normal infants, children, and adults (Table 14-1, p 269). 2. Intakes should be sufficient to maintain normal weight gain for infants and children and maintain appropriate weight for height for adults. D. Fluid 1. Prescribe amount that will supply water requirements (Table 14-1, p 269). Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL fluid to children and adults for each kcal ingested. 2. Requirements may be higher than recommended secondary to accompanying fever.

A. GAL 1. See Table 14-2, p 270, for foods allowed, foods excluded, and foods that may be limited. a. For more information on nutrient content of beikost (baby foods), contact the following manufacturers:
Beech-Nut Nutrition Corporation 100 S 4th Street St Louis, MO 63102 1-800-233-2468 Gerber Products Company c/o Consumer Affairs 445 State Street Fremont, MI 49413-0001 1-800-443-7237 Heinz North America Consumer Affairs USX Tower 600 Grant Street, 7th Floor Pittsburgh, PA 15219 1-800-872-2229
Galactosemia 269
b. Up-to-date lists of product ingredients are necessary to determine which foods may be included since ingredients change often. c. Exclude foods containing one or more ingredients excluded in Table 14-2, p 270. B. Protein 1. Calculate amount of Isomil Soy Formula With Iron powder, beikost, or table foods (Table 14-3, p 274) required to fill protein prescription. a. Protein intakes up to 2.0 times greater than Recommended Dietary Allowances (RDAs) (23) are not cause for concern if liver function is normal. Warning: ALL LIQUID SOY PROTEIN ISOLATE INFANT FORMULAS MANUFACTURED IN THE US CONTAIN CARRAGEENAN WHICH CONTAINS 27% GAL. 2. Add beikost or table foods to provide variety in taste, color, and texture after infant is 3 to 4 months old or is developmentally ready (Table 14-3, p 274). C. Energy 1. Calculate energy provided by Isomil powder, beikost, or table foods (Table 14-3, p 274) required to fill protein prescription. 2. If energy prescription is not met, increase number of food servings or increase volume or concentration of Isomil. 3. Isomil may be concentrated to 24 or 27 kcal/fl oz if additional energy is required and volume cannot be increased. 4. To make formula with 24 or 27 kcal fl oz from Isomil powder, follow the directions below: Isomil Powder Add Water to Make (g) (scoops) 24 kcal/fl oz 157 18 1 L (34 fl oz) 27 kcal/fl oz 177 20 1 L (34 fl oz) D. Fluid 1. Mix Isomil powder according to label directions to obtain a formula that provides 20 kcal/fl oz. 2. Offer infants additional fluid ad libitum between Isomil feeds if > 20 kcal/fl oz is used. E. Diet Guide 1. Provide parents, caretakers, or patient with completed Diet Guide (Appendix 22, p A-24) with each diet change.

A. Nutrient Adequacy 1. Determine if diet provides nutrients in amounts prescribed in Section VI, Establish Prescription, p 264. 2. Check diet to determine if it supplies Recommended Daily Nutrient Intakes of protein and energy (Table 14-1, p 269). 3. Check diet to determine if it supplies Recommended Dietary Intakes (RDIs) for minerals and vitamins (Appendices 12 and 13, pp A-11 and A-14). a. See Appendix 5, p A-5, for composition of Isomil. b. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. c. If diet provides < 100% of RDIs for infants and < 75% for children and adults, supplement diet with needed minerals and vitamins if not provided by beikost or table foods and laboratory tests indicate need (Appendix 11, p A-10, for composition of supplements). Warning: Calcium supplements are often required by children and adults with galactosemia (60, 73). B. Osmolarity 1. If concentration of prescribed medical food mixture is > 24 kcal/fl oz, determine if osmolarity is in acceptable range. a. Determine osmolarity by laboratory analysis or use mathematical formula given in Appendix 18, p A-20. b. Osmolarity per gram of Isomil powder is listed in Appendix 19, p A-21.
2. If osmolarity is > 450 mosm/L for neonates, > 750 mosm/L for children, > 1,000 mosm/L for adults, or greater than tolerated by patient, increase water content of prescribed medical food mixture and recalculate its osmolarity. C. Potential Renal Solute Load 1. Dehydration will result if renal solute load is greater than renal-concentrating ability of patient. 2. If concentration of medical food mixture prescribed is > 24 kcal/fl oz, estimate its potential renal solute load. a. This step is important to prevent dehydration of infants who may have renal-concentrating capacity as low as 600 mosm/L. b. Upper limit of renal solute load for neonates is approximately 1,100 mosm/L. 3. A method for estimating potential renal solute load is given in Appendix 20, p A-22. 4. If potential renal solute load is excessive, increase water content of medical food mixture and recalculate.

A. Galactokinase Deficiency 1. Evaluate urine GAL and galactitol concentrations weekly until patient is 6 months old, every 2 weeks until patient is 1 year old, and monthly thereafter if concentrations remain elevated. a. If GAL or galactitol is present in unacceptable concentrations (urine GAL > 140 mmol/mol creatinine; urine galactitol > 31 mmol/mol creatinine) (62, 81) obtain diet history and review diet records for use of excluded or limited foods (Table 14-2, p 270). 1) If excluded foods have been used, instruct parents or patients to remove them from diet. 2) If GAL or galactitol is still present after removal of excluded foods from diet, instruct parents or patients to remove limited foods. 3) Call food and drug manufacturers to determine if any processed foods or drugs used contain added GAL or lactose. B. GALT Deficiency 1. Evaluate blood for GAL and erythrocyte GAL-1-P concentrations weekly until patient is 6 months old, every 2 weeks until patient is 1 year old, and monthly thereafter. a. If erythrocyte GAL-1-P is > 2 mg/dL or 20 g/g hemoglobin, obtain diet history and review diet records for use of excluded or limited foods (Table 14-2, p 270). 1) If excluded foods have been used, instruct parents or patients to remove them from diet. 2) If GAL is still present or erythrocyte GAL-1-P is still elevated after removal of excluded foods from diet, instruct parents or patients to remove limited foods. 3) Call food and drug manufacturers to determine if any processed foods or drugs used contain added GAL or lactose. 2. Evaluate urine GAL and galactitol concentrations at same time erythrocyte GAL-1-P concentration is evaluated. C. Galactokinase and GALT Deficiencies 1. Protein status. a. Evaluate plasma albumin concentration every 6 months until patient is 1 year old and yearly thereafter (Appendix 17, p A-18, for standards). b. If plasma albumin concentration is below standard: 1) Increase prescribed amount of protein by 5% to 10% and reevaluate plasma albumin concentration in 1 month. 2) If plasma albumin concentration remains below standard, repeat above process until value is in normal range. 2. Iron status. a. Plasma ferritin concentration. 1) Evaluate at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17, p A-18, for standards). 2) If plasma ferritin concentration is below standard: i. Increase iron intake to 2 mg/kg with supplements (ferrous sulfate).
ii. Evaluate plasma ferritin concentration monthly on increased iron intake. iii. Continue iron supplements until plasma ferritin concentration is in normal range. b. Complete blood count. 1) Evaluate hemoglobin and hematocrit concentrations at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17, p A-18, for standards). 3. Growth status. a. Length/height and weight. 1) Measure monthly to 1 year, every 3 months to 4 years, and every 6 months thereafter. Plot measurements on NCHS growth charts. 2) Maintain length/height and weight between 10th and 90th percentiles. Some normal infants, children, and adults will fall above or below these percentiles. 3) If length/height or weight falls below usual growth channel: i. Increase prescribed protein and energy by 5% to 10% and remeasure in 1 month. ii. If length/height or weight remains low, repeat above process until usual growth channel is achieved. 4. Nutrient intake. a. Maintain records of food intake for 3 days immediately before each blood test (Appendices 24 and 25, pp A-26 and A-27). b. Evaluate intakes of protein and energy before each blood test. c. Evaluate mineral and vitamin intakes after each diet change. 1) Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. 2) See Appendix 28, p A-29, for information about ordering software for diet evaluation. 3) If supplements are recommended, contact manufacturer for confirmation that supplements are lactose- and GAL-free. Warning: Serum calcium does not reflect dietary calcium intake. DO NOT use Neocalglucon as calcium supplement since it contains GAL (33). 5. Clinical summary. a. A summary record of growth, laboratory, and nutrient intake data is useful for patient management (Table 14-4, p 275).
A. Example 1 Establish and fill prescription for newborn who weighs 3.5 kg using Recommended Daily Nutrient Intakes from Table 14-1, p 269, and average nutrient contents from Table 14-3, p 274. 1. Establish prescription.
Protein Energy Fluid 3.0 g/kg 120 kcal/kg 150 mL/kg x x x 3.5 kg 3.5 kg 3.5 kg = = = 10.5 g 420 kcal 530 mL
Medical Food Mixture Isomil powder mixed to 20 kcal/fl oz Measure 618 mL (21 fl oz) 10.2 Protein (g) 420 Energy (kcal)
Total per day Total per kg
10.2 2.9
420 120

A. Rationale 1. In normal persons, febrile illness and trauma are accompanied by catabolism of body protein (78).
2. Well-nourished patients with galactosemia respond to infection and trauma as do normal persons . B. Objectives of Nutrition Support 1. Maintain hydration and electrolyte balance. a. Offer infants and toddlers Pedialyte Oral Electrolyte Maintenance Solution ad libitum (Appendix 9, p A-9). 2. Depress catabolism. a. Enhance energy intake when possible by offering fruit juices ad libitum as tolerated; liquid Jell-O ; Polycose Glucose Polymers powder or liquid (Appendix 9, p A-9), or Pro-Phree Protein-Free Energy Module With Iron, Vitamins & Minerals (Appendix 11, p A-10) added to fruit juices or Pedialyte if tolerated and caffeine-free soft drinks (not diet drinks). b. Return patients to Isomil as rapidly as possible. 1) Begin with 1/2 original strength of Isomil formula. 2) Increase to original strength as tolerated.
XII. Prescription and Over-The-Counter Medications

A. Contact a local pharmacist or drug manufacturer for current information on excipients in drugs that may contain GAL (44). Warning: Neocalglucon, a liquid calcium supplement available only by prescription, contains GAL and should not be used (33). 1. Most tablets of estrogen contain GAL. 2. Lactulose also contains GAL.
Galactosemia 273
TABLE 14-1. Recommended Daily Nutrient Intakes (Ranges) for Infants, Children, and Adults With Galactosemia
Age Protein (g/kg) Infants 0 to < 3 mo 3 to < 6 mo 6 to < 9 mo 9 to < 12 mo
1
Nutrient Energy1 (kcal/kg) 120 (145 115 (145 110 (135 105 (135 - 95) - 95) - 80) - 80) Fluid2 (mL/kg) 150 - 125 160 - 130 145 - 125 135 - 120 (mL/day) 900 - 1,800 1,300 - 2,300 1,650 - 3,300
3.50 - 3.00 3.50 - 3.00 3.00 - 2.50 3.00 - 2.50 (g/day)
(kcal/day) 1,300 ( 900 - 1800) 1,700 (1300 - 2300) 2,400 (1650 - 3300)
Girls and Boys 1 to < 4 yr 4 to < 7 yr 7 to < 11 yr Women 11 to < 15 yr 15 to < 19 yr 19 yr Men 11 to < 15 yr 15 to < 19 yr
1
30.0 35.0 40.0
50.0 50.0 50.0
2,200 (1500 - 3000) 2,100 (1200 - 3000) 2,100 (1400 - 2500)
1,500 - 3,000 1,200 - 3,000 1,400 - 2,500
55.0 65.0
2,700 (2000 - 3700) 2,800 (2100 - 3900) 2,900 (2000 - 3300)
2,000 - 3,700 2,100 - 3,900 2,000 - 3,300
19 yr 65.0 Modified from reference 23. 2 Modified from reference 6. Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL fluid to children and adults for each kcal ingested.
274 Galactosemia
TABLE 14-2. Galactose-Restricted Diet: Foods Allowed, Limited and Excluded for Children and Adults With Galactosemia Where Available, mg of Free GAL are Given in Parentheses after Food. Foods Allowed Contain < 5 mg GAL/100 g, Foods Limited 5 < 20 mg/100 g, and Foods Excluded 20 mg/100 g.
FOODS ALLOWED (mg GAL 100/g) BEVERAGES
Carbonated drinks Drinks that do not contain lactose Fruit drinks that do not contain apple, banana, orange, papaya, pineapple and/or pear juices Health Source Soy Protein Shake Isomil , Soy Formula With Iron (powder) Non-dairy creamer with approved ingredients Tea Apple juice Beer Champagne Orange juice Pear juice 14 11 12 19 7 Buttermilk, coffee Drinks that contain whole milk, skim milk, nonfat dried milk, and/or evaporated or condensed milk Drinks containing calcium caseinate or sodium caseinate Hot chocolate Imitation or filled milks Kefir, Ovaltine , and malted milk Milk, untreated of any species Milk treated with Lactobacillus acidophilus culture or lactase (Lactaid ) Papaya juice Powdered soft drinks with lactose Soy milk containing carrageenan Soy milk made with soy flour Watermelon juice Wine
FOODS THAT MAY BE LIMITED (mg GAL/100 g)
FOODS EXCLUDED (mg GAL/100 g)
46 24
BREADS AND CEREALS

Breads, crackers, and rolls made with no milk or milk products Most bagels Italian and French bread Some cooked and prepared cereals (read labels) Contact bakeries in your area for the names of milk-free breads. Cornflakes 6 Biscuit, muffin, pancake, and waffle mixes containing milk Some dry cereals (read labels carefully for milk and/or milk products) Instant Cream of Wheat English muffins containing milk French toast made with milk Zwieback containing milk
CHEESE/OTHER MILK PRODUCTS

None All cheeses Mozzarella cheese > 700 Cream Curds, whey, whey solids Lactalbumin, lactoglobulin Sour cream Soy cheeses containing calcium caseinate or sodium caseinate
DESSERTS
Angel food cake Cakes, cookies, & pies made from allowed ingredients Gelatin Ice cream or puddings made with water or soy protein isolate formula Water and fruit ices made from allowable fruits Pie crust made with lard or shortening Popsicles Pudding mixes without milk Sorbets made with allowed fruits Any dessert containing chocolate Any dessert containing a questionable food Banana bread Chocolate syrup 23 Cocoa Commercially baked cakes, cookies & pies Custard Fig Newtons Ice cream made with milk Packaged cake, pie, or cookie mixes 22 containing milk or milk products Persimmon cookies Pie crust made with butter or margarine Puddings made with milk Sherbet
Galactosemia 275
FOODS ALLOWED (mg GAL 100/g) EGGS

Egg Egg Beaters <5
Omelets, souffls, and other dishes with added milk
FATS
Animal fat Bacon Margarines without milk or soy in any form Mayonnaise Nondairy coffee creamers free of milk products or soy products Oils, vegetable shortening Butter Cream Sour cream Whipping cream 30
FRUITS/JUICES
Avocado Cherries Fruit cocktail Grapefruit, raw or juice Grapes, green Mango Nectarines Melon, cantaloupe Strawberries 1 3 3 4 3 4 4 <5 <5 Apples Apple juice Apple chips Banana Dates Kiwi and juice Melon, watermelon Orange Orange juice Peaches Pears Plantains Plums, purple Plums, red Raisin, Golden, seedless Raspberries 9 14 15 10 11 10 17 5 19 6 9 9 7 6 10-15 10 Applesauce Apricots Blackberries Blueberries Boysenberries Cranberries Currants Figs, dried Fruit salad Fruit salad, tropical Gooseberries Grapes American European Grape juice Guava Lemons, limes Melon Casaba Honeydew Persian Mixed fruit Papaya Persimmon, American Persimmon, Japanese Pineapple Prunes Rhubarb Tangerines Watermelon juice 44 32 ND 34 ND ND ND 4100 ND ND ND ND 400 ND ND ND ND 29 ND ND 31 38 ND 22 ND ND ND 46
GRAINS/GRAIN PRODUCTS
Barley Buckwheat Corn, sweet Corn grits, meal, starch Hominy Oats Pasta (macaroni, noodles, spaghetti) Rice Rye Wheat 6 All packaged grain or flour mixes containing milk or milk products or soy flour
276 Galactosemia
FOODS ALLOWED (mg GAL 100/g) LEGUMES, NUTS, SEEDS

Almonds Brazil nuts Cashew nuts Hazelnuts Macadamia nuts Peanuts Peanut butter Pecans Soy protein isolate Walnuts 3 ND ND 3 ND 0 0 ND ND ND
Beans and franks Coconut
5 12
All beans Adzuki beans Black beans Broadbeans Cranberry beans Faba Great Northern beans Kidney beans King and Mungo beans Limas, baby Navy beans Pink beans Pinto beans Small white beans Soy beans Yellow beans Cottonseed flour Hazelnuts Lentils Miso Natto Peas Chickpeas (Garbonzas) Cowpeas Field peas Black-eyed peas Green split peas Pigeon peas Yellow split peas Pumpkin seeds Safflower seeds, kernels Sesame flour Sesame seeds Soy sauce, fermented Soya flour Tempeh Tofu
ND 17-82 ND 65 1,280 16-80 32-153 ND 29-175 71-104 ND 28-72 34 44 ND ND 500 78-116 ND ND 41-444 ND 32 24-62 199 55 159-188 ND 100 ND ND 170 ND ND ND
MEAT, FISH, POULTRY

Kosher frankfurters Plain beef, chicken, fish, ham, lamb, pork, veal Breaded or creamed fish, meat, or poultry Canned fish containing hydrolyzed protein Cold cuts containing nonfat milk solids Organ meats, including brains, kidney, liver, pancreas, spleen, and/or sweetbreads (meat by-products)
SNACK FOODS
Crackers, popcorn, potato chips, & pretzels free of milk products Graham crackers Plain saltines Soda crackers Apple chips 15 All foods containing milk products Banana bread Fig Newtons 23 22
Galactosemia 277
FOODS ALLOWED (mg GAL 100/g) SUGARS/SWEETENERS

Beet and cane sugar Corn syrup Jellies and marmalades containing allowed fruits Jelly beans Licorice Maple syrup, molasses Nutrasweet liquid Saccharin powder or liquid Taffy
7 Honey Jellies and marmalades containing limited fruits
Apple butter, apple jelly, caramel candy Equal tablets/other artificial sweeteners containing added lactose Jellies and marmalades containing excluded fruits Toffee
VEGETABLES/JUICES
Fresh, canned, or frozen: Artichokes Asparagus Bamboo shoots Bean sprouts, green Beets Cabbage Cauliflower Celery Chard, Swiss Corn, sweet Cucumber Kale Lettuce Mushrooms, common Mustard greens Olives, green Okra Parsley Peppers, hot Potato, white Radishes Spinach Squash, zucchini 0 2 0 <5 1 4 <5 3 ND 4 4 3 3 0 ND 0 ND ND 3 1 <1 <1 3 Any vegetable to which lactose is added during processing Breaded, buttered, or creamed vegetables Bell peppers Broccoli Brussels sprouts Carrots Corn curls Eggplant Instant white potatoes Leeks and onions Peas, green Pumpkin Sauerkraut Snap beans Sweet potatoes Tomato soup, no milk Turnip, parsnips Yams Frozen French fries/hash browns containing added lactose Pizza sauce, no milk Tomatoes, raw Tomatoes Paste Sauce Stewed V-8 juice 20 25 66 77 40 38
11 8 10 7 ND 5 6 6 6 12 16 5 8 18 6 11
INGREDIENTS/MISCELLANEOUS
Caramel coloring Gravy made with water Lactate, lactic acid, lactylate Olives Pure monosodium glutamate (MSG) Pure seasonings and spices Vegetable gums including gum Arabic, guar Worcestershire sauce Baker's cocoa, cocoa powder, semisweet chocolate, Carob powder Catsup 6 Lactoalbumin, lactoglobulin Vegetable gums, including acacia, agar, locust bean, tragacanth, or xanthan Bean-O Butterscotch and milk chocolate Carrageenan Dietetic foods containing milk products Drugs, mineral and vitamin preparations containing lactose Hydrolyzed protein Mocha Monosodium glutamate (MSG) extender Neocalglucon (a calcium supplement) Peppermint, toffee Spice blends containing lactose
Because of incomplete analysis on free and bound galactose in foods, this list should be considered transitional and subject to change. From references 1, 2, 5, 11-13, 18, 25, 26-36, 39, 45, 47, 49, 52-56, 61, 67-69, 74, 81. van Calcar S: Free galactose in foods. Unpublished data. Muscle meat may need to be restricted based on data from reference 79. ND = No data.
278 Galactosemia
TABLE 14-3. Exchange Lists for Children and Adults With Galactosemia1
Food Measure Protein (g) Energy (kcal)
Fat varies 0 45 2 Fruits, canned, heavy syrup 1/2 cup 0 80 dried 1/4 cup 0 60 fresh 1/2 cup 0 60 juice 4 fl oz 0 60 Isomil Soy Protein Isolate Formula With Iron, Powder 3 100 g 12.6 516 Meat: (Exclude organ meats and products containing milk) 1 oz 7.0 75 Soy milk4 8 fl oz 6.6 79 Starch/Bread varies 3 80 Vegetables 2 cooked 1/2 cup 2 25 raw 1 cup 2 25 1 Modified from Exchange Lists for Weight Maintenance. Chicago: The American Dietetic Association, 1995. 2 See Table 14-2 for Foods Allowed, Limited, and Excluded. 3 Supplies 20 kcal/fl oz when mixed according to label directions. 4 Only if made with soy protein isolate and supplemented with vitamins A, D, B12, calcium and phosphorus. Data for soy milk from reference 52. Must NOT contain carrageenan.
Galactosemia 279
TABLE 14-4. Galactosemia Clinical Summary Sheet Name: Date of Birth: __________/__________/__________
Mo Day Year
Hospital Number: Age Diagnosed: Supplements

Physical Data
Length/ Height (cm) Weight (kg) Head Circum (cm) GAL (mg/dL) Urine Galactitol (mmol/mol creat-)
Medications:
Date
(mo/d/yr)
Laboratory Data
EG1P
1

Albumin (g/dL) Hgb (g/dL) Calcium (mg) Phosphorus (mg) Protein (g) Energy (kcal)
Ferritin (ng/mL)
(mg/dL)
Indicate if mg/dL or g/g of hemoglobin, EG1P = erythrocyte GAL-1-phosphate.
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67. Reynolds LM, Henneberry GO, Baker BE: Studies on casein. II. The carbohydrate moiety of casein. J Dairy Sci 1959;42:1463-1471. 68. Ring SG, Selvendran RR: An arabino-galactoxyloglucan from the cell wall of Solanum tuberosum. Phytochemistry 1981;20:2511-2519. 69. Saunders RM: The sugars of safflower. J Am Oil Chem Soc 1970;47:254-255. 70. Segal S: Disorders of galactose metabolism. In Scriver CR, et al (eds): The Metabolic and Molecular Bases of Inherited Disease, ed 7. New York: McGraw-Hill Information Services Co, 1995, pp 967-1000. 71. Segal S: Galactosaemia today: The enigma and the challenge. J Inher Metab Dis 1998;21:455-471. 72. Shield JPH, Wadsworth EJK, MacDonald A, et al: The relationship between genotype to cognitive outcome in galactosaemia. Arch Dis Child 2000;83:248-250. 73. Stallings V, Oddleifson NW, Negrini BY, et al: Bone mineral content and dietary calcium intake in children prescribed a low lactose diet. J Pediatr Gastroent Nutr 1994;18:440-445. 74. Stepak Y, Lifshitz A: Identification and determination of sugars in some fruit juices. J Am Oil Chem Soc 1971;54:1215-1217. 75. Stibler H, von Dobeln V, Kristiansson B, Grithenberg C: Carbohydrate-deficient transferrin in galactosaemia. Acta Paediatr 1997;86:1377-1378. 76. Waggoner DD, Buist NRM, Donnell GN: Long term prognosis in galactosaemia: Results of a survey of 350 cases. J Inher Metab Dis 1990;13:802-818. 77. Waisbren SE, Norman TR, Schnell RR, Levy HL: Speech and language deficits in early treated children with galactosemia. J Pediatr 1983;102:75-77. 78. Wannemacher RW: Key role of various individual amino acids in host response to infection. Am J Clin Nutr 1977;30:1269-1280. 79. Weismann N, Ros-Beutler B, Schlchter R: Leguminosae in the diet: The raffinose-stachyose question. Eur J Pediatr 1995;154 (Suppl 2): S93-S96. 80. Wehrli SL, Berry GT, Palmieri M, et al: Urinary galactonate in patients with galactosemia: Quantitation by nuclear magnetic resonance spectroscopy. Pediatr Res 1997;42:855-861. 81. Wood PJ, Siddiqui IR: Isolation and structural studies of a water-soluble galactan from potato (Solanum tuberosum) tubers. Carbohydr Res 1972;22:212-220. 82. Yamazaki T, Mino M, Hayashi M: Urinary and serum galactitol in galactosemic patients. Acta Paediatr Jpn 1991;33:61-70.
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PROTOCOL 15 Glucose Transport Protein Defect, Pyruvate Dehydrogenase Complex Deficiency, and Intractable Seizures Nutrition Support of Infants, Children, and Adults With RCF Ross Carbohydrate-Free Soy Formula Base With Iron or ProViMin Protein-Vitamin-Mineral Formula Component With Iron Powder
I. Introduction
A. Glucose Transport Protein (GLUT1) Deficiency D-Glucose is the major fuel for cellular metabolism. Absorption and cellular uptake of glucose are regulated by a system of tissue-specific glycoproteins that maintain glucose homeostasis in the body (5, 20, 46). GLUT1 is a facilitative glucose transport protein found in erythrocytes, fibroblasts, and the blood-brain barrier. GLUT1 functions effectively in glucose uptake by tissue in the absence of insulin (20). DeVivo, et al (17) reported two patients with myoclonic seizures and developmental delay. These patients presented with depressed cerebrospinal fluid (CSF) glucose concentrations, normal concentrations of blood glucose, and normal to low CSF lactate, suggesting a defect in GLUT1 transport. The defect may be due to a nonsense mutation in the GLUT1 gene (61). Additional children with GLUT1 defect have been described (14). Clinical features include seizures, delayed mental and motor development, hypotonia, and impaired language skills and behavior. Onset of symptoms range from 2 to 27 months of age. Outcome of Nutrition Support of GLUT1 Deficiency The ketogenic diet has reduced or eliminated seizures within several days of diet onset (14) and improved psychomotor development. Mild cognitive impairment, speech and motor delay may persist. Early diagnosis and diet intervention may lessen the pathophysiology associated with the GLUT1 defect (14). B. Pyruvate Dehydrogenase (PDH) Complex Deficiency PDH complex irreversibly converts pyruvate, the end product of glycolysis, into acetyl-CoA (AcCoA), a major fuel for the Krebs Cycle and substrate for fatty acid synthesis. Pyruvate can also be carboxylated to oxaloacetate (OAA) via pyruvate carboxylase (PC), transaminated to alanine (ALA) via aminotransferases or anaerobically converted to lactate by lactate dehydrogenase (LDH) (Figure N).
PK
LDH
Glucose
PEP
PEPCK PC Biotin
Pyruvate*
AAT PDH Thiamin
Lactate*
Alanine* Fatty Acids
Aspartate
Oxaloacetate
AcCoA
Site of enzyme malfunction * Accumulates in untreated PDH deficiency
AAT = Alanine aminotransferase PEP = Phosphoenolpyruvate PEPCK = PEP carboxykinase PK = Pyruvate kinase LDH = Lactate dehydrogenase
Figure N. Metabolic fates of pyruvate

284 Glucose Transport Protein Defect, PDH Complex Deficiency, and Intractable Seizures 2001 Ross Products Division
PDH deficiency, a commonly recognized cause of lactic acidosis (11, 34), inhibits the normal oxidative metabolism of carbohydrate and prevents production of the majority of ATP. This enzyme complex contains several functional catalytic proteins; E1, E1, E2, E3, and protein X (56). This protocol discusses treatment of deficiencies of E1 or E1 subunits. A defect in a functional component of the PDH enzyme results in mild to severe lactic acidosis and elevated plasma ALA and pyruvate concentrations. Age of clinical presentation varies from neonatal to early childhood. Individuals presenting as neonates suffer severe lactic acidemia and have lower enzyme activity than individuals presenting in childhood. Outcome of Nutrition Support of PDH Deficiency The severity of lactic acidemia is a function of severity of the PDH defect. Patients presenting as neonates suffer the most severe lactic acidemia and usually die by 6 months of age (7, 34, 56). Children presenting later in life have greater residual enzyme function and milder phenotype. They have moderate lactic acidemia, transient acid-base perturbations, and psychomotor retardation. A percentage of these patients will die before age 3 years. Cerebral atrophy has been reported in many patients presenting neonatally and in some children with psychomotor retardation (62). The heterogeneity associated with severe lactic acidemia makes it difficult to predict outcome. Although patients with higher residual enzyme activity appear to have a less severe phenotype than patients with less enzyme activity, there is no good correlation between residual enzyme activity and morbidity and mortality (56). Use of dichloroacetate (DCA), an inhibitor of PDH kinase that maintains activity of PDH, can reduce cerebral lactate and CSF concentrations of lactate and pyruvate (67, 70). Use of DCA is beneficial in eliminating or reducing seizures, infantile spasms, and myoclonic seizures (38, 67). Efficacy of a ketogenic diet is not well established. Kerr (32) reported reduced concentrations of blood lactate and "probable" increased life span in two brothers with PDH deficiency. Initiation of a ketogenic diet at an early age may improve neurologic function and delay death (9, 22, 56, 73). Thiamin-responsive PDH has been described in several patients (51, 58) with decreased blood lactate, increased residual enzyme activity in cultured fibroblasts and lymphocytes (51), and improved facial muscle strength (58). C. Intractable Seizures Ketogenic diets high in dietary fat (ie, 87-92% of total energy) are used to control intractable seizures when other methods of treatment fail. Both long-chain-fats and medium-chain-fats are used in ketogenic diets with similar success in controlling seizures (19, 25, 31,35, 53, 59, 60). Use of ketogenic diets in treating seizures was based on early observations that starvation depressed seizure activity. In 1921, Wilder proposed a high-fat diet to mimic starvation (75). Diet therapy is most effective for control of myoclonic seizures, infantile spasms, and atonic/akinetic seizures. Variable success has been found in refractory seizures (54). The mechanism of antiepileptic action of the ketogenic diet is unknown. Several theories have been presented, including acid-base disturbances, increased serum lipids, and increased ratio of adenosine triphosphate (ATP) to adenosine diphosphate (ADP) in the brain (16, 18). Neither an excitatory nor an inhibitory effect of ketone bodies on neurotransmission has been shown (69). Outcome of Nutrition Support of Intractable Seizures Livingston (43) reported complete control of myoclonic seizures in 54% of his patients and reduction of seizures in another 26% of patients placed on ketogenic diets. Others have reported similar success showing that approximately 50% of patients with intractable seizures have improvement or elimination of seizures (26, 35, 53, 59, 72). Adults do not respond to diet as well as children (53, 54), but the ketogenic diet may be effective in adults with generalized and partial epilepsy (63). Length of time to clinical response on the ketogenic diet varies from days to weeks (3, 19, 25, 27, 35, 53, 59). Recommendations for length of time to maintain diet differ, but most clinicians recommend that diet continue for 2 years. Most patients who respond positively to diet either remain seizure-free or have continued improvement upon cessation of diet. Reported complications associated with diet are numerous. These include reduced bone mass, renal calculi (29), lipemia retinalis, cardiovascular complications (6), pancreatitis, impaired neutrophil function (77), hypoalbuminemia (2), hypertriacylglycerolemia (68), constipation, anorexia, dehydration, and refractory vomiting (2). Use of predominantly high-fat food as the mainstay of the ketogenic diet results in decreased nutrient intake, often requiring carbohydrate-free mineral/vitamin
2001 Ross Products Division Glucose Transport Protein Defect, PDH Complex Deficiency, and Intractable Seizures 285
supplements. Compliance to the ketogenic diet may be poor. Success is dependent on a multidisciplinary approach, constant supervision, and encouragement of families and patients.
II. Establish Diagnosis

A. The Defects 1. GLUT1 transport protein defect. 2. PDH deficiency of E1 or E1 subunit. 3. Intractable seizures unresponsive to standard pharmacologic therapy. B. Clinical Evaluation 1. Infants and toddlers with any of the following clinical or laboratory signs should be evaluated for GLUT1 transport protein defect: a. Seizures, psychomotor retardation, cognitive delays, hypotonia (14, 17), and ataxia. b. Below-normal CSF glucose with normal blood glucose and normal-to-low CSF lactate. 2. Infants with any of following clinical or laboratory signs should be evaluated for PDH deficiency (28, 34, 57). a. Hypotonia or hyporeflexia; failure to thrive; seizures; dysmorphic features including wide nasal bridge, narrow facial appearance; upturned nostrils; microcephaly; psychomotor retardation; ataxia; central hypoventilation or recurrent apnea (34). b. Lactic acidosis; elevated plasma ALA or elevated blood pyruvate concentrations (32, 34). Lactate:pyruvate ratio is frequently normal, except during acute illness (34). c. Enzyme activity for PDH deficiency 1) Many enzyme defects cause lactic acidosis (Figure N) (34). 2) Measure enzyme activity in 2 or more of following tissues: cultured skin fibroblasts, cultured lymphocytes, skeletal muscle, other organs. 3) See reference 34 for methods of diagnosis. 3. Any patient with intractable seizures not responsive to pharmacologic therapy should be evaluated for ketogenic diet.
III. Rationale for Nutrition Support

A. Correct Primary Imbalance in Metabolic Relationships 1. GLUT1 and intractable seizures: a. Provide high-fat, very-low-carbohydrate diet as tolerated to reduce or eliminate seizures. 2. PDH deficiency: a. Ketogenic diet may improve neurologic function and survival in patients with some residual enzyme activity (55, 56, 73, 74) b. Restrict carbohydrate, the primary precursor of pyruvic acid. B. Stabilize Altered Enzyme Protein 1. PDH Deficiency a. Supplement lipoic acid if lipoamide dehydrogenase deficiency is present, but it has not proven beneficial (34). b. Supplement thiamin to prolong half-life of any residual PDH (34, 56). c. Supplement DCA to prolong half-life of PDH (67). C. Supplement "Conditionally Essential" Nutrients 1. Supplement L-carnitine if hypocarnitinemia is present (13).
IV. Establish Goals of Nutrition Support

A. Growth, Development, and Nutrition Status 1. Support normal growth rate in infants and children; maintain appropriate weight for height in adults. 2. Support normal development. 3. Restrict psychomotor deterioration in GLUT1 transport defects. 4. Maintain urine ketones in range that reflects ketosis desired. 5. Maintain normal acid-base balance. 6. Maintain normoglycemia. 7. Maintain fluid status at level sufficient to eliminate or reduce seizures.
8. Maintain normal bowel function. 9. Provide sufficient vitamin D, calcium, and phosphorus to maintain adequate bone mass (29). B. Plasma Carnitine Concentration 1. Maintain normal concentration of plasma free carnitine 30 mol/L (13). C. PDH Deficiency Only 1. Maintain normal plasma concentrations of ALA, lactate, and pyruvate as determined by laboratory used. 2. Maintain CSF pyruvate concentrations between 40 and 150 m (56). Warning: Plasma pyruvate concentrations are difficult to ascertain. Proper laboratory methods are essential for interpreting data.
V. Establish Prescription
A. Diet 1. Energy. a. Prescribe amount that should support normal weight gain in infants and children and appropriate weight for height in adults (Table 15-1, p 288). b. For patients with intractable seizures, energy intakes of 75% to 125% of Recommended Dietary Allowances (RDAs) (24) have been used to maintain ketosis (19, 25, 35, 53, 59, 60). 2. Fat. a. Prescribe 87% to 92% of energy as fat (ie, 3:1-5:1 ratio of fat:carbohydrate plus protein). 3. Protein. a. Prescribe between 8% and 13% of energy as protein (Table 15-1, p 288). Warning: Long-term Inadequate protein intake will result in failure to thrive in infants, weight loss in children, low plasma transthyretin concentration, osteopenia, and hair loss. Hypoalbuminemia has been described in patients on ketogenic diets (2, 10). 4. Carbohydrate. a. Prescribe carbohydrate to provide remaining energy. 5. L-Carnitine. a. Prescribe sufficient carnitine to maintain normal plasma free carnitine concentrations. b. For patients with PDH deficiency, 50-100 mg/kg has been used (33, 71). Warning: High intakes of L-carnitine may interfere with ketogenesis (53). 6. Thiamin (PDH deficiency only) a. Prescribe pharmacologic amount. b. Amounts ranging from 100 to 1800 mg/day have been recommended (7, 9, 21, 51, 55, 74). 7. Fluid a. Provide amount that will supply water requirements (Table 15-1, p 288). Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL fluid to children and adults for each kcal ingested (4). b. Some physicians recommend restriction of fluid (800-1200 mL/day) to accelerate ketosis in children with intractable seizures (25, 27, 35). Others have reported maintenance of ketosis with adequate fluid intakes (19, 53). Warning: Over-restriction of fluid may lead to dehydration, constipation, renal calculi, and acid-base disturbances. B. Drugs 1. Bicarbonate (PDH deficiency only). a. Prescribe amount that, with diet and citrate, maintains normal blood pH. b. Amounts prescribed by various investigators are given below: 1) 10 mmol/kg/day (8). 2) 100 mEq/day (11). 3) 1 mEq/kg/day. 4) 15 mEq every 4 hours (33).
Glucose Transport Protein Defect, PDH Complex Deficiency, and Intractable Seizures 287
DCA (PDH deficiency/lactic acidemia only). a. Investigational New Drug application required or contact clinicians listed in Table 15-2, p 288, for referral of patients. b. Dosage of DCA for treatment of lactic acidosis ranges from 15 mg/kg every 2 days to 150 mg/kg daily (40, 41, 49, 55). Sufficient inhibitory effect of DCA on PDH kinase without toxic effects has been achieved at a dose of approximately 50 mg/kg/day (34). c. Plasma DCA concentrations should be routinely monitored to prevent toxicity (40). 3. Antiepileptic medication (if applicable). a. Modify as needed after initiation and stabilization of ketosis. b. Many patients with intractable seizures can be weaned from antiepileptic medications after ketosis is stabilized and patient has shown decreased number of seizures or complete seizure control. Warning: Many medications contain carbohydrate as inert ingredient (23, 42). Carbohydrate content of medications change frequently. Contact manufacturers with each new prescription for accurate, up-to-date information. Barbiturates may be contraindicated for patients with GLUT1 deficiency (36).
VI. Fill Prescription

A. Protein 1. Calculate amount of protein provided by RCF, ProViMin, beikost, or table foods (Tables 15-3 and 15-4, pp 289-290) required to fill protein prescription. a. For more information on nutrient content of beikost (baby foods), contact the following manufacturers:
Note:
ProViMin may be used in place of RCF or with RCF in filling the protein prescription.
B. Fat 1. Calculate amount of fat provided by RCF, ProViMin, beikost, or table foods required to fill protein prescription. 2. Subtract amount determined above from total fat prescription. 3. Supply remaining fat prescription with vegetable oil (8 kcal/mL) (19, 22, 53, 76). a. Fractionated coconut oil has been suggested as part of total daily fat prescription for treatment of intractable seizures to enhance ketogenesis (31, 59, 60) but is expensive and other vegetable oils are efficacious. C. Carbohydrate 1. Calculate amount of carbohydrate provided by RCF, ProViMin, beikost, or table foods required to fill protein and fat prescriptions (Tables 15-3 through 15-4, pp 289-290). 2. Subtract amount determined above from total carbohydrate prescription. 3. Supply any remaining carbohydrate with Polycose Glucose Polymers powder (23 kcal/Tbsp, 3.8 kcal/g) (Appendix 9, p A-9), sugar (48 kcal/Tbsp), beikost, or table food (Table 15-3, p 289). a. Do not use corn syrup or table sugar for infants because of osmolarity they yield (47). b. All foods and powdered carbohydrate sources must be carefully weighed using a gram scale. Warning: Antiepileptic medications may contain carbohydrate which must be calculated in the diet plan if alternative medications cannot be used. D. L-Carnitine (Appendix 26, p A-28) 1. Add prescribed liquid L-carnitine to RCF or ProViMin mixture. 2. If L-carnitine is not added to RCF/ProViMin mixture, administer with each meal. 3. L-carnitine tablets are available.
Warning:
Liquid L-carnitine may contain carbohydrate.
E. Thiamin (PDH Deficiency Only). 1. Administer orally with each feed (Table 15-2, p 288). F. Fluid and Mixing Instructions 1. RCF without ProViMin . a. Add sufficient boiled, cooled water to RCF, fat, and carbohydrate mixture to yield prescribed volume. Tap water may replace boiled, cooled water when preparing RCF for older infants, children, and adults. b. Shake well until contents are thoroughly mixed. 2. RCF with ProViMin or ProViMin alone. a. Measure or weigh specified amounts of boiled, cooled water, RCF, ProViMin, fat, and carbohydrate into clean containers. b. Pour 1/2 specified amount of boiled, cooled water into clean blender. Running blender at slow speed, gradually add ProViMin and blend total mixture for approximately 15 seconds. c. Slowly pour specified amount of RCF, fat, and carbohydrate and additional water to make prescribed volume into blender and continue blending for 1 to 3 seconds. 3. Refrigerate in sterilized, closed containers until used. Discard unused portion 48 hours after mixing because of nutrient loss. 4. Warm or cool medical food mixture to room temperature before feeding to infants. Shake well before feeding. 5. Do not warm medical food mixture for infants in microwave oven. Unevenly heated formula can burn infants and steam can make bottles explode. 6. Notify parents (caretakers) when they may discontinue using aseptic technique in preparing medical food mixture for infants. Warning: All fluid should be carefully measured using a graduated cylinder or other calibrated instrument. G. Diet Guide 1. Provide parents, caretakers, or patient with completed Diet Guide (Table 15-5, p 291) with each diet change. 2. Provide RCF/ProViMin mixture evenly with each feed throughout day. 3. Maintain fat:carbohydrate plus protein ratio evenly with each feed. 4. All foods must be carefully weighed on metric scale accurate to within 1 gram. Failure to accurately weigh all foods could result in reduction of ketosis and increased seizure activity.
VII. Diet Initiation

A. Intractable Seizures 1. Protocols for diet introduction requiring fasting and hospitalization are available for establishing ketosis (25, 35, 44). 2. Refer to references 25 and 44 for specific guidelines and protocol regarding hospitalization and fasting. 3. For patients with PDH deficiency and GLUT1 deficiency, hospitalization and fasting may not be required.

A. Nutrient Adequacy 1. Determine if diet provides nutrients in amounts prescribed in Section V, Establish Prescription, p 282 . a. See Table 15-3, p 289, for composition of RCF and ProViMin and Appendix 9, p A-9, for composition of Polycose. 2. Check diet to determine if it supplies Recommended Dietary Intakes (RDIs) of minerals and vitamins (Appendices 13 and 14, pp A-14 and A-15). a. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. b. If RCF or ProViMin mixture provides < 100% of RDIs for infants and < 75% for children and adults, supplement diet with needed minerals and vitamins if not provided by beikost
or table foods and laboratory tests indicate need (Appendix 11, p A-10, for composition of supplements). Warning: Carefully check all mineral and vitamin supplements for carbohydrate content. B. Osmolarity 1. If concentration of prescribed RCF or ProViMin mixture is > 27 kcal/fl oz, determine if osmolarity is in acceptable range. a. Determine osmolarity by laboratory analysis or use mathematical formula given in Appendix 18, p A-20. b. See Appendix 19, p A-21, for osmolarity of RCF and ProViMin. 2. If osmolarity is > 450 mosm/L for neonates (45), > 750 mosm/L for children, > 1,000 mosm/L for adults (65), or greater than tolerated by patient, increase water content of prescribed medical food mixture and recalculate its osmolarity. C. Potential Renal Solute Load 1. Dehydration will result if renal solute load is greater than renal-concentrating ability of patient. 2. If concentration of medical food mixture prescribed is > 27 kcal/fl oz, estimate its potential renal solute load. a. This step is important to prevent dehydration of infants who may have renal-concentrating capacity as low as 600 mosm/L. b. Upper limit of renal solute load for neonates is approximately 1,100 mosm/L (64). 3. A method for estimating potential renal solute load is given in Appendix 20, p A-22. 4. If potential renal solute load is excessive, increase water content of medical food mixture and recalculate.

A. Acid-Base Status 1. Measure blood pH, gases, electrolytes, lactate, and pyruvate as needed to maintain near normal acid-base status. B. Presence of Ketosis 1. Measure urine ketones after first void of morning using Ketostix (Bayer Corporation Division, Elkhart, IN). a. Ketones may be lowest in morning, which may lead to transient seizure activity (25, 53, 59, 60). 2. Urine ketone concentrations should be medium to large. 3. If urine contains no or low ketones: a. Increase fat in diet by 5% and decrease carbohydrate by ~ 10%, which will maintain prescribed energy intakes. b. Skipping 1 or 2 meals may accelerate ketosis. 4. If urine contains very large amount of ketones: a. Decrease fat in diet by 5% and increase carbohydrate by ~ 10%, which will maintain prescribed energy intakes. b. Excess ketosis can lead to nausea and vomiting. Warning: Infants may have difficulty maintaining ketosis and normoglycemia. C. Protein Status 1. Evaluate plasma albumin and transthyretin concentrations every 3 months (Appendix 17, p A-18, for standards). a. Plasma transthyretin concentration provides a more reliable and rapid indication of protein status than plasma albumin concentrations. b. Plasma albumin concentration may be in the normal range when plasma transthyretin concentration shows a clear deficiency (1). 2. If plasma albumin or transthyretin concentration is below standard: a. Increase prescribed protein by 5% to 10% using RCF/ProViMin and reevaluate plasma albumin or transthyretin concentration in 1 month.
290 Glucose Transport Protein Defect, PDH Complex Deficiency, and Intractable Seizures
D. Carnitine Status 1. Measure free plasma carnitine concentration every 3 months until patient is 12 months of age and every 6 months thereafter. 2. If free carnitine concentration is < 30 mol/L or below normal for laboratory used, increase amount of carnitine prescribed by 5% to 10%. E. Iron Status 1. Plasma ferritin concentration. a. Evaluate at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17, p A-18, for standards). b. If plasma ferritin concentration is below standard: 1) Increase iron intake to 2 mg/kg with supplements (carbohydrate-free ferrous sulfate ). 2) Evaluate plasma ferritin concentration monthly on increased iron intake. 3) Continue iron supplements until plasma ferritin concentration is in normal range. 2. Complete blood count. a. Evaluate hemoglobin and hematocrit concentration at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17, p A-18, for standards). F. Blood Glucose Concentrations 1. Transient hypoglycemia may occur during initial phase of ketogenic diet. a. Some researchers recommend no treatment unless blood glucose concentrations are < 40 mg/dL and symptoms occur (25, 53, 60). 1) Symptoms include paleness, sweaty forehead, excess sleep, rapid pulse, dizziness, and nausea. 2) If symptoms are present, offer 40 mL orange juice (approximately 5 g CH2O) or other simple carbohydrate (eg, liquid glucose) and recheck blood glucose in 1 hour. 3) If symptoms persist, offer another 40 mL orange juice (approximately 5 g CH2O) or simple carbohydrate and recheck. b. During initiation of fasting or diet, monitor blood glucose every 4-6 hours for first 48 to 72 hours and periodically for several days thereafter (19). Warning: Amount of carbohydrate offered may be greater than 5 g depending on blood glucose concentration and severity of symptoms. G. Growth Status 1. Length/height and weight. a. Measure monthly to 1 year of age, every 3 months to 4 years, and every 6 months thereafter. Plot measurements on NCHS growth charts. b Maintain length/height and weight between 10th and 90th percentiles. Some normal infants and children will fall above or below these percentiles. 2. If length/height or weight falls below usual growth channel: a. Increase protein and energy prescriptions by 5% to 10% and remeasure in 1 month. b. If length/height or weight remains low, repeat process until usual growth channel is achieved. H. Nutrient Intake 1. Maintain records of food intake for 3 days immediately before each blood test (Appendices 24 and 25, pp A-26 and A-27). 2. Evaluate intakes of protein, fat, and energy weekly or as needed to meet nutrition goals. 3. Evaluate mineral and vitamin intakes after each diet change. a. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. b. See Appendix 28, p A-29, for information about ordering software for diet evaluation. I. Hydration Status 1. Young infants and children cannot verbalize thirst and must be closely monitored. 2. Monitor urine for hydration status. 3. For some patients with intractable seizures, restriction of fluid may be necessary to maintain urine specific gravity between 1.020 and 1.025 (27). 4. Carefully monitor hydration status during hot summer months.
A. Example Establish and fill prescription for 1 year old weighing 9.8 kg using Recommended Daily Nutrient Intakes from Table 15-1, p 288, and average nutrient contents from Tables 15-3 and 15-4, pp 289 and 290 and Appendix 10, p A-9. 1. Establish prescription for a 3:1 fat:carbohydrate + protein ketogenic diet
Energy Protein Fat Carbohydrate Fluid Food List 105 kcal/kg 1,029 kcal 1,029 kcal 1,029 kcal 105 mL/kg x x x x x Measure 9.8 kg 0.10 0.87 0.03 9.8 kg = = = = = 1,029 kcal/day 103 kcal 895 kcal 31 kcal 1,029 mL/day Fat (g) 46.2 53.7 0.0 Carbohydrate (g) 0.05 0.00 7.70 Energy (kcal) 520 473 31 4 kcal/kg 9 kcal/g 4 kcal/kg = = = 25.7 g 99.5 g 7.7 g
2. Fill prescription using RCF:

Protein (g) 25.7 0.0 0.0
RCF Concentrate 642 mL Soy oil 59 mL Polycose powder 8.2 g Add water to make 1,029 mL (35 fl oz) Total per day
25.7
99.9
7.75
1024
Divide diet prescription evenly throughout day. Approximate osmolarity of RCF mixture is < 100 mosm/L. Estimated potential renal solute load 220 mosm.
3. Fill prescription using ProViMin:

Food List Measure Protein (g) 25.6 0.0 0.0 Fat (g) 0.5 101.9 0.0 Carbohydrate (g) 0.70 0.00 6.70 Energy (kcal) 109 898 27
ProViMin 35 g Soybean oil 112 mL Polycose powder 7.1 g Add water to make 1,029 mL (35 fl oz) Total per day
25.6
102.4
7.40
1,034
Divide diet prescription evenly throughout day. Approximate osmolarity of ProViMin mixture is < 110 mosm/L. Estimated potential renal solute load < 230 mosm.
TABLE 15-1. Recommended Daily Nutrient Intakes (Average and Ranges) for Infants and Children with Seizures 1
Age Fat (% of Energy) Infants 0 to < 3 mo 3 to < 6 mo 6 to < 9 mo 9 to < 12 mo Girls and Boys 1 to < 4 yr 4 to < 7 yr 7 to < 11 yr Women 11 < 15 yr 15 < 19 yr > 19 yr Men 11 < 15 yr 15 < 19 yr > 19 yr
1 2 2
Nutrient Protein (% of Energy) 8 - 13 8 - 13 8 - 13 8 - 13 Energy (kcal/kg) 120 (145 - 95) 115 (145 - 95) 110 (135 - 80) 105 (135 - 80) (kcal/day) 87 - 92 87 - 92 87 - 92 8 - 13 8 - 13 8 - 13 1,300 ( 900-1800) 1,700 (1300-2300) 2,400 (1600-3300) Fluid 3 (mL/kg) 150 - 125 160 - 130 145 - 125 135 - 120 (mL/day) 900 - 1800 1,300 - 2,300 1,600 - 3,300
87 - 92 87 - 92 87 - 92 87 - 92
87 - 92 87 - 92 87 - 92
8 - 13 8 - 13 8 - 13
2,200 (1500-3000) 2,100 (1500-3000) 2,100 (1400-2500)
1,500 - 3,000 1,200 - 3,000 1,400 - 2,500
87 - 92 87 - 92 87 - 92
8 - 13 8 - 13 8 - 13
2,700 (2000-3700) 2,800 (2100-3900) 2,900 (2000-3300)
2,000 - 3,700 2,100 - 3,900 2,000 - 3,300
Modified from references 35, 53, and 59. 87-92% energy as fat calculates to a 3:1 to 5:1 ratio of fat to carbohydrate + protein. 3 Modified from reference 4. Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL to older infants and children for each kcal ingested.
TABLE 15-2. Sources of Products to Treat PDH Deficiency

Product Dichloroacetate Source Peter W. Stacpoole, PhD, MD Division of Endocrinology and Metabolism University of Florida College of Medicine Box 100226 Gainesville, FL 32610 (352) 392-2321 Nature's Bounty, Inc. 90 Orville Drive Bohemia, NY 11716 (800) 645-5412 (516) 567-9500
Richard Haas, MD Division of Pediatric Neurology University of California/San Diego Medical Center 9500 Gilman Drive La Jolla, CA 92093-0935 (619) 587-4004 FAX (619) 587-8050
Oral Thiamin
TABLE 15-3. Composition of RCF Ross Carbohydrate-Free Soy Formula Base With Iron (Concentrated) and ProViMin Protein-Vitamin-Mineral Formula Component With Iron
Nutrient RCF 1 (Per 100 mL) ProViMin 2 (Per 100 g powder)
81 312 Energy, kcal 4.0 73.0 Protein, g Other Nitrogen-Containing Compounds Carnitine, mg 3.0 40 Taurine, mg 12.0 110 0.008 2.00 Carbohydrate, g 7.2 1.4 Fat, g Linoleic acid, g 0.81 0 0.04 0 -Linolenic acid, g Minerals Calcium, mg 140 2,400 Chloride, mg/mEq 83/2.34 2,300/65 Copper, mg 0.10 2.10 Iodine, g 20.3 335 Iron, mg 2.43 40 Magnesium, mg 10.0 200 Manganese, mg 0.04 0.20 Phosphorus, mg 100 1,700 Potassium, mg/mEq 146/3.73 3,300/84 Selenium, g 2.8 63 Sodium, mg/mEq 59.1/2.57 1,200/52 Zinc, mg 1.0 17 Vitamins A, g RE 122 2,024 D, g 2.00 25 2.8 45 E, mg -TE K, g 15 90 Ascorbic acid, mg 11 200 Biotin, g 6.1 100 B6, mg 0.08 1.35 B12, g 0.61 5.6 Choline, mg 10.5 335 Folate, g 20 320 Inositol, mg 6.5 105 Niacin, mg/mg NE 1.8/2.8 24.0/40.7 Pantothenic acid, mg 1.00 10.1 Riboflavin, mg 0.12 2.02 Thiamin, mg 0.08 2.24 89.0 4.0 Water, g Other Characteristics Approx. potential renal solute load mosm 34.8 673 Approx. osmolarity, mosm/L 8.0 200 1 Concentrated. 2 Approximate weights per g powder of ProViMin measured in level, dry US standard household measures: 1 Tbsp = 2.9 g 1/4 cup = 11 g 2/3 cup = 30 g 1 cup = 44 g
TABLE 15-4. Serving Lists for Ketogenic Diets1, 2

Food Group Fat 3 Grains/Starch 4 Meat, high-fat, and meat substitute Milk, high-fat Vegetables
5
Serving Size (approx) varies 1/2 c or 1 slice 0.0 3.0
Protein (g) 5.0 1.0 8.0 8.0 0.0
Fat (g)
Carbohydrate (g) 0.0 15.0 45 80
Energy (kcal)
1 2
3 4
1 oz 7.0 0.0 100 1 cup 8.0 12.0 150 1/2 cup, 2.0 5.0 25 cooked, 1 cup raw Modified from Exchange Lists for Meal Planning, American Dietetic Association, 1995. These are approximate values. For accuracy, calculate macronutrients and serving sizes for each specific food offered. Includes avocado, bacon, cream cheese, nuts, olives, and seeds. Includes beans; crackers and snacks; beans and lentils, and starchy vegetables. Serving sizes: 1/2 cup cooked cereal grain, pasta, or starchy vegetables; 1 slice bread. Includes cheese and peanut butter.
TABLE 15-5. Diet Guide for Ketogenic Diet

Name:________________________________________________ Mo Date: __________/_________/_________ Day Year
Medical Food Mixture RCF Concentrate

ProViMin
Amount mL g g/mL fl oz/ mL Servings
Protein (g)
Fat (g)
CH2O (g)
Energy (kcal)
Add water to make Daily Intake BREAKFAST RCF/ProViMin Mixture Fat Grains/Starch Meat, high-fat Milk, high-fat Vegetables MIDMORNING SNACK LUNCH RCF/ProViMin Mixture Fat Grains/Starch Meat, high-fat Milk, high-fat Vegetables MIDAFTERNOON SNACK DINNER RCF/ProViMin Mixture Fat Grains/Starch Meat, high-fat Milk, high-fat Vegetables EVENING SNACK Volume (mL) Daily Totals Comments
Protein (g)
Fat (g)
CH2O (g)
Energy (kcal)
Nutritionist
292 Glucose Transport Protein Defects, PDH Complex Deficiency, and Intractable Seizures 2001 Ross Products Division
TABLE 15-6. Ketogenic Diet Clinical Summary Sheet Name: Date of Birth: __________/__________/__________
Mo Day Year
Hospital Number: Age Diagnosed: Supplements:

Physical Data
Length/ Weight Head Height Circum Na/K/Cl/ 2 CO (mEq) Blood glucose (mg/dL/ mmol/L) Urine Ketones
Medications:
Date Laboratory Data
Lactate Pyruvate Plasma ALA Hgb/Hct

Albumin/ 1 TT (g/dL, mg/dL) Ferritin Protein Fat (g/day) (% energy) CH2O (g) (% energy) Energy Fluid
(mo/d/yr)
(cm)
(kg)
(cm)
(mmol/L) (mmol/L) (mol/L) (g/dL/%)
(ng/mL)
(g/day)
(kcal)
(mL)
Transthyretin
REFERENCES
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. Arnold GL, Vladutiu CJ, Kirby RS: Protein insufficiency and impaired growth in children with PKU. J Inher Metab Dis 2000;23 Suppl 1:29A. Ballaban-Gil K, Callahan C, O'Dell C, et al: Complications of the ketogenic diet. Epilepsia 1998;744-748. Barbosa E, Freeman J, Elfert G: Ketogenic diets for treatment of childhood epilepsy. In Walser M, et al (eds) Nutritional Management. The Johns Hopkins Handbook. Philadelphia: WB Saunders, CO, 1984, pp 272-292. Behrman RE, Kleigman RM, Arvin AA (eds): Nelson Textbook of Pediatrics, ed 15. Philadelphia: WB Saunders Co, 1996. Bell GI, Burant CF, Takeda J, Gould GW: Structure and function of mammalian facilitative sugar transporters. J Biol Chem 1993;258:19161-19164. Best TH, Franz DN, Gilbert DL, et al: Cardiac complications in pediatric patients on the ketogenic diet. Neurology 2000;54:2328-2330. Bonne G, Benelli C, DeMeirleir L, et al: E1 pyruvate dehydrogenase deficiency in a child with motor neuropathy. Pediatr Res 1993;33;284-288. Byrd DJ, Krohn HP, Winkler L, et al: Neonatal pyruvate dehydrogenase deficiency with lipoate responsive lactic acidaemia and hyperammonaemia. Eur J Pediatr 1989;148:543-547. Cederbaum SD, Blass JP, Minkoff N, et al: Sensitivity to carbohydrate in a patient with familial intermittent lactic acidosis and pyruvate dehydrogenase deficiency. Pediatr Res 1976;10:713-720. Couch SC, Schwarzman F, Carroll J, et al: Growth and nutritional outcomes of children treated with the ketogenic diet. J Amer Diet Assoc 1999;99;1573-1575. Cross JH, Connelly A, Gadian DG: Clinical diversity of pyruvate dehydrogenase deficiency. Pediatr Neurol 1994;10:276-283. DeMeirleir , Lissens W, Denis R, et al: Pyruvate dehydrogenase deficiency: Clinical and biochemical diagnosis. Pediatr Neurol 1993;9:216-229. DeVivo DC, Bohan TP, Coulter DL, et al: L-Carnitine supplementation in childhood epilepsy: Current perspectives. Epilepsia 1998;39:1216-1225. DeVivo DC, Burke C, Trifiletti R, et al: Glucose transporter protein deficiency: An emerging syndrome with therapeutic implications. Am Neurol 1994;36;491. DeVivo DC, Haymond MW, Obert KA, et al: Defective activation of the pyruvate dehydrogenase complex in subacute necrotizing encephalomyelopathy (Leigh disease). Ann Neurol 1979;6:483-494. DeVivo DC, Leckie MP, Ferrendelli JS, McDougal DB: Chronic ketosis and cerebral metabolism. Ann Neurol 1978;3:331-337 DeVivo DC, Trifiletti R, Jacobson RI, et al: Defective glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia, seizures and developmental delay. N Engl J Med 1991;325:703-709. Dodson WE, Prensky AL, DeVivo DC, et al: Management of seizure disorders: Selected aspects. Part II. J Pediatr 1976;89:695-703. Edelstein SI, Chisholm M: Management of intractable childhood seizures using the non-MCT oil ketogenic diet in 20 patients. J Amer Diet Assoc 1996:96:1181-1182. Elsas LJ, Longo N: Glucose transporters: Human disorders and insulin receptor regulation. Intl Pediatr 1995;10(1):57-68. Endo H, Hasegawa K, Narisawa K, et al: Defective gene in lactic acidosis: Abnormal pyruvate dehydrogenase E1 -subunit caused by a frame shift. Am J Hum Genet 1989;44:358-364. Falk RE, Cederbaum SD, Blass JP, et al: Ketonic diet in the management of pyruvate dehydrogenase deficiency. Pediatrics 1976;58:713-721. Feldstein TJ: Carbohydrate and alcohol content of 200 oral liquid medications for use in patients receiving ketogenic diets. Pediatrics 1996;97:506-511. Food and Nutrition Board, Committee on Dietary Allowances: Recommended Dietary Allowances, eds 9 and 10. Washington, DC: National Academy of Sciences, 1980 and 1989. Freeman JM, Freeman JB, Kelly MT: The Ketogenic Diet: Treatment for Epilepsy, ed 3. New York: Demos Publications, 2000. Freeman JM, Vinning EPG, Pillar DJ, et al: The efficacy of the ketogenic diet in 1998; A prospective evaluation of intervention in 150 children. Pediatrics 1998;102:1358-1363. Gasch AT: Use of the traditional ketogenic diet for treatment of intractable seizure epilepsy. J Amer Diet Assoc 1990;90:1433-1434. Harada M, Tanouchi M, Arai K, et al: Therapeutic efficacy of a case of pyruvate dehydrogenase complex deficiency monitored by localized proton magnetic resonance spectroscopy. Magn Res Imaging 1996;14:129-133. Herzberg GZ, Fivush BA, Kinsman SL, Gearhart JP: Urolithiasis associated with the ketogenic diet. J Pediatr 1990;117:743-745. Hommes FA, Berger R, Luit-DeHaan G: The effect of thiamine treatment on the activity of pyruvate dehydrogenase: Relation to the treatment of Leigh's encephalomyelopathy. Pediatr Res 1973;7:616-619.
31. Huttenlocher PR, Wilbourn AJ, Signore JM: Medium-chain-triglycerides as a therapy for intractable childhood epilepsy. Neurology 1971;21:1097-1103. 32. Kerr DS: Treatment of congenital lactic acidosis: A review. Intl Pediatr 1995;10:75-81. 33. Kerr DS, Lap H, Berlin CM, et al: Systemic deficiency of the first component of the pyruvate dehydrogenase complex. Pediatr Res 1987;22:312-318. 34. Kerr DS, Wexler ID, Zinn AB: Disorders of pyruvate metabolism and tricarboxylic acid cycle. In Fernandes J, et al (eds): Inborn Metabolic Diseases: Diagnosis and Treatment, ed 3. New York: Springer-Verlag, 2000, pp 126-138. 35. Kinsman SL, Vining EPG, Quaskey SA, et al: Efficacy of the ketogenic diet for intractable seizure disorders: Review of 58 cases. Epilepsia 1992;33:1132-1136. 36. Klepper J, Fischberg J, Vera JC, et al: GLUT1-deficiency: Barbiturates potentiate haploinsufficiency in vitro. Pediatr Res 1999;46:677-683. 37. Klip A, Tsakiridis T, Marette A, Ortiz PA: Regulation of expression of glucose transporters by glucose: A review of studies in vivo and in cell cultured. FASEB J 1994;8:43-53. 38. Kodama S, Yagi R, Ninomiya M, et al: The effect of a high fat diet on pyruvate decarboxylase deficiency without central nervous system involvement. Brain Dev 1983;5:381-389. 39. Kretzschmar HA, DeArmond SJ, Koch TK, et al: Pyruvate dehydrogenase complex deficiency as a cause of subacute necrotizing encephalopathy (Leigh disease). Pediatrics 1987;79:370-373. 40. Kuroda Y, Ito M, Toshima K, et al: Treatment of chronic congenital lactic acidosis by oral administration of dichloroacetate. J Inher Metab Dis 1986;9:244-252. 41. Kuroda Y, Naito E, Takeda E, et al: Congenital lactic acidosis. Enzyme 1987;38:108-114. 42. Kumar A, Aitas AT, Hunter AG, Beaman DC: Sweeteners, dyes and other excipients in vitamin and mineral preparations. Clin Pediatr 1996;Sept:443-450. 43. Livingston S, Pauli LL, Pruce I: Ketogenic diet in the treatment of childhood epilepsy. Dev Med Child Neurol 1977;19:833-834. 44. MacCracken KA, Scalisi JC: Development and evaluation of a ketogenic diet program. J Amer Diet Assoc 1999;99:1554-1558. 45. MacLean W, Graham G: Pediatric Nutrition in Clinical Practice. Menlo Park, Calif: Addison-Wesley Publishing Co, 1982. 46. Maher F, Vannucci SJ, Simpson IA: Glucose transport proteins in brain. FASEB J 1994;8:1003-1011. 47. Martin SB, Acosta PB: Osmotic behaviors of components of chemically-defined formulas. J Pediatr Perinat Nutr 1987;1:1-17. 48. Matalon R, Stumpf DA, Michals K, et al: Lipoamide dehydrogenase deficiency with primary lactic acidosis: Favorable response to treatment with lipoic acid. J Pediatr 1984;104:65-69. 49. McCormick K, Viscardi RM, Robinson B, Heininger J: Partial pyruvate decarboxylase deficiency with profound lactic acidosis and hyperammonemia: Responses to dichloracetate and benzoate. Am J Med Genet 1985;22:291-299. 50. Meites S (ed): Pediatric Clinical Chemistry: Reference Normal Values, ed 3. Washington, DC: AACC Press, 1989. 51. Naito E, Ito M, Takeda E, et al: Molecular analysis of abnormal pyruvate dehydrogenase in a patient with thiamineresponsive congenital lactic acidemia. Pediatr Res 1994;36:340-346. 52. Nordli DR, DeVivo DC: The ketogenic revisited: Back to the future. Epilepsia 1997;38:743-749. 53. Nordli DR, Koenigsberger D, Schroeder J, DeVivo DC: Ketogenic diets. In Resor SR, et al (eds): The Medical Treatment of Epilepsy. New York: Marcel Dekker, Inc. 1992, p 455-472. 54. Prasad AN, Stafstrom CR, Holmes GL: Alternative epilepsy therapies: The ketogenic diet, immunoglobulins, and steroids. Epilepsia 1996;37 (Suppl 1):531-593. 55. Przyrembel H: Therapy of mitochondrial disorders. J Inher Metab Dis 1987;10:129-146. 56. Robinson BH: Lactic acidemia: Disorders of pyruvate carboxylase, pyruvate dehydrogenase. In Scriver CR, et al (eds): The Metabolic and Molecular Bases of Inherited Disease, ed 8. New York: McGraw-Hill Medical Publishing Division, 2001, pp 2275-2296. 57. Robinson BH, MacMillan H, Petrova-Benedict R, Sherwood WG: Variable clinical presentation in patients with defective E1 component of pyruvate dehydrogenase complex. J Pediatr 1987;111:525-533. 58. Scholte HR, Busch HFM, Luyt-Houwen IEM: Vitamin responsive pyruvate dehydrogenase deficiency in a young girl with external ophthalmoplegia, myopathy and lactic acidosis. J Inher Metab Dis 1992;15:331-334. 59. Schwartz RM, Boyes S, Aynsley-Green A: Metabolic effects of three ketogenic diets in the treatment of severe epilepsy. Dev Med Child Neurol 1989;31:152-160. 60. Schwartz RH, Eaton J, Bower BD, Aynsley-Green A: Ketogenic diets in the treatment of epilepsy: Short-term clinical effects. Dev Med Child Neurol 1989;31:145-151. 61. Seidner G, Alvarez MG, Yeh JI, et al: GLUT-1 deficiency syndrome caused by haploinsufficiency of the blood-brain hexose carrier. Nat Genet 1998;18:188-191. 62. Shevell MI, Matthews PM, Scriver CR: Cerebral dysgenesis and lactic acidemia: An MRI/MRS phenotype associated with pyruvate dehydrogenase deficiency. Pediatr Neurol 1994;11:224-229. 63. Sirven J, Whedon B, Caplan D, et al: The ketogenic diet for intractable epilepsy in adults: Preliminary results. Epilepsia 1999;40:1721-1726.
64. Smith CA, Nelson NM: The Physiology of the Newborn Infant, ed 4. Springfield, IL: Charles C Thomas Publisher, 1976. 65. Smith JL, Heymsfield SB: Enteral nutrition support: Formula preparation from modular ingredients. JPEN 1983;7:280-288. 66. Spika JS, Shaffer N, Hargrett-Bean N, et al: Risk factors for infant botulism in the United States. Am J Dis Child 1989;143:828-832. 67. Stacpoole PW, Barnes CL, Harbanis MD, et al: Treatment of congenital lactic acidosis with dichloroacetate: A review. Arch Pediatr Adolesc Med 1997;77:535-541. 68. Theda C, Woody RC, Sakkubai N, et al: Increased very long-chain-fatty acids in patients on a ketogenic diet: A cause of diagnostic confusion. J Pediatr 1993;122:724-726. 69. Thio LL, Wong M, Yameda KA: Ketone bodies do not directly alter excitatory or inhibitory hippocampal synaptic transmission. Neurology 2000;54:325-331. 70. Toth PP, El-Shanti H, Eivins S, et al: Transient improvement of congenital lactic acidosis in a male infant with pyruvate decarboxylase deficiency treated with dichloroacetate. J Pediatr 1993;123:427-430. 71. Uziel G, Garavaglia B, DiDonato S: Carnitine stimulation of pyruvate dehydrogenase complex (PDHC) in isolated human skeletal muscle mitochondria. Muscle Nerve 1988;11:720-724. 72. Vinning EP, Freemen JM, Ballaban, GK, et al: A multicenter study of the efficacy of the ketogenic diet. Arch Neurol 1998;5:1433-1437. 73. Wexler I, Hemalatha S, McConnell J, et al: Outcomes of pyruvate dehydrogenase deficiency treated with ketogenic diets: Studies in patients with identical mutations. Neurology 1997;49:1655-1661. 74. Wick H, Schweizer K, Baumgartner R: Thiamine dependency in a patient with congenital lactic acidaemia due to pyruvate dehydrogenase deficiency. Agents and Actions 1977;7:405-410. 75. Wilder RM: Effects of ketonuria on the course of epilepsy. Mayo Clin Bulletin 1921;2:307-314. 76. Woody RC, Brodie M, Hampton DK, Fiser RH: Corn oil ketogenic diet for children with intractable seizures. J Child Neurol 1988;3:21-24. 77. Woody RC, Steele RW, Knapple WL, Pilkington NS: Impaired neutrophil function in children with seizures treated with the ketogenic diet. J Pediatr 1989;115:427-430.
PROTOCOL 16 Glycogen Storage Disease Types Ia and Ib Nutrition Support of Infants, Children, and Adults With RCF Ross Carbohydrate-Free Soy Formula Base With Iron or ProViMin Protein-Vitamin-Mineral Formula Component With Iron Powder
I. Introduction
Glycogen storage disease (GSD) type Ia (von Gierke's disease) results from a deficiency of glucose-6phosphatase, normally found in liver, kidney, and intestinal mucosa. GSD type Ib results from a defect in the enzyme glucose-6-phosphate translocase, affecting transfer of glucose-6-phosphate into endoplasmic reticulum (12). These diseases usually manifest during the first year of life as severe hypoglycemia or profound hepatomegaly. Secondary biochemical features include hypertriacylglycerolemia, hypercholesterolemia, hyperuricemia, and lactic acidemia. Platelet dysfunction, inflammatory bowel disease, and severe neutropenia (type Ib only) have been described (12). Other forms of GSD type I (ie, Ic and Id) have been reported. However, the subcategories may not be distinct clinical disorders from GSD type Ib (39, 40).
Glycogen Glucose-1-P ADP Glucose-6-P* H2O Fructose 6-P Pi Endoplasmic reticulum Adenine Fructose 1,6-P Phosphate Trap Inosine Lactate* Pyruvate Alanine* Uric acid* Fatty acids Triacylglycerols* TCA cycle Acetyl-CoA Cholesterol* * Accumulates in untreated GSD Type I Site of enzyme defect Site of transport defect Glucokinase ATP Glucose
Glucose-6-phosphatase
Figure O. Hepatic glycogen metabolism in GSD I

In the past, many patients with GSD type I died from complications associated with biochemical abnormalities. Patients who survived had a poor prognosis. Muscle wasting and stunted growth were common in poorly controlled individuals. Current diet regimens, resulting in normal blood glucose concentration, have proven beneficial in eliminating pathophysiologic sequelae found in poorly controlled patients. Well-controlled patients attain normal linear growth and have dramatically reduced risk for hepatic adenomas, renal insufficiency, gout, pancreatitis, osteoporosis, and atherosclerosis (23, 32, 37). Despite good metabolic control, renal insufficiency and hyperlipidemia may still occur.

A. The Defect 1. GSD type Ia results from deficiency of glucose-6-phosphatase, which is normally found in liver, kidney, and intestine.
2001 Ross Products Division Glycogen Storage Disease 301
2. GSD type Ib results from defect in glucose-6-phosphate translocase, affecting transfer of glucose-6-phosphate into endoplasmic reticulum. 3. GSD type Ic results from defect in microsomal phosphate or pyrophosphate transport. 4. GSD type Id results from defect in microsomal glucose transport caused by deficiency of GLUT7 transport protein. B. Clinical Evaluation 1. Infants or children with any of following clinical symptoms and biochemical findings should be evaluated for GSD type I (7, 12): a. Hepatomegaly. b. Growth retardation. c. Bleeding tendency (1). d. Severe neutropenia (type Ib) (15, 41). e. Hypoglycemia. f. Hyperlacticacidemia. g. Hyperuricemia (22). h. Hypertriacylglycerolemia. i. Hypercholesterolemia. C. Differential Diagnosis (7, 12) 1. Definitive diagnosis requires liver biopsy and DNA analysis to identify deficiency of glucose-6phosphatase or deficiency in any 1 of 3 microsomal translocase systems. 2. Cultured skin fibroblasts or blood CANNOT be used for enzyme diagnosis because glucose-6phosphatase is not present in these cell types.

A. Correct Primary Imbalance in Metabolic Relationships 1. Maintain normal blood glucose concentration by providing frequent complex dietary carbohydrate (CH2O). 2. Maintain normal blood glucose concentration throughout day and night to ameliorate secondary biochemical abnormalities.

A. Plasma Glucose Concentration 1. Maintain normal plasma glucose concentration between 70 and 120 mg/dL (3.9 and 6.7 mmol/L 2 hrs postprandial) or within normal range found in laboratory used (26, 36). B. Growth, Development, and Nutrition Status 1. Support normal growth rate of infants and children. 2. Maintain normal development. 3. Maintain normal nutrition status. a. Avoid prolonged fasting > 5 to 7 hours. Some patients cannot tolerate fasting > 3.5 hours. b. Avoid excessive hepatic lipid accumulation. C. Biochemistries 1. Maintain normal plasma biochemistries in ranges noted below or per laboratory used.
Analyte Cholesterol (plasma) 1 Lactate Normal Range < 201 mg/dL (5.20 mmol/L) Arterial 3.3 - 6.8 mg/dL (0.36 - 0.75 mmol/L) Venous 4.5 - 11.8 mg/dL (0.50 - 1.30 mmol/L) Triacylglycerols (plasma) 300 - 700 mg/dL2 (3.4 - 7.9 mmol/L) (treatment range) Uric acid (serum/plasma) 2.0 - 5.4 mg/dL (119 - 327 mmol/L) 1 Slightly higher lactate concentrations may be acceptable for treatment (12). 2 Patients with GSD type I usually do not attain normal plasma triacylglycerol concentrations and maintain concentrations of 300 to 700 mg/dL (28).
302 Glycogen Storage Disease

A. Sucrose/Fructose and Lactose/Galactose 1. Limit foods and medications containing sucrose, fructose, lactose, and galactose. a. Fructose and galactose are metabolized to glucose-6-phosphate and can elevate blood lactate and triacylglycerol concentrations (9, 29). b The amount of fructose allowed in the GSD diet is not well described. Very small amounts may be tolerated by some patients. Warning: Opinion varies as to extent galactose and fructose should be eliminated from diet, and age when relaxation in restriction should occur. Dietary lactose should be limited to ~23 g per day (based on 0.5 L 2% milk) (12). B. Energy 1. Recommended Dietary Allowances (RDAs) are same as for normal infants and children (14). 2. Intakes should be sufficient to support normal weight gain in infants and children and maintain normal weight for height in adults (Table 16-1, p 305). 3. Energy intake should be divided into daytime feedings (65% -75% total prescribed energy) and nocturnal CH2O infusion (25%-35% total prescribed energy). Warning: Excessive energy intakes may cause obesity and hypertriacylglycerolemia in individuals with GSD type I (6). C. Protein 1. Prescribe amount that supplies 10% to 15% of daily energy prescribed (Table 16-1, p 305). a. Additional protein is not recommended for GSD type I. D. Fat 1. Prescribe amount that provides 25% to 35% of daily energy requirement (Table 16-1, p 305). Fat intake may need to be reduced below 25% of energy to prevent obesity in severely affected patients who require dietary oligosaccharides that lead to energy excess. a. Prescribe minimum of 3% of total energy as linoleic acid. b. Prescribe minimum of 1% of total energy as -linolenic acid. E. Carbohydrate 1. Recommended amounts will vary based on age, weight, and maintenance of normoglycemia. a. Prescribe amount that provides remainder of prescribed energy (Table 16-1, p 305). b. Prescribe as complex CH2O. After 6-8 months of age, supply raw cornstarch at 1.25 to 2.5 g/kg body weight/feeding between meals (8, 16, 30, 31). Actual requirement may be above or below this range to maintain desired blood glucose concentrations. 1) Cornstarch should be calculated as part of prescribed CH2O energy. 2) Raw cornstarch is not recommended for use in intragastric infusions because of solidification and clogging of tube. Warning: Young infants (< 6 months) consuming large amounts of raw cornstarch may develop gastrointestinaI distress (flatulence, colicky symptoms, diarrhea) because pancreatic amylase has not reached normal adult activity (21). F. Fluid 1. Prescribe amount that will supply water requirements (Table 16-1, p 305). Under normal circumstances, offer minimum of 1.5 mL fluid to neonates for each kcal ingested and 1.0 mL to children and adults (4). 2. Requirements may be higher than recommended secondary to accompanying fever. G. Nocturnal Feedings 1. Nocturnal feedings usually provide between 25% and 35% of total daily energy requirements (30, 44).
Glycogen Storage Disease 303
2.
Intragastric infusion method: Calculation of glucose requirements a. Glucose requirements vary depending on individual glucose production rates (GPR). 1) The following are normal GPR for different ages (5). Neonates 5.61 - 6.53 mg/kg/min Infants < 6 yrs 6.86 - 7.34 mg/kg/min Late Childhood 5.12 - 5.68 mg/kg/min 2) Reported glucose supplements used to maintain normoglycemia are as follow: Infants 7 - 9 mg/kg/min (11) Children < 6 yrs 5 - 7 mg/kg/min (11, 44) 6 yrs 14 yrs 5 - 6 mg/kg/min (5) Adolescents 4 - 5 mg/kg/min (11) Adults 3 - 4 mg/kg/min (12)

A. Protein 1. Calculate amount of RCF, ProViMin (Table 16-3, p 308), beikost, or table foods (Table 16-4, p 308) required to fill protein prescription. Nutrient information for beikost (baby food) may be obtained by contacting the following manufacturers: Heinz North America Gerber Products Company Beech-Nut Nutrition Consumer Affairs c/o Consumer Affairs Corporation USX Tower 445 State Street 100 S 4th Street 600 Grant Street, 7th Floor Fremont, MI 49413-0001 St Louis, MO 63102 Pittsburgh, PA 15219 1-800-443-7237 1-800-233-2468 1-800-872-2229 2. Request list of ingredients and nutrient composition. B. Fat 1. Calculate amount of fat from RCF, ProViMin (Table 16-3, p 308), beikost, or table foods (Table 16-4, p 308) required to fill fat prescription 2. Subtract amount determined above from total fat prescription. Note: When using RCF, fat is calculated before protein because of possible excess fat. If ProViMin is used as sole protein source, protein is calculated first since ProViMin contains only trace amounts of fat (Table 16-3, p 308). 3. Supply remaining fat prescription (Table 16-1, p 305) with measured amount of oils (Appendix 10, p A-9), beikost, or table foods (Table 16-4, p 308). 4. Supply 3% of total energy as linoleic acid and 1.0% as -linolenic acid. Warning: Essential fatty acid deficiency may occur if intakes of linoleic and -linolenic acids are inadequate. C. Carbohydrate 1. Daytime feedings. a. Sucrose/Fructose and Lactose/Galactose 1) See Table 16-2, p 306, for foods allowed and restricted in GSD Type I diet. b. For infants and some toddlers, Polycose (Appendix 9, p A-9) or complex CH2O may be used to fill prescription (Table 16-1, p 305). Polycose may be added to RCF or ProViMin mixture. c. Raw cornstarch (Table 16-5, p 308) replaces complex CH2O when pancreatic amylase activity is present (beginning with very small amounts of raw cornstarch about midinfancy). 1) Infants < 12 months of age have tolerated cornstarch (38) but use of pancreatic enzyme may be needed. Introduction of very small amounts of raw cornstarch beginning at 6 months of age may be necessary to induce pancreatic amylase. Warning: Introduction of excess raw cornstarch may cause diarrhea and flatulence. d. Recommended complex CH2O supplementation, which makes up part of total CH2O prescription (Table 16-1 p 305), varies from 1.25 to 2.5 g CH2O/kg/feed. 1) Actual requirements vary. Individualize amount of CH2O to maintain normoglycemia and promote protein synthesis.
304 Glycogen Storage Disease 2001 Ross Products Division
Warning:
Inadequate CH2O administration may result in reduced whole body protein synthesis and elevated plasma lactate concentrations (12, 30, 45). e. Timing of daytime feeds varies depending on type of CH2O used and patient's ability to maintain normoglycemia. 1) Spacing of CH2O daytime feeds is usually every 2 to 3 hours for infants and every 3 to 4 hours for children. 2) Doses of raw cornstarch > 2.5 g/kg have maintained normoglycemia longer than 4 hours in some individuals (8, 12). 3) In contrast, feeds < 1.25 g/kg raw cornstarch given more frequently may be beneficial for some children (43). f. Administration of RCF or ProViMin/CH2O mixture for infants and children 1) Mix prescribed amounts of Polycose and/or uncooked cornstarch in RCF or ProViMin. i. Polycose and RCF or ProViMin may be mixed and stored for up to 48 hours. ii. Add prescribed amount of uncooked cornstarch to RCF or ProViMin at time of feeding. 2) Uncooked cornstarch may also be given in water and administered in 1:2 ratio. i. Sugar-free flavoring may be added to water/CH2O mixture to improve "acceptability." ii. Administer above mixture between meals at frequencies throughout day that maintain normoglycemia. Warning: Exceeding the 1:2 ratio of cornstarch to water will reduce its effectiveness in maintaining normoglycemia. Cooked cornstarch is not effective in maintaining normoglycemia. 3) Alternate complex carbohydrates (ie, cooked rice, pasta, rolled oats, millet, couscous, legumes and lentils) may substitute for raw cornstarch during daytime feeds (12) if they are effective in maintaining normoglycemia.
D. Fluid and Mixing Instructions 1. RCF without ProViMin a. Add sufficient boiled, cooled water to RCF and carbohydrate mixture to yield prescribed volume. Tap water may replace boiled, cooled water when preparing RCF for older infants, children, and adults. b. Shake well until contents are thoroughly mixed. 2. RCF with ProViMin or ProViMin alone. a. Measure or weigh specified amounts of boiled, cooled water, RCF, ProViMin, fat, and carbohydrate into clean containers. b. Pour 1/2 specified amount of boiled, cooled water into clean blender. Running blender at slow speed, gradually add ProViMin and blend total mixture for approximately 15 seconds. c. Slowly pour specified amount of RCF, fat, carbohydrate and additional water to make prescribed volume into blender and continue blending for 1 to 3 seconds. 3. Refrigerate in sterilized, closed containers until used. Discard unused portion 48 hours after mixing because of nutrient loss. 4. Warm or cool RCF/ProViMin mixture to room temperature before feeding to infants. Shake well before feeding. 5. Do not warm RCF/ProViMin mixture in microwave oven. Unevenly heated formula can burn infants and steam can make bottles explode. 6. Notify parents (caretakers) when they may discontinue using aseptic technique in preparing medical food mixture for infants. E. Nocturnal Feeding. 1. Several methods may be used to provide CH2O for night feedings. a. Intermittent oral feedings of raw cornstarch mixed with water (8, 12); Polycose, or raw cornstarch mixed with RCF or ProViMin. b. Continuous CH2O source (eg, Polycose Glucose Polymers) via intragastric infusion (8, 16, 17, 21, 35). 1) Intermittent oral feeding of raw cornstarch and continuous CH2O infusion have resulted in similar positive clinical outcomes (6, 30, 44).
2001 Ross Products Division Glycogen Storage Disease 305
2. Calculate amount of Polycose or raw cornstarch (oral feedings only) required to fill patient's glucose requirement. 3. Polycose may be added to RCF/ProViMin to provide prescribed CH2O (Table 16-1, p 305) and fed orally or by intragastric infusion. 4. For intragastric infusion, provide sufficient amount of prescribed CH2O mixture to meet volume required over total hours to prevent premature cessation of CH2O source. 5. Intragastric Infusion Rates. a. Infusion rates will differ with each patient. Adjust rate to supply prescribed amount of CH2O over selected period of infusion. b. To prevent severe hypoglycemia, nocturnal intragastric infusion usually extends for 8 to 10 hours beginning within 3 hours of last daytime feeding and ending 30 minutes after 1st meal of following morning or within 30 minutes of removal of tube feeding. Warning: Severe hypoglycemia may occur if oral feeding is not established soon after infusion is completed. F. Diet Guide 1. Provide parents, caregivers, or patient with completed Diet Guide (Table 16-6, p 309) with each diet change.

A. Nutrient Adequacy 1. Determine if diet provides nutrients in amounts prescribed in Section VI, Establish Prescription, p 298. a. See Protocol 15, Table 15-3, p 289, and Table 16-3, p 308, for composition of RCF and ProViMin. Nutrient composition of beikost and table foods are dependent on specific foods prescribed. Contact manufacturer or nutrient database in Amino Acid Analyzer software for composition. 2. Check diet to determine if it supplies Recommended Dietary Intakes (RDIs) for minerals and vitamins (Table 15-3, p 289, and Appendices 13 and 14, pp A-14 and A-15). a. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. b. If RCF or ProViMin mixture provides < 100% of RDIs for age, supplement diet with needed minerals and vitamins if not provided by beikost or table foods and laboratory tests indicate need. Warning: Low calcium intake (23) and chronic lactic acidosis (27) may result in poor bone mineralization in patients with GSD type I. B. Osmolarity 1. If concentration of prescribed medical food mixture is > 27 kcal/fl oz, determine if osmolarity is in acceptable range. a. Determine osmolarity by laboratory analysis or use mathematical formula given in Appendix 18, p A-20. b. Osmolarity of RCF is 0.08 mosm/mL concentrated. 2. If osmolarity is > 450 mosm/L for infants (24), > 750 mosm/L for children, < 1,000 mosm/L for adults (34), or is greater than tolerated by patient, increase water content of prescribed medical food mixture and recalculate its osmolarity. C. Potential Renal Solute Load 1. Dehydration will result if renal solute load is greater than renal-concentrating ability of patient (13). 2. If concentration of medical food mixture prescribed is > 27 kcal/fl oz, estimate its potential renal solute load. a. This step is important to prevent dehydration of infants who may have renal-concentrating capacity as low as 600 mosm/L . b. Upper limit of renal solute load for neonates is approximately 1,100 mosm/L (13, 33). 3. A method for estimating potential renal solute load is given in Appendix 20, p A-22. 4. If potential renal solute load is excessive, increase water content of RCF/ProViMin mixture and recalculate.
Warning:
Compromised renal failure, found in some patients with GSD type I, may result in inadequate handling of renal solute load.

A. Blood Glucose Concentration 1. Evaluate blood glucose concentrations (local laboratory measurements) as needed to maintain between 70 and 120 mg/dL (3.9 to 6.7 mmol/L). 2. Home monitoring. a. Monitor blood glucose concentrations daily in all children receiving nocturnal infusions or after diet changes using glucometer. b. Quantite blood glucose concentration early in morning soon after nocturnal infusion is completed. c. Monitor blood glucose concentration of all children until at least 5 years of age. Most common periods of hypoglycemia are midmorning and midafternoon. 3. If blood glucose concentration is below recommended range: a. Increase prescribed CH2O by approximately 10% to 15% and decrease fat by an equal number of kcalories and reevaluate after next feeding or following day at same time of day. b. If blood glucose concentration remains low, repeat above process until concentration is in normal range. B. Protein Status 1. Evaluate plasma albumin concentration every 3 months during infancy and twice yearly in children (Appendix 17, p A-18, for standards). a. Plasma transthyretin concentrations provide a more reliable and rapid indication of protein status than plasma albumin concentrations. b. Plasma albumin concentrations may be in the normal range when plasma transthyretin concentrations show a clear deficiency (3). 2. If plasma albumin or transthyretin concentration is below standard: a. Increase prescribed protein by 5% to 10% and reevaluate plasma albumin concentration in 1 month. b. If plasma albumin or transthyretin concentration remains low, repeat above process until value is in normal range. C. Iron Status 1. Plasma ferritin concentration: a. Evaluate at 6, 9, and 12 months of age and yearly thereafter (Appendix 17, p A-18, for standards). b. If plasma ferritin concentration is below standard: 1) Increase iron intake to 2 mg/kg body weight with supplements (ferrous sulfate). 2) Evaluate plasma ferritin concentration monthly on increased iron intake. 3) Continue iron supplements until plasma ferritin concentration is in normal range. 2. Complete blood count and differential. a. Evaluate hemoglobin, hematocrit and differential at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17, p A-18, for standards). D. Plasma Triacylglycerol, Cholesterol, Lactic Acid, and Uric Acid Concentrations 1. Evaluate every 3 months until 3 years of age and every 6 months or as indicated thereafter. 2. Above analytes should be measured along with blood glucose concentration. 3. If plasma triacylglycerol, lactic acid, and uric acid concentrations are above treatment range: a. Obtain a blood glucose concentration; 1) If low, either increase prescription of cornstarch or other CH2O or adjust schedule of feeding to provide sufficient CH2O to prevent hypoglycemia. b. Elevated concentrations of these analytes are negatively related to blood glucose concentration and indicate poor metabolic control.
E. Growth Status 1. Length/height and weight. a. Measure monthly until patient is 1 year old, every 3 months to 4 years of age, and every 6 months thereafter, or as needed. Plot measurements for infants and children on NCHS growth charts. b. Maintain length/height and weight between 10th and 90th percentile. Some normal infants, children, and adults will fall above or below these percentiles. c. If length/height or weight falls below usual growth channel: 1) Reassess degree of metabolic control (Section IX, Suggested Evaluation of Nutrition Support, p 302) for blood glucose concentration, and related analytes listed in IX.D, above. 2) Adjust nutrition support to normalize blood glucose concentration and related analytes and repeat anthropometrics in 1 month. 3) If length/height or weight remains low, readjust nutrition support until usual growth channel and/or catch-up growth is achieved. Warning: Failure to grow is often indicative of poor metabolic control. In GSD type Ib , neutropenia resulting in recurrent infections may inhibit growth (38). Some patients may not achieve growth potential even with good diet compliance (10). 2. Obesity may be chronic in children with GSD type I who are consuming excessive raw cornstarch and energy. a. If weight gain is excessive or above usual growth channel: 1) Calculate total energy intake per day including raw cornstarch regimen to determine if energy intake is excessive. 2) Adjust energy prescription to maintain acceptable weight and normal blood glucose concentration and related analytes. 3) If weight remains excessive, repeat steps 1) and 2) until acceptable weight is slowly achieved. F. Nutrient Intake 1. Maintain records of food intake for 3 days immediately before each blood test (Appendices 24 and 25, pp A-26 and A-27). 2. Evaluate intakes of CH2O, fat, protein, energy, minerals, and vitamins before each blood test. a. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. b. See Appendix 28, p A-29, for information about ordering software for diet evaluation. G. Clinical Summary 1. A summary record of growth, laboratory, and nutrient intake data is useful for patient management (Table 16-7, p 309).
A. Example 1 Establish and fill prescription for 1-month-old infant weighing 4 kg using Recommended Daily Nutrient Intakes from Table 16-1, p 305, and average nutrient contents from Tables 16-3 and 164, p 308. 1. Establish prescription
Energy Fat Protein CH2O Fluid 130 kcal/kg 30% of 520 kcal 10% of 520 kcal 60% of 520 kcal 1.5 mL x 4 kg = 156 kcal = 52 kcal = 312 kcal 9 kcal/g fat 4 kcal/g protein 4 kcal/g CH2O x 520 kcal = 520 kcal/day = 17.3 g/day = = 13.0 g/day (3.25 g/kg) 78 g/day
= 780 mL
Protein CH2O (g) (g) RCF Concentrate 236 mL 17.0 9.4 0.0 ProViMin Powder 5g 0.1 3.6 0.1 Polycose Powder 83 g 0.0 0.0 78.0 Add water to make 26 oz total volume (769 mL). Offer additional water ad libitum. Medical Food Mixture Measure Fat (g) Energy (kcal) 191 16 315
17.1 13.0 78.1 522 Total per day -3.3 -130 Total per kg Percent Energy 29.5 10 59.8 --Approximate osmolarity is < 250 mosm/L. Estimated potential renal solute load is < 150 mosm.
3. Feeding Schedule: a. Divide feedings equally and feed every 3 to 4 hours or as needed (12, 43). Each feeding of above formula mixture provides 3 g CH2O/fl oz. b. As child grows and pancreatic amylase activity normalizes, raw cornstarch may be substituted for Polycose to fill CH2O requirements. B. Example 2 Establish and fill prescription for 5-year old weighing 18 kg using Recommended Daily Nutrient Intakes from Table 16-1, p 305, and nutrients from Tables 16-3 through 16-5, p 308. 1. Establish prescription
Energy Fat Protein CH2O Nocturnal infusion Total CH2O feeds 25% of 1300 kcal = 325 kcal 10% of 1300 kcal = 130 kcal 65% of 1300 kcal = 845 kcal 25% of 1300 kcal = 325 kcal as CH2O 211 g/d - 81.25 g nocturnal 9 kcal/g fat 4 kcal/g protein 4 kcal/g CH2O 4 kcal/g CH2O = 1,300 kcal/day = = = = 36.0 g/day 32.5 g 211 g 81.25 g
= 130 g CH2O daytime = 1,300 mL
Raw cornstarch to be given as 2.0 g/kg body weight/feed as part of total CH2O prescription. Fluid
Medical Food Mixture Measure Fat (g) Protein (g) CH2O (g) Energy (kcal) 405 53 540
RCF Concentrate 500 mL 36.0 20.0 0.04 ProViMin Powder 17 g 0.2 12.4 0.34 Raw cornstarch1 15 Tbsp (120 g) 0.0 0.0 130.00 Add water to make 21 fl oz total volume (621 mL). Offer additional fluid ad libitum.
Total daytime feeds 36.2 32.4 130.4 998 1 Raw cornstarch should be added to RCF/ProViMin mix in 1:2 ratio. Additional water may be added to RCF or ProViMin if needed to meet 1:2 ratio criterion. Supply raw cornstarch (2.0 g/kg body weight/feed) divided throughout day.
3. Nocturnal infusion using Polycose powder

Carbohydrate Source Polycose Powder Add water to make 600 mL Infuse at 60 mL/hr for 10 hours (600 min) Measure 86 g CH2O (g) 81.2 Energy (g) 327
Calculation for glucose/kg/min 81.2 g CH2O x 1000 mg/g = 81,200 mg 81,200 mg CH2O 18 kg BW 600 min = 7.5 mg glucose/kg/min
TABLE 16-1. Recommended Daily Nutrient Intakes (Ranges) for Infants and Children with Glycogen Storage Disease Type I
Age Energy Infants 0 to < 3 mo 3 to < 6 mo 6 to < 9 mo 9 to < 12 mo
1
Nutrient Fat (% of energy) 25 - 35 25 - 35 25 - 35 25 - 35 (% of energy) 25 - 35 25 - 35 25 - 35 Protein (% of energy) 10 - 15 10 - 15 10 - 15 10 - 15 (% of energy) 10 - 15 10 - 15 10 - 15 CH2O (% of energy) 60-70 60-70 60-70 60-70 (% of energy) 60-70 60-70 60-70 Fluid2 (mL/kg) 150-125 160-130 145-125 135-120 (mL/day) 900 - 1800 1,300 - 2,300 1,650 - 3,300 (kcal/kg) 120 (145-95) 115 (145-95) 110 (135-80) 105 (135-80) (kcal/day)
Girls and Boys 1 to < 4 yr 4 to < 6 yr 7 to < 11 yr Women 11 < 15 yr 15 < 19 yr > 19 yr
1,300 (900-1800) 1,700 (1300-2300) 2,400 (1650-3300)
2,200 (1500-3000) 2,100 (1200-3000) 2,100 (1400-2500)
25 - 35 25 - 35 25 - 35
10 -15 10 -15 10 -15
60 - 70 60 - 70 60 - 70
1,500 - 3,000 1,200 - 3,000 1,400 - 2,500
Men 11 < 15 yr 2,700 (2000-3700) 25 - 35 10 -15 60 - 70 2,000 - 3,700 15 < 19 yr 2,800 (2100-3900) 25 - 35 10 -15 60 - 70 2,100 - 3,900 > 19 yr 2,900 (2000-3300) 25 - 35 10 -15 60 - 70 2,000 - 3,300 1 Modified from reference 14. 2 Modified from reference 4. Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL to older infants and children for each kcal ingested.
TABLE 16-2. Fructose-, Sucrose-, and Galactose-Restricted Diet

Foods Allowed BEVERAGES Coffee, RCF Ross Carbohydrate-Free Soy Formula Base With Iron, ProViMin Protein-Vitamin-Mineral Formula Component With Iron Powder, ProMod Protein Supplement, tea, artificially sweetened beverages, soy milk products made without sucrose or fructose, nondairy creamers (without sugar) Foods Restricted
All milk and milk products with added fructose, fruit, or flavors that contain honey, molasses, or sugar; beer; brandy; rum; vodka; carbonated beverages containing fructose, fruit juice, or sugar; fruit juices or drinks containing fruit juice; liqueur; sherry; vermouth
BREADS, CEREALS, AND GRAINS All
None
CHEESES AND OTHER MILK PRODUCTS Aged cheese, butter, buttermilk (fermented), or yogurt
DESSERTS Those made with glucose hydrolyzed corn starch, corn syrup, or Polycose Glucose Polymers and without milk or milk products
Any made with milk, milk products, fructose, fruit, fruit juice, high fructose corn syrups, honey, molasses, or sugar; cakes, pies, or pastries containing sucrose or lactose (galactose)
EGGS All
Any to which fructose, fruit, high fructose corn syrup, honey, molasses, or sugar has been added.
FATS Bacon; butter, margarines and salad dressings that do not contain milk/milk products; lard; non-dairy coffee creamers free of fructose, high fructose syrup, honey, molasses, and sugars; oils; shortening; whipping cream FRUITS/JUICES Avocado, raw lemons (limited), rhubarb; limited amounts of gooseberries, loganberries, blackberries, cranberries, currants, pomegranates, limes
Mayonnaise and salad dressings with added fructose, fruit, high fructose corn syrup, honey, molasses, or sugar; milk products; sour cream
All others
LEGUMES (BEANS & PEAS), NUTS, AND SEEDS All
None
MEAT, FISH AND OTHER SEAFOOD, AND POULTRY Plain meat, fish and other seafood; poultry; pork, veal
Any to which honey, molasses, syrup, or milk/milk products is added in processing or cooking
SUGARS/SWEETENERS NutraSweet (Aspartame); Sweetmate (acesulfame K), Splenda (sucralose)
Any containing fructose, high fructose corn syrup, honey, molasses, sugar
Foods Allowed VEGETABLES All
Foods Restricted
None
MISCELLANEOUS Carob powder; catsup; chile sauces; chocolate milk Bakers cocoa; bitter chocolate; monosodium or sweets; drugs, mineral/vitamin preparations glutamate (MSG); pure seasonings and spices; containing fructose, sorbitol, or sugar; seasonings dextrin; glucose, maltose; Polycose Glucose containing added fructose, high fructose syrup; Polymers; Pro-Phree Protein-Free Energy Module honey, molasses, sugar; maple syrup; jams; jellies; with Iron, Vitamin and Mineral supplements not preserves containing fructose, or lactose From reference 25. Galactose-restricted foods modified from references 18, 19, 20.
TABLE 16-3. Major Nutrients in RCF Ross Carbohydrate-Free Soy Formula Base With Iron and ProViMin Protein-Vitamin-Mineral Formula Component With Iron
Nutrient RCF 1 (Per 100 mL) ProViMin 2 (Per 100 g powder)
81 312 Energy, kcal 4.0 73.0 Protein, g 0.008 2.00 Carbohydrate, g 7.2 1.4 Fat, g Linoleic acid, g 0.81 0 0.04 0 -Linolenic acid, g 1 Concentrated. 2 Approximate weights per g powder of ProViMin measured in level, dry US standard household measures: 1 Tbsp = 2.9 g 1/4 cup = 11 g 2/3 cup = 30 g 1 cup = 44 g
TABLE 16-4. Serving List of Foods

Food List Carbohydrate Starch Other carbohydrates Fat Meat and meat substitutes Very lean Lean Vegetables
1
Serving Size (approx) 1/2 cup varies <1 varies 5 0-1 3 ---
Fat (g)
Protein (g) 3 varies -7 7 2 15 15 -----5
CH2O (g)
Energy (kcal) 80 varies 45 35 35 25
1 oz 1 oz 1/2 cooked, 1 cup raw
From reference 2.
TABLE 16-5. Nutrient Composition of Raw Cornstarch

Nutrient Energy, kcal Carbohydrate, g 36 8.7 Raw Cornstarch (per Tbsp; 8 g)
TABLE 16-6. Diet Guide for Glycogen Storage Disease Type I

Name:_____________________________ Mo MEDICAL FOOD MIXTURE RCF Concentrate, mL ProViMin, g Add water to make ________________ oz/mL (fl oz) Amount of CH2O /kg/feed ________________ Date: _______/_______/_______ Day Year Amount Fat (g) Weight: ______________________ kg Protein (g) CH2O (g) Energy (kcal)
Daily Intake BREAKFAST Medical Food Mixture Starch Other Carbohydrate Meat Fat MIDMORNING SNACK LUNCH Medical Food Mixture Starch Other Carbohydrate Vegetables Meat Fat MIDAFTERNOON SNACK DINNER Medical Food Mixture Starch Other Carbohydrate Vegetables Meat Fat BEDTIME SNACK NOCTURNAL FEEDS (g CH2O/kg/feed or mg CH2O/kg/min) DAILY TOTALS
Comments:
Servings
Fat (g)
Protein (g)
CH2O (g)
Energy (kcal)
Nutritionist
TABLE 16-7. Glycogen Storage Disease Type I Clinical Summary Sheet Name: Date of Birth: __________/__________/__________ Mo Day Year Medications:
Date Physical Data
Lt/Ht mo/d/yr (cm) Wt (kg) HC (cm) GLU (mg/dL) Plasma 1 TAG (mg/dL) Serum Chol (mg/dL)
Hospital Number: Age Diagnosed:
Supplements:
Laboratory Data
Lactate [P/S] (mg/dL) Uric Acid [P/S] (mg/dL) Albumin (g/dL) Hct (%) Hgb (g/dL) Fat (g) % energy
Nutrient Intake Data nighttime feeding

Pro (g) % energy CH2O (g/kg) % energy Energy (kcal) GLU (mg/kg/min)
Triacylglycerol
REFERENCES
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. Ambruso DR, McCabe ERB, Anderson D, et al: Infectious and bleeding complications in patients with glycogenosis type Ib. Am J Dis Child 1985;139:691-697. American Dietetic Association. Exchange Lists for Meal Planning. Chicago: American Dietetic Association, 1995. Arnold GL, Vladutiu CJ, Kirby RS: Protein insufficiency and impaired growth in children with PKU. J Inher Metab Dis 2000;23 Suppl 1:29A. Behrman RE, Kleigman RM, Arvin AA (eds): Nelson Textbook of Pediatrics, ed 15. Philadelphia: WB Saunders Co, 1996. Bier DM, Leake RD, Hayward MW, et al: Measurement of "true" glucose production rates in infancy and childhood with 6,6-dideuteroglucose. Diabetes 1977;26:1016-1023. Chen YT: Type I glycogen storage disease: Nine years of management with cornstarch. Eur J Pediatr 1993;152 (Suppl 1): S56-S59. Chen YT:: Glycogen storage diseases. In Scriver CR, et al (eds): The Metabolic and Molecular Bases of Inherited Disease, ed 8. New York: McGraw-Hill Medical Publishing Division, 2001, pp 1521-1552 Chen YT, Cornblath M, Sidbury JB: Cornstarch therapy in type I glycogen storage disease. N Engl J Med 1984;310:171-175. Fernandes J: The effect of disaccharides on the hyperlactacidaemia of glucose-6-phosphatase-deficient children. Acta Paediatr Scand 1974;63:695-698. Fernandes J, Alaupovic P, Wit JM: Gastric drip feeding in patients with glycogen storage disease type I: Its effects on growth and plasma lipids and apolipoproteins. Pediatr Res 1989;25:327-331. Fernandes J: Leonard JV, Moses SW, et al: Glycogen storage disease: Recommendations for treatment. Eur J Pediatr 1988;147:226-228. Fernandes J, Smit GMA: The glycogen storage diseases. In Fernandes J, et al (eds). Inborn Metabolic Diseases: Diagnosis and Treatment, ed 3. New York: Springer, 2000, pp 314-318. Fomon SJ, Ziegler EE: Water and renal solute load. In Fomon SJ (ed) Nutrition of Normal Infants. St.Louis: Mosby Books, 1993. Food and Nutrition Board, Committee on Dietary Allowances: Recommended Dietary Allowances, eds 9 and 10. Washington, DC: National Academy of Sciences, 1980 and 1989. Gitzelmann R, Bosshard NU: Defective neutrophil and monocyte functions in glycogen storage disease type Ib: A literature review. Eur J Pediatr 1993;152 (Suppl 1):S33-S38. Goldberg T, Slonim AE: Nutrition therapy for hepatic glycogen storage diseases. J Amer Diet Assoc 1993;93:14231430. Greene HL, Slonim AE, Burr IM, Moran JR: Type I glycogen storage disease: Five years of management with nocturnal intragastric feeding. J Pediatr 1980;96:590-595. Gropper SS, Olds SJ, Gross KC: The galactose content of selected fruits and vegetable baby foods: Implications for infants on galactose-restricted diets. J Amer Diet Assoc 1992;92 (Suppl):A-30. Gross KC: Changes in free galactose, myo-inositol, and other monosaccharides in normal and non-ripening mutant tomatoes. Phytochemistry 1983;22;1137-1139. Gross KC, Acosta PB: Fruits and vegetables are a source of galactose: Implications in planning the diets of patients with galactosaemia. J Inher Metab Dis 1991;14:253-258. Hayde M, Windhalm K: Effects of cornstarch treatment in very young children with type I glycogen storage disease. Eur J Pediatr 1990;149:630-633. Kelly WN, Rosenbloom FM, Seegmiller JE, Howell RR: Excessive production of uric acid in type I glycogen storage disease. J Pediatr 1968;72:488-496. Lee PJ, Patel JS, Fewtrell M, et al: Bone mineralization in Type I glycogen storage disease. Eur J Pediatr 1995;154:483-487. MacLean W, Graham G: Pediatric Nutrition in Clinical Practice. Menlo Park, Calif: Addison-Wesley Publishing, Co, 1982. Matthews RH, Pehrsson PR, Farhat-Sabet M: Sugar Content of Selected Foods: Individual and Total Sugars. Home Economics Research Report No. 48. US Govt Printing Office, 1987. Meites S (ed): Pediatric Clinical Chemistry: Reference Normal Values, ed 3. Washington, DC: AACC Press, 1989. Moses S: Pathophysiology and dietary treatment of the glycogen storage diseases. JPEN 1990;11:155-174. Parker PH, Ballew M, Greene HL: Nutrition management of glycogen storage disease. Ann Rev Nutr 1993;13:83-109. Perlman M, Aker M, Slonim AE: Successful treatment of severe type I glycogen storage disease with neonatal presentation by nocturnal intragastric feeding. J Pediatr 1979;94:772-774. Slonim AE, Terry A, Lacy WW, et al: Nocturnal intragastric therapy in type I glycogen storage disease: Effect on hormonal and amino acid metabolism. Metabolism 1979;28:707-715. Smit GPA, Berger R, Potasnick R, et al: The dietary treatment of children with type I glycogen storage disease with slow release carbohydrate. Pediatr Res 1984;18:879-881.
32. Smit GPA, Ferndandes J, Leonard JV, et al: The long-term outcome of patients with glycogen storage diseases. J Inher Metab Dis 1990;13:411-418. 33. Smith CA, Nelson NM: The Physiology of the Newborn Infant, ed 4. Springfield, IL: Charles C Thomas Publisher, 1976. 34. Smith JL, Heymsfield SB: Enteral nutrition support: Formula preparation from modular ingredients. JPEN 1983;7:280-288. 35. Stanley CA, Mills JL, Baker L: Intragastric feeding in type I glycogen storage disease: Factors affecting the control of lactic acidemia. Pediatr Res 1981;15:1504-1508. 36. Tietz NW (ed): Fundamentals of Clinical Chemistry. Philadelphia, PA: WB Saunders Company, 1976. 37. Ullrich K, Smit GPA: Clinical aspects of glycogen storage disease type I. Summary of the discussions. Eur J Pediatr 1993;152 (Suppl 1):S87-S88. 38. Vici CD, Bartuli A, Mazziotta MRM, Sabetta G: Early introduction of uncooked cornstarch for treatment of glycogen storage disease type I. Acta Paediatr Scand 1990;79:978-979. 39. Viega-da-Cunha M, Gerin I, van Schaftigen E: How many forms of glycogen disease type I. Eur J Pediatr 2000;159:314-318. 40. Visser G, Herwig J, Rake JP: Neutropenia and neutrophil dysfunction in glycogen storage disease type Ic. J Inher Metab Dis 1998;21:227-231. 41. Visser G, Rake JP, Fernandes J, et al: Neutropenia, neutrophil dysfunction, and inflammatory bowel disease in glycogen storage disease type Ib: Results of the European study on glycogen storage disease type I. J Pediatr 2000;137;187-191. 42. Wendel U, Schroten H, Burdach S, Wahn V: Glycogen storage disease type Ib: Infectious complications and measures for prevention. Eur J Pediatr 1993;152 (Suppl 1):S49-S51. 43. Wolfsdorf JI, Ehrlich S, Landy HS, Crigler JF: Optimal daytime feeding regimen to prevent postprandial hypoglycemia in type I glycogen storage disease. Am J Clin Nutr 1992;56:587-592. 44. Wolfsdorf JI, Plotkin RA, Laffel LMB, Crigler JF: Continuous glucose for treatment of patients with type I glycogen storage disease: Comparison of the effects of dextrose and uncooked cornstarch on biochemical variables. Am J Clin Nutr 1990;52:1043-1050. 45. Yudkoff M, Nisim I, Stanley C, et al: Glycogen storage disease: Effects of glucose infusions on [15N] glycine kinetics and nitrogen metabolism. J Pediatr Gastroenterol Nutr 1984;3:81-88.
PROTOCOL 17 Hereditary Fructose Intolerance Nutrition Support of Infants, Children, and Adults
I. Introduction
Hereditary fructose intolerance (HFI) is caused by a deficiency in activity of fructose-1-phosphate aldolase (aldolase B) (Figure P), an enzyme normally present in liver, intestine, and kidney cortex (1, 6, 9, 13, 14). Incidence has been estimated at 1/20,000 to 1/40,000 live births (19).
Glycogen Glucose
Sorbitol Sorbitol dehydrogenase Hexokinase Sucrose Fructokinase Fructose
Glucose-6-phosphate
Fructose-6-phosphate
Fructose-1-phosphate* Fructoaldolase B
Fructose-1:6-diphosphate* Fructoaldolase B
Glyceraldehyde
Dihydroxyacetone phosphate
Glyceraldehyde-3-phosphate
2-phosphoglycerate = site of enzyme malfunction * Accumulates in untreated HFI Pyruvate/lactate
Figure P. Fructose metabolism in hereditary fructose intolerance Fructoaldolase B deficiency results in accumulation of fructose-1-phosphate in tissues that possess fructokinase, which causes depletion of inorganic phosphate and ATP. Whether liver and renal impairment is due to the toxic effect of fructose-1-phosphate, the fall in tissue ATP content, or both, is unclear. Fructose-induced hypoglycemia results from inhibition of both gluconeogenesis and glycogenolysis (6). Interaction of phosphorylase a with its substrates, glycogen and inorganic phosphate, is blocked after fructose administration, and this block could result from a combination of ATP depletion and direct inhibition of activation of phosphorylase a by fructose-1-phosphate. Such an inhibition explains why fructose-induced hypoglycemia cannot be corrected by administration of glucagon (20, 31). Symptoms appear only when fructose, sucrose, or sorbitol is introduced into the diet (10). Symptoms are not specific, so diagnosis may be overlooked. Symptoms may occur early in life and be severe; later they are less marked as the child develops an aversion to sweets (31). Vomiting is such a constant finding that its absence in a subject ingesting fructose argues against the diagnosis. Poor feeding, diarrhea, and later, failure to thrive are less frequent. Some manifestations reflect liver impairment: hepatomegaly, bleeding tendency, jaundice, edema or ascites (11, 12). Postprandial hypoglycemic manifestations such as pallor, seizures, and shock are infrequent; they are
318 Hereditary Fructose Intolerance 2001 Ross Products Division
present in about one-third of patients and occasionally lead the pediatrician to suspect fructose intolerance (31). The main laboratory findings concern dysfunction of the liver. These are frequent and severe in infants with early clinical manifestations and may be lacking later: deficient clotting factors with occasional pattern of consumption-CoAgulopathy, hypoalbuminemia, hypocholesterolemia, increased transaminase activity, elevated blood concentrations of tyrosine (TYR) and methionine (MET), and hyperbilirubinemia. Other findings such as moderate proteinuria, glucosuria, generalized hyperaminoaciduria, metabolic acidosis with loss of bicarbonate, and high urinary pH are due to renal proximal tubular dysfunction (31). Histologic examination of liver after clotting factors have returned to normal shows fibrosis without evidence of inflammation, diffuse fatty vacuolization in liver cells, and necrosis of a few scattered hepatocytes (31).

Some infants with severe liver failure may die if the diagnosis is overlooked (8). In the majority of cases, outcome is excellent. With a fructose-free diet, vomiting disappears immediately, as does the bleeding tendency, in less than 24 hours. The renal tubular dysfunction disappears 2 or 3 days later, and the general condition improves within a few days. All the clinical and laboratory findings are normal within 1 or 2 weeks, except for hepatomegaly which persists for many years. Normal growth in length and weight is reached within 2 or 3 years. Liver biopsy shows rapid disappearance of intralobular fibrosis and a decrease of periportal fibrosis; in contrast, fatty vacuolization of liver cells persists or increases and its distribution changes from the diffuse to the periportal type. Hepatomegaly and steatosis disappear with the fructose-free diet between the ages of 5 and 10 years (31).

A. The Defect 1. HFI results from defect in fructoaldolase (aldolase B) in liver, kidney cortex, and small intestine (9-11). B. Clinical Evaluation (16, 17, 19, 24, 27, 28, 33) 1. Infants or children who have any of the following clinical or laboratory signs should be evaluated for HFI. a. Acute exposure: 1) Apathy, lethargy, coma, convulsions, dizziness, nausea, sweating, trembling, vomiting. b. Chronic exposure: 1) Abdominal distention, diarrhea, drowsiness, apathy, edema, ascites, failure to thrive, hemorrhages, hepatomegaly, jaundice, incessant crying or irritability, poor feeding, poor growth, vomiting (7). 2. Protracted exposure to fructose results in fibrosis, steatosis, cirrhosis of liver, and aversion to sweets. 3. Laboratory findings: a. Urinary: 1) Increased amino acids, bicarbonate; increased fructose; increased glucose, lactate, phosphorus, potassium, protein, and urate. b. Blood: 1) Increased bilirubin, fructose, lactate, liver enzymes, MET, TYR, and urate 2) Decreased bicarbonate,-CoAgulation factors, glucose, pH, phosphorus, potassium, and proteins. c. Anemia, thrombocytopenia. C. Differential Diagnosis 1. Molecular analysis of DNA is safest method of diagnosis (1, 2, 4-6, 13, 15-22, 30-32). 2. Assay of aldolase B activity in liver tissue obtained by needle biopsy when liver insufficiency has regressed after initiation of fructose-free diet (27).
IV. Rationale For Nutrition Support

A. Correct primary imbalance in Metabolic Relationships 1. Remove or restrict fructose, sorbitol, and sucrose to lowest amount compatible with nutritionally adequate diet.
2001 Ross Products Division Hereditary Fructose Intolerance 319

A. Growth and Nutrition Status 1. Support normal growth rate in infants and children and maintain appropriate weight for height in adults. 2. Maintain normal nutrition status. a. Prevent catabolism. b. Avoid prolonged fasting. B. Laboratory Indices 1. Maintain normal blood concentrations of: a. Bicarbonate. b. Coagulation factors. c. Glucose, lactate. d. Liver enzymes. e. MET, TYR. f. Phosphorus, potassium. g. Proteins. h. Urate. 2. Maintain normal liver and renal function.

A. Fructose, Sorbitol, Sucrose 1. Remove all foods containing fructose, sorbitol, or sucrose from diet until 3 years of age (3). 2. After age 3 years, 10 to 20 mg/kg body weight may be ingested if growth, laboratory indices and liver and renal functions remain normal (26, 33). B. Protein 1. Recommended Daily Nutrient Intakes are somewhat higher than for normal infants, children, and adults (Table 17-1, p 319). 2. Protein intakes may be up to 2 times recommended without any adverse effects if liver function is normal. C. Energy 1. Recommended Daily Nutrient Intakes are same as for normal infants, children, and adults (Table 17-1, p 319). 2. Intake should be sufficient to maintain normal weight gain in infants and children and maintain appropriate weight for height in adults. D. Fluid 1. Prescribe amount that will supply water requirements (Table 17-1, p 319). Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL to children and adults for each kcal ingested. 2. Requirements may be higher than recommended secondary to fever.

A. Fructose, Sorbitol, Sucrose 1. See Table 17-2, p 320 for foods allowed and excluded (25, 28, 29). a. For information on nutrient content of beikost (baby food), contact the following manufacturers: Beech-Nut Nutrition Gerber Products Company Heinz North America Corporation c/o Consumer Affairs Consumer Affairs 100 S 4th Street 445 State Street USX Tower St Louis, MO 63102 Fremont, MI 49413-0001 600 Grant Street, 7th Floor 1-800-233-2468 1-800-443-7237 Pittsburgh, PA 15219 1-800-872-2229
320 Hereditary Fructose Intolerance
b. Up-to-date lists of product ingredients are necessary to determine which foods may be included since ingredients change often. Request both nutrient composition and ingredients list. B. Protein 1. Calculate amount of Similac With Iron (use until 2nd birthday), beikost, whole cow's milk, or table foods (Tables 17-3 to 17-5, pp 321-321) required to fill protein prescription. a. Protein intakes up to 2 times greater than Recommended Dietary Allowances (RDAs) (18) are not cause for concern unless liver function is abnormal. 2. Add beikost or table foods to provide variety in taste, color, and texture after infant is 3 to 4 months old or is developmentally ready (Table 17-5, p 321, for appropriate portion sizes). C. Energy 1. Calculate energy provided by Similac, beikost, whole cow's milk, or table foods (Tables 17-3 to 17-5, pp 321-321) required to fill energy prescription. 2. If energy prescription is not met, increase number of food servings. D. Fluid 1. If Similac powder or concentrated liquid is prescribed, mix to obtain formula that provides 20 to 27 kcal/fl oz (Table 17-4, p 321). 2. See Table 17-5, p 321, for approximate amount of Similac to offer. 3. Offer infants additional fluid between Similac feeds of >20 kcal/fl oz. E. Diet Guide 1. Provide parents, caretakers or patient with completed Diet Guide (Table 17-6, p 322) with each diet change.

A. Nutrient Adequacy 1. Determine if diet provides nutrients in amounts prescribed in Section VI, Establish Prescription, p 315. 2. Check diet to determine if it supplies RDIs of protein, minerals, and vitamins. a. See Table 17-1, p 319, and Appendices 6, 13 and 14, pp A-7, A-14 and A-15. b. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. c. If diet provides < 100% of RDIs, supplement diet if laboratory tests indicate need. Vitamins A, C, and folate may be low. d. Care must be taken to ensure that supplements do not contain fructose, sorbitol, or sucrose.

A. Protein Status 1. Evaluate plasma albumin concentration every 3 months until patient is 1 year of age and twice yearly thereafter (Appendix 17, p A-18, for standards). 2. If plasma albumin concentration is below normal for age: a. Increase prescribed amount of protein by 5% to 10% and reevaluate plasma albumin concentration in 1 month. b. If plasma albumin concentration remains low, repeat above process until concentration is in normal range. B. Iron Status 1. Plasma ferritin concentration. a. Evaluate at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17, p A-18, for standards). b. If plasma ferritin concentration is below normal for age: 1) Increase iron intake to 2 mg/kg body weight with supplements (ferrous sulfate) 2) Evaluate plasma ferritin concentration monthly. 3) Continue iron supplements until plasma ferritin is in normal range.
2. Complete blood count. a. Evaluate hemoglobin and hematocrit concentrations at 6, 9, and 12 months of age and yearly thereafter (Appendix 17, p A-18, for standards). C. Growth Status 1. Length/height and weight a. Measure monthly until patient is 1 year old, every 3 months to 4 years of age, and every 6 months thereafter. Plot measurements for infants and children on NCHS growth charts. b. Maintain length/height and weight between 10th and 90th percentiles. Some normal infants and children will fall above or below these percentiles. If length/height or weight falls below usual growth channel: 1) Increase prescribed protein and energy by 5% to 10% and remeasure after 1 month. 2) If length/height or weight remains low, check to make sure all fructose, sorbitol, and sucrose are deleted from diet and repeat above process until usual growth channel is achieved. D. Nutrient Intake 1. Maintain records of food intake for 3 days monthly (Appendices 24 and 25, pp A-26 and A-27). 2. Evaluate intakes of protein, energy, minerals, and vitamins. Determine if foods used contain any fructose, sorbitol or sucrose. 3. If diet provides < 100% of RDIs, supplement with needed minerals, and vitamins if not provided by beikost or table foods and if laboratory test results indicate need. Vitamins A, C, and folate may require supplementation. E. Clinical Summary. 1. A summary record of growth, laboratory, and nutrient intake data is useful for patient management (Table 17-7, p 323)
A. Example 1 Establish and fill prescription for newborn weighing 3.5 kg using Recommended Daily Nutrient Intakes from Table 17-1, p 319, and average nutrient content from Table 17-3 through 17-5, p 321-321. 1. Establish prescription
Protein Energy Fluid 3.0 kg 140 kcal/kg 210 mL/kg x x x 3.5 kg 3.5 kg 3.5 kg = = = 10.5 g 490 kcal 735 mL Measure
1
Medical Food Mixture Similac with Iron 24 Ready to Feed Total per day Total per kg Protein (g) 10.1 10.1 2.9 490 490 120 Energy (kcal)
530 mL
Approximate osmolarity of medical food mixture is <450 mosm/L. Estimated potential renal solute load is < 75 mosm. 1 To meet energy needs, 175 mL of Similac (20 kcal/fl oz) per kg of body weight must be fed. If infant will not ingest 175 mL Ready to Feed Similac/kg, use Similac Concentrated Liquid and dilute to make 24-27 kcal/fl oz. 2 If 2.9 g protein/kg not tolerated, lower protein to 2.2 g/kg and use Pro-Phree (Appendix 11, p A-10) to help supply energy, minerals and vitamins.

A. Rationale 1. Infectious illness and trauma both cause catabolism of body protein (34). 2. Well-nourished persons with HFI respond to infection and trauma as do normal persons.
B. Objectives of Nutrition Support 1. Maintain hydration and electrolyte balance. a. Offer infants and toddlers Pedialyte Oral Electrolyte Maintenance Solution ad libitum (Appendix 9, p A-9). 2. Depress catabolism. a. Enhance energy intake when possible by offering Polycose Glucose Polymers liquid or powder (Appendix 9, p A-9) or Pro-Phree Protein-Free Energy Module With Iron, Vitamins & Minerals (Appendix 11, p A-10) added to water or Pedialyte, if tolerated. b. Return patients to Similac or usual diet as rapidly as possible. 1) Begin with 1/2 original strength of Similac formula 2) Increase to original strength as tolerated.
XII. Prescription and Over-The-Counter Medications

A. Contact local pharmacist or drug manufacturer for current information on excipients in drugs that may contain fructose, sorbitol or sucrose. B. Sucrose was present in 63% of vitamin and mineral preparations evaluated and sorbitol was also added to some products (23).
Hereditary Fructose Intolerance 323
TABLE 17-1. Recommended Daily Nutrient Intakes (Ranges) for Infants, Children, and Adults with Hereditary Fructose Intolerance
Age Protein (g/kg) Infants 0 to < 3 mo 3 to < 6 mo 6 to < 9 mo 9 to < 12 mo 3.0 < 4.5 3.0 < 4.5 2.5 < 4.0 2.5 < 4.0 (g/day) Girls and Boys 1 to < 4 yr 4 to < 7 yr 7 to < 11 yr Women 11 to <15 yr 15 to <19 yr 19 yr Men 11 to <15 yr 15 to <19 yr 19 yr
1 2 1
Nutrient Energy1 (kcal/kg) 120 (145 115 (145 110 (135 105 (135 - 95) - 95) - 80) - 80) (kcal/day) 1,300 ( 900 - 1800) 1,700 (1300 - 2300) 2,400 (1650 - 3300) 150 - 125 160 - 130 145 - 125 135 - 120 (mL/day) 900 - 1,800 1,300 - 2,300 1,650 - 3,300 Fluid2 (mL/kg)
30 < 60 35 < 70 40 < 80
50 < 100 50 < 100 50 < 100
2,200 (1500 - 3000) 2,100 (1200 - 3000) 2,100 (1400 - 2500)
1,500 - 3,000 1,200 - 3,000 1,400 - 2,500
60 < 120 65 < 130 65 < 130
2,700 (2000 - 3700) 2,800 (2100 - 3900) 2,900 (2000 - 3300)
2,000 - 3,700 2,100 - 3,900 2,000 - 3,300
Modified from reference 18. Under normal circumstances, offer a minimum of 1.5 mL fluid to neonates and 1.0 mL to children and adults for each kcal ingested.
TABLE 17-2. Fructose-, Sorbitol- and Sucrose-Restricted Diet (3)

Foods Allowed BEVERAGES Buttermilk, evaporated milk; coffee; cow's milk; human milk; RCF Ross Carbohydrate-Free Soy Formula Base With Iron; Similac Infant Formula With Iron; tea Foods Excluded Any milks with added fructose, fruit, or flavors that contain honey, molasses, sorbitol or sugar; beer; brandy; rum; vodka; carbonated beverages containing fructose, fruit juice, molasses, sorbitol or sugar; fruit juices or drinks containing fruit juice; liqueur; sherry; vermouth
BREADS, CEREALS AND GRAINS Corn, cornmeal, corn cereals; breads, some French and Italian breads without added sugar, pumpernickel or rye; flour, refined white; oats, oatmeal; pastas made with refined flour; rice, brown or white, rice cereals; Rye Crisp; tortillas, flour; wheat germ; wheat, shredded
All bran; breads or cereals containing fruit, nuts, honey, molasses, sugar, sorbitol, or high fructose corn syrup; Prepared cereals such as cornflakes, Grapenuts, muesli, Rice Krispies, sugar puffs, containing fruits, nuts, honey, molasses, sugar, sorbitol, or high fructose corn syrup
CHEESES/OTHER MILK PRODUCTS Cheese: cheddar, cottage, cream, mozzarella, Neufchatel, Ice cream; ice milk; shakes; sherbets; yogurt with fructose, ricotta, Swiss, pasteurized cheese food (American) all fruit, honey, molasses, sorbitol or sugar without fructose, sorbitol, or sugar; calcium and sodium caseinates; cream; whey; yogurt (plain) DESSERTS None unless made with glucose, hydrolyzed corn starch, corn syrup, or Polycose Glucose Polymers EGGS All
Any made with fructose, fruit, fruit juice, high fructose corn syrups, honey, molasses, sorbitol, or sugar
Any to which fructose, fruit, high fructose corn syrup, honey, molasses, sorbitol or sugar has been added
FATS Bacon; butter; cream; cream cheese; lard; margarines; non-dairy coffee creamers free of fructose, high fructose corn syrup, honey, molasses, sorbitol and sugar; oils; shortening FRUITS/JUICES Avocado, rhubarb LEGUMES (BEANS & PEAS), NUTS, SEEDS Tempeh, tofu MEAT, FISH AND OTHER SEAFOOD, POULTRY Plain meat, fish and other seafood, poultry
Mayonnaise and salad dressings to which fructose, fruit, high fructose corn syrup, honey, molasses, sorbitol or sugar have been added
All others
All others
Any to which fructose, fruit, high fructose corn syrup, honey, molasses, sorbitol, or sugar is added in processing or cooking
SUGARS/SWEETENERS None
Any containing fructose, high fructose corn syrup, honey, molasses, sorbitol, sugar
VEGETABLES Asparagus; broadbeans, immature; celery; chard, Swiss; cucumber; kale; lettuce; mustard greens; mushrooms; parsnips; peas, green; potato, white, mature; spinach; turnip greens; watercress
All others
Foods Allowed MISCELLANEOUS Cornstarch; gelatin without fruit or sugar; dextrin, galactose, glucose, maltose, lactose; Polycose Glucose Polymers; Pro-Phree Protein-Free Energy Module With Iron, Vitamins & Minerals
Foods Excluded Carob powder; catsup; chile sauces; chocolate; drugs, mineral/vitamin preparations containing fructose, sorbitol, or sugar; seasonings containing added fructose, high fructose; syrup; honey; molasses; sorbitol; sugar; maple syrup; jams; jellies: preserves
TABLE 17-3. Exchange Lists for Children and Adults with Hereditary Fructose Intolerance
Food Cow's milk, whole Meat Measure 8 fl oz. 1 oz 8.0 7.0 Protein (g) 240 75 Energy (kcal)
Fat Varies 0.0 45 Starch/bread Varies 3.0 80 Vegetables2 cooked 1/2 cup 2.0 25 raw 1 cup 2.0 25 Similac With Iron, concentrated liquid 100 mL 2.8 136 1 Modified from Exchange Lists for Weight Maintenance. Chicago: The American Dietetic Association, 1995. 2
See Table 17-2 for vegetables to exclude.
TABLE 17-4. Amounts of Similac Concentrated Liquid or Powder Required to Make Formulas of 24 or 27 kcal/fl oz
Concentration Concentrated Liquid 24 kcal/fl oz 27 kcal/fl oz
1 2
Similac Powder (g) 18.72 21.02 (water to make) 118 mL1 118 mL (mL) 71 mL 76 mL (water to make) 118 mL1 118 mL
4 fl oz 1 scoop of Similac powder = 8.5 g
TABLE 17-5. Foods that Will Supply Daily Nutrient Needs of Infants with Hereditary Fructose Intolerance
Food/Amount 0 to <3 Similac With Iron, mL/kg 2, 3 Infant cereals, Tbsp/kg Meats, pureed, Tbsp/kg Vegetables, pureed, Tbsp/kg
1 2 1
Age of Infant (mo) 3 to <6 125 - 140 1-2 0 1 6 to <9 120 - 135 2 0.5 - 1 1 9 to <12 115 - 130 2 0.5 - 1 1 130 - 150 0 0 0
2, 4
Mix concentrated liquid or powder to yield 24 to 27 kcal/ fl oz. Introduce teaspoon-size portions after infant is 3 to 4 months of age or developmentally ready. Allow 3 to 5 days between addition of each new food to determine if infant is allergic to it. Gradually increase portion sizes until recommended amounts are being ingested. 3 Use only cereals free of fruit, fruit juice or sugar. 4 See Table 17-2, p 320, for vegetables to exclude.
TABLE 17-6. Hereditary Fructose Intolerance Diet Guide Name:_____________________________________________ Date: _________/________/________
Mo Day Year
Birthdate: : _________/________/________ Age: _______________________

Mo Day Year
Length/Height: ____________________ (cm/in) Weight: __________________ (kg/lb)

Medical Food Similac with Iron Similac with Iron, powder Amount mL g g g mL mL Whole milk cups Protein (g) Energy (kcal)
Add water to make ______________________ mL _______________ (fl oz)
Beikost or table foods Cereals/Starch/Bread Fat Meat Vegetables Total per day Total per kg
Tbsp/Exchanges
Comments:
Nutritionist
TABLE 17-7. Hereditary Fructose Intolerance Clinical Summary Sheet Name: Date of Birth: __________/__________/__________ Mo Day Year
Date
Length/ Height (mo/d/yr) (cm)
Hospital Number:
Physical Data
Weight Head Circum (cm) Glucose Potassium
Laboratory Data
Phosphorus Ferritin Albumin Hgb Uric Acid (mg)

Fructose Sucrose Sorbitol (g) Protein Energy
(kg)
(mg/dL)
(mEq/L)
(mg/dL)
(ng/mL)
(g/dL)
(g/dL)
(g)
(kcal)
REFERENCES
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. Ali M, Rellos P, Cox TM: Hereditary fructose intolerance. J Med Genet 1988;35;353-365. Ali M, Rosiem U, Cox TM: DNA diagnosis of fatal fructose intolerance from archival tissue. Q J Med 1993;8:25-30. Bell L, Sherwood WG: Current practices and improved recommendations for treating hereditary fructose intolerance. J Amer Diet Assoc 1987;87:721-728. Brooks CC, Buist N, Tuerck J, Tolan DR: Identification of a splice-site mutation in the aldolase B gene from an individual with hereditary fructose intolerance. Am J Hum Genet 1991;49:1075-1081. Brooks CC, Tolan DR: A partially active mutant aldolase B from a patient with hereditary fructose intolerance. FASEB J 1994;8:107-113. Brooks CC, Tolan DR: Association of the widespread A149P hereditary fructose intolerance mutation with newly identified sequence polymorphisms in the aldolase B gene. Am J Hum Genet 1993;52:835-840. Burmeister LA. Valdivia T, Nuttall FQ: Adult hereditary fructose intolerance. Arch Intern Med 1991;151;773-776. Collins J: Time for fructose solutions to go. Lancet 1993;341-600. Cox TM: Aldolase B and fructose intolerance. FASEB J 1994;8:62-71. Cox TM: Fructose intolerance: Diet and inheritance. Proc Nutr Soc 1991;50:305-309. Cox TM: Hereditary fructose intolerance. Bailliere's Clin Gastroent 1990;4:61-78. Cross NCP, Cox TM: Hereditary fructose intolerance. Intl J Biochem 1990;22:685-689. Cross NCP, Cox TM: Molecular analysis of aldolase B genes in the diagnosis of hereditary fructose intolerance in the United Kingdom. Q J Med 1989;271:1015-2020. Cross NCP, Cox TM: Partial aldolase B gene deletions in hereditary fructose intolerance. Am J Hum Genet 1990;47:101-106. Dazzo C, Tolan DR: Molecular evidence for compound heterozygosity in hereditary fructose intolerance. Am J Hum Genet 1990;46:1194-1199. Edstrom CS: Hereditary fructose intolerance in the vomiting infant. Pediatrics 1990;85:600-603. Endres W, Sierck T, Shin YS: Clinical course of hereditary fructose intolerance in 56 patients. Acta Paediatr Jpn 1988;30:452-456. Food and Nutrition Board, Committee on Dietary Allowances: Recommended Dietary Allowances, eds 9 and 10. Washington, DC: National Academy of Sciences, 1980 and 1989. Froesch ER, Wold HP, Baitsch H: Hereditary fructose intolerance. An inborn defect of hepatic fructose-1phosphate splitting aldolase. Am J Med 1963;34:151-167. Gopher A, Viasman N, Mandel H, Lapidot A: Determination of fructose metabolic pathways in normal and fructose-intolerant children: A13C NMR study using [U-13C] fructose. Proc Natl Acad Sci 1990;87:5449-5453. Kaiser UB, Hegele RA: Case report: Heterogeneity of aldolase B in hereditary fructose intolerance. Am J Med Sci 1991;302:364-368. Kajihara S, Mukai T, Arai Y, et al: Hereditary fructose intolerance caused by a nonsense mutation of the aldolase B gene. Am J Hum Genet 1990;47:S62-S67. Kumar A, Aitas AT, Hunter AG, Beaman DC: Sweeteners, dyes and other excipients in vitamin and mineral preparations. Clin Pediatr 1996;Sept:443-450. Labrune P, Chatelon S, Huguet P, Odievre M: Unusual cerebral manifestations in hereditary fructose intolerance. Arch Neurol 1990;47:1243-1244. Matthews RH, Pehrsson PR, Farhat-Sabet M: Sugar Content of Selected Foods: Individual and Total Sugars. Home Economics Research Report No. 48. US Govt Printing Office, 1987. Mock DM, Perman JA, Thaler M, Morris RC: Chronic fructose intoxication after infancy in children with hereditary fructose intolerance. N Engl J Med 1983;309:764-770. Odievre M: Disorders of fructose metabolism. In Fernandes J, et al (eds): Inborn Metabolic Diseases: Diagnosis and Treatment. New York: Springer Verlag, 1990, pp 107-112. Odievre M, Gentil C, Gautier M, Alagille D: Hereditary fructose intolerance in childhood. Diagnosis, management and course in 55 patients. Am J Dis Child 1978;132-605-608. Rumessen JJ: Fructose and related food carbohydrates. Sources, intake, absorption and clinical implications. Scand J Gastroenterol 1992;27:819-828. Santamaria R, Scarano MI, Esposito G, et al: The molecular basis of hereditary fructose intolerance in Italian children. Eur J Clin Chem Clin Biochem 1993;31:675-678. Steinmann B, Gitzelmann R, Van den Berghe G: Disorders of fructose metabolism. In Scriver CR, et al (eds): The Metabolic and Molecular Bases of Inherited Disease, ed 8. New York: McGraw-Hill Medical Publishing Division, 2001, pp 1489-1520. Tolan DR, Brooks CC: Molecular analysis of common aldolase B alleles for hereditary fructose intolerance in North America. Biochem Med Metab Biol 1992;48:19-25. van den Berghe G: Disorders of fructose metabolism. In Fernandes J, et al (eds): Inborn Metabolic Diseases, ed 3. New York: Springer, 2000, pp 111-116. Wannamacher RW: Key role of various individual amino acids in host response to infection. Am J Clin Nutr 1977;30:1269-1280.
32. 33. 34.
PROTOCOL 18 Pyruvate Carboxylase Deficiency Nutrition Support of Infants and Children With PROVIMIN Protein-Vitamin-Mineral Formula Component With Iron
I. Introduction
Pyruvate can be converted to phosphoenolpyruvate (PEP), oxaloacetate (OAA), acetyl-CoA (AcCoA), alanine, or lactate. The enzymes involved are pyruvate kinase (PK), phosphoenolpyruvate carboxykinase (PEPCK), pyruvate dehydrogenase (PDH), pyruvate carboxylase (PC), alanine aminotransferase (AAT), and lactate dehydrogenase (LDH) (10, 32).
LDH
Carbohydrate
Pyruvate*
AAT
Lactate*
Glucose
PK
PC Biotin
PDH, Thiamin
Alanine*
AcCoA PEP
PEPCK
Fatty Acids
OAA
Aspartate
Site of enzyme malfunction * Accumulates in untreated PC deficiency
Figure Q. Metabolic fates of pyruvate (modified from reference 32) PC, a biotin-requiring enzyme, is located in the mitochondrial matrix where it catalyzes the first step in gluconeogenesis and supplies OAA from pyruvate. OAA is in equilibrium with aspartate. PC deficiency may result from biotinidase deficiency or from a structural change in the PC apoprotein (10, 32). Aspartic acid, made from OAA, or used to synthesize OAA, may become deficient in severe PC deficiency. With depletion of aspartate, the urea cycle does not function normally and citrullinemia, hyperammonemia, and hyperlysinemia result. Aspartate is important in the shuttle mechanism that transfers reducing equivalents across the mitochondrial membrane. Inadequate concentrations of aspartate in the cytosol result in an increase in the lactate/pyruvate ratio (9, 10, 32). Clinical symptoms of PC deficiency are heterogeneous ranging from a severe infantile (A and B) type to a benign variant (C) (3, 17, 18, 33, 45).

Patients with no PC apoenzyme activity often die in infancy. Patients with milder forms of PC deficiency (> 10% activity) treated with a moderate carbohydrate and protein and low-fat diet supplemented with citrate, glutamine (GLUNH2), aspartate, asparagine (ASPNH2), and thiamin have had good outcomes (4, 17, 33, 39, 45).

A. The Defect 1. Defective functioning of PC results from defective PC apoenzyme, biotinidase deficiency, or absence of an inhibitor of TPP-ATP phosphoryltransferase (40).
330 Pyruvate Carboxylase Deficiency
B. Clinical Evaluation 1. Any infant or child who presents with the following symptoms should be evaluated for PC deficiency: a. Clinical: 1) Anorexia, irritability, lethargy, delayed neurologic development, coma, mental retardation, hepatomegaly, hypotonia (4, 8, 15, 16, 30, 32). b. Laboratory: 1) Metabolic acidosis; -ketoglutarate in urine; elevated lactate/pyruvate ratio; elevated lactate and pyruvate; elevated acetoacetate/-hydroxybutyrate ratio; elevated blood ammonia; hypoglycemia; elevated plasma alaniSne (ALA), citrulline (CIT) (9), lysine (LYS), proline (PRO), absent or decreased PC activity in cultured skin fibroblasts, leukocytes or hepatocytes. 2. Prenatal diagnosis may be made by measuring PC activity in amniocytes and chorionic villus cells (4, 6, 8, 12, 14-16, 20, 25, 32). 3. See references 2, 3, 8, 27, 32, 34, 40, 44, and 46 for methods of diagnosis.

A. Correct Primary Imbalance in Metabolic Relationships 1. Provide energy from major nutrients as follows: 15% protein, 50% carbohydrate, 35% fat. 2. Administer sodium bicarbonate as needed to maintain normal acid-base status (2, 7, 10, 19). B. Stimulate Pyruvate Dehydrogenase Activity. 1. Supplement with oral thiamin (5, 7, 19, 20). C. Supply Product of Blocked Primary Pathway 1. Supplement with precursors of OAA; ASP, citric acid, GLUNH2 (2, 4, 5, 21, 28).

A. Maintain Following Analytes in Plasma in Ranges Noted or in Normal Range for Age Established by Laboratory Used:
Analyte Acetoacetate -Hydroxybutyrate Citric acid Glucose Lactate Pyruvate Ammonia 0.03 - 0.30 mmol/L < 0.100 mmol/L 0.060 - 0.160 mmol/L 3.9 - 6.1 mmol/L 0.5 - 2.0 mmol/L (37) 0.035 - 0.100 mmol/L (37) 0 - 35 mol/L (37)
B. Maintain Following Plasma Amino Acids and Glucose in Ranges Noted or in Normal Range for Age Established by Laboratory Used:
Amino Acid (37) Alanine Arginine Aspartate CIT Glutamine LYS PRO 163- 653 34 - 140 1 -25 1 - 55 250 - 823 50 - 254 50 - 273
(mol/L)
Growth, Development, and Nutrition Status 1. Support normal growth rate in infants and children. 2. Support normal development. 3. Maintain normal nutrition status. a. Prevent catabolism.
Pyruvate Carboxylase Deficiency 331
b. Avoid prolonged fasting.

A. Energy 1. Prescribe amount that should support normal weight gain for infants and children and maintain appropriate weight for height in adults (Table 18-1, p 332). 2. Requirements vary widely. 3. For infants who sleep more than 4 hours at night, add uncooked Argo cornstarch (2 g/kg body weight) to last feed at night (43). Warning: Inadequate energy intake will result in growth failure (22). B. Fat (22) 1. Prescribe amount of total fat that promotes goals of nutrition support. a. Supply about 35% of total daily energy as fat (11). 1) Prescribe 3% of total energy as linoleic acid and 1.0% as -linolenic acid. Warning: Essential fatty acid deficiency may occur if intakes of linoleic acid and -linolenic acid are inadequate. C. Protein 1. Prescribe amount that supplies about 15% of total energy for infants (Table 18-1, p 332). D. Carbohydrate 1. Prescribe remaining energy as carbohydrate. E. Thiamin (15, 16 19, 24, 31, 42) 1. Supplement diet with 32-64 mg/kg of thiamin daily. F. Citric Acid, L-Arginine, L-ASPNH2, L-ASP , L-GLUNH2 (15, 21, 28, 29, 31, 41) 1. Supplement diet with any or all nutrients listed in F required to maintain plasma citrate concentrations in normal range. 2. Supplement with citrate daily (up to 7.5 mmol/kg/day, part as sodium and part as potassium salt) (1) to maintain normal plasma citrate and OAA concentrations. 3. Supplement with following amounts of L-amino acids daily, if required. Modify based on plasma concentrations. L-Arginine L-Asparagine L-Aspartic acid L-Glutamic acid L-Glutamine To maintain normal plasma concentration 68 mg/kg 18 - 360 mg/kg 52 mg/kg 460 mg/kg
G. Biotin Has Not Proven To Be of Benefit in Patients With No PC Activity (35). H. Fluid 1. Prescribe amount that will supply water requirements (Table 18-1, p 332). Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL to children and adults for each kcal ingested. 2. Requirements may be higher than recommended secondary to accompanying fever. I. Fasting 1. Instruct parents and/or caretakers to prevent infants from fasting > 4 hours, children > 6 hours, and adults > 8 hours.

A. Fat 1. Determine amount of infant formula with iron, beikost, or table foods (Tables 18-2, p 332, and 18-3, p 333) required to supply about 35% of energy prescription as fat.
332 Pyruvate Carboxylase Deficiency 2001 Ross Products Division
B. Protein 1. Calculate grams of protein required to provide about 15% of energy prescription. 2. Determine protein provided by infant formula with iron, beikost, or table foods (Tables 18-2 and 18-3, pp 332 and 333) required to supply fat prescription. 3. Subtract amount determined above from total protein prescription (Table 18-2, p 332). 4. Supply any remaining prescribed protein with ProViMin (Table 6-4, p 118), skim milk (Appendix 8, A-8), or other fat-free or low-fat protein sources (Table 18-3, p 333). C. Energy 1. Calculate energy supplied by infant formula with iron (until 1st birthday), beikost, or table foods required to supply fat and that supplied by ProViMin (Table 18-2, p 332), skim milk (Appendix 8, A-8), and other protein-containing foods (Table 18-2, p 332). 2. Subtract amount determined above from total energy prescription. a. Use infant formula with iron until 2nd birthday to help supply needed iron. 3. Supply remaining prescribed energy with Polycose Glucose Polymers powder (23 kcal/Tbsp, 3.8 kcal/g) or liquid (2 kcal/mL) (Appendix 9, p A-9), sugar (48 kcal/Tbsp), beikost, or table foods containing little or no fat (Tables 18-2 and 18-3 pp 332 and 333). a. Do not use corn syrup or table sugar for infants because of osmolarity they yield (26). b. Do not use honey for infants because it may contain botulinum toxin (38). 4. Add beikost or table foods after infant is 3 to 4 months old or is developmentally ready to provide variety in taste, color, and texture (Table 18-2, p 332). D. Fluid and Mixing Instructions 1. Boil bottles, nipples, rings and mixing utensils for 5 minutes and cool. Boil more water for 5 minutes and cool to room temperature. 2. Measure or weigh specified amounts of boiled, cooled water; infant formula; ProViMin; carbohydrate; citric acid; and L-amino acids into clean containers. 3. Pour 1/2 of specified amount of boiled, cooled water into clean blender. Running blender at slow speed, gradually add ProViMin and blend mixture for at least 15 seconds. 4. Slowly pour specified amount of infant formula, citric acid, and L-amino acids into blender and continue blending for no longer than 1 to 3 seconds. 5. Dissolve powdered carbohydrate in some of remaining water and pour into ProViMin mixture, mix well, add water to yield prescribed volume and pour into opaque sterilized nursing bottles or cups. Prepared formula not used immediately should be refrigerated and used within 24 hours. Shake well before feeding. 6. Do not use microwave oven to warm formula. Unevenly heated formula can burn infants and steam can make bottles explode. 7. Discard formula remaining in bottle or cup after feeding. 8. Store unopened cans at room temperature. Cover opened can and store in dry place (not in refrigerator). Use within 1 month after opening. 9. Notify parents or caretakers when they may discontinue aseptic technique in making formula. E. Diet Guide 1. Provide parents, caretakers, or patient with completed Diet Guide (Table 18-4, p 335) with each diet change. 2. If necessary, use uncooked Argo cornstarch (2 g/kg body weight, 1:2 ratio cornstarch to water) in daytime feeds to prevent hypoglycemia (43). Warning: Never permit patient to fast > 4 hours if an infant, > 6 hours if child, and less time if patient is febrile, has diarrhea, or is vomiting.

A. Nutrient Adequacy 1. Determine if diet provides nutrients in amounts prescribed in Section VI, Establish Prescription, p 327. a. See Table 18-2, p 332, for composition ProViMin, skim milk, and infant formulas with iron. b. See Appendix 9, p A-9, for composition of Polycose.
2001 Ross Products Division Pyruvate Carboxylase Deficiency 333
2. Check diet to determine if it supplies Recommended Dietary Intakes (RDIs) for minerals and vitamins (Table 6-4, p 118 and Appendices 13 and 14, pp A-14 and A-15). a. See Appendices 4 through 7, pp A-4 to A-7, for complete nutrient composition of infant formulas. b. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. c. If ProViMin mixture provides < 100% of RDIs for infants and < 75% for children and adults, supplement diet with needed minerals and vitamins if not provided by beikost or table foods and laboratory tests indicate need (Appendix 11, p A-10, for composition of supplements). B. Osmolarity 1. If concentration of prescribed medical food mixture is > 27 kcal/fl oz, determine if osmolarity is in acceptable range. a. Determine osmolarity by laboratory analysis or use mathematical formula given in Appendix 18, p A-20. b. Osmolarity per gram of ProViMin powder is 2.74 mosm. 2. If osmolarity is > 450 mosm/L for infants (23), > 750 mosm/L for children, > 1,000 mosm/L for adults, or is greater than tolerated by patient, increase water content of prescribed medical food mixture and recalculate its osmolarity (26). C. Potential Renal Solute Load 1. Dehydration will result if renal solute load is greater than renal-concentrating ability of patient. 2. If concentration of medical food mixture prescribed is > 27 kcal/fl oz, estimate its potential renal solute load. a. This step is important to prevent dehydration of infants who may have renal-concentrating capacity as low as 600 mosm/L (36). b. Upper limit of renal solute load for neonates is approximately 1,100 mosm/L (36). 3. A method for estimating potential renal solute load is given in Appendix 20, p A-22. 4. If potential renal solute load is excessive, increase water content of medical food mixture and recalculate.

A. Protein Status 1. Evaluate plasma albumin concentration every 3 months until patient is 1 year old and every 6 months thereafter (Appendix 17, p A-18, for standards). 2. If plasma albumin concentration is below standard: a. Increase prescribed amount of protein by 5% to 10% and reevaluate plasma albumin concentration in 1 month. b. If plasma albumin concentration remains low, repeat above process until value is in normal range. B. Iron Status 1. Plasma ferritin concentration. a. Evaluate at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17, p A-18, for standards). b. If plasma ferritin concentration is below standard: 1) Increase iron intake to 2 mg/kg with supplements (ferrous sulfate). 2) Evaluate plasma ferritin concentration monthly in increased iron intake. 3) Continue iron supplements until plasma ferritin concentration is in normal range. 2. Complete blood count. a. Hemoglobin and hematocrit should be evaluated at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17, p A-18, for standards). C. Growth Status 1. Length/height and weight. a. Measure monthly to 1 year, every 3 months to 4 years, and every 6 months thereafter. Plot measurements on NCHS growth charts.
334 Pyruvate Carboxylase Deficiency 2001 Ross Products Division
b. Maintain length/height and weight between 10th and 90th percentiles. Some normal infants and children will fall above or below these percentiles. Maintain appropriate weight for height in adults. 2. If infant's or child's length/height or weight falls below usual growth channel: a. Increase prescribed protein and energy by 5% to 10% and remeasure in 1 month. b. If length/height or weight remains low, repeat above process until usual growth channel is achieved. D. Nutrient Intake 1. Maintain records of food intake for 3 days immediately before each blood test (Appendices 24 and 25, pp A-26 and A-27). 2. Evaluate intakes of fat, linoleic and -linolenic acids, protein, energy, minerals, and vitamins after each diet change. a. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. b. See Appendix 28, p A-29, for information about ordering software for diet evaluation. This software does not calculate fatty acids. F. Clinical Summary 1. A summary record of growth, laboratory, and nutrient intake data is useful for patient management (Table 18-5, p 335).
A. Example Establish and fill prescription for newborn weighing 3.5 kg using Recommended Daily Nutrient Intakes from Table 18-1, p 332, and average nutrient content from Tables 18-2 and 18-3, pp 332 and 333. 1. Establish prescription.
Energy Fat Protein Carbohydrate Fluid 120 kcal/kg 420 kcal 420 kcal 420 kcal 150 mL/kg x x x x 3.5 kg 0.35 0.15 3.5 kg = 420 kcal = 147 kcal = 63 kcal = 210 kcal = 525 mL Fat (g) 16.3 0.0 1.8 0.0 Protein (g) 5.8 10.0 0.0 0.0 282 43 16 80 Energy (kcal) 9 kcal = 4 kcal = 4 kcal = 16.3 g 15.8 g 52.5 g
- 210 kcal
Food List Similac With Iron Ready to Feed ProViMin Soy oil Polycose Liquid Add water to make 525 mL (18 fl oz). Total per day Percentage of energy as fat 18.1 39% 15.8 421 Measure 415 mL 13.7 g 2 mL 40 mL
Approximate osmolarity of medical food mixture is < 400 mosm/L. Estimated potential renal solute load is < 170 mosm. Linoleic acid is 3.49 g or 7.5% of energy; -linolenic acid is 0.36 g or 0.9% of energy.

A. Rationale 1. In normal persons, febrile illness and trauma are accompanied by catabolism of body fat and protein (47). 2. Well-nourished patients respond to infection and trauma as do normal persons.
B. Objectives of Nutrition Support 1. Maintain hydration and electrolyte balance. a. Offer infants and toddlers Pedialyte Oral Electrolyte Maintenance Solution ad libitum (Appendix 9, p A-9). 2. Depress catabolism a. Enhance energy intake when possible by offering uncooked Argo cornstarch (1:2 ratio cornstarch to fluid) ad libitum as tolerated, liquid Jell-O , Polycose powder or liquid (Appendix 9, p A-9) added to fruit juices or Pedialyte if tolerated, and caffeine-free soft drinks (not diet drinks). 1) 1/3 cup Polycose powder may be added to liquid Pedialyte to yield 8 fl oz. b. Return patient to ProViMin medical food mixture and pre-illness diet as rapidly as possible. 1) Begin with 1/2 original strength of ProViMin medical food mixture. 2) Increase to original strength as tolerated. c. Feed Polycose solution (5-7 g/kg of carbohydrate) or carbohydrate-containing foods every 2 to 3 hours. 1) If unable to feed every 2 to 3 hours, administer solution of raw cornstarch (2-3 g/kg) to infants older than 6 months. 2) Begin with very small amounts of raw cornstarch and gradually increase to prevent gas, bloating and diarrhea. d. Administer 10% glucose solution intravenously if oral intake cannot be maintained. 3. Prevent low blood glucose concentrations. a. Add uncooked cornstarch, 2 to 3 g/kg/day to any liquids and feed every 2 to 3 hours (43).
TABLE 18-1. Recommended Daily Nutrient Intakes (Ranges) for Infants, Children, and Adults With Pyruvate Carboxylase Deficiency
Age Protein (% of energy) Infants 0 to < 3 mo 3 to < 6 mo 6 to < 9 mo 9 to < 12 mo 12 - 15 12 - 15 12 - 15 12 - 15 (% of energy)
1
Nutrient Fat (% of energy) 30 - 35 30 - 35 30 - 35 30 - 35 (% of energy) Energy1 (kcal/kg) 120 (145 - 95) 115 (145 - 95) 110 (135 - 80) 105 (135 - 80) (kcal/day) Fluid2 (mL/kg) 150 - 125 160 - 130 145 - 125 135 - 120 (mL/day)
Girls and Boys 1 to < 4 yr 4 to < 7 yr 7 to < 11 yr Women 11 to < 15 yr 15 to < 19 yr 19 yr Men 11 to < 15 yr 15 to < 19 yr
1 2
12 - 15 12 - 15 12 - 15
30 - 35 30 - 35 30 - 35
1,300 ( 900 - 1800) 1,700 (1300 - 2300) 2,400 (1650 - 3300)
900 - 1,800 1,300 - 2,300 1,650 - 3,300
12 - 15 12 - 15 12 - 15
30 - 35 30 - 35 30 - 35
2,200 (1500 - 3000) 2,100 (1200 - 3000) 2,100 (1400 - 2500)
1,500 - 3,000 1,200 - 3,000 1,400 - 2,500
19 yr Modified from reference 13. Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL to children and adults for each kcal ingested.
12 - 15 12 - 15 12 - 15
30 - 35 30 - 35 30 - 35
2,700 (2000 - 3700) 2,800 (2100 - 3900) 2,900 (2000 - 3300)
2,000 - 3,700 2,100 - 3,900 2,000 - 3,300
TABLE 18-2. Average Nutrient Contents of Ross Infant Formulas and Gerber Baby Foods1
Food Measure Fat (g) 0.17 < 0.10 < 0.04 0.00 0.00 0.67 0.04 3.74 3.70 0.19 2.00 3.65 Protein (g) 0.25 0.16 0.11 0.09 0.07 1.58 0.20 1.86 1.66 3.53 73.00 1.40 Energy (kcal) 15 11 12 10 16 14 6 68 68 36 312 68
Cereals, dry, Ready To Serve 1 Tbsp2 Cereals, with fruit, 2nd and 3rd Foods, jarred 1 Tbsp2 2 Desserts: 2nd and 3rd Foods 1 Tbsp 2 Fruits, 1st, 2nd and 3rd Foods 1 Tbsp Fruit, juice 1 fl oz Meat with gravy, 2nd and 3rd Foods 1 Tbsp2 2 Vegetables: 1st, 2nd and 3rd Foods 1 Tbsp 3 Alimentum Protein Hydrolysate Formula With Iron, Ready to Feed 100 mL 3 Isomil Soy Formula With Iron, Ready to Feed 100 mL 4 Milk, skim 100 mL ProViMin Protein-Vitamin-Mineral Formula Component With Iron 100 g Similac With Iron, Ready to Feed 3 100 mL 1 Nutrient Values. Fremont, Michigan: Gerber Products Co, 2000. 2 US standard level measure. 3 See Appendices 4 through 7, pp A-4 to A-7, for complete nutrient composition. 4 See Appendix 8, p A-8 for complete nutrient composition.
TABLE 18-3. Exchange Lists for Nutrition Support of Children and Adults With Pyruvate Carboxylase Deficiency1
Food List Meat, lean Milk, skim Fat2 Fruit Measure Fat (g) Protein (g) Energy (kcal)
1 oz 3 7 55 1 cup trace 8 90 varies 5 0 45 1/2 cup canned or 1/2 cup fresh or juice 0 0 80 1/2 cup dried 0 0 60 Starch/Bread varies trace 3 25 Vegetable 1/2 cup cooked, or 1 cup raw 0 2 25 1 Exchange Lists for Weight Maintenance. Chicago: The American Dietetic Association, 1995. 2 Care must be taken to select fats that provide adequate linoleic and -linolenic acids, such as those high in canola or soybean oil.
TABLE 18-4. Pyruvate Carboxylase Deficiency Diet Guide Name:______________________________________________________________ Date: __________/_________/_________
Mo Day Year
Birthdate: __________/_________/__________ Age: _______________________

Mo Day Year

Medical Food ProViMin Amount g mL mg mg mg Skim milk cups Protein (g) Fat (g) Energy (kcal)
Add water to make ________________________ mL ________________ (fl oz)
Beikost or table foods Tbsp/Exchanges Cereals/Starch/Bread Cereals: With Fruit Desserts Fruits/Juices Meats Vegetables
Total per day Total per kg Percentage of energy
Comments:
____________________________________________________ Nutritionist
2001 Ross Products Division Pyruvate Carboxylase Deficiency 335
TABLE 18-5. Pyruvate Carboxylase Deficiency Clinical Summary Sheet Name: Date of Birth: __________/__________/__________ Mo Day Year
Date
(mo/d/yr)
Hospital Number:
Physical Data
Length/ Height (cm) Weight (kg) Head Circum (cm) ALA (mol/L) CIT (mol/L) LYS (mol/L) PRO (mol/L)
Laboratory Data
Plasma NH3 (mol/L) Blood Lactate (mmol/L) Citrate (mmol/L) Blood Glucose (mg/dL) Ferritin (ng/mL) Albumn (g/dL) Hgb (g/dL) (g) Fat (%) ASP ASPNH2 (mg)

Citrate (mg) GLU GLUNH2 (mg) Protein (g) Energy (kcal) B1 (mg/day)
REFERENCES
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Ahmad A, Kahler SG, Kishnani PS, et al: Treatment of pyruvate carboxylase deficiency with high doses of citrate and aspartate. Am J Med Genet 1999;87:331-338. Atkin BM, Buist NRM, Utter MF, et al: Pyruvate carboxylase deficiency and lactic acidosis in a retarded child without Leigh's Disease. Pediatr Res 1979;13:109-116. Atkin BM, Utter MF, Weinberg MG: Pyruvate carboxylase and phosphoenolpyruvate carboxykinase activity in leukocytes and fibroblasts from a patient with pyruvate carboxylase deficiency. Pediatr Res 1979;13:38-43. Baal MG, Gabreels FJM, Renier WO, et al: A patient with pyruvate carboxylase deficiency in the liver: Treatment with aspartic acid and thiamine. Dev Med Child Neurol 1981;23:521-530. Bartlett K, Ghneim HK, Stirk JH, et al: Pyruvate carboxylase deficiency. J Inher Metab Dis 1984;7:Suppl 1:74-78. Besley GTN: First trimester diagnosis of pyruvate carboxylase deficiency. J Inher Metab Dis 1996;19 Suppl 1:69 (Abs). Brunette MG, Delvin E, Hazel B, Scriver CR: Thiamine-responsive lactic acidosis in a patient with deficient low-Km pyruvate carboxylase activity in liver. Pediatrics 1972;50:702-711. Caruso U, Adami A, Bertini E, et al: Respiratory chain and pyruvate metabolism defects: Italian collaborative survey on 72 patients. J Inher Metab Dis 1996;19:143-148. Coude FX, Ogier H, Marsac C, et al: Secondary citrullinemia with hyperammonemia in four neonatal cases of pyruvate carboxylase deficiency. Pediatrics 1981;68:914. DeVivo DC, DiMauro S: Disorders of pyruvate metabolism, the citric acid cycle, and the respiratory chain. In Fernandes J, et al (eds): Inborn Metabolic Diseases. Diagnosis and Treatment. New York: Springer Verlag, 1990, pp 127-157. DeVivo DC, Haymond MW, Leckie MP, et al: The clinical and biochemical implications of pyruvate carboxylase deficiency. J Clin Endocrinol Metab 1977;45:1281-1296. Feldman GL, Wolf B: Letter to the Editor: Measurement of pyruvate carboxylase activity in amniotic fluid cells. Pediatr Res 1979;14:153. Food and Nutrition Board, Committee on Dietary Allowances: Recommended Dietary Allowances, eds 9 and 10. Washington DC: National Academy of Sciences, 1980 and 1989. Greter J, Gustafsson J, Holme E: Pyruvate carboxylase deficiency with urea cycle impairment. Acta Paediatr Scand 1985;74:982-986. Grbe H, Bassewitz DB, Dominick H-Chr, Pfeiffer RA: Subacute necrotizing encephalomyelopathy. Clinical, ultrastructural, biochemical and therapeutic studies in an infant. Acta Paediatr Scand 1975;64:755-762. Grover WD, Auerbach VH, Patel MS: Biochemical studies and therapy in subacute necrotizing encephalomyelopathy (Leigh's Syndrome). J Pediatr 1972;81;39-44. Hamilton J, Rae MD, Logan RW, Robinson PH: A case of benign pyruvate carboxylase deficiency with normal development. J Inher Metab Dis 1996;19 (Suppl 1):68 (Abs). Hansen TL, Christensen E, Brandt NJ: Studies on pyruvate carboxylase, pyruvate decarboxylase, and lipoamide dehydrogenase in subacute necrotizing encephalomyelopathy. Acta Paediatr Scand 1982;71:263-267. Haworth JC, Robinson BH, Perry TL: Lactic acidosis due to pyruvate carboxylase deficiency. J Inher Metab Dis 1981;4:57-58. Hommes FA, Polman A, Reefrink JD: Leigh's encephalomyelopathy: An inborn error of gluconeogenesis. Arch Dis Child 1968;43:423-426. Kerr DS, Wexler ID, Zinn AB: Disorders of pyruvate metabolism and the tricarboxylic acid cycle. In Fernandes J, et al (eds): Inborn Metabolic Diseases, ed 3. New York, Springer, 2000, pp 127-138. Lipshitz F, Moses N: Growth failure: A complication of dietary treatment of hypercholesterolemia. Am J Dis Child 1989;143:537-542. MacLean W, Graham G: Pediatric Nutrition in Clinical Practice. Menlo Park, Calif: Addison-Wesley Publishing Co, 1982. Maesaka H, Komiya K, Misugi K, Tada K: Hyperalaninemia, hyperpyruvicemia and lactic acidosis due to pyruvate carboxylase deficiency of the liver: Treatment with thiamine and lipoic acid. Eur J Pediatr 1976;122:159-168. Marsac C, Augerseau CH, Feldman G, et al: Prenatal diagnosis of pyruvate carboxylase deficiency. Clin Chim Acta 1982;119:121-127. Martin SB, Acosta PB: Osmotic behaviors of components of chemically-defined formulas. J Pediatr Perinat Nutr 1987;1:1-17. Merinero B, Perez-Cerda C, Ugarte M: Investigation of enzyme defects in children with lactic acidosis. J Inher Metab Dis 1992;15:696-706. Oizumi J, Ng WG, Donnell GN: Pyruvate carboxylase defect: Metabolic studies on cultured skin fibroblasts. J Inher Metab Dis 1986;9:120-128. Oizumi J, Shaw KNF, Carter M, et al: Neonatal pyruvate carboxylase deficiency with renal tubular acidosis and cystinuria. J Inher Metab Dis 1983;6:89-94. Pollock MA, Cumberbatch M, Bennett MJ, et al: Pyruvate carboxylase deficiency in twins. J Inher Metab Dis 1986;9:29-30.
11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30.
31. Przyrembel H: Therapy of mitochondrial disorders. J Inher Metab Dis 1987;10:129-146. 32. Robinson BH: Lactic acidemia: Disorders of pyruvate carboxylase, pyruvate dehydrogenase). In Scriver C, et al (eds): The Metabolic and Molecular Bases of Inherited Disease, ed 8. New York: McGraw-Hill Medical Publishing Division, 2001, pp 2275-2296. 33. Robinson BH, Oei J, Sherwood WG, et al: The molecular basis for two different clinical presentations of classical pyruvate carboxylase deficiency. Am J Hum Genet 1984;36:283-294. 34. Robinson BH, Sherwood WG: Lactic acidaemia. J Inher Metab Dis 1984;7 Suppl 1:69-73. 35. Saudubray JM, Marsac C, Charpentier C, et al: Neonatal congenital lactic acidosis with pyruvate carboxylase deficiency in two siblings. Acta Paediatr Scand 1976;65:717-724. 36. Smith CA, Nelson NM: The Physiology of the Newborn Infant, ed 4. Springfield, IL: Charles C Thomas Publisher, 1976. 37. Soldin SJ, Brugnara C, Hicks JM (eds): Pediatric Reference Ranges, ed 3. Washington, DC: AACC Press, 1999. 38. Spika JS, Shaffer N, Hargrett-Bean N, et al: Risk factors for infant botulism in the United States. Am J Dis Child 1989;143:828-832. 39. Stern HJ, Nayar R, DePalma L, Rifai N: Prolonged survival in pyruvate carboxyl's deficiency: Lack of correlation with enzyme activity in cultured fibroblasts. Clin Biochem 1995;28:85-89. 40. Tada K, Takada G, Omura K, Itokawa Y: Congenital lactic acidosis due to pyruvate carboxylase deficiency: Absence of an inhibitor of TPP-ATP phosphoryltransferase. Eur J Pediatr 1978;127:141-147. 41. Tang TT, Good TA, Dyken PR, et al: Pathogenesis of Leigh's encephalomyelopathy. J Pediatr 1972;81:189-190. 42. Tsuchiyama A, Dyanagi K, Hirano S, et al: A case of pyruvate carboxylase deficiency with later prenatal diagnosis of an unaffected sibling. J Inher Metab Dis 1983;6:85-88. 43. Ullrich K, Schmidt H, van Teeffelen-Heithoff A: Glycogen storage disease type I and III and pyruvate carboxylase deficiency: Results of long-term treatment with uncooked cornstarch. Acta Paediatr Scand 1988;77:531-536. 44. van Biervliet JPGM, Bruinvis L, van der Heiden C, et al: Report of a patient with severe, chronic lactic acidaemia and pyruvate carboxylase deficiency. Dev Med Child Neurol 1977;19:392-401. 45. van Coster RN, Fernhoff PF, DeVivo DC: Pyruvate carboxylase deficiency: A benign variant with normal development. Pediatr Res 1991;30:1-4. 46. Vidailhet M, Lefebvre E, Beley G, Marsac C: Neonatal lactic acidosis with pyruvate carboxylase inactivity J Inher Metab Dis 1981;4:131-132. 47. Wannemacher RW: Key role of various individual amino acids in host response to infection. Am J Clin Nutr 1977;30:1269-1280.
PROTOCOL 19 Fasting Chylomicronemia Nutrition Support of Infants, Children, and Adults With PROVIMIN Protein-Vitamin-Mineral Formula Component With Iron
I. Introduction
Lipoprotein lipase (LPL) is required for hydrolysis of triacylglycerols and their conversion to intermediate-and low-density lipoproteins. Apolipoprotein C-II is required for activation of LPL (5, 12, 29). LPL deficiency is transmitted as an autosomal recessive disorder and is characterized by fasting chylomicronemia, abdominal pain, pancreatitis, eruptive xanthomas, and hepatosplenomegaly. Symptoms of apolipoprotein C-II deficiency are the same as for LPL deficiency since LPL does not function without apoprotein C-II. Some patients develop fasting chylomicronemia because they have a LPL inhibitor in their plasma. LPL inhibitor appears to be inherited differently than LPL deficiency (5, 12, 21, 28).

LPL deficiency is not associated with atherosclerosis. However, recurring pancreatitis can be life threatening. Restriction of dietary fat to 8% to 15% of energy is usually adequate to prevent symptoms (5, 9, 17, 19, 22, 25).

A. The Defect 1. Fasting chylomicronemia may result from 1 of 3 defects (5): a. Lipoprotein lipase deficiency (5). b. Apolipoprotein C-II deficiency (4, 13). c. Inhibitor of lipoprotein lipase (5). B. Clinical Evaluation 1. Infants or children with any of the following clinical symptoms resulting from unknown causes should be evaluated for chylomicronemia (5, 11, 14 18): a. Abdominal pain presenting as colic. b. Abdominal distention. c. Hepatomegaly. d. Splenomegaly. e. Acute or chronic pancreatitis. f. Eruptive xanthomas. g. Lipemia retinalis. h. "Milk" or "cream" layer on blood or plasma that is refrigerated overnight. C. Differential Diagnosis 1. Differential diagnosis is required for genetic counseling. 2. See references 5, 17, and 29 for methods of diagnosis.

A. Correct Primary Imbalance in Metabolic Relationships 1. Restrict dietary fats to level that maintains fasting plasma triacylglycerol concentrations in treatment range.

A. Fasting Plasma Triacylglycerol Concentrations 1. Maintain fasting plasma concentrations < 500 mg/dL in infants and < 750 mg/dL in children and adults. a. 5th and 95th percentiles in normal infants are 34 and 112 mg/dL b. 5th and 95th percentiles in normal children and adults are 29 and 324 mg/dL (12, 17, 23, 25).
Fasting Chylomicronemia 343
B. Growth and Nutrition Status 1. Support normal growth rate in infants and children (3, 15) and maintain appropriate weight for height in adults. 2 Maintain normal nutrition status. C. Prevent Symptoms and Physical Manifestations of Chylomicronemia (5) D. Prevent Fat-Soluble Vitamin Deficiency (24)

A. Energy 1. Prescribe amount that should support normal weight gain for infants and children and maintain appropriate weight for height in adults (Table 19-1, p 344). 2. Requirements vary widely. Warning: Inadequate energy intake will result in growth failure (15) in infants and children and weight loss in adults. B. Fat 1. Prescribe amount of total fat that promotes goals of nutrition support. a. Tolerance for fat varies depending on defect present (2, 6-9, 22, 24, 25) and is determined by measuring fasting plasma triacylglycerol concentrations. b. Supply 8 % to 15% of energy as fat (Table 19-1, p 344) (3, 7-9, 22, 24, 25). 1) Prescribe minimum of 3% of total energy as linoleic acid and 1% of total energy as -linolenic acid. 2) Addition of soy oil for infants and canola oil for children and adults may be required as source of -linolenic acid. Warning: Essential fatty acid deficiency may occur if intakes of linoleic acid and -linolenic acid are inadequate. C. Protein 1. Prescribe amount that supplies 15% to 20% of total energy for infants (Table 19-1, p 344). D. Carbohydrate 1. Prescribe remaining energy as carbohydrate. E. Fluid 1. Prescribe amount that will supply water requirements (Table 19-1, p 344). Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL to children and adults for each kcal ingested. 2. Requirements may be higher than recommended secondary to fever. F. Fat-Soluble Vitamins (24) 1. Prescribe amounts that maintain normal plasma concentrations. a. Plasma retinol should be maintained > 20 g/dL. b. Plasma 25-dihydroxyvitamin D should be maintained between 30 and 60 ng/mL. c. Plasma -tocopherol should be maintained > 0.6 mg/dL. G. High-Dose Antioxidant Therapy (13) 1. Heaney, et al (13) used the following antioxidant therapy to prevent pancreatitis in three patients with lipoprotein lipase deficiency.
Beta-carotene Methionine (not an antioxidant) Selenium Vitamin C Vitamin E 9,000 IU/day 500 mg/day 600 g/day 1 540 mg/day 270 IU/day
Warning:
THIS AMOUNT OF SELENIUM MAY CAUSE TOXIC SYMPTOMS IF GIVEN FOR A

PROLONGED TIME.
344 Fasting Chylomicronemia

A. Protein 1 Supply prescribed protein for neonates and infants with ProViMin until the 2nd birthday to supply iron (Table 19-2, p 344). 2. Supply prescribed protein for children (> 2.0 years of age) and adults with lean meat, poultry and fish; skim milk; and egg whites (Table 19-3, p 345). Fat in lean meat, poultry, and sea foods must be counted as part of fat prescription. B. Fat 1. Use soy or walnut oil to provide fat required for infant (Appendix 10, p A-9). 2. Use measured amounts of soy, walnut, or canola oil; beikost; or table foods to provide fat for children and adults. C. Energy 1. Calculate energy supplied by ProViMin, skim milk, other protein-containing foods, and fat. 2. Subtract amount determined above from total energy prescription. 3. Provide any remaining prescribed energy with Polycose Glucose Polymers powder (23 kcal/Tbsp, 3.8 kcal/g) or liquid (2 kcal/mL) (Appendix 9, p A-9), sugar (48 kcal/Tbsp), beikost, or table foods containing little or no fat (Tables 19-2 and 19-3, pp 344 and 345). a. Do not use honey for infants because it may contain botulinum toxin. 4. Add beikost or table foods after infant is 3 to 4 months old to provide variety in taste, color, and texture (Table 19-2, p 344). 5. See Table 19-4, p 345, for types and amounts of foods that will supply infant's daily nutrient needs. D. Fluid and Mixing Instructions 1. Boil bottles, nipples, rings and mixing utensils for 5 minutes and cool. Boil more water for 5 minutes and cool to room temperature. 2. Measure or weigh specified amounts of boiled, cooled water, ProViMin, fat, and carbohydrate into clean containers. 3. Pour 1/2 of specified amount of boiled, cooled water into clean blender. Running blender at slow speed, gradually add ProViMin and blend mixture for at least 15 seconds. 4. Slowly pour specified amount of fat into blender and continue blending for no longer than 1 to 3 seconds. 5. Dissolve powdered carbohydrate in some of remaining water and pour into ProViMin and fat mixture, mix well, add water to yield prescribed volume, 6 Refrigerate in sterilized, closed containers until used. Discard unused portion 24 hours after mixing because of nutrient loss. Shake well before feeding. 7. Do not use microwave oven to warm formula. Unevenly heated formula can burn infants and steam can make bottles explode. 8. Discard formula remaining in bottle or cup after feeding. 9. Notify parents or caretakers when they may discontinue aseptic technique in making formula. E. Diet Guide 1. Provide parents, caretakers, or patient with completed Diet Guide (Table 19-5, p 346, or 19-6, p 347) with each diet change.

A. Nutrient Adequacy 1. Determine if diet provides nutrients in amounts prescribed in Section VI, Establish Prescription, p 339. a. See Table 19-2, p 344 for composition of ProViMin and beikost, Table 19-3, p 345, for Exchange Lists of foods for children and adults, Appendix 8, A-8, for composition of skim milk, and Appendix 9, p A-9, for composition of Polycose.
2. Check diet to determine if it supplies Recommended Dietary Intakes (RDIs) of minerals and vitamins (Table 6-4, p 118, and Appendices 13 and 14, pp A-14 and A-15). a. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. b. If ProViMin mixture provides < 100% of RDIs for infants and < 75% for children and adults, supplement diet with needed minerals and vitamins if not provided by beikost or table foods and laboratory tests indicate need (Appendix 11, p A-10, for composition of supplements). B. Osmolarity 1. If concentration of prescribed medical food mixture is > 27 kcal/fl oz, determine if osmolarity is in acceptable range. a. Determine osmolarity by laboratory analysis or use mathematical formula given in Appendix 18, p A-20. b. Osmolarity per gram ProViMin powder is 2.74 mosm. 2. If osmolarity is > 450 mosm/L for infants, or is greater than tolerated by patient, increase water content of prescribed medical food mixture and recalculate its osmolarity (16). C. Potential Renal Solute Load 1. Dehydration will result if renal solute load is greater than renal-concentrating ability of patient. 2. If concentration of prescribed food mixture prescribed is > 27 kcal/fl oz, estimate its potential renal solute load. a. This step is important to prevent dehydration of infants who may have renal-concentrating capacity as low as 600 mosm/L. b. Upper limit of renal solute load for neonates is approximately 1,100 mosm/L (26). 3. A method for estimating potential renal solute load is given in Appendix 20, p A-22. 4. If potential renal solute load is excessive, increase water content of medical food mixture and recalculate.

A. Fat Tolerance 1. Initial. a. Evaluate fasting plasma triacylglycerol concentrations weekly by quantitative methods until fat intake as percentage of total daily energy maintains triacylglycerol concentration in treatment range (18). 2. Ongoing. a. After fat tolerance is determined, measure fasting plasma triacylglycerol concentrations monthly until patient is 3 months of age, every 2 months to 1 year of age, and every 3 months thereafter, unless patient is noncompliant. B. Protein Status 1. Evaluate plasma albumin concentration every 3 months until patient is 1 year old and 6 months thereafter (Appendix 17, p A-18, for standards). 2. If plasma albumin concentration is below standard: a. Increase prescribed amount of protein by 5% to 10% and reevaluate plasma albumin concentration in 1 month. b. If plasma albumin concentration remains low, repeat above process until value is in normal range. C. Iron Status 1. Plasma ferritin concentration. a. Evaluate at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17, p A-18, for standards). b. If plasma ferritin concentration is below standard: 1) Increase iron intake to 2 mg/kg body weight with supplements (ferrous sulfate). 2) Evaluate plasma ferritin concentration monthly on increased iron intake. 3) Continue iron supplements until plasma ferritin concentration is in normal range.
2. Complete blood count. a. Hemoglobin and hematocrit concentrations should be evaluated at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17, p A-18, for standards). D. Growth Status 1. Length/height and weight. a. Measure monthly to 1 year and every 6 months thereafter. Plot measurements on NCHS growth charts. b. Maintain length/height and weight between 10th and 90th percentiles. Some normal infants and children will fall above or below these percentiles. Maintain appropriate weight for height in adults. 2. If infant's or child's length/height or weight falls below usual growth channel: a. Increase prescribed protein and energy by 5% to 10% and remeasure after 1 month. b. If length/height or weight remains low, repeat above process until usual growth channel is achieved. E. Nutrient Intake 1. Maintain records of food intake for 3 days immediately before each blood test (Appendices 24 and 25, pp A-26 and A-27). 2. Evaluate intakes of fat, linoleic and -linolenic acids, protein, energy, minerals, and vitamins after each diet change. a. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. b. See Appendix 28, p A-29, for information about ordering software for diet evaluation. This software does not calculate fatty acids. F. Clinical Summary 1. A summary record of growth, laboratory, and nutrient intake data is useful for patient management (Table 19-7, p 348).
A. Example 1 Establish and fill prescription for newborn weighing 3.5 kg using Recommended Daily Nutrient Intakes from Table 19-1, p 344, and nutrient composition of ProViMin from Table 19-2, p 344, and soy oil from Appendix 10, p A-9. 1. Establish prescription.
Energy Fat Protein Fluid 120 kcal/kg 420 kcal 420 kcal 150 mL/kg x x x x 3.5 kg 0.13 0.12 3.5 kg = = = = 420 kcal 55 kcal 50 kcal 525 mL Measure 17.0 g 7 mL 156 mL 0 6.3 0 Fat (g) Protein (g) 12.4 0.0 0.0 Energy (kcal) 53 56 312 9 kcal = 6.1 g 4 kcal = 12.6 g
Medical Food Mixture ProViMin Soy oil Polycose Liquid Add water to make 540 mL (18 fl oz) 6.3 12.4 421 Total per day 13.5% Percentage of energy as fat Approximate osmolarity of medical food mixture is < 350 mosm/L. Estimated potential renal solute load is < 180 mosm. Linoleic acid is 3.2 g or 6.8% of energy. -Linolenic acid is 0.44 g or 0.9% of energy.
B. Example 2 Establish and fill prescription for 3-year-old child using Recommended Daily Nutrient Intakes from Table 19-1, p 344, and nutrient contents from Table 19-3, p 345. 1. Establish prescription.
Energy Fat Protein Fluid 1,300 kcal 1,300 kcal x 0.15 = 195 kcal 9 = 22 g 23 g (minimum) 1,400 mL Measure Fat Fruits Milk, skim Meat, lean Starch/Breads Vegetables Total per day
1
Fat (g) 20 0 trace 3 trace 0 23 15% 0 0 24 7 12 8 51 Protein (g) 180 420 270 55 320 100 1,396 Energy (kcal)
4 exchanges1 6 exchanges 3 cups 1 oz 4 exchanges 4 exchanges
Percentage of energy as fat Use 1 Tbsp of canola oil as 3 exchanges

A. Rationale 1. In normal persons, febrile illness and trauma are accompanied by catabolism of body fat and protein (29). 2. Well-nourished patients with chylomicronemia respond to infection and trauma as do normal persons. B. Objectives of Nutrition Support 1. Maintain hydration and electrolyte balance. a. Offer infants and toddlers Pedialyte Oral Electrolyte Maintenance Solution ad libitum (Appendix 9, p A-9). 2. Depress catabolism. a. Enhance energy intake when possible by offering fruit juices ad libitum as tolerated, liquid Jell-O , Polycose powder or liquid (Appendix 9, p A-9) added to fruit juices or Pedialyte if tolerated, and caffeine-free soft drinks (not diet drinks). 1) Add 1/3 cup Polycose powder to Pedialyte liquid to yield 8 fl oz. b. Return patient to ProViMin medical food mixture and pre-illness diet as rapidly as possible. 1) Begin with 1/2 original strength ProViMin medical food mixture. 2) Increase to original strength as tolerated. Warning: Intravenous lipid solutions supplying > 15% of energy are contraindicated in treatment of chylomicronemias.
XII. Contraindicated Drugs (22)

A. Alcohol B. -Adrenergic Blocking Agents C. Diuretics D. Estrogens E. Isoretinoin
TABLE 19-1. Recommended Daily Nutrient Intakes (Ranges) for Infants, Children, and Adults With Chylomicronemia
Age Protein (% of energy) Infants 0 to < 3 mo 3 to < 6 mo 6 to < 9 mo 9 to < 12 mo 15 - 20 15 - 20 15 - 20 15 - 20 (g/day) Girls and Boys 1 to < 4 yr 4 to < 7 yr 7 to < 11 yr Women 11 to < 15 yr 15 to < 19 yr 19 yr Men 11 to < 15 yr 15 to < 19 yr 19 yr
1 1
Nutrient Fat (% of energy) 8 - 15 8 - 15 8 - 15 8 - 15 (% of energy) 8 - 15 8 - 15 8 - 15 120 (145 115 (145 110 (135 105 (135 Energy1 (kcal/kg) - 95) - 95) - 80) - 80) (kcal/day) 1,300 ( 900 - 1800) 1,700 (1300 - 2300) 2,400 (1650 - 3300) Fluid2 (mL/kg) 150 - 125 160 - 130 145 - 125 135 - 120 (mL/day) 900 - 1,800 1,300 - 2,300 1,650 - 3,300
23 - 30 30 - 37 37 - 44
46 - 53 46 - 53 53 - 60
8 - 15 8 - 15 8 - 15
2,200 (1500 - 3000) 2,100 (1200 - 3000) 2,100 (1400 - 2500)
1,500 - 3,000 1,200 - 3,000 1,400 - 2,500
45 - 52 59 - 66 63 - 69
8 - 15 8 - 15 8 - 15
2,700 (2000 - 3700) 2,800 (2100 - 3900) 2,900 (2000 - 3300)
2,000 - 3,700 2,100 - 3,900 2,000 - 3,300
Modified from reference 10. 2 Modified from reference 1. Under normal circumstances, offer a minimum of 1.5 mL fluid to neonates and 1.0 mL to children and adults for each kcal ingested.
TABLE 19-2. Approximate Macronutrient Contents of Gerber Baby Foods (Beikost) and ProViMin 1
Food Cereals, dry, Ready To Serve Cereals, with fruit, 2nd and 3rd Foods, jarred Desserts: 2nd and 3rd Foods Fruits, 1st, 2nd and 3rd Foods Fruit, juice Meats, 2nd and 3rd Foods ProViMin Vegetables: 1st, 2nd and 3rd Foods
1 2
Measure 1 Tbsp2 1 Tbsp 1 Tbsp 1 Tbsp 1 fl oz 1 Tbsp 100 g 1 Tbsp

2 2 2 2 2
Fat (g) 0.18 < 0.10 0.04 0.00 0.00 0.67 2.00 0.12
Protein (g) 0.35 0.16 0.11 0.09 0.07 1.58 73.00 0.20
Energy (kcal) 15 10 11 10 16 15 312 6
Nutrient Values. Fremont, Michigan: Gerber Products Co, 2000. US standard level measure.
TABLE 19-3. Exchange Lists for Nutrition Support of Children and Adults With Fasting Chylomicronemias1
Food List Meat, lean Milk, skim Fat 3 Fruit
2
Amount 1 oz 1 cup varies 1/2 cup canned 1/2 cup fresh or juice, or 1/2 cup dried
Fat (g) 3 trace 5 0 0 trace 0
Protein (g) 7 8 0 0 0 2 2
Energy (kcal) 55 90 45 80 60 25 25
Starch/Bread Vegetable
1 2 3
varies 1/2 cup cooked or 1 cup raw
Exchange Lists for Weight Maintenance. Chicago: The American Dietetic Association, 1995. From reference 20. Care must be taken to select fats that provide adequate linoleic and -linolenic acids, such as those high in canola or soybean oil.
TABLE 19-4. Types and Amounts of Infant Foods That Will Supply the Daily Nutrient Needs of Infants With Chylomicronemia
Food ProViMin, 20 kcal/oz, mL Infant cereals, Tbsp Fruits, pured, Tbsp
2 2 2 1
0 to < 3 months 175 - 150/kg None None None None
Amount of Food Required by Age 3 to < 6 months 6 to < 9 months 160 - 130/kg 130 - 110/kg 0.5 - 1/kg 1/kg None 1/kg 1/kg 1/kg 1/kg 1/kg
9 to < 12 months 110 - 90/kg 1/kg 1/kg 1/kg 1/kg
Meats, 2nd & 3rd Foods, Tbsp Vegetables, pured, Tbsp

1 2 2
Formula must be sufficient to supply energy normally supplied by fat. Introduce teaspoon-size portions after infant is 3 to 4 months of age, or when tongue thrust disappears. Allow 3 to 5 days to elapse between addition of each new food to determine if infant is allergic to food. Gradually increase portion sizes until recommended amounts are consumed.
TABLE 19-5. Diet Guide for Infants With Fasting Chylomicronemia Date: ____________/___________/__________
Mo Day Year
Name:_____________________________________________________________________ Birthdate: ____________/___________/__________ Age: ___________________________

Mo Day Year
Length: ____________________________ (cm/in) Weight: __________________ (kg/lb)

Fat (g) g g g/Tbsp mL mL mL Protein (g) Energy (kcal)
Medical Food Mixture ProViMin
Amount
Add water to make
mL
(fl oz)
Baby Food Cereals Desserts Fruits/Juices Meats, 2nd & 3rd Foods Vegetables
Amount Tbsp Tbsp Tbsp/fl oz Tbsp Tbsp
Comments:
______________________________________________ Nutritionist
TABLE 19-6. Diet Guide for Children and Adults With Fasting Chylomicronemia Date: _____________/______________/______________
Mo Day Year
Name:_____________________________________________________________________ Date: _____________/______________/______________ Age: ______________________

Mo Day Year
Length: __________________ (cm/in) Weight: _______________________ (kg/lb)
Food List
Exchanges
Fat (g)
Protein (g)
Energy (kcal)
Meat, lean Milk, skim Fat Fruit Starch/Bread Vegetables
Total per day Percentage of energy
Comments:
______________________________________________ Nutritionist
TABLE 19-7. Fasting Chylomicronemia Clinical Summary Sheet Name: Date of Birth: __________/__________/__________ Mo Day Year
Date Physical Data Length/ Weight Head Height Circum (cm) (kg) (cm) TAG1 (mg/dL) Laboratory Data Ferritin Albumin (g/dL) (ng/mL) Hgb (g/dL) (g) Fat (% kcal) Nutrient Intake Data Linoleic -Linolenic Acid Acid (g) (g) Protein (g) Energy (kcal)
348 Fasting Chylomicronemia 2001 Ross Products Division
Hospital Number:
(mo/d/yr)
Triacylglycerols
REFERENCES
1. 2. 3. 4. 5. Behrman RE, Kliegman RM, Arvin AA (eds): Nelson Textbook of Pediatrics, ed 15. Philadelphia: WB Saunders Co, 1996. Berger GMB: An incomplete form of familial lipoprotein lipase deficiency presenting with Type I hyperlipoproteinemia. Am J Clin Pathol 1987;88:369-373. Black DM, Sprecker DL: Dietary treatment and growth of hyperchylomicronemic children severely restricted in dietary fat. Am J Dis Child 1993;147:60-62. Brechenridge WC, Alaupovic P, Cox DW, Little JA: Apolipoprotein and lipoprotein concentrations in familial apolipoprotein C-II deficiency. Atheroscler 1982;44:233-235. Brunzell JD, Deeb SS: Familial lipoprotein lipase deficiency, apoC-II deficiency and hepatic lipase deficiency. In Scriver CR, et al (eds): The Metabolic and Molecular Bases of Inherited Disease, ed 8. New York: McGraw-Hill Medical Publishing Division, 2001, pp 2789-2816. Brunzell JD, Chait A, Nikkila EA, et al: Heterogeneity of primary lipoprotein lipase deficiency. Metabolism 1980;29:624-628. Bucher H, Rampini S, James RW, et al: Marked changes of lipid levels during puberty in a patient with lipoprotein lipase deficiency. Eur J Pediatr 1997;156:121-125. Deckelbaum RJ, Dupont C, LeTarte J, Pencharz P: Primary hypertriglyceridemia in childhood. Am J Dis Child 1983;137:396-398. Feoli-Fonseca JC, Levy E, Godard M, Lambert M: Familial lipoprotein lipase deficiency in infancy: Clinical, biochemical, and molecular study. J Pediatr 1998;133:417-423. Food and Nutrition Board, Committee on Dietary Allowances: Recommended Dietary Allowances, eds 9 and 10. Washington, DC: National Academy of Sciences, 1980 and 1989. Gasbarrini G, Mingrone G, Greco AV, Castagneto M: An 18-year old woman with familial chylomicronaemia who would not stick to diet. Lancet 1996;348:794. Havel RJ, Kane JP: Introduction: Structure and metabolism of plasma lipoproteins. In Scriver CR, et al (eds): The Metabolic and Molecular Bases of Inherited Disease, ed 8. New York: McGraw-Hill Medical Publishing Division, 2001, pp 2705-2716. Heaney AP, Sharer N, Rameh B, et al: Prevention of recurrent pancreatitis in familial lipoprotein lipase deficiency with high-dose antioxidant therapy. J Clin Endocrinol Metab 1999;84:1203-1205. Levy RI, Rifkind BM: Diagnosis and management of hyperlipoproteinemia in infants and children. Am J Cardiol 1973;31:547-556. Lipshitz F, Moses N: Growth failure: A complication of dietary treatment of hypercholesterolemia. Am J Dis Child 1989;143:537-542. MacLean W, Graham G: Pediatric Nutrition in Clinical Practice. Menlo Park, Calif: Addison-Wesley Publishing Co, 1982. Nyhan WL, Ozand PT: Lipoprotein lipase deficiency type I hyperlipoproteinemia. In Atlas of Metabolic Diseases, New York: Chapman and Hall Medical 1998, pp 515-522. Ohno M, Ishibashi S, Nakao K, et al: A neonatal case of apolipoprotein C-II deficiency. Eur J Pediatr 1989;148:550-552. Ohta T, Nakamura R, Ikeda Y, et al: Follow up study on children with dyslipidaemia detected by mass screening at 18 months of age: Effect of 12 months dietary treatment. Eur J Pediatr 1993;152:939-943. Posati LP, Orr ML: Composition of Foods: Dairy and Egg Products, Agriculture Handbook No. 8-1. Washington, DC: US Dept of Agriculture, Agricultural Research Service, 1976. Rane HS, Garu R, Lahari KR, Desai AJ: Primary hyperlipoproteinemia type I. Indian J Pediatr 1984;51:243-245. Santamarina-Fojo S: The familial chylomicronemia syndrome: Endocrinol Metab Clin NA 1998;27:551-567. Schaefer EJ, Levy RI: Pathogenesis and management of lipoprotein disorders. N Engl J Med 1985;312:1300-1310. Shankar KN, Bara HS, Shetty J, Joshi MK: Lipoprotein lipase deficiency. J Postgrad Med 1997;43:81-82. Siafakas CG, Brown MR, Miller TL: Neonatal pancreatitis associated with familial lipoprotein lipase deficiency. J Pediatr Gastroenterol Nutr 1999;29:95-98. Smith CA, Nelson NM: The Physiology of the Newborn Infant, ed 4. Springfield, IL: Charles C Thomas Publisher, 1976. Taskinen MR: Hypolipoproteinemia and lipoprotein lipase deficiency. In Fernandes J, et al (eds): Inborn Metabolic Diseases: Diagnosis and Treatment. New York: Springer-Verlag, 1990, pp 381-394. Wannemacher RW: Key role of various individual amino acids in host response to infection. Am J Clin Nutr 1977;30:1269-1280.
6. 7. 8. 9. 10. 11. 12.
13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28.
PROTOCOL 20 Mitochondrial Fatty Acid Oxidation Defects Nutrition Support of Infants, Children, and Adults With PROVIMIN Protein-Vitamin-Mineral Formula Component With Iron
I. Introduction
Fatty acids are a primary metabolic fuel for the body when fasting is prolonged and a direct source of energy for heart and skeletal muscle. Ketones such as acetoacetate and -hydroxybutyrate, obtained during hepatic fat metabolism, are an important energy source for the brain in particular, as well as other tissues. Infants and young children may have problems adapting to fasting due to their high basal energy needs required to maintain body temperature; the high rate of brain metabolism; and the low activity of several enzymes involved in energy production (42). During fasting, fatty acids are released from adipocytes and carried to other tissues by lipoproteins or albumin. Fatty acids with > 10 carbons are activated to-CoA esters in the cytosol. These acyl-CoA compounds are carried to the mitochondria by carnitine palmitoyl transferase types I and II (CPT I and II). Fatty acids with < 10 carbons do not require CPT I and II to enter the mitochondria, where they are activated to-CoA esters (42). In the mitochondria, fatty acids are degraded by the sequential removal of 2-carbon fragments as acetyl-CoA (Figure R). Four carbon chain length-specific enzymes are required: an acyl-CoA dehydrogenase, an enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase, and a 3-ketoacyl-CoA thiolase (Figure R). In the liver, most of the acetyl-CoA is used for ketone body synthesis (42). Deficiencies of very long-chain-, long-chain-, medium-chain-, short-chain-, 3-hydroxy-, and shortchain-hydroxyacyl-CoA dehydrogenases and mitochondrial trifunctional protein (51, 54) have been reported. Medium-chain-acyl-CoA dehydrogenase deficiency (MCADD) was found to occur in about 1/8,900 live births in Pennsylvania (63). Similar initial symptoms are found in all the dehydrogenase deficiencies. Some patients may develop symptoms as neonates. Symptoms are often induced by fasting or an infection with vomiting or diarrhea. Lethargy, muscle weakness, seizures, coma, and death may occur. Fatty infiltration of organs is often found on autopsy (37, 42).
Substrate
Acyl -CoA
Chemical structure
R-CH 2-CH 2-CH 2-CO -S-CoA FAD
Enzyme
Acyl - CoA dehydrogenase FADH 2 Enoyl -CoA R-CH 2-CH -CH -CO -S-CoA H2O Enoyl -CoA hydratase 3-Hydroxyacyl -CoA R-CH 2-CHOH -CH 2-CO -SCoA NAD NADH 2 3-Ketoacyl -CoA R-CH2 -CO -CH2 -CO -S-CoA 3-Ketoacyl -CoA thiolase 3-Hydroxyacyl -CoA dehydrogenase
Acetyl -CoA
CH3 -CO -S-CoA
Site of possible enzyme defect.
Figure R. Mitochondrial -oxidation (modified from reference 42) Development of pigmentary retinopathy or peripheral neuropathy is specifically associated with longchain-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency (3, 19, 37, 46). Some mothers who are heterozygous for mitochondrial fatty acid oxidation (FAO) defects develop acute fatty liver of pregnancy during the 3rd trimester of pregnancy (49, 60).
Mitochondrial FAO Defects 355

Variable outcomes of nutrition support have been reported in infants and children with long-chain-FAO defects. As with most metabolic disorders, severity of the enzyme defect, time of diagnosis, and longterm metabolic control influence the long-term outcome for these patients. Although fatal hypoketotic hypoglycemic episodes may occur in children with any long-chain-FAO defect, long-term intensive nutrition support has been associated with positive outcomes in several reports (14, 23, 32, 39, 52, 61). A diet restricted in long-chain-fatty acids but supplemented with fractionated coconut oil (MCT) is the most effective treatment for infants and children affected with disorders of long-chain-FAO. Reported benefits include decreased frequency of metabolic crises, improved muscle tone, sustained physical growth, and developmental gains. Of 120 patients with MCADD reported in the United States, 23 expired; of the 97 surviving patients, 16% had muscle weakness, 14% had failure to thrive, 40% had developmental delay, 22% had speech disabilities, 11% had attention deficit disorder, and 9% had cerebral palsy. All children were told to avoid fasting, 70 received supplemental L-carnitine, 60 received a low-fat diet, 2 were given supplemental glycine (GLY), and 1 received supplemental riboflavin (22).

A. The Defect (24, 42, 46, 52-54, 62) 1. Disorders of mitochondrial FAO may result from 1 of several defects: a. Very-long-chain-acyl-CoA dehydrogenase deficiency. b. Long-chain-acyl-CoA dehydrogenase deficiency. c. Long-chain-3-hydroxyacyl-CoA dehydrogenase deficiency. d. Medium-chain-acyl-CoA dehydrogenase deficiency. e. Short-chain-acyl-CoA dehydrogenase deficiency. f. Short-chain-hydroxyacyl-CoA dehydrogenase deficiency. g. Mitochondrial trifunctional protein deficiency. B. Differential Diagnosis (44, 58, 59) 1. Infants or children who, on fasting, have episodes of arrhythmias (4), lethargy, vomiting, hepatomegaly, or Reye-like syndrome, seizures, cardiomyopathy, peripheral neuropathy, pigmentary retinopathy, or coma associated with any of the following laboratory findings should have a diagnostic work-up for FAO defect: a. Hypoketotic hypoglycemia. b. Minimal metabolic acidosis. c. Elevated blood urea nitrogen (BUN) concentration. d. Elevated blood ammonia concentration. e. Elevated plasma urate concentration (11). f. Elevated concentration of transaminases. g. Myoglobinuria (13). h. Plasma carnitine deficiency. i. Dicarboxyluria. j. Rhabdomyolysis (43). 2. Siblings of children who have died with sudden infant death syndrome (SIDS) or Reye's syndrome should be evaluated for FAO defect (11, 21, 35, 42). 3. See references 5, 9, 17-19, 28, 31, 42, 51, and 57 for methods of diagnosis to determine which defect is present.

A. Correct Primary Imbalance in Metabolic Relationships 1. Restrict type and amount of dietary fat to level tolerated by patient and appropriate to diagnosis to decrease production of abnormal metabolites (6, 16). B. Supply "Conditionally Essential" Nutrients 1. Supplement L-carnitine to maintain plasma free carnitine in normal range ( 30 mol/L). C. Provide Alternate Pathway to Decrease Accumulated Toxic Precursors 1. Supplement GLY to enhance urinary loss of toxic acyl compounds as nontoxic acylglycine (41).
356 Mitochondrial FAO Defects 2001 Ross Products Division
D. Stabilize Altered Enzyme Proteins 1. Supplement oral riboflavin in pharmacologic amounts (12, 26).

A. Blood Glucose and Plasma Carnitine Concentrations 1. Maintain normal blood glucose concentrations. 2. Maintain normal plasma free carnitine 30 mol/L (26, 45, 56). 3. Prevent accumulation of abnormal metabolites. B. Growth, Development, and Nutrition Status 1. Support normal growth rate in infants and children, and maintain appropriate weight for height in adults. 2. Prevent EFA deficiency. 3. Support normal development. 4. Maintain normal nutrition status. a. Prevent catabolism. b. Avoid prolonged fasting 5. Maintain adequate hydration 6. Avoid lipid storage in heart, liver and muscles (22, 45).

A. Energy 1. Prescribe amount that should support normal weight gain for infants and children and maintain appropriate weight for height in adults (Table 20-1, p 359). 2. Requirements vary widely. Warning: Inadequate energy intake will result in growth failure in infants and children, weight loss in adults, and can adversely affect metabolic control if catabolism of fat stores occurs (27). B Protein 1. Prescribe amount that supplies 10-12% of total energy (Table 20-1, p 359).
C. Fat (44) 1. Prescribe amount of total fat that promotes goals of nutrition support (10, 16). a. Very-long chain and long-chain-FAO defects: 1) Prescribe ~30% of energy as fat. 2) About 50% of fat energy should be derived from MCT and remainder from fats that supply linoleic and -linolenic acids (20, 34). 3) Docosahexaenoic acid may be essential for the patient with long-chain-3-hydroxyacylCoA dehydrogenase deficiency. i. Harding, et al (20) suggest 65 mg/day for children < 20 kg and 130 mg/day for children > 20 kg. b. Medium- and short-chain-FAO defects: 1) Provide 15-25% of total daily energy as fat (7, 33). c. Prescribe 3% of total energy as linoleic acid and 1.0% as -linolenic acid. Warning: EFA deficiency may occur if intakes of linoleic acid and -linolenic acid are inadequate. Symptoms include dermal scaliness and increased skin permeability, reduced growth rate, renal abnormalities, increased erythrocyte fragility, increased susceptibility to infections, and decreased rate of development (26, 40, 50). D. Carbohydrate 1. Prescribe remaining energy as carbohydrate.
E. Fluid 1. Prescribe amount that will supply water requirements (Table 20-1, p 359). Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL fluid to children and adults for each kcal ingested (2). 2. Requirements may be higher than recommended secondary to accompanying fever. F. L-Carnitine 1. Prescribe amount that maintains normal plasma free carnitine concentration > 30 mol/L. 2. Amounts of 50 to 150 mg/kg have been suggested (41, 46). 3. Efficacy of carnitine supplementation in treatment of FAO defects is debated but use is almost standard therapy. G. Glycine 1. Supplement diet with 100 to 200 mg/kg/day (41). H. Riboflavin 1. Supplement diet with 100 to 200 mg/day, if beneficial (12, 26). I. Fasting 1. Instruct parents, patient, or caretakers to prevent infants from fasting > 4 hours, children > 6 hours, and adults > 8 hours. 2. Raw cornstarch (1.75-2.5 g/kg) helps prevent hypoglycemia (8). Warning: Increased frequency of feeding, tube feedings, and IV glucose may be necessary if patient is febrile, has diarrhea, or is vomiting.

A. Protein 1. Calculate grams of protein required to provide 10% to 12% of energy prescription. 2. Determine amount of protein provided by ProViMin, (Table 20-2, p 359), beikost, table foods (Tables 20-2 and 20-3, pp 359 and 360), or skim milk (Appendix 8, p A-7) required to fill protein prescription. Warning: Do not use skim milk before patient is 2 years old. B. Fat 1. Very-long-chain and long-chain-FAO defects: a. Calculate grams of fat required to provide 30% of energy prescription. 1) Supply about 50% of fat energy with MCT oil (Appendix 26, p A-28). i. MCT oil contains 8.2 kcal/g, 114.8 kcal/Tbsp, and 7.6 kcal/mL. Warning: Administer MCT oil ONLY if defect in long-chain-FAO is confirmed since addition of MCT oil is harmful to individuals with medium- or short-chain-FAO defects. b. If fat sources fail to supply 3% of energy as linoleic acid and 1% as -linolenic acid, add adequate amount of appropriate vegetable oil to supply (Appendix 10, p A-9). c. Amount of MCT oil will need to be decreased if sources of EFAs increase dietary fat to > 30% of energy. d. Order docosahexaenoic acid from Martek Biosciences Corp, Columbia, MD, USA. 2. Medium- and short-chain-FAO defects: a. Calculate grams of fat required to provide 15% to 25% of energy prescription. b. Determine amount of vegetable oil (Appendix 10, p A-9), beikost, or table foods (Tables 20-2 and 20-3, pp 359 and 360) required to fill fat prescription. c. Use fat source that supplies adequate linoleic acid and -linolenic acid. C. Energy 1. Add energy supplied by beikost or table foods to those required to supply fat and to those supplied by ProViMin, skim milk, carbohydrate, or other protein-containing foods. 2. Subtract amount determined above from total energy prescription.
358 Mitochondrial FAO Defects
3. Supply any remaining prescribed energy with Polycose Glucose Polymers powder (23 kcal/Tbsp, 3.8 kcal/g) or liquid (2 kcal/mL) (Appendix 9, p A-9), sugar (48 kcal/Tbsp), or pured or table foods containing little or no fat (Tables 20-2 and 20-4, pp 359 and 360). a. Do not use corn syrup or table sugar for infants because of osmolarity they yield (28). b. Do not use honey for infants because it may contain botulinum toxin (50). 4. Add beikost or table foods after infant is 3 to 4 months old or is developmentally ready to provide variety in taste, color, and texture (Table 20-2, p 359). 5. If additional carbohydrate is needed, see Table 20-4, p 360. D. L-Carnitine (Appendix 26, p A-28) 1. Add liquid L-carnitine to ProViMin medical food mixture. 2. L-carnitine tablets may be used if patient is old enough to swallow them. E. Glycine (Appendix 26, p A-28) 1. Weigh GLY on scale that reads in grams. 2. Add sufficient boiled, cooled water to yield 100 mg/mL. (eg, 10 g GLY to yield 100 mL). 3. Store in refrigerator for 1 week, if not frozen. 4. Measure into medical food mixture with disposable syringe. F. Riboflavin (Appendix 26, p A-28) 1. Have parents or patients finely crush number of tablets required to supply prescribed milligrams of riboflavin if patient cannot swallow tablets. 2. Mix with medical food mixture. 3. Give 25 to 30 mg with each feed. Additional will not be absorbed. A greater amount is absorbed when given with food than when fasting. G. Fluid and Mixing Instructions for ProViMin 1. Boil bottles, nipples, rings, and mixing utensils for 5 minutes and cool. Boil more water for 5 minutes, then cool to room temperature. 2. Measure or weigh specified boiled, cooled water, ProViMin, fat, carbohydrate, L-carnitine, GLY, and riboflavin into clean containers. 3. Pour about 1/2 specified volume of boiled, cooled water into clean blender. Running blender at slow speed, gradually add ProViMin and fat and blend for at least 15 seconds. 4. Dissolve powdered carbohydrate in part of the water and pour into blended ProViMin and infant formula mixture, add boiled, cooled water to yield final prescribed volume, mix well, and pour into opaque sterilized nursing bottles or cups. Prepared formula not used immediately should be refrigerated and used within 24 hours. Shake well before feeding. 5. Do not use microwave oven to warm formula. Unevenly heated formula can burn infants and steam can make bottles explode. 6. Discard formula remaining in bottle or cup after feeding. 7. Store unopened cans at room temperature. Cover opened can of ProViMin and store in dry place (not in refrigerator). Use within 1 month after opening. 8. Notify parents or caretakers when they may discontinue use of aseptic technique in making formula. F. Diet Guide 1. Provide parents, caretakers, or patient with completed Diet Guide (Table 20-5, p 361) with each diet change. Warning: Never permit patient to fast > 4 hours if infant, > 6 hours if child, or > 8 hours if adult; shorten fasting time if patient is febrile, has diarrhea, or is vomiting.

A. Nutrient Adequacy 1. Determine if diet provides nutrients in amounts prescribed in Section VI, Establish Prescription, p 352. a. See Table 20-2, p 359, for composition of ProViMin and Appendix 8, A-8, for skim milk. b. See Appendix 9, p A-9, for composition of Polycose.
2001 Ross Products Division Mitochondrial FAO Defects 359
2. Check diet to determine if it supplies Recommended Dietary Intakes (RDIs) of minerals and vitamins (Table 6-4, p 118, and Appendices 13 and 14, pp A-14 to A-15). a. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. b. If ProViMin mixture provides < 100% of RDIs for infants and < 75% for children, supplement diet with needed minerals and vitamins if not provided by beikost or table foods and laboratory tests indicate need (Appendix 11, p A-10, for composition of supplements). B. Osmolarity 1. If concentration of prescribed medical food mixture is > 27 kcal/fl oz, determine if osmolarity is in acceptable range. a. Determine osmolarity by laboratory analysis or use mathematical formula given in Appendix 18, p A-20. b. Osmolarity per gram ProViMin powder is 2.74 mosm. 2. If osmolarity is > 450 mosm/L for infants, > 750 mosm/L for children, > 1,000 mosm/L for adults (30, 48), or is greater than tolerated by patient, increase water content of prescribed medical food mixture and recalculate its osmolarity. C. Potential Renal Solute Load 1. Dehydration will result if renal solute load is greater than renal-concentrating ability of patient. 2. If concentration of medical food mixture prescribed is > 27 kcal/fl oz, estimate its potential renal solute load. a. This step is important to prevent dehydration of infants who may have renal-concentrating capacity as low as 600 mosm/L. b. Upper limit of renal solute load for neonates is approximately 1,100 mosm/L (47). 3. A method for estimating potential renal solute load is given in Appendix 20, p A-22. 4. If potential renal solute load is excessive, increase water content of medical food mixture and recalculate.

A. Quantitative Urine Organic Acids 1. Dicarboxylic aciduria may be detected in children with poorly controlled fat intake. a. Fatty acids, either intact or partially oxidized, may undergo peroxisomal oxidation to produce enzyme defect-specific dicarboxylic acids (36, 42). b. Decrease in production of these metabolites will be seen with good dietary control. c. Analyze urine organic acids every 2 to 3 months during 1st year and every 6-months thereafter. 2. MCT supplementation is associated with increased urinary excretion of sebacic and suberic acids (60). B. Essential Fatty Acids 1. Low concentrations of docosahexaenoic (< 20 g/mL), linoleic or -linolenic acids in fasting or preprandial plasma sample and triene to tetraene ratio > 0.03 are indicators of EFA deficiency (20, 25). 2. With adequate EFA intake, plasma linoleic and -linolenic acid concentrations will be within normal limits and triene to tetraene ratio will be normal (0.02 0.01). a. Triene to tetraene ratio is considered more sensitive measure of deficiency than plasma EFA concentration (25). 3. Evaluate EFA profile monthly for 1 year or when first establishing diet treatment. 4. If plasma linoleic or -linolenic acid concentration is low or if triene to tetraene ratio is elevated: a. Increase linoleic or -linolenic acid intake by 5% and reevaluate in 1 month. b. If concentrations continue to be abnormal, repeat above until value is in normal range. c. Correction in intake may require changing type of EFA oil source (Appendix 10, p A-9). 5. Decrease frequency of monitoring to every 3 months for older patients when diet treatment is established and plasma EFA concentrations and triene/tetraene ratio are in normal range.
C. Plasma Carnitine Concentrations 1. Measure plasma free and total carnitine monthly until patient is 6 months of age; every 3 to 6 months thereafter. 2. If either free or total carnitine concentration is below normal: a. Increase prescribed L-carnitine by 5% and reevaluate plasma concentrations after 1 month. b. If either concentration continues below normal, repeat above process until value is in normal range. 3. Plasma acylcarnitine concentrations are useful for monitoring (1). D. Protein Status 1. Evaluate plasma albumin concentration every 3 months until patient is 1 year old, thereafter measure twice yearly (Appendix 17, p A-18, for standards). 2. If plasma transthyretin concentration is below standard: a. Increase prescribed amount of protein by 5% to 10% and reevaluate plasma albumin concentration after 1 month. b. If plasma albumin concentration remains low, repeat above process until value is in normal range. E. Iron Status 1. Plasma ferritin concentration. a. Evaluate at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17, p A-18, for standards). b. If plasma ferritin concentration is below standard: 1) Increase iron intake to 2 mg/kg body weight with supplements (ferrous sulfate). 2) Evaluate plasma ferritin concentration monthly on increased iron intake. 3) Continue iron supplements until plasma ferritin concentration is in normal range. 2. Complete blood count. a. Hemoglobin and hematocrit concentrations should be evaluated at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 15, p A-17, for standards). F. Growth Status 1. Length/height and weight. a. Measure monthly to 1 year, every 3 months to 4 years, and twice yearly thereafter. Plot measurements on NCHS growth charts. b. Maintain length/height and weight between 10th and 90th percentiles. Some normal infants and children will fall above or below these percentiles. Maintain appropriate weight for height in adults. 2. If infant's or child's length/height or weight falls below usual growth channel: a. Increase prescribed protein and energy by 5% to 10% and remeasure after 1 month. b. If length/height or weight remains low, repeat above process until usual growth channel is achieved. G. Nutrient Intake 1. Maintain records of food intake for 3 days immediately before each blood test (Appendices 24 and 25, pp A-26 and A-27). 2. Evaluate intakes of fat, linoleic and -linolenic acids, protein, energy, minerals, and vitamins after each diet change. a. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. b. See Appendix 28, p A-29, for information about ordering software for diet evaluation. This software does not calculate fatty acids. H. Clinical Summary 1. A summary record of growth, laboratory, and nutrient intake data is useful for patient management (Table 20-6, p 362).
A. Establish and fill prescription for 2 month-old infant weighing 5.2 kg who has LCHAD deficiency using Recommended Daily Nutrient Intakes from Table 20-1, p 359, and nutrient contents from Table 20-2, p 359, and Appendix 9, p A-9. 1. Establish prescription.
Energy Fat Docosahexaenoic acid Linoleic acid -Linolenic acid MCT oil Protein Fluid L-Carnitine 120 kcal/kg x 624 kcal x 65 mg 624 kcal 624 kcal 187 kcal 624 kcal x x x x x 5.2 kg 0.30 5.2 kg 0.03 0.01 0.50 0.12 5.2 kg 5.2 kg = = = = = = = = = 624 kcal 187 kcal 338 mg 18.7 kcal 6.2 kcal 93.5 kcal 74.9 kcal 754 mL (25 oz) 260 mg MCT (g) 0.37 0.00 0.00 11.30 Protein (g) 18.7 0.0 0.0 0.0 Energy (kcal) 80 84 365 94 9 9 8.2 4 = = 2.1 g 0.69 g 9 = 20.8 g
= 11.4 g = 18.7 g
145 mL/kg x 50 mg x Measure Fat (g)
Medical Food Mixture Linoleic -Linolenic Acid Acid (g) (g) 0.00 4.78 0.00 0 00 0.00 0.73 0.00 0.00
ProViMin 25.6 g 0.37 Soy oil 10.4 mL 9.40 Polycose Powder 96 g 0.0 MCT oil 12.3 mL 11.30 Add water to make 754 mL (25 fl oz).
21.07 4.78 0.73 11.67 18.7 623 Total per day 29 6.90 1.05 15 11.98 Percentage of energy Approximate osmolarity of medical food mixture is < 300 mosm/L. Estimated potential renal solute load is < 200 mosm.
B. Example 2 Establish and fill prescription for newborn weighing 3.5 kg who has MCADD using Recommended Daily Nutrient Intakes from Table 20-1, p 359, and nutrient content from Table 20-2, p 359, and Appendix 9, p A-9. 1. Establish prescription.
Energy Fat Protein Fluid L-Carnitine Glycine Riboflavin 120 kcal/kg 420 kcal 420 kcal 150 mL/kg 50 mg 100 mg 200 mg x x x x x x 3.5 kg 0.25 0.12 3.5 kg 3.5 kg 3.5 kg = = = = = = = 420 kcal 105 kcal 9 kcal = 11.7 g 50 kcal 4 kcal = 12.5 g 525 mL 175 mg 350 mg 200 mg
Medical Food Mixture ProViMin Glycine Soy oil Polycose Liquid Add water to make 525 mL (18 fl oz). 11.9 12.4 420 Total per day 25% Percentage of energy Approximate osmolarity of medical food mixture is < 400 mosm/L. Estimated potential renal solute load is < 170 mosm. Linoleic acid is 5.98 g or 12.8% of energy; -linolenic acid is 0.81 g or 1.73% of energy. Measure 16.9 g 350 mg 13 mL 132 mL 0.2 0.00 11.7 0.0 Fat (g) Protein (g) 12.4 0.00 0.0 0.0 Energy (kcal) 53 0.0 103 264

A. Rationale 1. In normal persons, febrile illness and trauma are accompanied by catabolism of body fat and protein (55). 2. Well-nourished patients with FAO defects respond to infection and trauma as do normal persons B. Objectives of Nutrition Support 1. Maintain hydration and electrolyte balance. a. Offer infants and toddlers Pedialyte Oral Electrolyte Maintenance Solution ad libitum (Appendix 9, p A-9). 2. Depress catabolism a. Enhance energy intake when possible by offering fruit juices ad libitum as tolerated, liquid Jell-O , Polycose powder or liquid (Appendix 9, p A-9) added to fruit juices or Pedialyte if tolerated, and caffeine-free soft drinks (not diet drinks). 1) Add 1/3 cup Polycose powder to Pedialyte liquid to yield 8 fl oz. b. Return patient to ProViMin medical food mixture and pre-illness diet as rapidly as possible. 1) Begin with 1/2 original strength ProViMin medical food mixture. 2) Increase to original strength as tolerated. c. Feed Polycose solution (5-7 g/kg of carbohydrate) or carbohydrate-containing foods every 2 to 3 hours. 1) If unable to feed every 2 to 3 hours, administer solution of raw cornstarch (2 to 3 g/kg) (1:2 ratio cornstarch to fluid) to children older than 9 months. d. Administer 10% glucose solution intravenously if oral intake cannot be maintained. 3. Decrease intake of fatty acids. a. Decrease fat content of diet or medical food mixture. 1) Increase Polycose in medical food mixture. 2) Remove oil prescribed for EFAs. 3) Remove MCT oil if not tolerated. 4. Prevent low blood glucose concentrations. a. Add uncooked cornstarch, 2 to 3 g/kg/day, to any liquids and feed every 2 to 3 hours. 5. Prevent accumulation of toxic fatty acyl groups. a. Add liquid L-carnitine to Pedialyte. Warning: Intravenous administration of lipids is contraindicated.
TABLE 20-1. Recommended Daily Nutrient Intakes (Ranges) for Infants, Children, and Adults With a Mitochondrial FAO Defect
Age Protein (% of energy) Infants 0 to < 3 mo 3 to < 6 mo 6 to < 9 mo 9 to < 12 mo Girls and Boys 1 to < 4 yr 4 to < 7 yr 7 to < 11 yr Women 11 to < 15 yr 15 to < 19 yr 19 yr Men 11 to < 15 yr 15 to < 19 yr 19 yr
1 1
Nutrient Energy1 (kcal/kg) 120 (145 115 (145 110 (135 105 (135 (g/day) 23 30 34 46 46 50 45 59 63 - 95) - 95) - 80) - 80) (kcal/day) Fluid2 (mL/kg) 150 - 125 160 - 130 145 - 125 135 - 120 (mL/day) 900 - 1,800 1,300 - 2,300 1,650 - 3,300 1,500 - 3,000 1,200 - 3,000 1,400 - 2,500 2,000 - 3,700 2,100 - 3,900 2,000 - 3,300
10 - 12 10 - 12 10 - 12 10 - 12
1,300 ( 900 - 1800) 1,700 (1300 - 2300) 2,400 (1650 - 3300) 2,200 (1500 - 3000) 2,100 (1200 - 3000) 2,100 (1400 - 2500) 2,700 (2000 - 3700) 2,800 (2100 - 3900) 2,900 (2000 - 3300)
From reference 15. 2 From reference 2. Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL to children and adults for each kcal ingested.
TABLE 20-2. Average Nutrient Contents of Gerber Baby Foods (Beikost), ProViMin , and MCT Oil1
Food Cereals, dry, Ready To Serve Cereals, with fruit, 2nd and 3rd Foods , jarred Desserts: 2nd and 3rd Foods Fruits, 1st , 2nd and 3rd Foods Juices 3 MCT oil Meats, 2nd and 3rd Foods ProViMin Vegetables: 1st , 2nd and 3rd Foods
1 2 3
Measure 1 Tbsp2 1 Tbsp2 1 Tbsp 1 Tbsp2 1 fl oz 100 mL 2 1 Tbsp 100 g 1 Tbsp2

2
Fat (g) 0.17 0.07 0.04 0.00 0.00 93.30 0.67 2.00 0.04
Protein (g) 0.35 0.16 0.10 0.19 0.07 0.00 1.58 73.00 0.19 15 10 12 10 16 765 14 312 6
Energy (kcal)
Nutrient Values. Fremont, Michigan: Gerber Products Co, 2000. US standard level measure. MCT oil contains 8.2 kcal/g fat.
TABLE 20-3. Exchange Lists for Nutrition Support of Children and Adults With Mitochondrial FAO Defects 1
Food List Meat, lean Meat, very lean Milk, skim Fat 3 Fruit Starch/Bread
2
Measure 1 oz 1 oz 1 cup varies 1/2 cup canned or 1/2 cup fresh or juice 1/2 cup dried varies 3.0 1.0 0.5 5.0 0.0 0.0 trace
Fat (g) 7 7 8 0 0 0 3
Protein (g) 55 35 90 45 60 80 25
Energy (kcal)
Vegetable 1/2 cup cooked, or 1 cup raw 0.5 2 25 1 Exchange Lists for Weight Maintenance. Chicago: The American Dietetic Association, 1995. 2 From reference 38. 3 Care must be taken to select fats that provide adequate linoleic and -linolenic acids, such as those high in canola or soybean oil.
TABLE 20-4. Fat-Free Foods to Help Supply Energy in Low-Fat Diets

Foods/Supplement Carbonated beverages Corn syrup Fruit and juice drinks Hard candy Jam, jelly Jell-O Polycose Glucose Polymers, liquid Polycose Glucose Polymers, powder Popsicles , frozen juice bars Slush Drinks (ie, Mr. Misty ) Syrup Measure 4 fl oz 1 Tbsp 4 fl oz 3 pieces, approx 1 Tbsp 1/4 cup, prepared 1 fl oz 2 Tbsp 1/2 cup 3 fl oz 1 Tbsp 60 57 60 60 50 65 59 45 50 60 55 Energy (kcal)
TABLE 20-5. Mitochondrial FAO Defects Diet Guide Name: Date: __________/_________/_________
Mo Day Year
Diagnosis:
Birthdate: __________/_________/__________
Mo Day Year
Age:
Length/Height: ____________________ (cm/in)
Weight:
(kg/lb)
Medical Food
Amount
Fat (g)
Protein (g)
Energy (kcal)
ProViMin L-carnitine Glycine Riboflavin Skim milk
g mg mg mg cups
Add water to make _______________ mL/fl oz
Beikost or table foods Cereals/Starch/Bread Cereals: With Fruit Desserts, low fat Fruits/Juices Meats, lean Vegetables
Tbsp/Exchanges

Comments:
____________________________________________________ Nutritionist
TABLE 20-6. Mitochondrial FAO Defects Clinical Summary Sheet Name: Date of Birth: __________/__________/__________
Mo Date Day Physical Data
Length/ Weight Head Organic Height Circum acids (mo/d/yr) (cm) (kg) (cm) (mol/L) Plasma Carnitine Total (mol/L) Free (mol/L)
362 Mitochondrial FAO Defects 2001 Ross Products Division
Hospital Number: Diagnosis:

Laboratory Data
Triene/ Tetraene Ratio Blood Glucose (mg/dL) Ferritin Albumin Hgb Fat
Year Nutrient Intake Data

Linoleic Acid -Linolenic Acid (g) (%) L-Carn Protein Energy
(ng/mL)
(g/dL)
(g/dL)
(g)
(%)
(g)
(%)
(mg)
(g)
(kcal)
REFERENCES
1. 2. 3. Abdenur JE, Chamoles NA, Specola N, et al: MCAD deficiency. Acylcarnitines (AC) by tandem mass spectrometry (MS-MS) are useful to monitor dietary treatment. Adv Exp Med Biol 1999;466:353-363. Behrman RE, Kliegman RM, Arvin AA (eds): Nelson Textbook of Pediatrics, ed 15. Philadelphia: WB Saunders Co, 1996. Bertini E, Dionisi-Vici C, Garavaglia AB, et al: Peripheral sensory-motor polyneuropathy, pigmentary retinopathy, and fatal cardiomyopathy in long-chain-3-hydroxy-acyl-CoA dehydrogenase deficiency. Eur J Pediatr 1992;151;121-126. Bonnet D, Martin D, de Lonlay P, et al: Arrhythmias and conduction defects as presenting symptoms of fatty acid oxidation disorders in children. Circulation 1999;100:2248-2253. Brivet M, Boutron A, Slama A, et al: Defects in activation and transport of fatty acids. J Inher Metab Dis 1999;22:428-441. Brown-Harrison MC, Nada MA, Sprecher H, et al: Very long chain acyl-CoA dehydrogenase deficiency: Successful treatment of acute cardiomyopathy. Biochem Mol Med 1996;58:59-65. Catzeflis C, Bachmann C, Hale DE, et al: Early diagnosis and treatment of neonatal medium-chain-acyl-CoA dehydrogenase deficiency: Report of two siblings. Eur J Pediatr 1990;149:577-581. Chen YT, Cornblath M, Sidbury JB: Cornstarch therapy in type I glycogen storage disease. N Engl J Med 1984;310:171-175. Coates P: New developments in the diagnosis and investigation of mitochondrial fatty acid oxidation disorders. Eur J Pediatr 1994;153:S49-S56. Costa CG, Dorland L, Tavares de Almeida I, et al: The effect of fasting, long-chain-triglyceride load and carnitine load on plasma long-chain-acylcarnitine levels in mitochondrial very long-chain-acyl-CoA dehydrogenase deficiency. J Inher Metab Dis 1998;21:391-399 Davidson-Mundt A, Luder AS, Greene CL: Hyperuricemia in medium-chain-acyl-coenzyme A dehydrogenase deficiency. J Pediatr 1992;120:444-446. DiDonato S, Gellera C, Peluchetti D, et al: Normalization of short-chain-acylcoenzyme A dehydrogenase after riboflavin treatment in a girl with multiple acylcoenzyme A dehydrogenase-deficient myopathy. Ann Neurol 1989;25:479-484. Dionisi-Vici C, Burlina AB, Bertini E, et al: Progressive neuropathy and recurrent myoglobinuria in a child with long-chain-3-hydroxyacyl-coenzyme A dehydrogenase deficiency. J Pediatr 1991;118:744-746. Duran M, Wanders RJA, deJager JP, et al: 3-Hydroxydicarboxylic aciduria due to long-chain-3-hydroxyacylcoenzyme A dehydrogenase deficiency associated with sudden neonatal death: Protective effect of mediumchain-triglyceride treatment. Eur J Pediatr 1991;150:190-195. Food and Nutrition Board, Committee on Dietary Allowances: Recommended Dietary Allowances, eds 9 and 10. Washington, DC: National Academy of Sciences, 1980 and 1989. Gillingham M, van Calcar S, Ney D, et al: Dietary management of long-chain-3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD). A case report and survey. J Inher Metab Dis 1999;22:123-131. Gregersen N, Winter V, Jensen PKA, et al: Prenatal diagnosis of medium-chain-acyl-CoA dehydrogenase (MCAD) deficiency in a family with a previous fatal case of sudden unexpected death in childhood. Prenat Diagn 1995;15:82-86. Hagenfeldt L, Venizelos N, von Dobeln U: Clinical and biochemical presentation of long-chain-3-hydroxyacyl-CoA dehydrogenase deficiency. J Inher Metab Dis 1995;18:245-248. Hale DE, Bennett MJ: Fatty acid oxidation disorders: A new class of metabolic diseases. J Pediatr 1992;121:1-11. Harding CO, Gillingham MB, van Calcar SC, et al: Docosahexaenoic acid and retinal function in children with longchain-3-hydroxyacyl-CoA dehydrogenase deficiency. J Inher Metab Dis 1999;22:276-280. Harpey JP, Charpentier C, Paturneau-Jouas M: Sudden infant death syndrome and inherited disorders of fatty acid -oxidation. Metab Prob Newborn 1990;58 (Suppl 1):70-80. Iafolla AK, Thompson RJ, Roe CR: Medium-chain-acyl-coenzyme-A dehydrogenase deficiency: Clinical course in 120 affected children. J Pediatr 1994;124:409-415. Jackson S, Bartlett K, Land J, et al: Long-chain-3-hydroxyacyl-CoA dehydrogenase deficiency. Pediatr Res 1991;29:406-411. Jackson S, Kler RS, Bartlett K, et al: Combined enzyme defect of mitochondrial fatty acid oxidation. J Clin Invest 1992;90:1219-1225. Jones PJH, Kubow S: Functions of essential fatty acids. In Shils ME, et al (eds): Modern Nutrition in Health and Disease ed 9. Philadelphia: Williams & Wilkins, 1999, pp 84-88. Kmoch S, Zeman J, Hrebicek M, et al: Riboflavin-responsive epilepsy in a patient with SER209 variant form of short-chain-acyl-CoA dehydrogenase. J Inher Metab Dis 1995;18:227-229. Lipshitz F, Moses N: Growth failure: A complication of dietary treatment of hypercholesterolemia. Am J Dis Child 1989;143:537-542. Losty HC, Lee P, Alfaham M, et al: Fatty infiltration in the liver in medium-chain-acyl-CoA dehydrogenase deficiency. Arch Dis Child 1991;66:727-728.
4. 5. 6. 7. 8. 9. 10.
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29. MacLean W, Graham G: Pediatric Nutrition in Clinical Practice. Menlo Park, Calif: Addison-Wesley Publishing Co, 1982. 30. Martin SB, Acosta PB: Osmotic behaviors of components of chemically-defined formulas. J Pediatr Perinat Nutr 1987;1:1-17. 31. Millington DS, Terada N, Chace DH, et al: The role of tandem mass spectrometry in the diagnosis of fatty acid oxidation disorders. In Coates PM, et al (eds): New Developments in Fatty Acid Oxidation. New York: Wiley Liss, 1992, p 339. 32. Moore R, Glasgow JFT, Bingham MA, et al: Long-chain-3-hydroxyacyl-coenzyme A dehydrogenase deficiency Diagnosis, plasma carnitine fractions and management in a further patient. Eur J Pediatr 1993;152:433-436. 33. Nada MA, Vianey-Saban C, Roe CR, et al: Prenatal diagnosis of mitochondrial fatty acid oxidation defects. Prenat Diagn 1996;16:117-124. 34. Parini R, Invernizzi F, Menni F, et al: Medium-chain-triglyceride loading test in carnitine acylcarnitine translocase deficiency. Insights on treatment. J Inher Metab Dis 1999;22:733-739. 35. Perper JA, Ahdab-Barmada M: Fatty liver, encephalopathy and sudden unexpected death in early childhood due to medium-chain-acyl-coenzyme A dehydrogenase deficiency. Am J Med Path 1992;131;329-334. 36. Pitt JJ: Novel glycine conjugates in medium-chain-acyl-CoA dehydrogenase deficiency. J Inher Metab Dis 1993;16:392-398. 37. Pollitt RJ: Disorders of mitochondria long-chain-fatty acid oxidation. J Inher Metab Dis 1995;18:473-490. 38. Posati LP, Orr ML: Composition of Foods: Dairy and Egg Products, Agriculture Handbook No. 8-1. Washington, DC: US Dept of Agriculture, Agricultural Research Service, 1976. 39. Przyrembel H, Jakobs C, Ijlst L, et al: Long-chain-3-hydroxyacyl-CoA dehydrogenase deficiency. J Inher Metab Dis 1991;14:674-679. 40. Report of a Joint Expert Consulation: Fats and Oils in Human Nutrition. Rome: World Health Organization,1993. 41. Rinaldo P, Schmidt-Sommerfeld E, Posca AP, et al: Effect of treatment with glycine and L-carnitine in mediumchain-acyl-CoA dehydrogenase deficiency. J Pediatr 1993;122:580-584. 42. Roe CR, Ding J: Mitochondrial fatty acid oxidation disorders. In Scriver CR, et al (eds): The Metabolic and Molecular Bases of Inherited Disease, ed 8. New York: McGraw-Hill Medical Publishing Division, 2001, pp 2297-2326. 43. Ruitenbeek W, Poels PJE, Turnbull DM, et al: Rhabdomyolysis and acute encephalopathy in late onset mediumchain-acyl-CoA dehydrogenase deficiency. J Neurol Neurosurg Psychiatry 1995;58:209-214. 44. Saudubray JM, Martin D, de Lonlay P, et al: Recognition and management of fatty acid oxidation defects. A series of 107 patients. J Inher Metab Dis 1999;22:488-502. 45. Schulpis KH, Nounopoulos C, Scarpalezou A, et al: Serum carnitine level in phenylketonuric children under dietary control in Greece. Acta Paediatr Scand 1990;79:930-934. 46. Sewell AC, Bender SW, Wirth S, et al: Long-chain-3-hydroxyacyl-CoA dehydrogenase deficiency: A severe fatty acid oxidation disorder. Eur J Pediatr 1994;153:745-750. 47. Smith CA, Nelson NM: The Physiology of the Newborn Infant, ed 4. Springfield, IL: Charles C Thomas Publisher, 1976. 48. Smith JL, Heymsfield SB: Enteral nutrition support: Formula preparation from modular ingredients. JPEN 1983;7:280-288. 49. Treem WR, Rinaldo P, Hale DE, et al: Acute fatty liver of pregnancy and long-chain-3-hydroxyacyl-coenzyme A dehydrogenase deficiency. Hepatology 1994;19:339-345. 50. Uauy R, Treen M, Hoffman DR: Essential fatty acid metabolism and requirements during development. Semin Perinatol 1989;13:118-130 51. Venizelos N, Ijlst L, Wanders JA, et al: Beta-oxidation enzymes in fibroblasts from patients with 3-hydroxydicarboxylic aciduria. Pediatr Res 1994;36:111-114. 52. Wanders RJA, Ijlst L, Duran M, et al: Long-chain-3-hydroxyacyl-CoA dehydrogenase deficiency: Different clinical expression in three unrelated patients. J Inher Metab Dis 1991;14:325-328. 53. Wanders RJA, Ijlst L, Poggi F, et al: Human trifunctional protein deficiency: A new disorder of mitochondrial fatty acid oxidation. Biochem Biophys Res Commun 1992;180:1139-1145. 54. Wanders RJA, Vreken P, DenBoer MEJ, et al: Disorders of mitochondrial fatty acyl-CoA -oxidation. J Inher Metab Dis. 1999;22:442-487. 55. Wannemacher RW: Key role of various individual amino acids in host response to infection. Am J Clin Nutr 1977;30:1269-1280. 56. Warshaw JB, Curry E: Comparison of serum carnitine and ketone body concentrations in breast- and in formulafed newborn infants. J Pediatr 1980;97:122-125. 57. Whyte RK, Whelen D, Hill R, et al: Excretion of dicarboxylic and w-1 hydroxy fatty acids by low birth weight infants fed with medium chain triglycerides. Pediatr Res 1986;20:122-125. 58. Wilcken B, Carpenter KH, Hammond J: Neonatal symptoms in medium-chain-acyl-coenzyme A-dehydrogenase deficiency. Arch Dis Child 1993;69:292-294. 59. Wilcken B, Hammond J, Silink M: Morbidity and mortality in medium-chain-acyl-CoA dehydrogenase deficiency. Arch Dis Child 1994;70:410-412.
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60. Wilcken B, Leung KC, Hammond J, et al: Pregnancy and fetal long-chain-3-hydroxyacyl coenzyme A dehydrogenase deficiency. Lancet 1993;314:407-408. 61. Wilson CJ, Champion MP, Collins JE, et al: Outcome of medium-chain-acyl-CoA dehydrogenase deficiency after diagnosis. Arch Dis Child 1999;80;459-462. 62. Yamaguchi S, Indo Y,-CoAtes P, et al: Identification of very-long-chain-acyl-CoA dehydrogenase deficiency in three patients previously diagnosed with long-chain-acyl-CoA dehydrogenase deficiency. Pediatr Res 1993:34:111-113. 63. Ziadeh R, Hoffman EP, Finegold DN, et al: Medium-chain-acyl-CoA dehydrogenase deficiency in Pennsylvania: Neonatal screening shows high incidence and unexpected mutation frequencies. Pediatr Res 1995;37;675-678.
PROTOCOL 21 Hypercalcemia Nutrition Support of Infants, Children, and Adults With CALCILO XD Low-Calcium/Vitamin D-Free Infant Formula With Iron
I. Introduction: Hypercalcemia Results from Four Disorders Described Below
A. Williams Syndrome (WS) is an autosomal dominant disorder characterized by supravalvular aortic stenosis, which may include peripheral pulmonary stenosis, elfin facies, and psychomotor retardation (28). Developmental delay is found in approximately 72% of patients (34). The phenotype of WS may be due to a hemizygous defect in the elastin gene (7q11.3) (25) or genes contiguous to the elastin locus (38) which may account for some of the vascular problems and dysmorphism associated with WS. Hypercalcemia and central nervous symptoms may result from deletion of adjacent genes (25). Infantile hypercalcemia is found in approximately 40% of patients with WS and usually resolves by 4 years of age (26, 34). A dysfunction of the human calcitonin gene receptor, a transmembrane peptide that acts both as a calcitonin receptor and extracellular calcium sensor, has been reported in this disorder (38). Reports of patients with WS also identify defects in vitamin D metabolism (12, 23, 48) and calcitonin secretion (8). Nephrocalcinosis secondary to hypercalcemia has been reported (39). B. Osteopetrosis is a group of diseases of defective osteoclast function resulting in reduced resorption of calcified cartilage. Consequently, patients exhibit increased skeletal mass and bone density and abnormal bone remodeling (13). Inheritance is either autosomal recessive or autosomal dominant. The milder dominant form exhibits in adult life (5). Autosomal recessive malignant infantile osteopetrosis is a rare disease affecting approximately 1:200,000 live births with increased incidence in Saudi Arabia and Costa Rica. The cause of osteopetrosis is unknown except for a small number of patients with a carbonic anhydrase II deficiency (44). The accumulation of bone in osteopetrotic patients results in narrowing of the cranial nerve foramina and reduction in the bone marrow cavity (38). Immunodeficiency results from reduced leukocyte superoxide generation (2, 22, 27). These defects can lead to hearing loss, blindness, and/or sepsis. C. Primary Neonatal Hyperparathyroidism (PNH) is a rare disorder resulting in excessive production of parathyroid hormone (PTH) due to parathyroid hyperplasia (7, 17). A defect in the gene that expresses the calcium-sensing receptor protein in parathyroid, thyroid, and renal cells (24) may be responsible for PNH (15, 16). Patients with PNH present early in infancy with failure to grow, anorexia, irritability, lethargy, respiratory distress, bone demineralization, and fractures. Severe hypercalcemia (> 15 to 20 mg/dL, 3.75 to 5.00 mmol/L) and increased plasma PTH concentrations are found. D. Idiopathic Hypercalcemia may be due, in part, to disorders that result in excessive intestinal calcium absorption, increased resorption of bone calcium, or enhanced renal resorption. Additionally, disturbances of vitamin D and calcium-phosphate metabolism may be evident (31, 40). Phenotypes may be benign or malignant. Any infant or child with hypercalcemia must have a thorough clinical evaluation for diagnosis (3).

A. Growth retardation is evident in many patients with WS. Skeletal development proceeds at a normal rate, but remains at approximately the 3rd percentile (36). Poor growth has been reported in the first years of life (37). B. Only 30% of patients with osteopetrosis survive until 6 years of age, with life expectancy less than 10 years (13, 20, 49). Bone marrow transplantation, beneficial in ameliorating the clinical consequences of autosomal recessive osteopetrosis, improves survival in some patients (18, 42). Recombinant human interferon gamma has been used with mixed success to stimulate osteoclast activity and bone resorption (21, 22, 27). Mixed findings have also been shown with administration of large doses of Calcitriol (1, 25-dihydroxycholecalciferol), an active form of vitamin D3 and a
2001 Ross Products Division Hypercalcemia 371
potent stimulator of osteoclastic bone resorption (20, 49). Hematopoietic stem cell transplantation is successful in correcting hematologic manifestations (10). Failure to grow and poor stature are common findings in patients with severe osteopetrosis (43). Growth retardation may be exacerbated by poor dentition and difficulty ingesting adequate nutrient intake (52). C. PNH is fatal if not recognized and treated early in life. Parathyroidectomy normalizes plasma calcium concentration and improves prognosis (7, 17). Pharmacologic therapy to activate the calcium-sensing receptor is undergoing clinical trial. D. Outcomes for patients with idiopathic hypercalcemia are variable and depend on the specific disorder. Latent nephrocalcinosis has been reported (40).

A. The Disorder 1. Hypercalcemia may be identified in several disorders, including the following: a. Williams syndrome. b. Osteopetrosis (marble bone disease) . 1) Autosomal-recessive. 2) Autosomal-dominant, types I and II. c. Neonatal hyperparathyroidism. d. Idiopathic infantile hypercalcemia. B. Differential Diagnosis 1. For methods of diagnosis, see references 1, 4-6, 32, 33, 35, 41, 44. 2. Therapy depends on disorder present.

A. Correct Primary Imbalance in Metabolic Relationships 1. Restrict dietary calcium (Ca) and vitamin D to that tolerated by patient to maintain treatment plasma total Ca and 1,25-dihydroxyvitamin D concentrations.

A. Plasma Calcium Concentration 1. Maintain plasma total Ca concentration in near normal to normal range: 1.9 to 2.7 mmol/L (7.6-10.8 mg/dL) (12, 14, 18, 19, 54). B. Plasma 1,25-Dihydroxyvitamin D Concentration 1. Maintain normal plasma concentration (12, 23, 31, 54) (52-60 pg/mL, radioreceptor binding assay, Quest Diagnostics, San Juan Capistrano, CA). Warning: In osteopetrosis, high doses of Calcitriol result in elevation of 1,25-dihydroxyvitamin D. C. Growth, Development, and Nutrition Status 1. Support normal growth rate in infants and children; maintain appropriate weight for height in adults. 2. Support normal development. 3. Maintain normal nutrition status. a. Prevent rickets.

A. Calcium 1. Prescribe Ca intake that produces normal or near normal plasma Ca concentration. a. Ca intakes ranging from 50 to 400 mg/day have been used (4, 9, 12, 14, 21, 48, 53). 2. Dietary Ca restriction is usually just one component of total treatment for osteopetrosis. B. Vitamin D 1. No additional dietary vitamin D or vitamin D supplements should be added to Ca-restricted diet. 2. Do not prescribe mineral/vitamin supplements that contain vitamin D or Ca.
372 Hypercalcemia 2001 Ross Products Division
3. Exception: Patients with osteopetrosis who develop rachitic changes are treated with either Calcitriol (1-2 g/kg per day) or interferon gamma (1.5 g/kg subcutaneous injection 3 times per week), in addition to other therapies (20, 22). C. Protein 1. Prescribe amount that promotes normal growth and development (Table 21-1, p 373). D. Energy 1. Prescribe amount that should support normal weight and length gain for infants and children and maintain appropriate weight for height for adults (Table 21-1, p 373). E. Fluid 1. Prescribe amount that will supply water requirements (Table 21-1, p 373). Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL to children and adults for each kcal ingested (3). Note: Interferon-gamma therapy in patients with osteopetrosis may elevate body temperature (21) resulting in increased water loss.

A. Calcium 1. Calculate amount of Ca supplied by Calcilo XD (Table 21-3, p 374), beikost, or table foods required to fill protein prescription. a. Ca content of beikost (baby food) may be obtained by contacting the following manufacturers:
b. Ca content of table foods may be obtained from the USDA Nutrient Data Laboratory; Ph (301) 504-0630; Fax (301) 504-0632; web site www.nal.usda.gov.fnic/foodcomp. 1) General guidelines: i. Meat/meat substitutes. a) Exclude soybeans and soybean products (tofu, miso, natto, and tempeh), canned salmon, smelt, mackerel, sardines with bones, canned shrimp, baked beans, northern beans, French beans, mung beans, California red kidney beans. ii. Fruits. a) Exclude juices with added calcium. iii. Vegetables a) Exclude collard, dandelion and turnip greens, kale, oriental radish, rhubarb, and spinach. Warning: Avoid all prepackaged foods containing milk and milk products, all soups prepared with milk, and batter-dipped fried foods. 2. If additional Ca is needed, sources of Ca may be added to diet. a. For infants, infant formula with iron may be used (Table 21-2, p 373). b. For children, food sources of Ca are listed in Table 21-2, p 373. 3. Local water supply may contain significant amounts of Ca and should be assayed, unless deionized water is used. B. Protein 1. Calculate amount of Calcilo XD (Table 21-3, p 374) and beikost or table foods containing little or no Ca required to fill protein prescription. a. Weigh Calcilo XD powder on scale that reads in grams because of variability of household measuring equipment (Practical Aspects of Nutrition Support, p vii) and changes in density during shipping.
Hypercalcemia 373
b. See Table 21-3 (p 374, footnote 1) for approximate weight of Calcilo XD powder in level, dry US standard household measures. 2. Requirements for children and adults may be met using beikost, table foods, or Calcilo XD. C. Energy 1. Calculate energy provided by Calcilo XD (Table 21-3, p 374) and beikost or table foods containing little or no Ca required to fill protein and Ca prescriptions. 2. Subtract amount determined above from total energy prescription. 3. Provide any remaining prescribed energy by concentrating Calcilo XD, or by supplementing with Polycose Glucose Polymers powder (23 kcal/Tbsp, 3.8 kcal/g) or liquid (2 kcal/mL) (Appendix 9, p A-9), sugar (48 kcal/Tbsp), or other Ca-free energy sources. a. Do not use corn syrup or table sugar for infants because of osmolarity they yield (30). b. Do not use honey for infants because it may contain botulinum toxin (47). D. Fluid and Mixing Instructions 1. To prepare 20-kcal/fl-oz formula, add sufficient boiled, cooled water to three scant scoops (19.3 g) of Calcilo XD to yield 5 fl oz. Tap water may replace boiled, cooled water when preparing Calcilo XD for older infants and children. a. To make different amounts of a 20 kcal/fl oz formula, follow appropriate directions below using level measures: 1) To prepare 1-8 fl oz bottle of formula, add water to 31 g (1/4 cup + 1 tsp) of Calcilo XD to make 8 fl oz. 2) To make 1 L of formula, add water to 131 g (1-1/4 cups) of Calcilo XD to make 1 L. 3) To make 1 qt of formula, add water to 125 g (1 cup + 2-1/2 Tbsp) of Calcilo XD to make 32 fl oz. 2. Refrigerate in sterilized, closed containers until used. Discard unused portion 48 hours after mixing because of nutrient loss. Store unopened cans at room temperature. Cover opened can and store in dry place (not in refrigerator). Use within 1 month after opening. 3. Warm or cool prepared Calcilo XD to room temperature before feeding to infants. Shake well before feeding. 4. Do not use microwave oven to warm infant formula. Unevenly heated formula can burn infants and steam can make bottles explode. 5. Notify parents or caretakers when they may discontinue use of aseptic technique in making formula. Warning: Municipal water may contain substantial quantities of calcium. Contact the local public utilities office for information. Bottled deionized water may be used to prepare Calcilo XD. E. Diet Guide 1. Provide parents, caretakers, or patient with completed Diet Guide (Table 21-4, p 375) with each diet change.

A. Nutrient Adequacy 1. Determine if diet provides nutrients in amounts prescribed in Section VI, Establish Prescription, p 367. a. See Table 21-3, p 374, for composition of Calcilo XD. 2. Check diet to determine if it supplies Recommended Dietary Intakes (RDIs) of minerals (except Ca) and vitamins (except vitamin D) (Appendices 13 and 14, pp A-14 and A-15). a. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. b. If Calcilo XD mixture provides < 100% of RDIs for infants, supplement diet with needed minerals and vitamins free of Ca and vitamin D if not provided by beikost or table foods and laboratory tests indicate need (Appendix 11, p A-10, for composition of supplements).
374 Hypercalcemia
B. Osmolarity 1. If concentration of prescribed medical food mixture is > 27 kcal/fl oz, determine if osmolarity is in acceptable range. a. Determine osmolarity by laboratory analysis or use mathematical formula given in Appendix 18, p A-20. b. Osmolarity of Calcilo XD is 2.02 mosm/g of powder. 2. If osmolarity is > 450 mosm/L for neonates (29), > 750 mosm/L for toddlers, > 1,000 mosm/L for adults (46), or greater than tolerated by patient, increase water content of prescribed medical food mixture and recalculate its osmolarity. C. Potential Renal Solute Load 1. Dehydration will result if renal solute load is greater than renal-concentrating ability of patient. 2. If concentration of medical food mixture prescribed is > 27 kcal/fl oz, estimate its potential renal solute load. a. This step is important to prevent dehydration of infants who may have renal-concentrating capacity as low as 600 mosm/L. b. Upper limit of renal solute load for neonates is approximately 1,100 mosm/L (45). 3. A method for estimating potential renal solute load is given in Appendix 20, p A-22. 4. If potential renal solute load is excessive, increase water content of medical food mixture and recalculate.

A. Plasma Calcium Concentration 1. Evaluate weekly by quantitative methods until patient is 6 months of age and monthly thereafter, or as indicated. 2. If plasma Ca concentrations remain high, reduce Ca intake by 5% to 10% and reevaluate in 1 week. 3. Pharmacologic therapy may also need to be modified in response to elevated calcium concentrations. B. Urinary Calcium Excretion 1. Evaluate monthly until patient is 6 months of age and every 3 months thereafter. C. Plasma 1,25-Dihydroxyvitamin D Concentration 1. Elevated plasma concentrations have been found in patients with WS (12, 23) and osteopetrosis (27, 44, 50). 2. Measure as needed to maintain normal plasma concentration (ie, 52-60 pg/mL). D. Protein Status 1. Evaluate plasma albumin concentration every 3 months until patient is 1 year of age and every 6 months thereafter (Appendix 17, p A-18, for standards). 2. If plasma albumin concentration is below standard: a. Increase prescribed protein by 5% to 10% and reevaluate plasma albumin concentration in 1 month. b. If plasma albumin concentration continues below standard, repeat above process until value is in normal range. E. Rachitic Changes in Osteopetrosis 1. Evaluate plasma alkaline phosphatase concentration routinely to maintain normal plasma concentration. a. If plasma alkaline phosphatase concentration is elevated, reevaluate both nutrition support and medical treatment and modify if needed. 2. Evaluate radiographs of long bones routinely. F. Iron Status 1. Plasma ferritin concentration. a. Evaluate at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17, p A-18, for standards).
Hypercalcemia 375
b. If plasma ferritin concentration is below standard: 1) Increase iron intake to 2 mg/kg with supplements (ferrous sulfate). 2) Evaluate plasma ferritin concentration monthly on increased iron supplementation. 3) Continue iron supplements until plasma ferritin concentration is in normal range. 2. Complete blood count and differential. a. Hemoglobin and hematocrit concentrations and differential should be evaluated at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17, p A-18, for standards). b. Hemoglobin and hematocrit improve with therapy but remain low (21). c. Measure neutrophils and platelets as needed to monitor hematologic status. Nutrition support alone may not normalize leukoerythroblastic anemia (space-occupying lesions of marrow, decreased immature granulocytes, normal leukocytes, and low erythrocyte concentrations) and thrombocytopenia found in osteopetrosis. G. Growth Status 1. Length/height and weight. a. Measure monthly to 1 year, every 3 months to 4 years, and every 6 months thereafter. Plot measurements on NCHS growth charts. b. Maintain length/height and weight between 10th and 90th percentiles. Some normal infants, children, and adults will fall above or below these percentiles. Growth retardation has been described in these disorders (32, 37, 51, 53). 2. If length/height or weight falls below usual growth channel: a. Increase prescribed protein and energy by 5% to 10% and remeasure in 1 month. b. If length/height or weight remains low, repeat above process until usual growth channel is achieved. Warning: Use of recombinant human interferon gamma therapy for osteopetrosis may cause anorexia and weight loss (21, 22). H. Nutrient Intake 1. Maintain records of food intake for 3 days immediately before each blood test (Appendices 24 and 25, pp A-26 and A-27). 2. Evaluate intakes of Ca, phosphorus, vitamin D, protein, and energy weekly in infants and monthly for children and adults. 3. Evaluate mineral and vitamin intakes after each diet change. a. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. b. See Appendix 28, p A-29, for information about ordering software for diet evaluation. This program does not quantitate vitamin D. Warning: Ca prescription must be modified based on frequently obtained plasma Ca concentrations and growth in infants and children. Side effects of severe anemia as seen in patients with osteopetrosis may negatively affect appetite. I. Clinical Summary 1. A summary record of growth, laboratory, and nutrient intake data is useful for patient management (Table 21-5, p 376).
A. Example Establish and fill prescription for 4-month-old girl weighing 5.0 kg using Recommended Daily Nutrient Intakes from Table 21-1, p 373, and nutrient contents from Tables 21-2 and 21-3, pp 373 and 374.
376 Hypercalcemia
Calcium Protein Energy Fluid < 50 mg total 2.2 g/kg 115 kcal/kg 160 mL/kg x x x 5.0 kg 5.0 kg 5.0 kg Measure 111 g = = = = < 50 mg/day 11.0 g 575 kcal 800 mL Calcium (mg) < 50.0 Protein (g) 12.6 575 Energy (kcal)
Medical Food Mixture Calcilo XD
Add water to make 750 mL (25 fl oz). Offer additional water ad libitum. < 50.0 12.6 573 Total per day < 10.0 2.5 115 Total per kg Approximate osmolarity of medical food mixture is < 300 mosm/L. Estimated potential renal solute load is < 100 mosm.
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TABLE 21-1. Recommended Daily Nutrient Intakes (Ranges) for Infants, Children, and Adults With Hypercalcemia
Age Protein1 (g/kg) Infants 0 to < 3 mo 3 to < 6 mo 6 to < 9 mo 9 to < 12 mo 3.00 - 2.20 3.00 - 2.20 2.50 - 2.00 2.50 - 2.00 (g/day) Girls and Boys 1 to < 4 yr 4 to < 7 yr 7 to < 11 yr Women 11 to < 15 yr 15 to < 19 yr 19 yr 23.0 30.0 34.0 Nutrient Energy1 (kcal/kg) 120 (145 115 (145 110 (135 105 (135 - 95) - 95) - 80) - 80) Fluid2 (mL/kg) 160 - 125 160 - 130 145 - 125 135 - 120 (mL/day) 900 - 1,800 1,300 - 2,300 1,650 - 3,300
(kcal/day) 1,300 ( 900 - 1800) 1,700 (1300 - 2300) 2,400 (1650 - 3300)
46.0 46.0 50.0
2,200 (1500 - 3000) 2,100 (1200 - 3000) 2,100 (1400 - 2500)
1,500 - 3,000 1,200 - 3,000 1,400 - 2,500
Men 11 to < 15 yr 45.0 15 to < 19 yr 59.0 19 yr 63.0 1 From reference 11. 2 From reference 3. Under normal circumstances, offer minimum adults for each kcal ingested.
2,700 (2000 - 3700) 2,800 (2100 - 3900) 2,900 (2000 - 3300)
2,000 - 3,700 2,100 - 3,900 2,000 - 3,300
of 1.5 mL fluid to neonates and 1.0 mL to children and
TABLE 21-2. Foods That May Be Added IF Additional Dietary Calcium Is Required
Food List Dairy Products 1 Buttermilk Cheese, American, pasteurized, processed Cheese, Cheddar Cheese, cottage (2% fat) Cheese, Mozzarella (part skim milk) Ice cream, vanilla (regular) Ice cream, vanilla (French; soft serve) Milk (2% fat) Milk, goat's Milk, whole (3.3% fat) Sherbet, orange Yogurt, plain (made with whole cow's milk) Measure Calcium (mg) 285 174 204 155 183 84 113 297 326 291 40 296 Protein (g) 8.1 6.2 7.1 31.1 6.9 2.3 3.5 8.1 8.7 8.0 0.8 8.5 Energy (kcal) 99 106 114 203 72 133 185 121 168 150 102 150
8 fl oz 1 oz 1 oz 1 cup 1 oz 1/2 cup 1/2 cup 8 fl oz 8 fl oz 8 fl oz 1/2 cup 8 fl oz
Infant Formulas Alimentum Protein Hydrolysate Formula With Iron, Ready to Feed 100 mL
2 2
71
1.86
68 68 68
Isomil Soy Formula With Iron, Ready to Feed 100 mL 71 1.66 2 Similac With Iron Infant Formula, Ready to Feed 100 mL 53 1.40 1 USDA Nutrient Data Laboratory website (www.nal.usda.gov/fnic/foodcomp). 2 See Appendices 4 through 7, pp A-4 to A-7, for complete nutrient composition of infant formulas.
378 Hypercalcemia
Hypercalcemia 379
TABLE 21-3. Nutrient Composition of Calcilo XD Low-Calcium/Vitamin D-Free Infant Formula With Iron1, 2
Nutrient Per 100 g Powder
513 Energy, kcal 11.4 Protein, g 52.3 Carbohydrate, g 28.7 Fat, g Linoleate, g 6.66 Minerals Calcium, mg < 50 Chloride, mg/mEq 292/8.24 Copper, mg 0.46 Iodine, g 31.0 Iron, mg 9.2 Magnesium, mg 31.0 Manganese, g 26.0 Phosphorus, mg 128.0 Potassium, mg/mEq 420/10.74 Selenium, g 11.3 Sodium, mg/mEq 125/5.4 Zinc, mg 3.8 Vitamins A, g RE 462 D, g 0 6.7 E, mg -TE K, g 41.0 Ascorbic acid, mg 46.0 Biotin, g 23.0 B6, mg 0.31 B12, g 1.28 Choline, mg 62.0 Folacin, g 77.0 Inositol, mg 123.0 Niacin, mg 5.4 Pantothenic acid, mg 2.3 Riboflavin, mg 0.77 Thiamine, mg 0.51 Other Osmolarity, mosm/100 g 202 Estimated potential renal solute load, mosm/100 g 93 1 Approximate weights of Calcilo XD Powder measured in level, dry US standard household measures: 1 scoop = 8 g powder 1 Tbsp = 8.5 g powder 1/4 cup = 28 g 1/2 cup = 57 g 1 cup = 103 g 2 19.3 g powder with water added to yield 5 fl oz supplies 20 kcal/fl oz.
380 Hypercalcemia
TABLE 21-4. Diet Guide for Children and Adults With Hypercalcemia Name: Date:
Mo Mo
Hospital Number: ______/__________/__________

Day Day Year
Birthdate: _________/__________/__________
Year
Age: (cm/in) Weight: (kg/lb)
Length:
Measure
Calcium (mg)
Protein (g)
Energy (kcal)
Calcilo XD Add water to make
g/Tbsp/cup mL/fl oz
Food List Fat Fruit Meat Starch/Bread Vegetables
Measure/Servings
oz
Total per day Total per kg
Comments:
______________________________________________ Nutritionist
Hypercalcemia 381
TABLE 21-5. Hypercalcemia Clinical Summary Sheet Name: Date of Birth: __________/__________/__________
Mo Day Year
376 Hypercalcemia 2001 Ross Products Division
Hospital Number: Age at Diagnosis: Supplements:

Laboratory Data
Calcium Serum (mol/L) Urine (mol/mg Cr) Serum Phos (mol/L) Serum 1,25-OH D (pg/mL) Alk Phos (/L) Ferritin (ng/mL) Hgb (g/dL) Albumin (g/dL) Platelets (x 10 /L)
9 9
Medications:
Date Physical Data
Ht (mo/d/yr) (cm) Wt (kg) HC (cm)

Neutrophils Calcium (x 10 /L) (mg) Protein (g) Energy (kcal)
REFERENCES
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. Andersen PE, Bollerslev J: Heterogeneity of autosomal dominant osteopetrosis. Radiology 1987;164:223-225. Beard CJ, Key LL, Newburger PE, et al: Neutrophil defect associated with malignant osteopetrosis. J Lab Clin Med 1986;108:498-505. Behrman RE, Kleigman RM, Arvin AA: Nelson Textbook of Pediatrics, ed 15. Philadelphia: WB Saunders Co, 1996. Bergman H, Brown J, Rogers A, Bourke E: Osteopetrosis with combined proximal and distal renal tubular acidosis. Am J Kidney Dis 1992;2:357-362. Bollerslev J: Osteopetrosis: Genetic and epidemiological study. Clin Genet 1987;31:86-90. Brewer CM, Morrison N, Tolmie JL: Clinical and molecular cytogenetic (FISH) diagnosis of Williams syndrome. Arch Dis Child 1996;74:59-61. Cakmak O, Agis ER, Tezic T, Ates G: Primary hyperparathyroidism in infancy: A case report. J Pediatr Surg 1996;31:437-438. Culler FL, Jones KL, Deftos LJ: Impaired calcitonin secretion in patients with Williams syndrome. J Pediatr 1985;107:720-729. Dorantes LM, Mejia AM, Dorantes S: Juvenile osteopetrosis: Effects on blood and bone of prednisone and a low calcium, high phosphate diet. Arch Dis Child 1986;61:666-670. Eapen M, Davies S, Ramsay NK, Orehard PJ: Hematopoietic stem cell transplantation for infantile osteopetrosis. Bone Marrow Transplant 1998;22;941-946. Food and Nutrition Board, Committee on Dietary Allowances: Recommended Dietary Allowances, eds 9 and 10. Washington, DC: National Academy of Sciences, 1980 and 1989. Garabdian M, Jacqz E, Guillozo H, et al: Elevated plasma 1,25-dihydroxyvitamin D concentrations in infants with hypercalcemia and elfin facies. N Engl J Med 1985;312:948-952. Gerritsen EJA, Vossen JM, van Loo IHG, et al: Autosomal recessive osteopetrosis: Variability of findings at diagnosis and during the natural course. Pediatrics 1994;93:247-253. Goodyer PR, Frank A, Kaplan BS: Observations on the evolution and treatment of idiopathic infantile hypercalcemia. J Pediatr 1984;105:771-773. Ho C, Connor DA, Pollak CR, et al: A mouse model of human familial hypocalcuric hypercalcemia and neonatal severe hyperparathyroidism. Nat Genet 1995;11:389-394. Hosokawa YM, Pollak MR, Brown EM, Arnold A: Mutational analysis of the extracellular Ca (2+)-sensing receptor gene in human parathyroid tumor. J Clin Endocrinol Metab 1995;80:3107-3110. Huang CB, Huang SC, Chou FF, Chen WJ: Primary hyperparathyroidism in children: Report of a case and a brief history of the literature. J Formos Med Assoc 1993;92:1095-1098. Kaplan FS, August CS, Fallon MD, et al: Successful treatment of infantile malignant osteopetrosis by bone-marrow transplantation (case report). J Bone Joint Surg 1988;70:617-623. Kaplan P, Kirchner M, Watters G, Costa MT: Contractures in patients with Williams syndrome. Pediatrics 1989;84:895-899. Key L, Carnes D, Cole S, et al: Treatment of congenital osteopetrosis with high dose calcitriol. N Engl J Med 1984;310:409-415. Key LL, Oexmann MJ, Green L: Nutrition in patients with osteopetrosis on interferon gamma (editorial comments). Nutrition 1997;13:988-990. Key LL, Ries WL, Rodriguiz RM, Hatcher HC: Recombinant human interferon gamma therapy for osteopetrosis. J Pediatr 1992;121:119-124. Knudtzon J, Aksnes L, Akslen LA, Aarskog D: Elevated 1,25-dihydroxyvitamin D and normocalcaemia in presumed familial Williams syndrome. Clin Genet 1987;32:369-374. Kobayashi M, Tanaka H, Tzuzuku K, et al: Two novel mutations in calcium-sensing receptor gene associated with neonatal severe hyperparathyroidism. J Clin Endocrin Metab 1997;82:2716-2719. Kotzot D, Bernasconi F, Brecevic L, et al: Phenotype of the Williams-Beuren syndrome associated with hemizygosity at the elastin locus. Eur J Pediatr 1995;154:477-482. Kruse K, Pankau R, Gosch A, Wohlfahrt K: Calcium metabolism in Williams-Beuren syndrome. J Pediatr 1992;121:902-907. Kubo T, Tanaka H, Ono H, et al: Malignant osteopetrosis treated with high doses of 1--hydroxyvitamin D3 and interferon gamma. J Pediatr 1993;123:264-268. Lashkari A, Smith AK, Graham JM: Williams-Beuren syndrome: An update and review for the primary physician. Clin Pediatr 1999;38;189-208. MacLean W, Graham G: Pediatric Nutrition in Clinical Practice. Menlo Park, Calif: Addison-Wesley Publishing Co, 1982. Martin SB, Acosta PB: Osmotic behaviors of components of chemically-defined formulas. J Pediatr Perinat Nutr 1987;1:1-17. McGraw ME: Vitamin D metabolites in idiopathic infantile hypercalcemia. Arch Dis Child 1986;61:1246.
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32. Morris CA, Demsey SA, Leonard CO, Dilts C, Blackburn BL: Natural history of Williams syndrome: Physical characteristics. J Pediatr 1988;113:318-326. 33. Morris CA, Leonard CO, Dilts C, Demsey SA: Adults with Williams syndrome. Am J Med Genet 1990;6(suppl):102-107. 34. Nicholson WR, Hockey KA: Williams syndrome: A clinical study of children and adults. J Pediatr Child Health 1993;29:468-472. 35. Ohlsson A, Cumming WA, Paul A, Sly WS: Carbonic anhydrase II deficiency syndrome: Recessive osteopetrosis with renal tubular acidosis and cerebral calcification. Pediatrics 1986;77:371-381. 36. Pankau R, Paitsch CJ, Gosch A, et al: Statural growth in Williams Beuren syndrome. Eur J Pediatr 1992;151:751-755. 37. Partsch CJ, Dreyer G, Gosch A, et al: Longitudinal Evaluation of growth, puberty, and bone maturation in children with Williams syndrome. J Pediatr 1999;134:82-89. 38. Perez-Jurado LA, Li X, Francke U: The human calcitonin receptor gene (CALCR) at 7q21.3 is outside the deletion associated with Williams syndrome. Cytogenet Cell Genet 1995;70:246-249. 39. Pober BR, Lacio RB, Rice C, et al: Renal findings in 40 individuals with Williams syndrome. Am J Med Genet 1993;46:271-274. 40. Pronicka E, Rowinska E, Kulczycka H, et al: Persistent hypercalcinuria and elevated 25-hydroxyvitamin D3 in children with infantile hypercalcaemia. Pediatr Nephrol 1997;11:2-6. 41. Ruprecht A, Wagner H, Engel H: Osteopetrosis: Report of a case and discussion of differential diagnosis. Oral Surg Oral Med Oral Pathol 1988;66:674-679. 42. Schroeder RE, Johnson FL, Silberstein MJ, et al: Longitudinal follow-up of malignant osteopetrosis by skeletal rediography and restriction fragment lengths polymorphism analysis after bone marrow transplantation. Pediatrics 1992;20:986-989. 43. Shapiro F: Osteopetrosis: Current clinical considerations. Clin Orthop 1993;294:34-44. 44. Sly WS, Shah GN: The carbonic anhydrase II deficiency syndrome: Osteopetrosis with renal tubular acidosis and cerebral calcification. In Scriver CR, et al (eds): The Metabolic and Molecular Bases of Inherited Disease, ed 8. New York: McGraw-Hill Medical Publishing Division, 2001, pp 5331-5343. 45. Smith CA, Nelson NM: The Physiology of the Newborn Infant, ed 4. Springfield, IL: Charles C Thomas Publisher, 1976. 46. Smith JL, Heymsfield SB: Enteral nutrition support: Formula preparation from modular ingredients. JPEN 1983;7:280-288. 47. Spika JS, Shaffer N, Hargrett-Bean N, et al: Risk factors for infant botulism in the United States. Am J Dis Child 1989;143:828-832. 48. Taylor AB, Stern PH, Bell NH: Abnormal regulation of circulating 25-hydroxyvitamin D in the Williams syndrome. N Engl J Med 1982;306:972-975. 49. van Lie Peters EM, Aronson DC, Everts V, Dooren JL: Failure of calcitriol treatment in a patient with malignant osteopetrosis. Eur J Pediatr 1993;152:818-821. 50. Whyte MP, Murphy WA, Fallon MD, et al: Osteopetrosis, renal tubular acidosis, and basal ganglia calcification in three sisters. Am J Med 1980;69:64-74. 51. Wu YO, Sutton VR, Nickerson E, et al: Delineation of the common critical region in Williams' syndrome and clinical correlation of growth, heart defects, ethnicity, and parental origin. Am J Med Genet 1998;78:82-89. 52. Williams R, Wang W: Managing osteopetrosis in children: a nutrition challenge. J Amer Diet Assoc 1996:96:172-175. 53. Yu JS, Oates RK, Walsh KH, Stuckey SJ: Osteopetrosis. Arch Dis Child 1971;46:257-263. 54. Zerwekh JE, Marks SC, McGuire JL: Elevated serum 1,25-dihydroxyvitamin-D in osteopetrotic mutations in three species. Bone Miner 1987;2:193-199.
384 Hypercalcemia
PROTOCOL 22 Gyrate Atrophy of the Choroid and Retina Nutrition Support of Infants, Children, and Adults With CYCLINEX -1 and CYCLINEX -2 Amino Acid-Modified Medical Foods
I. Introduction
Gyrate atrophy (GA) of the choroid and retina results from a defect in the enzyme ornithine-aminotransferase (OAT) (Figure S). A consequence of OAT deficiency is progressive chororetinal degeneration starting in the first decade of life with myopia, night-blindness and loss of peripheral vision. Without treatment, tunnel vision and blindness are evident by the 3rd or 4th decade of life. Cataracts are common in all untreated patients by late in the 2nd decade of life (3, 21, 47). Biochemical consequences of OAT defect are elevated plasma ornithine (ORN) concentration ranging from 400 to 1,400 mol/L and reduced concentration of plasma glutamate, glutamine, lysine, creatine, and its precursor, guanidinoacetate. In addition, GA patients have low creatine and creatine phosphate concentrations in skeletal muscle and brain that negatively affect energy metabolism (31, 42). Mutations in OAT demonstrate allelic heterogeneity that may account for differences in clinical and biochemical phenotypes (15, 27). Some patients with gyrate atrophy show a reduction in plasma ORN concentrations in response to pharmacologic doses of pyridoxine (6, 14, 23, 41). The actual incidence of gyrate atrophy is not known. There are over 150 documented cases of gyrate atrophy; one-third are of Finnish origin.
Dietary protein Body protein breakdown Glutamate
NH4*
+ + HC03
Ornithine-aminotransferase
Ornithine*
Urea Cycle Citrulline Urea
Arginine*
* Accumulates in untreated gyrate atrophy Indicates site of enzyme malfunction
Figure S. Ornithine metabolism in gyrate atrophy of the choroid and retina.

Pyridoxine-responsive patients have a milder phenotype and preservation of visual acuity to later in life than patients who do not respond to vitamin B6 (40). Dietary restriction of arginine (ARG) has been successfully used to reduce plasma ORN and ARG concentrations. Long-term reduction in plasma ORN concentration has reduced progression of retinal atrophy and improved visual function (19, 20, 21, 28, 38, 40). Creatine therapy improves muscle and brain creatine concentrations, but does not prevent progression of retinal degradation (31, 42).
2001 Ross Products Division Gyrate Atrophy 385

A. The Defect 1. GA results from defect in OAT (22, 32, 40). B. Diagnostic Studies 1. Diagnostic studies should be conducted in any person with the following symptoms: a. Concentration of plasma ORN 10 to 15 times greater than normal (400 - 1,400 mol/L) and hyperornithinuria (21, 42, 48, 49). b. Retinopathy of unknown etiology. The following progression of visual impairment may occur in patients with GA (3, 40): 1) 1st decade of life: myopia and night-blindness. 2) 2nd decade of life: progressive loss of peripheral vision. 3) 3rd decade of life: cataracts 4) 4th and 5th decades of life: progressive impairment leading to total blindness. 2. See references 8, 32, 40, and 47 for methods of diagnosis.

A. Correct Primary Imbalance in Metabolic Relationships 1. Restrict dietary ARG to intake that maintains near normal plasma concentrations of ARG and ORN (19, 32, 48). B. Stabilize Altered Enzyme Protein 1. Prescribe pharmacologic doses of pyridoxine if any residual enzyme activity is present. 2. Pyridoxine-responsive patients should be stabilized and maintained on appropriate dose of pyridoxine before beginning nutrition support.

A. Plasma ORN Concentration 1. Maintain 2- to 4-hour postprandial plasma concentrations < 200 mol/L when measured by quantitative methods (47) or in normal range for age established in laboratory used. a. Biochemical control has been classified as good (< 200 mol/L), fair (200 - 400 mol/L), and poor (> 400 mol/L). b. In practice, obtaining blood 2 to 4 hours postprandially is not always possible. Acceptable local standards should be developed if plasma amino acids are evaluated at other times (Practical Aspect of Nutrition Support, p viii). B. Plasma ARG Concentration 1. Maintain 2- to 4-hour postprandial plasma ARG concentrations at the following approximate means for age:
Age (yr) Infants and children (birth < 5) (29) Children and adolescents (5 < 18) (1) Adults (> 18) (1) Mean SD for Age 65 40 mol/L 89 20 mol/L 82 25 mol/L
C. Plasma Ammonia Concentration 1. Maintain normal concentrations of plasma ammonia < 35 mol/L or within normal limits in laboratory used. D. Growth and Nutrition Status 1. Support normal growth rate in infants and children; maintain appropriate weight for height in adults. 2. Maintain normal nutrition status (7, 48). E. Physical Manifestations 1. Arrest progression of atrophy of choroid and retina and preserve or improve visual function.
386 Gyrate Atrophy

A. Pyridoxine Therapy 1. Some patients with GA may respond to pharmacologic doses of pyridoxine (vitamin B6): a. Doses of 15 to 1500 mg of pyridoxine administered for 2 to 8 weeks have been used (6, 24, 28, 39, 40, 52). b. Biochemical response to pyridoxine therapy is exhibited by up to 60% reduction in plasma ORN (6, 14 , 23, 24, 39, 40, 51, 52). c. A 2-week trial of pyridoxine therapy (300 - 600 mg/day) is suggested for all newly diagnosed patients (40). Warning: Prolonged use of high doses of pyridoxine results in peripheral neuropathy (36). B. L-ARG 1. L-ARG is an essential amino acid in patients with GA (49) and a precursor of ORN. 2. Prescribe ARG intake that promotes goals of nutrition support (Table 22-1, p 387). 3. Requirements vary widely: a. From patient to patient, depending on activity of OAT and responsiveness to pyridoxine therapy. b. In same patient, depending on: 1) Age. 2) Growth rate. 3) Adequacy of protein and energy intakes. 4) State of health. 5) Plasma ORN concentrations i. Hyperornithinemia and ornithinuria result in increased excretion of ARG (47, 49). 4. ARG intake suggested for beginning therapy depends on whether patient is responsive to pyridoxine. Since most GA patients are not pyridoxine-responsive (47, 49), initial ARG prescription should be at lower limit of ranges listed in Table 22-1, p 387. 5. Changing requirements of patients are determined by frequent monitoring of plasma ARG concentrations (Section IX, Suggestion Evaluation of Nutrition support, p 383). a. Hypoargininemia secondary to over-restriction of ARG may result in concomitant hyperammonemia (28) and urinary excretion of orotic acid (30, 40). Warning: ARG deficiency results in poor wound healing (4, 50), generalized skin lesions (11), growth retardation (53), and hyperammonemia (28). C. Protein 1. Prescribe, initially, amount at highest end of Recommended Dietary Allowances (RDAs) for age (Table 22-1, p 387) (12, 13, 16, 18, 44). Warning: Inadequate protein intake will result in failure to thrive in infants; weight loss, low plasma transthyretin concentration, osteopenia, and hair loss in children and adults. Excess protein intake will promote ammonia production and increase the patient's requirement for ARG (7). D. Energy 1. Prescribe amount that will support normal weight gain in infants and children and maintain appropriate weight for height for adults (Table 22-1, p 387). 2. Requirements will vary widely and may be greater than normal when L-amino acids supply majority of protein equivalent (34, 35). Warning: Inadequate energy intake will result in failure to thrive in infants, poor growth in children, and weight loss in adults. Weight loss will result in elevated plasma ARG concentration as a result of protein catabolism. Poor growth results in lower than expected tolerance of ARG. E. Fluid 1. Prescribe amount that will supply water requirements (Table 22-1, p 387). Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL fluid to children and adults for each kcal ingested (5).

A. Pyridoxine 1. Administer orally with each feed or several times per day, if beneficial. 2. Contact pharmacist for sources of pyridoxine. B . L-ARG 1. Calculate amount of infant formula with iron, beikost, whole cow's milk, or table foods (Table 22-2, p 387) required to fill ARG prescription. a. Low iron infant formula, whole cow's milk, and evaporated milk should not be used as ARG source for infants. 2. Measure liquid infant formula and whole cow's milk with disposable syringe. Weigh powdered infant formula on scale that reads in grams 3. Add beikost or table foods (Table 22-2, p 387) to gradually displace ARG provided by infant formula after infant is 3 to 4 months of age or developmentally ready. 4. Parents or patients may select any food in prescribed food lists (Table 22-3, pp 388-401) in specified amounts to fill ARG prescription. C. Protein 1. Calculate amount of protein provided by infant formula with iron, beikost, whole cow's milk, or table foods (Table 22-2, p 387) required to fill ARG prescription. 2. Subtract amount determined above from protein prescription. 3. Supply any remaining prescribed protein with Cyclinex (Table 22-4, p 402). a. Cyclinex-1 is for infants and toddlers and Cyclinex-2 is for children, adolescents, and adults but may be used at earlier age if child's appetite is small. b. Weigh Cyclinex powder on scale that reads in grams because of variability of household measuring equipment (Practical Aspects of Nutrition Support, p vii) and changes in density during shipping. c. See Table 22-4 (p 402, footnote 3) for approximate packed weight of Cyclinex powder in level, dry US standard household measures. D. Energy 1. Calculate energy provided by infant formula with iron, beikost, whole cow's milk, or table foods (Table 22-2, p 387) and Cyclinex (Table 22-4, p 402) required to fill ARG and protein prescriptions. 2. Subtract amount determined above from total energy prescription. 3. Provide remaining prescribed energy with Polycose Glucose Polymers powder (23 kcal/Tbsp, 3.8 kcal/g) or liquid (2 kcal/mL) (Appendix 9, p A-9); Pro-Phree Protein-Free Energy Module With Iron, Vitamins & Minerals (Appendix 11, p A-10); sugar (48 kcal/Tbsp); or Free Foods B (Table 22-2, p 387), depending on age of patient. a. Do not use corn syrup or table sugar for infants because of osmolarity they yield (26). b. Do not use honey for infants because it may contain botulinum toxin (46). E. Fluid and Mixing Instructions 1. Add sufficient boiled, cooled water to infant formula, Cyclinex, and carbohydrate to yield prescribed volume. Tap water may replace boiled, cooled water when preparing Cyclinex for older infants, children, and adults. 2. Mix with sterilized blender at lowest speed for no longer than 3 to 4 seconds. Excess mixing may destabilize emulsion. May also be mixed in sterilized, tightly closed container by shaking vigorously for 10 to 12 seconds. 3. Refrigerate in sterilized, closed containers until used. Discard unused portion 24 hours after mixing because of nutrient loss. Store unopened cans at room temperature. Cover opened can and store in refrigerator. Use within 1 month after opening. 4. Do not use terminal sterilization or boil because of Maillard reaction (Practical Aspects of Nutrition Support, p viii). 5. Warm or cool medical food mixture to room temperature before feeding to infants. Shake mixture well before feeding. 6. Do not warm medical food mixture for infants in microwave oven. Unevenly heated formula can burn infants, and steam can make bottles explode.
388 Gyrate Atrophy
7. Notify parents or caretakers when they may discontinue using aseptic technique in preparing medical food mixture for infants. 8. For children and adults, chill Cyclinex medical food mixture to improve taste. F. Diet Guide 1. Provide parents, caretakers, or patient with completed Diet Guide (Appendix 22, p A-24) with each diet change. 2. Feed young infants 6 to 8 times daily (16, 37). 3. Feed older infants, children, and adults 4 to 6 times daily (16, 37).

A. Nutrient Adequacy 1. Determine if diet provides nutrients in amounts prescribed in Section VI, Establish Prescription, p 381. a. See Table 22-2, p 387, for composition of infant formulas, foods, and whole cow's milk and Table 22-4, p 402, for composition of Cyclinex. b. See Appendix 9, p A-9, for composition of Polycose and Appendix 11, p A-10, for composition of Pro-Phree. 2. Check diet to determine if it supplies Recommended Dietary Intakes (RDIs) of minerals and vitamins (Table 22-4, p 402, and Appendices 4 through 7, 13, and 14, pp A-4 to A-7, A-14 and A-15). a. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. b. If Cyclinex mixture provides < 100% of RDIs for infants and < 75% for children and adults, supplement diet with needed minerals and vitamins if not provided by beikost or table foods and laboratory tests indicate need (Appendix 11, p A-10, for composition of supplements). B. Osmolarity 1. If concentration of prescribed medical food mixture is > 24 kcal/fl oz, determine if osmolarity of Cyclinex mixture is in acceptable range. a. Determine osmolarity by laboratory analysis or use mathematical formula given in Appendix 18, p A-20. b. Osmolarity per gram of Cyclinex is listed in Appendix 19, p A-21. 2. If osmolarity is > 450 mosm/L for infants (25), > 750 mosm/L for children, > 1,000 mosm/L for adults (45), or greater than tolerated by patient, increase water content of prescribed medical food mixture and recalculate its osmolarity. C. Potential Renal Solute Load 1. Dehydration will result if renal solute load is greater than renal-concentrating ability of patient. 2. If concentration of medical food mixture prescribed is > 24 kcal/fl oz, estimate its potential renal solute load. a. This step is important to prevent dehydration of infants who may have renal-concentrating capacity as low as 600 mosm/L. b. Upper limit of renal solute load for neonates is approximately 1,100 mosm/L (43). 3. A method for estimating potential renal solute load is given in Appendix 20, p A-22. 4. If potential renal solute load is excessive, increase water content of medical food mixture and recalculate.

A. Plasma ARG and ORN Concentrations 1. Initial. a. Evaluate twice weekly by quantitative methods until plasma concentrations stabilize and approximate dietary ARG requirements are known. 2. Ongoing. a. Frequent evaluations help ensure adherence to nutrition support plan. b Evaluate plasma concentrations of ARG and ORN by quantitative methods weekly until the patient is 12 months of age and monthly thereafter.
3. Unacceptable ARG and/or ORN Concentrations. a. If plasma ARG concentration is below lower limit of normal or is not detected, ORN is < 100 mol/L, patient has ingested full prescription, and hyperammonemia (> 35 mol/L) is present: 1) Immediate intervention using intravenous ARG hydrochloride may be required. 2) Once hyperammonemia is corrected and patient's condition is stabilized, add 75 mg ARG to ARG prescription and then reevaluate ARG and ORN concentrations in 3 days. 3) If plasma ARG concentration continues undetected, repeat above process until ARG and ORN values are in treatment range. b. If plasma ARG concentration is below lower limit of normal or is not detected, ORN is < 100 mol/L, patient has ingested full prescription, and hyperammonemia (> 35 mol/L) is not present: 1) Add 75 mg ARG to ARG prescription and reevaluate ARG and ORN concentrations in 3 days. 2) If plasma ARG concentration continues undetected, repeat above process until ARG and ORN values are in treatment range. c. If plasma ORN concentration is between 200 and 400 mol/L, ARG concentration is in normal range, and patient has ingested full prescription: 1) Decrease ARG prescription by 30 mg and reevaluate plasma ARG and ORN concentrations in 3 days. 2) If plasma ORN concentration continues between 200 and 400 mol/L, repeat above process until value is in treatment range. d. If plasma ORN concentration is > 400 mol/L, patient is not ill and has not ingested more ARG or significantly less protein and energy than prescribed: 1) Decrease ARG prescription by 60 mg and reevaluate plasma ARG and ORN concentrations in 3 days. 2) If plasma ORN concentration is > 400 mol/L, repeat above process until value is in treatment range. Warning: Elevated plasma ORN concentrations may result in subnormal plasma concentrations of lysine and increased urinary excretion of cystine, lysine, ARG, and glutamine (3). Hemolysis or mishandling of sample may overestimate plasma ORN concentrations. B. Protein Status 1. Evaluate plasma transthyretin concentration every 3 months until patient is 1 year of age and every 6 months thereafter (Appendix 17, p A-18, for standards). a. Plasma transthyretin concentrations provide a more reliable and rapid indication of protein status than plasma albumin concentrations. b. Plasma albumin concentrations may be in the normal range when plasma transthyretin concentrations show a clear deficiency (2). 2. If plasma transthyretin concentration is below standard: a. Increase prescribed protein by 5% to 10% and reevaluate plasma transthyretin concentration in 1 month. If plasma ARG and ORN concentrations are in treatment range, use Cyclinex to increase protein. b. If plasma transthyretin concentration continues below standard, repeat above process until value is in normal range. C. Iron Status 1. Plasma ferritin concentration. a. Evaluate at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17, p A-18, for standards). b. If plasma ferritin concentration is below standard: 1) Increase iron intake to 4 mg/kg body weight with supplements (ferrous sulfate). 2) Evaluate plasma ferritin concentration monthly on increased iron intake. 3) Continue iron supplements until plasma ferritin concentration is in normal range. 2. Complete blood count. a. Hemoglobin and hematocrit concentrations should be evaluated at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17, p A-18, for standards).
390 Gyrate Atrophy 2001 Ross Products Division
D. Growth Status 1. Length/height and weight. a. Measure monthly to 1 year, every 3 months to 4 years, and every 6 months thereafter. Plot measurements on NCHS growth charts. b. Maintain length/height and weight between 10th and 90th percentiles. Some normal infants, children, and adults will fall above or below these percentiles. 2. If length/height or weight falls below usual growth channel: a. Increase prescribed protein and energy by 5% to 10% and remeasure in 1 month. b. If length/height or weight remains low, repeat above process until usual growth channel is achieved. E. Nutrient Intake 1. Maintain records of food intake for 3 days immediately before each blood test (Appendices 24 and 25, pp A-26 and A-27). 2. Evaluate intakes of ARG, protein, and energy before each blood test. 3. Evaluate mineral and vitamin intakes after each diet change. a. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. b. See Appendix 28, p A-29, for information about ordering software for diet evaluation. F. Clinical Summary 1. A summary record of growth, laboratory, and nutrient intake data is useful for patient management (Table 22-5, p 403).
A. Example 1 Establish and fill prescription for 3-month-old infant weighing 5.6 kg using Recommended Daily Nutrient Intakes from Table 22-1, p 387, and nutrient contents from Tables 22-2 and 22-4, pp 387 and 402. 1. Establish prescription.
ARG Protein Energy Fluid 35 mg 2.0 g/kg 135 kcal/kg 160 mL/kg x x x x 5.6 kg 5.6 kg 5.6 kg 5.6 kg Measure 478 mL 60 g 25 g 196 0 0 = = = = 196 mg/day 11.2 g 756 kcal 896 mL ARG (mg) 6.7 4.5 0.0 Protein (g) 325 306 128 Energy (kcal)
Medical Food Mixture Similac With Iron Ready to Feed Cyclinex-1 Pro-Phree Add water to make 896 mL (30 fl oz). Total per day 196 11.2 759
B. Example 2 Establish and fill prescription for 2-year-old boy weighing 13.0 kg using Recommended Daily Nutrient Intakes from Table 22-1, p 387, and nutrient contents from Tables 22-2 and 22-4, pp 387 and 402.
Gyrate Atrophy 391
ARG Protein Energy Fluid 25 mg x 13.0 kg = = = = 325 mg/day 13.0 g 1,430 kcal 1,430 mL ARG (mg) Protein (g) 5.7 0.0 Energy (kcal) 388 388
Medical Food Mixture Measure
Cyclinex-1 76 g 0 Pro-Phree 76 g 0 Add water to make 710 mL (24 fl oz). Offer additional water ad libitum daily. Food List Breads/Cereals Fats Fruits Vegetables Free Foods A Free Foods B 4 2 3 2 2 1 Servings 180 10 75 50 10 0
3.6 0.2 2.1 1.0 0.4 0.0 13.0
200 70 195 40 100 55 1,436
325 Total per day Approximate osmolarity of medical food mixture is < 425 mosm/L.
C. Example 3 Establish and fill prescription for 12-year-old girl weighing 40.0 kg using Recommended Daily Nutrient Intakes from Table 22-1, p 387, and nutrient contents from Tables 22-2 and 22-4, pp 387 and 402. 1. Establish prescription.
ARG Protein Energy Fluid 15 mg x 40.0 kg = = = = 600 mg/day 23.0 g 2,200 kcal 2,400 mL ARG (mg) 0 0 Protein (g) 9.8 0.0 Energy (kcal) 286 418
Medical Food Mixture Cyclinex-2 Pro-Phree Measure 65 g 82 g
Add water to make 710 mL (24 fl oz). Offer additional water ad libitum daily. Food List Breads/Cereals Fats Fruits Vegetables Free Foods A Free Foods B 8 5 5 3 3 7 Servings 360 25 125 75 15 0 7.2 0.5 3.5 1.5 0.6 0.0 23.1 400 175 325 60 150 385 2,199
600 Total per day Approximate osmolarity of medical food mixture is < 450 mosm/L.
392 Gyrate Atrophy
TABLE 22-1. Recommended Daily Nutrient Intakes (Ranges) for Infants, Children, and Adults With Gyrate Atrophy of the Choroid and Retina
Age ARG (mg/kg) Infants 0 to < 3 mo 3 to < 6 mo 6 to < 9 mo 9 to < 12 mo 40 - 35 35 - 33 33 - 30 30 - 25 (mg/kg) Girls and Boys 1 to < 4 yr 4 to < 7 yr 7 to < 11 yr Women 11 to < 15 yr 15 to < 19 yr 19 yr 25 - 23 23 - 20 20 - 18 8 - 13 12 - 15 14 - 17
1
Nutrient Protein (g/kg) 2.20 - 1.25 2.00 - 1.15 1.80 - 1.05 1.60 - 0.90 (g/day)
2
Energy 2, 3 (kcal/kg) 150 - 125 140 - 120 130 - 115 120 - 110 (kcal/day) 945 - 1,890 1,365 - 2,415 1,730 - 3,465
Fluid 4 (mL/kg) 160 - 130 160 - 130 145 - 125 135 - 120 (mL/day) 945 - 1,890 1,365 - 2,415 1,730 - 3,465
18 - 15 15 - 13 15 - 13
20 -23 20 - 23 22 - 25
1,575 - 3,150 1,260 - 3,150 1,785 - 2,625
1,575 - 3,150 1,260 - 3,150 1,785 - 2,625
Men 11 to < 15 yr 18 - 15 20 - 23 2,100 - 3,885 2,100 - 3,885 15 to < 19 yr 15 - 13 21 - 24 2,200 - 4,095 2,200 - 4,095 15 - 13 23 - 32 2,625 - 3,465 2,625 - 3,465 19 yr 1 Recommended ARG intakes are estimates of requirements. ARG is an essential amino acid. Modify prescription based on frequently obtained blood and/or plasma values and growth in infants and children and frequently obtained plasma values and weight maintenance in adults. 2 Modified from references 9 and 10. 3 Energy intakes may be greater than normal when using L-amino acids for protein (34). 4 Modified from reference (5). Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL to children and adults for each kcal ingested.
TABLE 22-2. Serving Lists for ARG-Restricted Diets: Average Nutrient Content per Serving
Food List ARG (mg) Breads/Cereals Fats 1 Fruits Vegetables Free Foods A Free Foods B 2 Alimentum Protein Hydrolysate Formula With Iron, Ready to Feed, 100 mL 2 Isomil Soy Formula With Iron, Ready to Feed, 100 mL Pro-Phree Protein-Free Energy Module With Iron, Vitamins & Minerals, 100 mL
2
Nutrient Protein (g) 0.9 0.1 0.7 0.5 0.2 0.0 1.86 1.66 0.00 Energy (kcal) 50 35 65 20 50 55 68 68 510 68 63
45 5 25 25 5 0 77 122 0
Similac With Iron Infant Formula, Ready to Feed, 100 mL 2 41 1.40 Whole cow's milk, 100 mL 3 123 3.39 1 Watermelon contains large amounts of citrulline, a precursor of ARG (17). 2 See Appendices 4 through 7, pp A-4 to A-7, for complete nutrient composition of infant formulas. 3 From reference 33. See Appendix 8, A-8, for complete nutrient composition.
Gyrate Atrophy 393
TABLE 22-3. Serving Lists for ARG-Restricted Diets: Gerber Baby Foods (Beikost) 1
Weight Approximate ARG (g) Measure (mg) For greatest accuracy, weigh food on scale that reads in grams. All measures are level. BREADS AND CEREAL Baked Finger Snacks, Graduates Animal crackers, cinnamon graham Apple cinnamon cookies Banana cookies Strawberry fruit bars Veggie crackers Cereals, Dry Barley Mixed Oatmeal Oatmeal/banana Oatmeal/mixed fruit Rice Rice/apples Rice/apple bits Rice/bananas Rice/mixed fruit Cereals, Jarred 2nd Foods Mixed/applesauce/banana Oatmeal/applesauce/banana Rice/applesauce 3rd Foods Mixed/apples/banana Oatmeal/apples/cinnamon Vegetables 1st Foods peas potatoes sweet potatoes 2nd Foods creamed corn creamed spinach garden vegetables peas sweet Potatoes 3rd Foods peas/rice sweet potatoes Tender Harvest butternut squash/corn garden carrots/brown rice greenbean/potato spring garden vegetable FRUITS/JUICES 1st Foods bananas peaches prunes 394 Gyrate Atrophy Food Protein (g) Energy (kcal)
20 24 20 20 19
5 crackers 2-1/2 cookies 2-1/2 cookies 2 bars 19 crackers
45 45 45 45 45
1.5 1.4 1.4 1.1 1.6
83 106 84 83 89
7 10 5 6 7 7 11 9 9 6
1 Tbsp + 2-3/4 tsp 2 Tbsp + 2 tsp 4 tsp 4-1/2 tsp 5-3/4 tsp 5-3/4 tsp 3 Tbsp 7-1/4 tsp 7-1/4 tsp 5 tsp
45 45 45 45 45 45 45 45 45 45
0.9 1.0 0.7 0.6 0.8 0.6 0.6 0.6 0.7 0.4
28 39 19 23 29 27 43 36 36 23
79 64 90 75 69
5-1/2 Tbsp 4-1/2 Tbsp 6-1/4 Tbsp 5-1/4 Tbsp 4-3/4 Tbsp
45 45 45 45 45
0.8 0.8 0.7 0.9 0.8
66 53 82 57 46
7 48 81 36 17 14 7 83 10 63 21 42 28 24
1/2 Tbsp 3-1/2 Tbsp 5-3/4 Tbsp 2-1/2 Tbsp 1-1/4 Tbsp 1 Tbsp 1/2 Tbsp 5-3/4 Tbsp 2 tsp 4-1/4 Tbsp ND ND ND ND
25 25 25 25 25 25 25 25 25 25 45 45 25 25
0.2 0.5 0.9 0.6 0.5 0.3 0.2 0.8 0.2 0.6 0.4 0.4 0.6 0.3
3 23 53 22 8 5 4 52 5 34 10 18 18 8
50 125 125
3-1/2 Tbsp 8-3/4 Tbsp 8-3/4 Tbsp
25 25 25
0.6 0.9 1.3
50 54 126
Food
Weight Approximate ARG (g) Measure (mg) For greatest accuracy, weigh food on scale that reads in grams. All measures are level. 2nd and 3rd Foods bananas 50 3-1/2 Tbsp 25 bananas/apples/pears 62 4-1/4 Tbsp 25 banana/pineapple 62 4-1/4 Tbsp 25 banana/strawberry 62 4-1/4 Tbsp 25 Hawaiian delight dessert - 2nd Foods 50 3-1/2 Tbsp 25 Hawaiian delight dessert - 3rd Foods 50 3-1/2 Tbsp 25 peach cobbler dessert 25 1-3/4 Tbsp 25 peaches - 2nd Foods 125 1/2 c + 2 tsp 25 peaches - 3rd Foods 63 1/4 c + 1/4 Tbsp 25
Protein (g)
Energy (kcal)
0.6 0.6 0.5 0.6 0.7 0.7 0.1 0.9 0.4
45 52 46 59 43 44 19 80 40
Fruit Dices, Graduates Apples Mixed fruit Peaches Pears Fruit/Vegetable, Tender Harvest Banana/oatmeal/peach Pear/winter squash Tropical fruit blend VEGETABLES 1st Foods carrots green beans squash 2nd Foods carrots green beans mixed vegetables squash 3rd Foods carrots green beans/rice squash Vegetable Dices, Graduates Carrots Green beans FREE FOODS A Apple juice Apple/banana juice Apple/carrot juice Apple/cherry juice Apple/cranberry juice Apple/grape juice Apple/prune juice Apple/sweet potato juice Mango/banana/passion fruit juice Mixed fruit juice Orange juice Pear juice Desserts Fruit medley tropical fruit dessert* 2001 Ross Products Division
83 83 63 63
ND ND ND ND
25 25 25 25
0.1 0.3 0.3 0.2
40 40 31 54
50 25 125
ND ND ND
25 25 25
0.6 0.3 0.8
37 13 92
83 42 36 83 50 100 63 83 42 83
5-3/4 Tbsp 3 Tbsp 2-1/2 Tbsp 5-3/4 Tbsp 3-1/2 Tbsp 1-3/4 Tbsp 4-1/4 Tbsp 5-3/4 Tbsp 3 Tbsp 5-3/4 Tbsp
25 25 25 25 25 25 25 25 25 25
0.8 0.5 0.3 0.7 0.7 0.3 0.5 0.7 0.5 0.7
29 13 12 25 14 9 20 24 18 28
63 36
ND ND
25 25
0.4 0.4
14 9
167 167 50 167 167 167 167 63 50 500 50 125
5-3/4 oz 5-3/4 oz 1-3/4 oz 5-3/4 oz 5-3/4 oz 5-3/4 oz 5-3/4 oz 4-2/3 Tbsp 1-3/4 oz 17 oz 1-3/4 oz 4-1/4 oz
5 5 5 5 5 5 5 5 5 5 5 5
0.2 0.2 0.1 0.2 0.2 0.2 0.2 0.2 0.1 0.5 0.3 0.2
77 85 21.5 80 73 80 88 36 36 240 24 59
50
3-1/2 Tbsp
0.1
32 Gyrate Atrophy 395
Food
Weight Approximate ARG (g) Measure (mg) For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Guava tropical fruit dessert* 50 3-1/2 Tbsp 5 Mango tropical fruit dessert* 50 3-1/2 Tbsp 5 Papaya tropical fruit dessert * 50 3-1/2 Tbsp 5 1st & 2nd Foods applesauce 50 3-1/2 Tbsp 5 apple/blueberry 50 3-1/2 Tbsp 5 pears 50 3-1/2 Tbsp 5 3rd Foods applesauce/apricot 50 3-1/2 Tbsp 5 apricots/mixed fruit 50 3-1/2 Tbsp 5 Fruit salad 50 3-1/2 Tbsp 5 Pear/pineapple 50 3-1/2 Tbsp 5 Pears 50 3-1/2 Tbsp 5 Plums/apples, 2nd Foods 50 3-1/2 Tbsp 5 Plums/apples, 3rd Foods 50 3-1/2 Tbsp 5 Prunes/apples 50 3-1/2 Tbsp 5 Tender Harvest Pear/wild blueberry 50 3-1/2 Tbsp 5 Beverages Graduates Berry punch Fruit punch Tender Harvest Apple/mango/kiwi Apple/strawberry
1
Protein (g) 0.1 0.1 0.1 0.1 0.1 0.2 0.2 1.5 0.2 0.3 0.3 0.2 0.2 0.3 0.2 35 37 32 28 25 28
Energy (kcal)
52 150 32 185 37 35 34 38 30
500 167 167 125
17 oz 5-3/4 oz ND ND
5 5 5 5
0.5 0.2 0.2 0.2
255 87 100 75
Prepared from 1998 and 1999 data from Gerber Products Co, Fremont, MI 49413. ND = No data.
Weights and Measures Except for Dry Cereals and Food Dices, the following weights apply: Level Level 1 tsp = 1/3rd Tbsp = 4.8 g 1 Tbsp = 1/16th cup = 14.3 g 1/4 cup = 4 Tbsp = 57.2 g 1/3 cup = 5-1/3rd Tbsp = 76.2 g 1/2 cup = 8 Tbsp = 114.3 g 2/3 cup = 10 2/3rd Tbsp = 152.5 g 3/4 cup = 12 Tbsp = 171.5 g 1 cup = 16 Tbsp = 228.6 g
396 Gyrate Atrophy
TABLE 22-3. Serving Lists for ARG-Restricted Diets: Table Foods

Food
Weight Approximate (g) Measure For greatest accuracy, weigh food on scale that reads in grams. All measures are level. BREADS AND CEREALS Cereals, Cooked. Measure after cooking Cream of Rice Cream of Wheat instant Mix'n Eat flavored plain quick regular Farina Grits Malt-o-Meal Oats, regular, quick, instant Wheatena Cereals, Ready To Eat All Bran Alpha-Bits Apple Jacks Bran Buds Bran Chex 40% Bran Flakes (Post) Cap'n Crunch Cap'n Crunch's Crunch Berries Cap'n Crunch's Peanut Butter Cheerios Cinnamon Toast Crunch Cocoa Krispies Cocoa Pebbles Cocoa Puffs Cookie Crisp Corn Bran Corn Chex Corn Flakes Crispy Wheat'n Raisins C W Post plain w/ raisins Froot Loops Frosted Mini-Wheats Frosted Rice Krinkles Frosted Rice Krispies Fruit Wheat Squares Fruity Pebbles Golden Grahams Grape Nuts Grape Nut Flakes Heartland , plain Honey Nut Cheerios Honey Nut Corn Flakes Honeycomb King Vitaman Kix 2001 Ross Products Division
ARG (mg)
Protein (g)
Energy (kcal)
61 56 61 48 65 60 73 91 75 23 46
1/4 cup 3 Tbsp + 2 tsp 1/3 packet 1/3 packet 4 Tbsp + 1 tsp 1/4 cup 1/4 cup + 1 Tbsp 1/4 cup + 2 Tbsp 1/4 cup + 1 Tbsp 1 Tbsp + 1-1/2 tsp 3 Tbsp
44 44 45 41 43 48 42 43 46 44 42
0.5 1.0 1.0 1.3 1.0 1.1 1.0 1.3 1.1 0.6 0.9
32 36 54 49 35 39 36 54 38 14 26
5 9 19 4 8 7 18 18 8 4 33 11 12 5 15 13 19 17 13 7 7 14 8 11 11 18 14 20 7 8 7 5 9 16 18 12
1 Tbsp + 3/4 tsp 1/4 cup + 1 t 2/3 cup 2-1/2 cups 2 Tbsp + 2 tsp 2 Tbsp + 1 tsp 1/2 cup 1/2 cup 3 Tbsp + 1-3/4 tsp 3 Tbsp 3/4 cup + 2 Tbsp 1/4 cup + 1 Tbsp 1/4 cup + 2 Tbsp 1-1/4 cups 1/2 cup 1/4 cup + 2 Tbsp 2/3 cup 3/4 cup 1/4 cup + 1 Tbsp 1 Tbsp + 1/4 tsp 1 Tbsp + 1/4 tsp 1/4 cup + 3 Tbsp 1 piece 1/3 cup 1/3 cup 3 Tbsp + 1-1/2 tsp 1/4 cup + 3 Tbsp 1/2 cup 1 Tbsp 1/4 cup 1 Tbsp 2 Tbsp + 3/4 tsp 1/4 cup 3/4 cup 3/4 cup + 2 Tbsp 1/2 cup + 2 Tbsp
45 45 49 43 44 46 44 42 45 48 43 46 46 43 45 43 44 45 42 43 43 41 43 42 42 46 47 43 42 44 42 45 46 44 44 47
0.6 0.7 1.0 0.6 0.9 0.8 0.9 0.9 0.6 0.6 1.2 0.6 0.6 1.2 0.8 0.9 1.3 1.4 0.9 0.6 0.6 0.8 0.8 0.5 0.5 1.2 0.6 1.1 0.8 0.9 0.7 0.6 0.6 1.0 1.0 1.1
14 35 72 11 26 22 78 74 34 17 140 43 50 138 60 47 73 66 46 29 31 56 29 41 41 62 57 75 25 29 31 20 38 64 75 46 Gyrate Atrophy 397
Food
Weight Approximate (g) Measure For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Life 3 1 Tbsp + 1/2 tsp Lucky Charms 7 3 Tbsp + 1 tsp Nutri-Grain corn 16 1/4 cup + 5 tsp rye 10 1/4 cup wheat 11 1/4 cup Oat Flakes 4 1 Tbsp + 3/4 tsp Product 19 12 1/4 cup + 2 Tbsp Quisp 20 2/3 cup Raisin Bran (Post) 9 2 Tbsp + 2 tsp Rice Chex 9 1/4 cup + 2 Tbsp Rice Krispies 8 1/4 cup + 1-1/2 tsp Rice, puffed 9 2/3 cup Special K 3 1 Tbsp + 2-1/2 tsp Sugar Frosted Flakes 26 3/4 cup Sugar Pops 28 1 cup Sugar Smacks 12 1/3 cup Super Sugar Crisp 14 1/4 cup + 3 Tbsp Team 11 1/4 cup Total 8 1/4 cup Trix 21 3/4 cup Wheat puffed 6 1/2 cup shredded 8 2 Tbsp + 1/2 tsp Wheat Chex 9 3 Tbsp Wheaties 9 1/4 cup + 1 Tbsp Grains Corn cob, medium ear cooked cream style whole kernel Rice, prepared brown fried Rice-A-Roni pilaf Spanish white instant regular Pasta, Cooked Macaroni Noodles, egg Ramen noodles spaghetti Tubers Potatoes, sweet baked no skin, mashed w/ skin, mashed canned, packed in syrup Potatoes, white baked, no skin boiled 398 Gyrate Atrophy
ARG (mg) 45 45 42 43 46 45 43 46 45 41 45 48 45 43 47 42 45 47 43 48 42 43 42 45
Protein (g) 0.6 0.6 1.3 0.9 1.0 0.7 1.2 1.0 0.9 0.5 0.5 0.6 0.6 1.3 1.4 0.9 0.9 0.7 0.8 1.1 0.9 0.8 0.9 0.9
Energy (kcal) 26 26 60 36 40 14 47 82 29 37 32 37 13 100 108 47 54 41 29 81 22 27 32 32
32 4 31 26 20 26 20 30 22 26
1/2 ear 1/4 cup 3 Tbsp 2 Tbsp + 1 tsp 1 Tbsp + 1 tsp 1 Tbsp + 2 tsp 1 Tbsp + 1 tsp 2 Tbsp 2 Tbsp 2 Tbsp
40 45 42 45 44 43 44 41 42 46
1.0 1.1 1.0 0.6 0.8 0.8 0.8 0.5 0.5 0.5
29 33
30 30 33 30 26 24 28
22 27 20 21
2 Tbsp + 2 tsp 2 Tbsp + 2 tsp 2 Tbsp 2 Tbsp + 1 tsp
44 44 41 43
1.1 1.1 1.1 1.1
32 33 45 32
62 56 110 40
3 Tbsp 1/4 cup + 1-1/2 tsp 1/2 cup + 1 Tbsp 1/3 cup
47 45 44 42
1.0 1.0 1.0 0.9
65 58 151 43
Food
Weight Approximate (g) Measure For greatest accuracy, weigh food on scale that reads in grams. All measures are level. no skin 59 1/4 cup + 2 Tbsp w/ skin 49 1/4 cup + 1 Tbsp canned 20 2 potatoes French fries (1/2" x 1/2" x 2"), 25 5 pieces hash browns, frozen, cooked 29 3 Tbsp Tater Tots 47 5 pieces Yams, baked or boiled, mashed 34 1/4 cup Miscellaneous Chocolate sauce (Hershey's ) Chow Mein noodles Jell-O , prepared w/ sugar Succotash Snack Foods Barnum's Animal Crackers Cookies chocolate chip fig bar gingersnap oatmeal raisin Oreo sandwich Sno Balls Social Tea Biscuits Sugar (butter) Sugar Wafers (Nabisco) vanilla wafer Crackers graham (2" x 2") Melba toast Ritz Ritz Bits , cheese Rykrisp saltines Triscuits Waverly Wheat Thins Ding Dongs Doodads , original Doritos , plain Doughnut, cake Fritos Ho Hos Ice cream cone, wafer type Popcorn buttered caramel plain Potato chips (2" diameter) Pretzels Raisins, chocolate covered Rice cakes Tortillas (6" diameter) corn flour Twinkies
ARG (mg) 46 42 46 48 44 45 42
Protein (g) 1.0 0.9 1.0 1.0 0.9 1.0 0.5
Energy (kcal) 50 42 42 79 64 77 39
51 11 35 4
2-3/4 Tbsp 3 Tbsp 2 Tbsp + 1 tsp 1 Tbsp
46 43 46 34
2.4 1.1 0.5 0.6
249 56 21 14
17 18 28 21 11 22 22 43 21 20 30 20 14 9 17 11 9 12 14 16 16 36 8 16 23 22 28 11 13 10 10 14 18 13 6 18 15 32
6-1/2 crackers 1-1/2 cookies 1-3/4 bars 3 cookies 3/4 cookie 2 cookies 2 cookies 1 cookie 4 biscuits 1-1/2 cookie 5-1/2 cookies 5 cookies 2 crackers 1-1/2 pieces 5 crackers 16 crackers 1-1/2 pieces 4 crackers 3 crackers 2-1/4 crackers 9 crackers 3/4 cake 2 Tbsp + 1 tsp 9 chips 1/2 doughnut 11 chips 1 roll 2 (cones only) 1-1/2 cups 1-3/4 cups 1-3/4 cups 7 chips 3 pretzles 10 raisins 2/3 cake 3/4 piece 1/2 piece 3/4 roll
45 45 44 47 42 41 43 48 47 47 45 44 45 45 43 44 47 44 45 44 46 41 47 43 43 46 48 44 45 44 44 41 42 25 43 46 46 40
1.1 1.0 1.1 1.2 0.7 1.1 1.1 1.3 1.2 1.2 1.2 1.1 1.1 1.2 1.2 1.1 1.0 1.1 1.2 1.2 1.2 1.1 0.9 1.2 1.1 1.5 1.1 1.1 1.3 1.3 1.3 0.9 1.8 0.7 0.5 0.9 1.2 1.0
73 93 100 88 48 107 109 149 96 83 147 92 54 31 83 55 34 52 79 78 78 164 41 79 90 120 119 41 6 40 40 73 70 55 23 26 48 115
Gyrate Atrophy 399
Food
Weight Approximate (g) Measure For greatest accuracy, weigh food on scale that reads in grams. All measures are level. FATS Butter stick whipped Gravy mushroom, canned mushroom, dry onion, dry Margarine imitation soft stick or brick Nondairy creamer w/ sodium caseinate liquid powder Rich's Coffee Rich Polyrich Olives black green Salad dressings, commercial French Italian mayonnaise Miracle Whip ranch Russian Thousand Island Tartar sauce Toppings, commercial Cool Whip extra creamy regular Dessert toppings w/ sodium caseinate, pressurized Richwhip pressurized prewhipped Whipped cream, pressurized
ARG (mg)
Protein (g)
Energy (kcal)
14 16 12 1 1 27 19 15 6 2 24 24 5 4 12 10 7 16 5 4 8 6
1 Tbsp 1 Tbsp + 2 tsp 2-1/2 tsp 2 tsp 1 Tbsp 1 Tbsp + 2-1/2 tsp 1 Tbsp + 1 tsp 1 Tbsp + 1/4 tsp 1-1/4 tsp 1-1/4 tsp 1 Tbsp + 2 tsp 2 Tbsp + 2 tsp 1 olive 3/4 olive 2-1/4 tsp 2 tsp 1-1/2 tsp 1 Tbsp + 1/2 tsp 1 tsp 3/4 tsp 1-1/2 tsp 1-1/4 tsp
4 5 6 4 5 5 5 5 5 5 5 5 6 5 5 5 5 5 6 4 5 5
0.1 0.1 0.2 0.1 0.1 0.1 0.2 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1
101 113 6 3 5 92 135 110 8 13 37 37 9 4 50 46 49 82 26 19 29 31
5 9 13 12 6 4
1 Tbsp 2 Tbsp + 1 tsp 3 Tbsp 1 Tbsp + 2 tsp 1 Tbsp + 1-1/2 tsp 1 Tbsp + 1/2 tsp
4 5 5 5 6 5
0.1 0.1 0.1 0.1 0.1 0.1
15 26 34 34 18 11
FRUITS. Fruits are raw unless otherwise noted. Weight of raw fruits is only for parts that can be eaten. Drain canned, cooked, and frozen fruits before measuring or weighing. Apricots canned, heavy syrup dried cooked, mashed uncooked, halves frozen, sweetened nectar, canned sliced Avocadoes, all varieties, mashed Bananas, sliced Blackberries canned, heavy syrup frozen, sweetened raw 400 Gyrate Atrophy
129 47 18 121 157 51 43 56 48 50 72
1/2 cup 3 Tbsp 5 halves 1/2 cup 5 fl oz 1/3 3 Tbsp 1/4 cup 3 Tbsp 1/3 cup 1/2 cup
27 23 25 27 24 23 26 26 26 25 22
0.7 0.6 0.6 0.9 0.6 0.7 0.9 0.6 0.6 0.6 0.5
107 40 42 119 88 25 69 52 44 32 38
Food
Weight Approximate (g) Measure For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Blueberries canned, heavy syrup 64 1/4 cup frozen, sweetened 115 1/2 cup raw 72 1/2 cup Cherries canned, heavy syrup sour, red, 175 3/4 cup sweet 127 3/4 cup + 2 Tbsp Coconut, dried, sweetened 5 1 Tbsp Currants, black, raw 35 1/4 cup + 1 Tbsp Dates 33 4 dates Figs canned, heavy syrup 259 1 cup dried cooked, mashed 85 1/3 cup uncooked, chopped 37 3 Tbsp whole, medium 150 3 fruits Fruit cocktail, canned, heavy syrup 168 2/3 cup Gooseberries, canned, light syrup 79 1/4 cup + 1 Tbsp Grapefruit, all varieties canned, light syrup 63 1/4 cup juice, canned, unsweetened 77 2-1/2 fl oz sections 57 1/4 cup Grapes adherent skin 50 1/4 cup + 1 Tbsp juice, canned 47 1-1/2 fl oz slipskin 124 3/4 cup Thompson, seedless, canned, heavy syrup 64 1/4 cup Guavas 124 3/4 cup Kiwi fruit 95 1-1/4 fruits Lemons 33 1/2 fruit Mangoes, sliced 124 3/4 cup Melons, cubed cantaloupe 40 1/4 cup honeydew 85 1/2 cup Nectarines 103 3/4 cup Oranges juice canned 54 1-3/4 fl oz frozen, diluted 34 3 Tbsp sections 245 1-3/4 cups Papayas Peaches canned, heavy syrup, sliced dried cooked, mashed 89 1/3 cup uncooked, halves 26 2 frozen, sweetened 165 2/3 cup sliced 127 3/4 cup Persimmons, Japanese 84 1/2 fruit Pineapple canned, heavy syrup 191 3/4 cup cubed 136 3/4 cup + 2 Tbsp tidbits, crushed 64 3/4 cup Plantains, cooked, sliced 38 1/4 cup Plums sliced 198 3 plums Raisins golden 9 1 Tbsp 2001 Ross Products Division
ARG (mg)
Protein (g)
Energy (kcal)
22 23 25 21 24 26 25 22 23 26 26 27 27 25 25 27 25 25 22 26 22 26 25 25 23 22 25 25
0.4 0.5 0.5 1.3 1.5 0.2 0.5 0.7 1.0 1.1 1.1 1.1 0.7 0.5 0.4 0.4 0.4 0.3 0.3 1.0 0.3 1.0 0.9 0.4 0.6 0.4 0.4 1.0
56 93 41 160 91 23 22 91 228 92 95 111 123 57 38 29 18 35 29 63 47 63 58 9 81 14 30 51
24 22 25
0.4 0.3 1.5
24 16 95
25 24 26 23 21 23 24 23 25 26 23
1.0 0.9 1.0 0.9 0.5 0.7 0.5 0.7 0.3 1.6 0.3
56 62 155 55 59 140 66 149 45 109 27 Gyrate Atrophy 401
Food
Weight Approximate (g) Measure For greatest accuracy, weigh food on scale that reads in grams. All measures are level. seedless 11 1 Tbsp + 1/2 tsp Raspberries canned, heavy syrup 64 1/4 cup frozen, red, sweetened 94 1/4 cup + 2 Tbsp raw 61 1/2 cup Strawberries, sliced frozen, sweetened 112 1/4 cup + 3 Tbsp raw 61 1/4 cup + 1 Tbsp Tangerines canned, w/ light syrup 84 1/3 cup juice, canned 62 2 fl oz sections 61 1/4 cup + 1 Tbsp
ARG (mg) 25 22 27 23 26 27 26 22 27
Protein (g) 0.3 0.5 0.7 0.6 0.6 0.4 0.4 0.3 0.4
Energy (kcal) 32 58 97 30 107 27 51 32 27
VEGETABLES Vegetables are raw unless otherwise noted. Weight of raw vegetables is only for parts that can be eaten. Drain canned and cooked vegetables before measuring or weighing. Asparagus fresh or frozen, cooked raw Bamboo shoots, canned, sliced Beans snap green, cooked fresh or canned frozen mung, seed attached to sprout, cooked yellow wax, canned Beets greens, cooked, chopped red, sliced fresh, canned, cooked pickled Broccoli, fresh or frozen cooked raw Brussels sprouts, fresh or frozen, cooked Cabbage, shredded Chinese (Pak-choi) cooked raw red cooked raw white cooked raw Carrots, sliced canned cooked raw Cauliflower fresh, cooked frozen, cooked raw Celery, diced cooked raw Chard, Swiss, cooked Chayote fruit, cooked 402 Gyrate Atrophy
20 17 40
1-1/3 spears 2 Tbsp 1/3 cup
24 24 23
0.5 0.5 0.6
5 4 5
31 45 16 54 36 85 114 16 17 16
1/4 cup 1/3 cup 2 Tbsp 3 Tbsp + 1 tsp 1/4 cup 1/2 cup 1/2 cup 1 Tbsp + 2 tsp 3 Tbsp 3/4 sprout
24 25 23 25 26 24 24` 25 24 24
0.6 0.6 0.3 0.6 0.9 0.9 0.9 0.5 0.5 0.4
11 12 3 11 10 26 75 5 5 6
28 31 37 31 47 35 91 52 55 27 52 25 150 120 22 80
2 Tbsp + 2 tsp 1/4 cup + 3 Tbsp 1/4 cup 1/4 cup + 3 Tbsp 1/4 cup + 1 Tbsp 1/2 cup 1/2 cup + 2 Tbsp 1/3 cup 1/2 cup 3 Tbsp + 1-1/2 tsp 1/3 cup 1/4 cup 1 cup 1 cup 2 Tbsp 1/2 cup
25 26 23 24 25 24 24 23 24 24 23 24 23 24 27 21
0.4 0.5 0.4 0.4 0.4 0.4 0.6 0.6 0.6 0.5 0.6 0.5 0.6 0.8 0.4 0.5
3 4 8 8 10 8 21 23 24 7 6 6 22 19 5 19
Food
Weight Approximate (g) Measure For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Collards, cooked, chopped fresh 22 1/4 cup frozen 15 1 Tbsp + 1 tsp Eggplant, cubed cooked 78 1/2 cup + 1 Tbsp raw 54 1/2 cup Endive, raw, shredded 41 3/4 cup Kale, cooked fresh 37 3 Tbsp frozen 16 2 Tbsp Kohlrabi, sliced cooked 24 2 Tbsp raw 26 3 Tbsp Leeks, diced cooked 21 1/2 cup raw 52 1/4 cup + 1 tsp Lettuce, shredded bibb and Boston 37 2/3 cup iceberg 42 3/4 cup leaf 37 1/2 cup + 2 T Romaine and cos 28 1/2 cup Mushrooms Agaricus bisporus cooked or canned 24 2 mushrooms raw, diced 22 1/4 cup + 1 Tbsp Shitake cooked, pieces 27 3 Tbsp dried 4 1 mushroom Mustard greens, fresh or frozen, chopped cooked 15 1 Tbsp + 2 tsp raw 13 3 Tbsp + 2 tsp Okra, cooked 30 3 Tbsp Onions cooked 20 1 Tbsp + 1-1/2 tsp raw, diced 17 1 Tbsp + 2 tsp rings, canned 26 1/2 cup Parsnips, cooked 78 1/2 cup Peas green canned or frozen 6 1-3/4 tsp w/ carrots 10 1 Tbsp pods (edible) cooked 15 1 Tbsp + 1-1/2 tsp raw 18 2 Tbsp Peppers, green, sweet, diced cooked 76 1/2 cup + 1 Tbsp raw 56 1/2 cup + 1 Tbsp Pickles dill relish 56 1/4 cup whole, small 60 1 pickle sweet relish 83 1/3 cup sliced 60 2 pieces Pumpkin, canned 46 3 Tbsp Radishes, sliced red 58 1/2 cup white icicle 33 1/3 cup 2001 Ross Products Division
ARG (mg)
Protein (g)
Energy (kcal)
27 27 27 25 25 23 26 26 27 23 22 26 27 27 25
0.4 0.4 0.4 0.4 0.5 0.5 0.5 0.5 0.4 0.4 0.4 0.5 0.4 0.5 0.5
5 5 10 15 11 6 5 8 7 6 16 5 5 7 4
23 23 24 26 24 25 23 24 26 25 27
0.5 0.5 0.4 0.4 0.3 0.3
6 5 15 12 2 3
0.2 0.2 0.4 1.0
6 6 92 63
25 23 24 24 23 233
0.3 0.3 0.5 0.5 0.5 0.5
5 5 6 8 14 14
25 26 27 26 27 23 21
0.4 0.4 0.4 0.4 0.5 0.3 0.4
11 7 114 88 16 10 5 Gyrate Atrophy 403
Food
Weight Approximate (g) Measure For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Rutabagas cooked, mashed 18 1 Tbsp + 2 tsp cubed 18 2 Tbsp Sauerkraut 49 3 Tbsp + 1 tsp Shallots, chopped 13 1 Tbsp + 1 tsp Spinach, chopped fresh or frozen, cooked 15 1 Tbsp 8 1 tsp raw 14 1/4 cup Squash, summer, all varieties fresh or frozen, cooked 67 1/4 cup + 2 Tbsp raw, sliced 49 1/4 cup + 2 Tbsp Squash, winter acorn, baked, cubed 38 3 Tbsp butternut baked, cubed 51 1/4 cup boiled, mashed 35 2 Tbsp + 2 tsp Hubbard baked, cubed 29 1/4 cup boiled, mashed 30 2 Tbsp spaghetti, boiled 98 1/2 cup + 2 Tbsp Taro, cooked leaves 19 2 Tbsp root, sliced 66 1/2 cup Tomatoes catsup 62 1/4 cup fresh cooked 90 1/4 cup + 2 Tbsp chopped 119 2/3 cup juice 153 5 fl oz paste 33 2 Tbsp pure 78 1/4 cup + 1 Tbsp sauce marinara 92 1/4 cup + 2 Tbsp spaghetti 62 1/4 cup w/ onions, green peppers, and celery 61 1/4 cup stewed, canned 112 1/4 cup + 3 Tbsp Turnips greens, cooked, chopped 36 1/4 cup root, diced cooked 127 3/4 cup + 1 Tbsp raw 98 3/4 cup Vegetable cocktail juice (V8 ) 212 7 fl oz Vegetables, mixed canned 12 1 Tbsp + 1/4 tsp frozen, cooked 12 1 Tbsp Watercress 17 1/2 cup Soups, Campbell's , Condensed. Weigh or measure before diluting and dilute with water only. Asparagus, Cream of 37 2 Tbsp + 1 tsp Celery, Cream of 47 3 Tbsp Minestrone 15 1 Tbsp Mushroom, Cream of 37 2 Tbsp + 1 tsp Onion 6 1-1/4 tsp Potato, Cream of 42 2 Tbsp + 2 tsp Scotch broth 13 2-1/2 tsp Tomato 47 3 Tbsp Tomato Bisque 47 3 Tbsp Tomato Rice 48 3 Tbsp 404 Gyrate Atrophy
ARG (mg)
Protein (g)
Energy (kcal)
24 26 25 24 24 23 26 24 24 26 24 24 25 25 23 24 26 24 26 23 25 26 25 22 23 25 26 24 23 25 24 23 26
0.2 0.2 0.4 0.3 0.4 0.4 0.6 0.6 0.4 0.5 0.4 0.7 0.4 0.6 0.5 0.3 1.2 1.0 1.1 1.2 1.2 1.3 1.2 1.1 0.6 1.0 0.4 0.9 0.9 1.3 0.4 0.3 0.4
6 6 9 10 3 3 13 10 22 21 14 14 9 29 5 94 66 23 23 26 28 32 27 68 25 29 7 23 26 40 7 7 2
25 22 25 25 26 25 24 23 24 23
0.7 0.6 0.5 0.6 0.2 0.6 0.5 0.8 0.8 0.8
25 34 10 38 3 25 8 32 45 45
Food
Weight Approximate (g) Measure For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Vegetable 31 2 Tbsp Vegetable, Old Fashioned 31 2 Tbsp Vegetable, Chunky, Ready To Serve 30 2 Tbsp
ARG (mg) 25 25 24
Protein (g) 0.5 0.8 0.4
Energy (kcal) 18 45 15
FREE FOODS A Limit to prescribed number of servings. Beverages Chocolate drink powder (Quik ) Fruit juice Cranberry cocktail Fruit drink Lemon Lime Pineapple Prune Tangerine sweetened w/ sugar Lemonade Nectar Papaya Peach Pear Desserts Apple butter Fruit bars, frozen orange pineapple Fruit ice Fruit Roll-Ups M & M's, plain Mocha Mix, frozen chocolate vanilla Sherbet, orange Sorbet peach pineapple strawberry Fruit/Fruit Products Apples canned, w/ sugar dried raw cooked raw, small sauce sweetened w/ sugar unsweetened Cranberry sauce w/ sugar Fruit juice bar Fruit salad, heavy syrup Fun fruits Guava sauce Mixed fruit, heavy syrup Pie filling apple cherry 2001 Ross Products Division
3 253 78 15 31 63 64 16 92 173 78 250
1 tsp 8 fl oz 2-1/2 fl oz 1/2 fl oz 1 fl oz 2 fl oz 2 fl oz 1 Tbsp 3 fl oz 5-1/2 fl oz 2-1/2 fl oz 8 fl oz
5 5 5 4 5 5 7 5 6 5 6 4
0.1 0.1 0.1 0.1 0.1 0.2 0.4 0.1 0.1 0.3 0.2 0.3
11 144 39 3 6 35 46 8 37 98 43 150
40 19 24 18 14 3 4 5 12 44 30 30
2 Tbsp 1/4 bar 1/3 bar 1 Tbsp + 1-1/2 tsp 1 piece 3-1/2 pieces 1-1/2 tsp 2 tsp 1 Tbsp 3 Tbsp 2 Tbsp 2 Tbsp
5 5 4 5 5 5 4 5 5 5 5 5
0.2 0.1 0.1 0.1 0.2 0.2 0.1 0.1 0.1 0.2 0.1 0.1
74 18 23 23 55 14 8 11 17 45 29 29
76 16 64 91 80 91 80 26 53 77 59 48 184 63
1/4 cup + 2 Tbsp 3 Tbsp 1/4 cup 1/3 apple 1/4 cup + 1 Tbsp 1/4 cup + 2 Tbsp 1/4 cup + 1 Tbsp 1/2 bar 3 Tbsp + 1 tsp 3 pieces 1/4 cup 3 Tbsp 3/4 cup 1/4 cup
5 5 5 6 5 5 5 4 5 5 5 5 6 5
0.1 0.1 0.1 0.2 0.1 0.2 0.1 0.0 0.2 0.3 0.2 0.2 0.2 0.3
51 39 36 54 61 39 51 22 39 300 21 34 203 65 Gyrate Atrophy 405
Food
Weight Approximate (g) Measure For greatest accuracy, weigh food on scale that reads in grams. All measures are level. peach 67 1/4 cup strawberry 24 1 Tbsp + 1-1/2 tsp Pears canned, heavy syrup 160 1/2 cup + 2 Tbsp dried cooked, mashed 32 2 Tbsp uncooked, halves 18 1 sliced 72 1/4 cup + 3 Tbsp Plums, purple, canned, heavy syrup 86 1/3 cup Prunes canned, heavy syrup 37 2 Tbsp + 1-1/2 tsp dried cooked, mashed 26 2 Tbsp uncooked, halves 13 1-1/2 Rhubarb, cooked, sweetened 45 3 Tbsp Miscellaneous Barbecue sauce Chives Frosting, chocolate Goldfish crackers, original Horseradish Jalepeo peppers, sliced Jams and preserves Marmalade
ARG (mg) 5 5 5 5 6 5 5 5 5 5
Protein (g) 0.2 0.1 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.2
Energy (kcal) 71 29 118 40 46 43 77 38 28 30 52
16 3 8 2 12 17 20 13
1 Tbsp 1 Tbsp 1-1/2 tsp 3 crackers 2 tsp 2 Tbsp 1 Tbsp 2 tsp
6 6 5 5 5 7 5 5
0.3 0.1 0.1 0.1 0.1 0.1 0.1 0.1
12 1 32 10 1 4 54 33
FREE FOODS B These foods contain little or no ARG. They may be used as desired if patient is not overweight and if they do not depress appetite for prescribed foods. Beverages Apple juice Carbonated beverages cola cream soda Dr Pepper ginger ale grape soda lemon-lime soda orange soda root beer Beer light regular Coffee brewed instant powder Exceed Energy Drink Fruit drink (Hi-cup ) Gatorade Thirst Quencher Kool-Aid , sweetened w/ sugar Orange drink powder (Tang ) Strawberry drink powder (Quik ) Tea brewed instant powder sweetened unsweetened
124 123 124 123 122 124 123 124 123 30 30 30 5 124 124 121 123 8 8 30 13 1
4 fl oz 4 fl oz 4 fl oz 4 fl oz 4 fl oz 4 fl oz 4 fl oz 4 fl oz 4 fl oz 1 fl oz 1 fl oz 1 fl oz 1 Tbsp 4 fl oz 4 fl oz 4 fl oz 4 fl oz 2 tsp 1 Tbsp 1 fl oz 1 Tbsp 1 Tbsp
1 0 0 0 0 0 0 0 0 2 3 0 3 0 0 0 0 1 0 0 0 0
0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.1 0.0 0.7 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.0
58 50 63 50 41 53 49 60 50 8 12 1 13 35 58 30 49 31 33 1 51 3
406 Gyrate Atrophy
Food
Weight Approximate (g) Measure For greatest accuracy, weigh food on scale that reads in grams. All measures are level. Desserts/Sweeteners Candies candy corn 16 10 pieces gumdrops 4 2 pieces hard candy 10 2 pieces jelly beans 28 10 pieces Frosting, strawberry and vanilla 16 1 Tbsp Honey 21 1 Tbsp Jellies 20 1 Tbsp Lemon pudding (Hunts ) 120 1 container Molasses 21 1 Tbsp Popsicle twin 128 1 pop Sugar brown 14 1 Tbsp powdered 8 1 Tbsp table 12 1 Tbsp Syrup corn 20 1 Tbsp maple 20 1 Tbsp table 20 1 Tbsp Miscellaneous Lard Oil, olive or vegetable Richwhip liquid Salad dressing, oil/vinegar Shortening
1
ARG (mg)
Protein (g)
Energy (kcal)
1 0 0 0 0 1 2 0 0 0 0 0 0 0 0 0
0.0 0.0 0.0 0.0 0.0 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
58 14 39 103 69 64 54 151 48 95 52 31 48 58 50 50
13 14 14 16 13
1 Tbsp 1 Tbsp 1 Tbsp 1 Tbsp 1 Tbsp
0 0 0 0 0
0.0 0.0 0.0 0.0 0.0
115 120 40 70 113
For nutrient composition of very-low-protein foods, see Appendix 12, p A-11.
Gyrate Atrophy 407
TABLE 22-4. Nutrient Composition of CYCLINEX -1 1, 3 and CYCLINEX -2 2, 3

Nutrient (per 100 g pwd) Cyclinex-1 (per g protein equiv) 68 1.000 0.160 1.287 0.040 0.048 0.170 0.289 0.148 0.045 0.100 0.100 0.037 0.117 0.190 (per 100 g pwd) Cyclinex-2 (per g protein equiv) 32 1.000 0.160 1.287 0.040 0.048 0.170 0.289 0.148 0.045 0.100 0.100 0.037 0.117 0.190 24.67 4.00 3.00 1.13 0.121 0.019 77 88.3/2.49 2.47 0.09 10 1.13 20.0 0.07 2.67 68 120/3.07 2.47 78.3/3.41 1.13 61 0.54 1.10 4.67 5 10 0.12 0.487 8.7 35.33 7.3 2.02 0.726 0.160 0.267
Energy, kcal 510 440 Protein equiv, g 7.50 15.00 Nitrogen, g 1.20 2.40 9.65 19.30 Amino acids, g Cystine, g 0.30 0.60 Histidine, g 0.36 0.72 Isoleucine, g 1.28 2.56 Leucine, g 2.17 4.34 Lysine, g 1.11 2.22 Methionine, g 0.34 0.68 Phenylalanine, g 0.75 1.50 Threonine, g 0.75 1.50 Tryptophan, g 0.28 0.56 Tyrosine, g 0.88 1.76 Valine, g 1.43 2.86 Other Nitrogen-Containing Compounds L-Carnitine, mg 190 25.00 370 Taurine, mg 40 5.3 60 Carbohydrate, g 57.0 7.60 45.0 Fat, g 24.6 3.28 17.0 Linoleic acid, g 2.00 0.266 1.82 0.41 0.055 0.28 -Linolenic acid, g Minerals 650 86 1,150 Calcium, mg Chloride, mg/mEq 390/11.00 52.0/1.47 1,325/37.37 Chromium, g 12 1.60 37 Copper, mg 1.25 0.167 1.30 Iodine, g 80 10.67 150 Iron, mg 10.0 1.33 17.0 Magnesium, mg 55 7.3 300 Manganese, mg 0.50 0.067 1.00 Molybdenum, g 13 1.73 40 Phosphorus, mg 455 60 1,020 Potassium, mg/mEq 760/19.44 101/2.59 1,800/46.03 Selenium, g 25 3.33 37 Sodium, mg/mEq 215/9.35 28.7/1.25 1,175/51.11 Zinc, mg 9.5 1.27 17.0 Vitamins 480 64 908 A, g RE D, g 7.50 1.00 8.12 11.40 1.52 16.11 E, mg -TE K, g 60 8.0 70 Ascorbic acid, mg 60 8 75 Biotin, g 75 10 150 B6, mg 0.85 0.113 1.75 B12, g 5.60 0.750 7.30 Choline, mg 100 13.3 130 Folate, g 250 33.00 530 Inositol, mg 50 6.7 110 Niacin equiv, mg 16.70 2.23 30.3 Pantothenic acid, mg 7.80 1.040 10.90 Riboflavin, mg 1.0 0.133 2.4 Thiamin, mg 2.0 0.267 4.0 1 2 Designed for infants and toddlers. Designed for children, adolescents, and adults. 3 Approximate packed weight of Cyclinex-1 and Cyclinex-2 in level, dry US standard household measures: Cyclinex-1 Cyclinex-2 1 Tbsp = 8g 8g 1/4 cup = 26 g 32 g 1/3 cup = 35 g 41 g 1/2 cup = 53 g 61 g 1 cup = 105 g 117 g
408 Gyrate Atrophy
TABLE 22.5. Gyrate Atrophy Clinical Summary Sheet Name: Date of Birth: __________/__________/__________
Mo Date
(mo/d/yr)
Hospital Number : Age at Diagnosis:

Laboratory Data
Head Circum (cm) Hgb (g/dL) Hct (%) Ferritin (ng/mL) Transthyretin (mg/dL) Ammonia (mol/L) ARG (mol/L) ORN (mol/L)
Day Age
(yrs/mo) Length/ Height (cm)
Year Physical Data

Weight (kg)

ARG (mg) Protein (g) Energy (kcal)
REFERENCES
1. 2. 3. 4. 5. 6. 7. 8. Armstrong MD, Stave U: A study of plasma free amino acid levels. II. Normal values for children and adults. Metabolism 1973;22:561-569. Arnold GL, Vladutiu CJ, Kirby RS: Protein insufficiency and impaired growth in children with PKU. J Inher Metab Dis 2000;23 Suppl 1:29A. Bakker HD, Abeling NG, van Schooneveld MJ, et al: A far advanced case of gyrate atrophy in a 12-year-old girl. J Inher Metab Dis 1991;14:379-381. Barbul A: Arginine: Biochemistry, physiology, and therapeutic implications. JPEN 1986;10:227-238. Behrman RE, Kleigman RM, Arvin AA (eds): Nelson Textbook of Pediatrics, ed 15. Philadelphia: WB Saunders Co, 1996. Berson EL, Shih VE, Sullivan PL: Ocular findings in patients with gyrate atrophy on pyridoxine and low-protein, low-arginine diets. Ophthalmology 1981;88:311-315. Bell L, McInnes RR, Arshinoff SA, McCulloch JC: Dietary treatment of hyperornithinemia in gyrate atrophy. J Amer Diet Assoc 1981;79:139-145. Botschner J, Smth DW, Simell O, Scriver CR: Comparison of ornithine metabolism in hyperornithinemiahyperammonaemia-homocitrulluria syndrome, lysinuric protein intolerance, and gyrate atrophy fibroblasts. J Inher Metab Dis 1989;12:33-40. Elsas LJ, Acosta PB: Nutrition support of inherited metabolic diseases. In Shils ME, et al (eds): Modern Nutrition in Health and Disease, ed 9. Baltimore: Williams & Wilkins, 1999, pp 1003-1056. Food and Nutrition Board, Committee on Dietary Allowances: Recommended Dietary Allowances, eds 9 and 10. Washington, DC: National Academy of Sciences, 1980 and 1989. Goldblum OM, Brusilow SW, Maldonado YA, Farmer ER: Neonatal citrullinemia associated with cutaneous manifestations and arginine deficiency. J Am Acad Dermatol 1986;14:321-326. Gropper SS; Acosta PB: Effect of simultaneous ingestion of L-amino acids and whole protein on plasma amino acid and urea nitrogen concentrations in humans. J Parenteral and Enteral Nutrition 1991;15:48-53. Gropper SS; Gropper DM; Acosta PB. Plasma amino acid response to ingestion of L-amino acids and whole protein. J Pediatr Gastroenterol Nutr 1993;16:143-150. Hayasaka S, Saito T, Nakajima H, et al: Gyrate atrophy with hyperornithinaemia: Different types of responsiveness to vitamin B6. Brit J Ophthalmol 1981;65:478-483. Heinanen K, Nanto-Salonen K, Leino L, et al: Gyrate atrophy of the choroid and retina: Lymphocyte ornithinedelta-aminotransferase activity in different mutations and carriers. Pediatr Res 1998;44:381-385. Herrmann ME, Broesicke HG, Keller M, et al: Dependence of the utilization of a phenylalanine-free amino acid mixture on different amounts of single dose ingested. A case report. Eur J Pediatr 1994;153:501-503. Inatomi H, Sasaki T, Suyama Y, Inukai F: Studies on nonprotein amino acids in plants. IV. Distribution of citrulline in watermelon fruit. Bull Fac Agr , Meiji Univ 1969;24:23-29. Jones BJM, Lees R, Andrews J, et al: Comparison of an elemental and polymeric enteral diet in patients with normal gastrointestinal function. Gut 1983;24:78-84. Kaiser-Kupfer MI, Caruso RC, Valle D: Gyrate atrophy of the choroid and retina. Long-term reduction of ornithine slows retinal degeneration. Arch Ophthalmol 1991;109:1539-1548. Kaiser-Kupfer MI, DeMonasterio FM, Valle D, et al: Gyrate atrophy of the choroid and retina. Improved visual function following reduction of plasma ornithine by diet. Science 1980;210:1128-1131. Kaiser-Kupfer MI, Valle D, Bron AJ: Clinical and biochemical heterogeneity in gyrate atrophy. Am J Ophthalmol. 1980;89:219-222. Kaiser-Kupfer MI, Valle D, del Valle LA: A specific enzyme defect in gyrate atrophy. Am J Ophthalmol 1978;85:200204. Kennaway NG, Stankova L, Wirtz MK, Weleber RG: Gyrate atrophy of the choroid and retina: Characterization of mutant ornithine aminotransferase and mechanism of response to vitamin B6. Am J Hum Genet 1989;44:344352. Kennaway NG, Weleber RG, Buist NR: Gyrate atrophy of the choroid and retina with hyperornithinemia: Biochemical and histologic studies and response to vitamin B6. Am J Hum Genet 1980;32:529-541. MacLean W, Graham G: Pediatric Nutrition in Clinical Practice. Menlo Park, Calif: Addison-Wesley Publishing Co, 1982. Martin SB, Acosta PB: Osmotic behaviors of components of chemically-defined formulas. J Pediatr Perinat Nutr 1987;1:1-17. Mashima YG, Weleber RG, Kennaway NG, Inana G: Genotype-phenotype correlation of a pyridoxine-responsive form of gyrate atrophy. Ophthalmic Genet 1999;20;219-224. McInnes RR, Arshinoff SA, Bell L, et al: Hyperornithinemia and gyrate atrophy of the retina: Improvement of vision during treatment with a low-arginine diet. Lancet 1981;1:513-517. Meites S (ed): Pediatric Clinical Chemistry: Reference Normal Values, ed 3. Washington, DC: AAAC Press, 1989. Milner JA, Visek WJ: Urinary metabolites characteristic of urea-cycle amino acid deficiency. Metabolism 1975;24:643-651.
9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23.
24. 25. 26. 27. 28. 29. 30.
410 Gyrate Atrophy
31. Nanto-Salonen K, Komu M, Luudbom N, et al: Reduced brain creatine in gyrate atrophy of the choroid and retina with hyperornithinemia. Neurology 1999;53;303-307. 32. O'Donnell JJ, Sandman RP, Martin SR: Gyrate atrophy of the retina: Inborn error of L-ornithine:2-oxoacid aminotransferase. Science 1978;200:200-201. 33. Posati LP, Orr ML: Composition of Foods: Dairy and Egg Products, Agriculture Handbook No. 8-1. Washington, DC: US Dept of Agriculture, Agricultural Research Service, 1976. 34. Pratt EL, Snyderman SE, Cheung MW, et al: The threonine requirement of the normal infant. J Nutr 1955;56:231-51. 35. Rose WC: The amino acid requirements of adult man. Nutr Abstr Rev 1975;27;631-647. 36. Schaumburg H, Kaplan J, Windebank A, et al: Sensory neuropathy from pyridoxine abuse. A new megavitamin syndrome. N Engl J Med 1983;309:445-448. 37. Schoeffer A, Herrmann ME, Broesicke HG, Moench E: Effect of dosage and timing of amino acid mixtures on nitrogen retention in patients with phenylketonuria. J Nutr Med 1994;4 :415-418. 38. Shih VE, Berson EL, Garguilo M: Reduction of hyperornithinemia with a low-protein, low-arginine diet and pyridoxine in patients with a deficiency of ornithine-ketoacid transaminase (OKT) activity and gyrate atrophy of the choroid and retina. Clin Chim Acta 1981;113:243-251. 39. Shih VE, Mandell R, Berson EL: Pyridoxine effects on ornithine ketoacid transaminase activity in fibroblasts from carriers of two forms of gyrate atrophy of the choroid and retina. Am H Hum Genet 1988;43:929-933. 40. Shih VE, Stckler-Ipsiroglu S: Disorders of ornithine and creatine metabolism. In Fernandes J, et al (eds): Inborn Metabolic Diseases: Diagnosis and Treatment, ed 3. New York: Springer Verlag, 2000, pp 233-240. 41. Simell O, Takki K: Raised plasma ornithine and gyrate atrophy of the choroid and retina. Lancet 1973;1:1031-1033. 42. Sipila I, Simell O: Creatine corrects muscle 31P spectrum in gyrate atrophy with hyperornithinemia. Eur J Clin Invest 1999;29:1060-1065. 43. Smith CA, Nelson NM: The Physiology of the Newborn Infant, ed 4. Springfield, IL: Charles C Thomas Publisher, 1976. 44. Smith JL, Arteaga C, Heymsfield SB: Increased ureagenesis and impaired nitrogen use during infusion of a synthetic amino acid formula - A controlled trial. N Engl J Med 1982;306(17):1013-1018. 45. Smith JL, Heymsfield SB: Enteral nutrition support: Formula preparation from modular ingredients. JPEN 1983;7:280-288. 46. Spika JS, Shaffer N, Hargrett-Bean N, et al: Risk factors for infant botulism in the United States. Am J Dis Child 1989;143:828-832. 47. Valle D, Simell O: The hyperornithinemias. In Scriver CR, et al (eds): The Metabolic and Molecular Bases of Inherited Disease, ed 8. New York: McGraw-Hill Medical Publishing Division, 2001, pp 1857-1895. 48. Valle D, Walser M, Brusilow SW, Kaiser-Kupfer M: Gyrate atrophy of the choroid and retina. Amino acid metabolism and correction of hyperornithinemia with an arginine-deficient diet. J Clin Invest 1990;5:371-378. 49. Valle D, Walser M, Brusilow S, Kaiser-Kupfer MI, Takki K: Gyrate atrophy of the choroid and retina. Biochemical considerations and experience with an arginine-restricted diet. Ophthalmology 1981;88:325-330. 50. Visek WJ: Arginine needs, physiological state and usual diets, a reevaluation. J Nutr 1986;116:36-46. 51. Weleber RG, Kennaway NG, Buist NR: Vitamin B6 in management of gyrate atrophy of choroid and retina. Lancet 1978;2:213. 52. Weleber RG, Wirtz MK, Kennaway NG: Gyrate atrophy of the choroid and retina: Clinical and biochemical heterogeneity and response to vitamin B6. Birth Defects 1982;18:219-231. 53. Zieve L: Conditional deficiencies of ornithine and arginine. J Am Coll Nutr 1986;5:167-176.
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PROTOCOL 23 Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome Nutrition Support of Infants, Children, and Adults With CYCLINEX -1 and CYCLINEX -2 Amino Acid-Modified Medical Foods
I. Introduction
Ornithine (ORN), an amino acid not used for protein synthesis, has several metabolic pathways. ORN is used in synthesis of creatine, glutamate, proline, and polyamines and is important in the urea cycle. The hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is believed to result from a mitochondrial transport defect for ORN (9, 32, 33, 42). Plasma concentrations of ammonia, ORN, glutamine, and alanine are often increased and lysine concentration may be decreased (42). Urinary excretion of homocitrulline, polyamines, and orotic acid are increased many-fold above normal (3234). Symptoms of HHH syndrome may appear in neonates, children, or adults. Periods of ataxia, lethargy, vomiting, choreoathetosis, seizures, or coma coupled with delayed development may be some of the presenting symptoms. Muscle hypotonia followed later by spasticity may occur. Some patients have had a deficiency of-CoAgulation factors VII and X (7, 38). Prenatal diagnosis is available (6, 14).

Outcome appears to be dependent on extent of deficiency of ORN transporter protein, the subsequent mitochondrial deficiency of ORN, the resulting hyperammonemia, and the age at which therapy begins. Mitochondrial ORN is essential as a stimulator of carbamylphosphate synthetase (3, 4, 11, 45).

A. The Defect 1. Hyperornithinemia results from defect in: a. Mitochondrial ORN transport protein (17, 20). b. Ornithine--aminotransferase (Protocol 22). B. Diagnostic Studies 1. Diagnostic studies should be conducted in any person with the following symptoms: a. Poor feeding, vomiting, lethargy, hypotonia, spasticity, irritability, twitching, seizures, apnea or coma (23, 27) b. Developmental delay (23). c. Plasma ammonia > 150 mol/L in newborn period and > 80 mol/L thereafter (23). 2. See references 6, 14, 23, 28, 33, and 34 for methods of diagnosis. 3. Other causes of inherited hyperammonemia must be ruled out, including the following: a. Abnormalities of fatty acid metabolism (Protocol 20). b. Defects of urea cycle enzymes (Protocol 24). c. Lysinuric protein intolerance (Protocol 11). d. Organic acidurias (Protocols 5, 6, 10, 13, 18, 20). 4. Causes of acquired hyperammonemia that must be ruled out include the following: a. Deficient arginine (ARG) supply. b. Reye's syndrome. c. Transient hyperammonemia of newborn. d. Valproate therapy. Warning: Laboratory results MUST be available within 4 to 8 hours when disorder of urea cycle enzyme is suspected as hyperammonemia is a metabolic emergency.

A. Correct Primary Imbalance in Metabolic Relationships 1. Restrict dietary protein to amount tolerated without causing hyperammonemia (7, 9, 12, 30). 2. Prevent excessive body protein catabolism.
412 HHH Syndrome
B. Provide Alternate Metabolic Pathways 1. Prescribe L-citrulline (CIT) or L-ORN as indicated (7, 9, 19, 27, 30, 35). 2. Prescribe sodium phenylbutyrate to help decrease accumulated toxic precursors (1, 22, 43). C. Supplement "Conditionally Essential" and Essential Nutrients 1. Supply L-carnitine in adequate amounts to maintain normal plasma concentration of free carnitine (> 30 mol/L). 2. Use Cyclinex to supply approximately 50% of prescribed protein.

A. Plasma Amino Acid Concentrations (28) 1. Maintain 2- to 4-hour postprandial plasma concentrations of selected amino acids in following ranges or within normal range for age established in laboratory used (15).
Amino Acid Alanine ORN Glutamine (GLUNH2) mol/L 163 - 653 10 - 800 335 - 755
2. In practice, obtaining blood 2 to 4 hours postprandially is not always possible. Acceptable local standards should be developed if plasma amino acids are evaluated at other times (Practical Aspects of Nutrition Support, p viii). B. Plasma Ammonia Concentration (28) 1. Maintain plasma ammonia concentration < 35 mol/L or within normal range for age established in laboratory used. C. Growth, Development, and Nutrition Status 1. Support normal growth rate in infants and children and maintain appropriate weight for height in adults. 2. Support normal development. 3. Maintain normal nutrition status. a. Prevent catabolism. b. Prevent orotic aciduria. c. Prevent bone demineralization. D. Behavior and Neurologic Status 1. Prevent anorexia. 2. Maintain normal neurologic status. E. Physical Manifestations 1. Prevent liver disease.

A. L-CIT or L-ORN 1. Prescribe L-CIT or L-ORN for patients (7, 9, 13). 2. Requirements vary: a. From patient to patient, depending on: 1) Age. 2) Extent of transport protein defect. 3) Plasma ammonia concentration b. In most cases, amount prescribed is between 75 and 150 mg/kg (7). B. Protein (7-10, 39) 1. Prescribe amount that promotes goals of nutrition support (Table 23-1, p 414). 2. Amount prescribed may need to be increased if sodium benzoate or phenylbutyrate is administered daily.
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Warning:
Inadequate protein intake will result in failure to thrive in infants; weight loss, low plasma transthyretin concentration, osteopenia, and hair loss in children and adults (4-9); and may result in hyperammonemia.
C. Energy 1. Prescribe amount greater than Recommended Dietary Allowances (RDAs) (10) to prevent catabolism (Table 23-1, p 414). 2. Requirements will vary widely and may be 5% to 10% greater than those listed in Table 23-1, p 414, when infection or hyperammonemia is present. Warning: Inadequate energy intake will result in poor growth in infants and weight loss in children and adults, decreased dietary protein tolerance, and increased body protein catabolism causing hyperammonemia. D. Fluid 1. Prescribe amount that will supply water requirements (Table 23-1, p 414). Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL fluid to children and adults for each kcal ingested. E. Cyanocobalamin, Niacin, Folate, Pantothenic Acid, Pyridoxine 1. Sodium phenylacetate and sodium phenylbutyrate. a. Phenylacetic acid conjugates with GLUNH2 in the liver (1) and with GLUNH2 or taurine in kidney (22) and enhances excretion of waste nitrogen as phenylacetylglutamine. b. Cyanocobalamin, folate, niacin, and pantothenic acid are required for conjugation reactions (46). c. Prescribe vitamins listed above at 3 to 5 times RDAs for age (Appendices 13 and 14, pp A-14 and A-15) when sodium benzoate or sodium phenylbutyrate is administered (Appendix 26, p A-28).

A. L-CIT or L-ORN (Appendix 26, p A-28) 1. Solutions of L-CIT and L-ORN: a. Mix weighed amounts of L-CIT or L-ORN with boiled, cooled water to make known volumes of each that supply 100 mg/mL (eg, 100 g of L-CIT or L-ORN with water to make 1 liter). b. Refrigerate in sterilized, closed containers until used. Discard unused suspensions after 1 week, if not frozen. c. Shake well before using. Measure into Cyclinex mixture with disposable syringe. B. Protein 1. Calculate amount of infant formula with iron, beikost, whole cow's milk, or table foods (Table 23-2, p 414) required to fill approximately 50% of the protein prescription. Use infant formula with iron until 1st birthday. a. See Servings Lists for PHE-Restricted Diets (Protocol 1, pp 13-26) for portion sizes. 2. Subtract amount determined above from total protein prescription. 3. Supply any remaining prescribed protein with Cyclinex (Table 23-2, p 414). a. Cyclinex-1 is for infants and toddlers and Cyclinex-2 is for children, adolescents, and adults. b. Weigh Cyclinex powder on scale that reads in grams because of variability of household measuring equipment (Practical Aspects of Nutrition Support, p vii) and changes in density during shipping. c. See Table 22-4 (p 402, footnote 3) for approximate packed weight of Cyclinex powder in level, dry US standard household measures. C. Energy 1. Calculate energy provided by infant formula, beikost, table foods, and Cyclinex (Table 23-2, p 414) required to fill protein prescription. 2. Subtract amount determined above from total energy prescription. 3. Provide remaining prescribed energy with Polycose Glucose Polymers powder (23 kcal/Tbsp, 3.8 kcal/g) or liquid (2 kcal/mL) (Appendix 9, p A-9); Pro-Phree Protein-Free
414 HHH Syndrome 2001 Ross Products Division
Energy Module With Iron, Vitamins and Minerals (Appendix 11, p A-10), sugar (48 kcal/Tbsp), or Free Foods B (Table 23-2, p 414), depending on age of patient. a. Do not use corn syrup or table sugar for infants because of osmolarity they yield (25). b. Do not use honey for infants because it may contain botulinum toxin (40). D. Fluid and Mixing Instructions 1. Add sufficient boiled, cooled water to infant formula, Cyclinex, and carbohydrate (if needed) to yield prescribed volume. 2. Mix with sterilized blender at lowest speed for no longer than 3 to 4 seconds. Excess mixing may destabilize emulsion. Medical food may also be mixed in sterilized, tightly closed container by shaking vigorously for 10 to 12 seconds. 3. Refrigerate in sterilized, closed containers until used. Discard unused portion 24 hours after mixing because of nutrient loss. Store unopened cans at room temperature. Cover opened can of Cyclinex and store in refrigerator. Use within 1 month after opening. 4. Do not use terminal sterilization or boil because of Maillard reaction (Practical Aspects of Nutrition Support, p viii). 5. Warm or cool medical food mixture to room temperature before feeding to infants. Shake mixture well before feeding. 6. Do not warm medical food mixture for infants in microwave oven. Unevenly heated formula can burn infants, and steam can make bottles explode. 7. Notify parents or caretakers when they may discontinue using aseptic technique in preparing medical food mixture for infants. 8. For children and adults, chill Cyclinex medical food mixture to improve taste. E. Cyanocobalamin, Niacin, Folate, Pantothenic Acid, Pyridoxine (Appendix 11, p A-10, for composition of supplement) 1. Prescribe daily supplement, if required. 2. Folate requires prescription. F. Sodium Phenylbutyrate or Sodium Benzoate (Appendix 26, p A-28) 1. Administer appropriate amount with each feed or 1/4th to 1/3rd daily dose with each meal, depending on number of meals fed daily (3). G. Diet Guide 1. Provide parents, caretakers, or patient with completed Diet Guide (Appendix 22, p A-24) with each diet change. 2. Feed young infants 6 to 8 times daily (16, 31). 3. Feed older infants, children, and adults 4 to 6 times daily (16, 31).

A. Nutrient Adequacy 1. Determine if diet provides nutrients in amounts prescribed in Section VI, Establish Prescription, p 407. a. See Table 23-2, p 414, for composition of infant formulas, beikost, whole cow's milk, and Cyclinex. 2. Check diet to determine if it supplies Recommended Dietary Intakes (RDIs) of minerals and vitamins (Appendices 13 and 14, pp A-14 and A-15). a. See Table 22-4, p 402, for Cyclinex and Appendices 4 through 7, pp A-4 to A-7, for complete nutrient composition of infant formulas. b. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. c. If Cyclinex mixture provides < 100% of RDIs for infants and < 75% for children and adults, supplement diet with needed minerals and vitamins if not provided by beikost or table foods and laboratory tests indicate need (Appendix 11, p A-10, for composition of supplements).
HHH Syndrome 415
B. Osmolarity 1. If concentration of prescribed medical food mixture is > 24 kcal/fl oz, determine if osmolarity is in acceptable range. a. Determine osmolarity by laboratory analysis or use mathematical formula given in Appendix 18, p A-20. b. Osmolarity per gram of Cyclinex is listed in Appendix 19, p A-21. 2. If osmolarity is > 450 mosm/L for infants (24), > 750 mosm/L for children, > 1,000 mosm/L for adults (37), or greater than tolerated by patient, increase water content of prescribed medical food mixture and recalculate its osmolarity. C. Potential Renal Solute Load 1. Dehydration will result if renal solute load is greater than renal-concentrating ability of patient. 2. If concentration of medical food mixture prescribed is > 24 kcal/fl oz, estimate its potential renal solute load. a. This step is important to prevent dehydration of infants who may have renal-concentrating capacity as low as 600 mosm/L. b. Upper limit of renal solute load for neonates is approximately 1,100 mosm/L (36). 3. A method for estimating potential renal solute load is given in Appendix 20, p A-22. 4. If potential renal solute load is excessive, increase water content of medical food mixture and recalculate.

A. Plasma Amino Acid Concentrations 1. Initial. a. Evaluate twice weekly by quantitative methods until plasma concentrations stabilize. 2. Ongoing. a. Frequent evaluations help ensure adherence to nutrition support plan. b Evaluate every 2 to 3 months when patients condition is stable. 3. Unacceptable concentrations. a. If any plasma amino acid concentration is below lower limit of normal noted in Section V, Establish Goals of Nutrition Support, p 407, and patient has ingested full prescription: 1) Increase prescribed amount of Cyclinex by 10% and reevaluate plasma concentrations in 3 to 7 days. 2) If any amino acid concentration continues below its lower limit of normal, repeat above process until value is in the treatment range. b. If any plasma amino acid concentration is greater than upper limit of normal noted in Section V, Establish Goals of Nutrition Support, p 407, and patient has ingested full prescription: 1) Decrease prescribed amount of amino acid that is elevated by 10% and reevaluate in 3 days. 2) If any amino acid concentration continues above its upper limit of normal, repeat above process until value is in the treatment range. 4. Elevated plasma glutamine concentrations may indicate impending hyperammonemia. a. Obtain 3-day diet diary. b. Evaluate for infection. c. Obtain plasma ammonia concentration. d. If no infection is present, protein intake is not greater than prescribed, and energy intake is adequate, decrease prescribed protein by 10% and reevaluate plasma glutamine concentrations in 3 days. e. Repeat above process until plasma ammonia and glutamine concentrations are in treatment ranges. B. Plasma Ammonia Concentration (26) 1. Initial. a. Evaluate daily until concentration is in normal range, < 35 mol/L. 2. Ongoing. a. Evaluate weekly until patient is 6 months old, twice monthly until 1 year of age, and monthly thereafter if patient is well.
416 HHH Syndrome 2001 Ross Products Division
3. Elevated plasma ammonia concentration. a. Obtain 3-day diet diary and evaluate patient for infection. If no infection is found, protein intake is not greater than prescribed, and energy intake is not less than prescribed: 1) Increase L-CIT or L-ORN by 10% or increase sodium phenylbutyrate by 10% (if not already at upper limit tolerated) and reevaluate plasma ammonia concentration in 1 to 2 days. 2) If plasma ammonia concentration remains above upper limit of normal, repeat process until value is in normal range. Warning: Over-restriction of protein and/or energy will result in increase in plasma ammonia concentration. C. Protein Status (41) 1. Evaluate plasma transthyretin concentration every 3 months until patient is 1 year of age and every 6 months thereafter (Appendix 17, p A-18, for standards). a. Plasma transthyretin concentrations provide a more reliable and rapid indication of protein status than plasma albumin concentrations. b. Plasma albumin concentrations may be in the normal range when plasma transthyretin concentrations show a clear deficiency (2). 2. If plasma transthyretin concentration is below standard: a. Increase prescribed protein by 5% to 10% and reevaluate plasma transthyretin concentration in 1 month. b. If plasma transthyretin concentration continues below standard, repeat above process until value is in normal range. c. Evaluate plasma ammonia and plasma glutamine concentrations within 3 to 7 days after each increase in prescribed protein. 3. If protein catabolism is suspected, verify by measuring 3-methylhistidine in urine. a. Urinary 3-methylhistidine excretion > 25 mol/mol creatinine suggests catabolism (21). D. Iron Status 1. Plasma ferritin concentration. a. Evaluate at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17, p A-18, for standards). b. If plasma ferritin concentration is below standard: 1) Increase iron intake to 4 mg/kg with supplements (ferrous sulfate). 2) Evaluate plasma ferritin concentration monthly on increased iron intake. 3) Continue iron supplements until plasma ferritin concentration is in normal range. 2. Complete blood count. a. Hemoglobin and hematocrit concentrations should be evaluated at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17, p A-18, for standards). E. Plasma Sodium and Potassium Concentrations 1. Plasma sodium concentration. a. If sodium phenylbutyrate or sodium benzoate is prescribed, evaluate within 2 to 3 days after each prescription change. 2. Plasma potassium concentration a. If Polycitra K Oral Solution is used, evaluate on a routine basis. F. Growth Status 1. Length/height and weight. a. Measure monthly to 1 year, every 3 months until prepubertal growth spurt is completed, and every 6 months thereafter. Plot measurements on NCHS growth charts. b. Maintain length/height and weight between 10th and 90th percentiles. Some normal infants, children, and adults will fall above or below these percentiles. 2. If length/height or weight falls below usual growth channel: a. Increase prescribed protein and energy by 5% to 10% and remeasure in 1 month. b. If length/height or weight remains low, repeat above process until usual growth channel is achieved.
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c.
Evaluate plasma ammonia and GLUNH2 concentrations with each increase in prescribed protein.
G. Nutrient Intake 1. Maintain records of food intake for 3 days immediately before each blood test (Appendices 24 and 25, pp A-26 and A-27). 2. Evaluate intakes of protein and energy before each blood test. 3. Evaluate mineral and vitamin intakes after each diet change. a. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. b. See Appendix 28, p A-29, for information about ordering software for diet evaluation. H. Clinical Summary 1. A summary record of growth, laboratory, and nutrient intake data is useful for patient management (Table 23-3, p 415).
A. Example 1 Establish and fill prescription for male neonate weighing 3.0 kg using Recommended Daily Nutrient Intakes from Table 23-1, p 414, and approximate nutrient contents from Table 23-2, p 414. 1. Establish prescription.
L-CIT 150 mg X Protein 2.2 g/kg x Energy 150 kcal/kg x Fluid 160 mL/kg x Vitamin B supplements, if indicated 3.0 kg 3.0 kg 3.0 kg 3.0 kg = = = = 450 mg/day 6.6 g 450 kcal 480 mL
Medical Food Mixture Cyclinex-1 Similac With Iron, Ready to Feed L-CIT 1 Polycose Liquid Add water to make 480 mL (16 fl oz). Total per day Total per kg 450 150 6.6 2.2 450 150 Measure 44 g 236 Ml 4.5 mL 33 mL 0 0 450 0 L-CIT (mg) 3.3 3.3 0.0 0.0 Protein (g) 224 160 0 66 Energy (kcal)
Approximate osmolarity of medical food mixture is < 400 mosm/L. Estimated potential renal solute load is < 110 mosm. 1 Solution is 100 mg/mL.
B. Example 2 Establish and fill prescription for 24-month-old child weighing 13.0 kg using Recommended Daily Nutrient Intakes from Table 23-1, p 414, and approximate nutrient contents from Table 23-2, p 414. 1. Establish prescription.
L-ORN 1,950 mg /day Protein 20 g Energy 1,365 kcal Fluid 1,495 mL Vitamin B supplements, if indicated
418 HHH Syndrome
Medical Food Mixture Measure ORN (mg) Protein (g) 13.5 0.0 Energy (kcal) 927 0
Cyclinex-1 180 g 0 L-ORN 19.5 mL 1,950 Add water to make 710 mL (24 fl oz). Offer additional water ad libitum daily. Food List Breads/Cereals Fats Fruits Vegetables Total per day 4 1 4 4 Servings 0 0 0 0 1,950
2.4 0.1 2.0 2.0 20.0
120 60 240 40 1,387
C. Example 3 Establish and fill prescription for 7-year-old child weighing 25.0 kg using Recommended Daily Nutrient Intakes from Table 23-1, p 414, and approximate nutrient contents from Table 23-2, p 414. 1. Establish prescription.
L-ORN 3,750 mg /day Protein 25 g Energy 1,730 kcal Fluid 2,125 mL Vitamin B supplements
Medical Food Mixture Measure ORN (mg) Protein (g) 15.0 0.0 0.0 Energy (kcal) 410 0 192
Cyclinex-2 100 g 0 L-CIT 1 37.5 mL 3,750 Sugar 1/4 cup 0 Add water to make 710 mL (24 fl oz). Offer additional water ad libitum daily. Food List Breads/Cereals Fats Fruits Vegetables Total per day 6 8 7 4 Servings 0 0 0 0 3,750
3.6 0.8 3.5 2.0 24.9
180 480 420 40 1,722
Approximate osmolarity of medical food mixture is < 600 mosm/L

A. Rationale 1. In normal persons, febrile illness and trauma are accompanied by catabolism of body protein (44). 2. Well-nourished patients with HHH syndrome respond to infection and trauma as do normal persons. Warning: Prolonged use (> 2 days) of protein-free or low-energy diet will lead to body protein catabolism and rebound hyperammonemia.
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TABLE 23-1. Recommended Daily Nutrient Intakes (Ranges) for Infants, Children, and Adults With HHH Syndrome
Age Protein (g/kg) Infants 0 to < 3 mo 3 to < 6 mo 6 to < 9 mo 9 to < 12 mo 2.20 - 1.25 2.00 - 1.80 1.80 - 1.60 1.60 - 1.40 (g/day) Girls and Boys 1 to < 4 yr 4 to < 7 yr 7 to < 11 yr Women 11 to < 15 yr 15 to < 19 yr 19 yr Men 11 to < 15 yr 15 to < 19 yr
1 2 3 4 1-3
Nutrient Energy 2, (kcal/kg) 150 - 125 140 - 120 130 - 115 120 - 110 (kcal/day) 945 - 1,890 1,365 - 2,415 1,730 - 3,465 160 - 130 160 - 130 150 - 125 130 - 120 (mL/day) 945 - 1,890 1,365 - 2,415 1,730 - 3,465 Fluid 4 (mL/kg)
16 - 20 20 - 25 25 - 30
42 - 46 40 - 44 42 - 46
1,575 - 3,150 1,260 - 3,150 1,785 - 2,625
1,575 - 3,150 1,260 - 3,150 1,785 - 2,625
19 yr From references 8 and 10. From reference 10. Protein intake may need to be increased if sodium benzoate or sodium phenylbutyrate is prescribed. From reference 5. Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL fluid to children and adults for each kcal ingested.
50 - 55 55 - 60 60 - 65
2,100 - 3,885 2,200 - 4,095 2,625 - 3,465
2,100 - 3,885 2,200 - 4,095 2,625 - 3,465
TABLE 23-2. Serving Lists for Protein-Restricted Diets: Approximate Nutrient Content per Serving
Food List Protein (g) Breads/Cereals 0.6 Fats 0.1 Fruits 0.5 Vegetables 0.5 Free Foods A 0.1 Free Foods B 0.0 1 Alimentum Protein Hydrolysate Formula With Iron, Ready to Feed, 100 mL 1.86 Cyclinex-1 , 100 g 7.50 Cyclinex-2 , 100 g 15.00 1 Isomil Soy Formula With Iron, Ready to Feed, 100 mL 1.66 1 Similac With Iron Infant Formula, Ready to Feed, 100 mL 1.40 2 Whole cow's milk, 100 mL 3.39 1 See Appendices 4 through 7, pp A-4 to A-7, for complete nutrient composition of infant formulas. 2 From reference 29. See Appendix 8, A-8, for complete nutrient composition. 30 60 60 10 65 55 68 510 440 68 68 63 Nutrient Energy (kcal)
420 HHH Syndrome
TABLE 23.3 HHH Syndrome Clinical Summary Sheet Name: Date of Birth: __________/__________/__________
Mo Day Year
2001 Ross Products Division HHH Syndrome 415
Hospital Number:
Date
Age
Physical Data
Length/ Height (cm) Weight (kg) Head Circum (cm) ALA (mol/L) GLUNH2 (mol/L) ORN (mol/L)
Laboratory Data
Creatine (mol/L) Ammonia (mol/L) Hgb (g/dL) Hct (%) Ferritin (ng/mL) Transthyretin (mg/dL)

L-CIT / ORN (mg) Protein (g) Energy (kcal)
(mo/d/yr) (yrs/mo)
REFERENCES
1. 2. 3. 4. 5. 6. 7. Ambrose AM, Powder FW, Sherwin CP: Further studies on the detoxification of phenylacetic acid. J Biol Chem 1933;101:669-675. Arnold GL, Vladutiu CJ, Kirby RS: Protein insufficiency and impaired growth in children with PKU. J Inher Metab Dis 2000;23 (Suppl 1):29A. Bachman C: Diagnosis of urea cycle disorders. In Tada K, et al (eds): Recent Advances in Inborn Errors of Metabolism. New York: S Karger, 1987, pp 233-241. Bachman C: Urea cycle disorders. In Fernandes J, et al (eds): Inborn Metabolic Diseases: Diagnosis and Treatment. New York: Springer-Verlag, 1990, pp 211-228. Behrman RE, Kleigman RM, Arvin AA (eds): Nelson Textbook of Pediatrics, ed 15. Philadelphia: WB Saunders Co, 1996. Chadefaux B, Bonnefont JP, Rabier D, et al: Potential for the prenatal diagnosis of hyperornithinemia, hyperammonemia and homocitrullinuria syndrome. Am J Med Genet 1989;32:264 (letter). Dionisi Vici C, Bachmann C, Gambarara M, et al: Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome: Low creatine excretion and effect of citrulline, arginine or ornithine supplement. Pediatr Res 1987;22:364-367. FAO/WHO/UNU Expert Consultation: Energy and Protein Requirements. Geneva: World Health Organization, 1985. Fell V, Pollitt RJ, Sampson GA, Wright T: Ornithinemia, hyperammonemia, and homocitrullinuria. Am J Dis Child 1974;127:752-746. Food and Nutrition Board, Committee on Dietary Allowances: Recommended Dietary Allowances, eds 9 and 10. Washington, DC: National Academy of Sciences, 1980 and 1989. Gatfield PD, Taller, E, Wolfe, DM, Haust D: Hyperornithinemia, hyperammonemia, and homocitrullinuria associated with decreased carbamylphosphate synthetase I activity. Pediatr Res 1975;9:488-497. Gjessing LR, Lunde HA, Undrum T, et al: A new patient with hyperornithinemia, hyperammonemia and homocitrullinuria syndrome treated early with low protein diet. J Inher Metab Dis 1986;9:186-192. Gordon BA, Gatfield DA, Haust AD: The hyperornithinemia, hyperammonemia, homocitrullinuria syndrome: An ornithine transport defect remediable with ornithine supplements. Clin Invest Med 1987;10:329-336. Gray RGF, Green A, Hall S, McKeown C: Prenatal exclusion of HHH syndrome. Prenatal Diagn 1995;15:474-476. Gregory DM, Sovetts D, Clow CR: Plasma free amino acid values in normal children and adolescents. Metabolism 1986;35:967-969. Herrmann ME, Broesicke HG, Keller M, et al: Dependence of the utilization of a phenylalanine-free amino acid mixture on different amounts of single dose ingested. A case report. Eur J Pediatr 1994;153:501-503. Hommes FA, Ho CR, Roesel RA, et al: Decreased transport of ornithine across the inner mitochondrial membrane as a cause by hyperornithinaemia. J Inher Metab Dis 1982;5:41-47. Hommes FA, Roesel RA, Metoki K, et al: Studies on a case of HHH-syndrome (hyperornithinemia, hyperammonemia,homocitrullinuria). Neuropediatr 1986;17:48-52. Inoue I, Koura M, Saheki T, et al: Abnormality of citrulline synthesis in liver mitochondria from patients with hyperornithinaemia, hyperammonaemia and homocitrullinuria. J Inher Metab Dis 1987;10:227-280. Inoue I, Saheki T, Kayanuma K, et al: Biochemical analysis of decreased ornithine transport activity in the liver mitochondria from patients with hyperornithinemia, hyperammonemia and homocitrullinuria . Biochem Biophys Acta 1988;964:90-95. Jackson AA, Badaloo AV, Forrester T, et al: Urinary excretion of 5-oxoproline (pyroglutamic aciduria) as an index of glycine insufficiency in normal man. Brit J Nutr 1987;58:207-214. James MO, Smith RL, Williams RT, Reidenberg M: The conjugation of phenylacetic acid in man, sub-human primates and some non-primate species. Proc R Soc Lond 1972;182:25-35. Koike R, Fujimori K, Yuasa T, et al: Hyperornithinemia, hyperammonemia and homocitrullinuria: Case report and biochemical study. Neurol 1987;37:1813-1815. MacLean W, Graham G: Pediatric Nutrition in Clinical Practice. Menlo Park, Calif: Addison-Wesley Publishing Co, 1982. Martin SB, Acosta PB: Osmotic behaviors of components of chemically-defined formulas. J Pediatr Perinat Nutr 1987;1:1-17. Meites S (ed): Pediatric Clinical Chemistry: Reference Normal Values, ed 3. Washington, DC: American Association for Clinical Chemistry, 1989. Nakajima M, Ishii S, Mito T, et al: Clinical, biochemical and ultrastructural study on the pathogenesis of hyperornithinemia-hyperammonemia-homocitrullinuria syndrome. Brain Dev 1988;10:181-185. Oyanagi K, Tsichiyama A, Itakura Y, et al: The mechanism of hyperammonaemia and hyperornithinaemia in the syndrome of hyperornithinaemia, hyperammonaemia and homocitrullinuria. J Inher Metab Dis 1983;6:133-134. Posati LP, Orr ML: Composition of Foods: Dairy and Egg Products, Agriculture Handbook No. 8-1. Washington, DC: US Dept of Agriculture, Agricultural Research Service, 1976.
8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.
21. 22. 23. 24. 25. 26. 27. 28. 29.
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30. Rodes M, Ribes a, Pineda M, et al: A new family affected by the syndrome of hyperornithinaemia, hyperammonaemia and homocitrullinuria. J Inher Metab Dis 1987;10:73-81. 31. Schoeffer A, Herrmann E, Broesicke HG, Moench E: Effect of dosage and timing of amino acid mixtures on nitrogen retention in patients with phenylketonuria. J Nutr Med 1994;4 :415-418. 32. Shih VE, Mandell R, Herzfeld A: Defective ornithine metabolism in cultured skin fibroblasts from patients with the syndrome of hyperornithinemia, hyperammonemia, and homocitrullinuria. Clin Chim Acta 1982;118:149-157. 33. Shih VE, Efron ML, Moser HW: Hyperornithinemia, hyperammonemia and homocitrullinuria: A new disorder or amino acid metabolism associated with myoclonic seizures and mental retardation. Am J Dis Child 1969;117:83-92. 34. Shimizu H, Maekawa K, Eto Y: Abnormal urinary excretion of polyamines in HHH syndrome. Brain Dev 1990;12:533-535. 35. Simell O, MacKenzie S, Clow CL, Scriver CR: Ornithine loading did not prevent induced hyperammonemia in a patient with hyperornithinemia-hyperammonemia-homocitrullinuria syndrome. Pediatr Res 1985;19:1283-1287. 36. Smith CA, Nelson NM: The Physiology of the Newborn Infant, ed 4. Springfield, IL: Charles C Thomas Publisher, 1976. 37. Smith JL, Heymsfield SB: Enteral nutrition support: Formula preparation from modular ingredients. JPEN 1983;7:280-288. 38. Smith L, Lambert P, Brochu P, et al: Hyperornithinemia, hyperammonemia, homocitrullinuria (HHH) syndrome: Presentation as acute liver disease with-CoAgulopathy. J Pediatr Gastroenterol Nutr 1992;15:431-436. 39. Snyderman SE, Holt LE, Dancis J, et al: "Unessential" nitrogen: A limiting factor for human growth. J Nutr 1962;78:57-52. 40. Spika JS, Shaffer N, Hargrett-Bean N, et al: Risk factors for infant botulism in the United States. Am J Dis Child 1989;143:828-832. 41. Torun B, Chew F: Protein-energy malnutrition. In Shils ME, et al (eds): Modern Nutrition in Health and Disease, ed 9. Philadelphia: Williams & Wilkins, 1999, pp 963-1001. 42. Tsujino S, Suzuki T, Azuma T, et al: Hhyperornithinemia, hyperammonemia, and homocitrullinuria A case report and study of ornithine metabolism using in vivo deuterium labeling. Clin Chim Acta 1991;201:129-134. 43. Tuchman M, Knopman DS, Shih VE: Episodic hyperammonemia in adult siblings with hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome. Arch Neurol 1990;47;1134-1137. 44. Wannemacher RW: Key role of various individual amino acids in host response to infection. Am J Clin Nutr 1977;30:1269-1280. 45. Zammarchi E, Ciani F, Pasquini E, et al: Neonatal onset of hyperornithinemia-hyperammonemia-homocitrullinuria syndrome with favorable outcome. J Pediatr 1997;131:440-443. 46. Zeman FJ: Clinical Nutrition and Dietetics, ed 2. New York: MacMillan Publishing Co, 1991.
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PROTOCOL 24 Urea Cycle Disorders Nutrition Support of Infants, Children, and Adults With CYCLINEX -1 and CYCLINEX -2 Amino Acid-Modified Medical Foods
I. Introduction
Disorders of the urea cycle result from inherited defects in any one of six enzymes which function in urea production (Figure T). With the exception of ornithine transcarbamylase (OTC) deficiency, all have an autosomal recessive mode of inheritance. OTC deficiency is inherited as an X-linked dominant trait that is often lethal in males (3,4, 8, 9). Ammonia is normally converted to urea in the liver through the Krebs-Henseleit cycle (Figure T) and excreted in urine. The first three enzymes of the cycle and N-acetylglutamate synthetase (NAGS) are mitochondrial. NAGS catalyzes conversion of acetyl-CoA plus glutamate to N-acetylglutamine, an essential cofactor for carbamylphosphate synthesis. Carbamylphosphate synthetase (CPS) catalyzes conversion of ammonia, ATP, and bicarbonate to carbamylphosphate. OTC utilizes carbamylphosphate and ornithine (ORN) as cosubstrates to form citrulline (CIT). CIT is exported from mitochondria to the cytoplasm where cytosolic reactions are linked to those three mitochondria functions. CIT and aspartate form argininosuccinic acid, in a reaction catalyzed by argininosuccinic acid synthetase (AS). Fumarate is cleaved from argininosuccinic acid by argininosuccinic acid lyase (AL), yielding arginine (ARG). Urea is then formed by the action of arginase, regenerating cytosolic ORN which is transported back into the mitochondria to react with OTC (3, 4, 8, 9).
Restrict dietary protein Prevent tissue protein catabolism (N) (N) Therapeutic phenylacetate
Serine Folate
Glutamine
Phenylacetylglutamine Therapeutic benzoate Glycine (N) Carbamylphosphate synthetase Hippurate (N) Carbamylphosphate Orotic acid + (NH4) + CO2 N-acetylglutamate N-acetylglutamate synthetase
(N) (N)
Urine
Acetyl-CoA + Glutamate Oxaloacetate
L-citrulline Urine
L-aspartate
= Site of enzyme defect (N) = nitrogen L-ornithine
Ornithine transcarbamylase
Argininosuccinate synthetase
L-argininosuccinate
Urea
Arginase
Argininosuccinate lyase
Urine
L-arginine Therapeutic L-arginine Fumarate
Figure T. Nitrogen metabolism in urea cycle enzyme defects. Hyperammonemia is a biochemical manifestation of all disorders of the urea cycle. Other biochemical characteristics of each defect follow: CPS deficiency causes decreased plasma CIT concentration; OTC deficiency results in orotic aciduria and X-linked patterns of transmission; AS deficiency is
424 Urea Cycle Disorders 2001 Ross Products Division
associated with increased plasma CIT concentration accompanied by orotic aciduria; AL deficiency causes increased argininosuccinate in plasma and urine; and arginase deficiency results in increased ARG concentration in plasma and urine. Clinical features in the newborn suggestive of urea cycle enzyme defects occur with protein ingestion or infection with body protein catabolism. In increasing order of severity, these defects include poor feeding, vomiting, lethargy, hypotonia, stupor, bleeding diatheses, convulsions, coma, shock, and death (19). Mental retardation occurs in survivors of these newborn episodes (3,4, 8, 9, 52). Orthoptic liver transplantation has been successfully used for patients with CPS and OTC deficiencies (9). Retroviral-mediated gene therapy is being studied in ASdeficient cell cultures (12). Tamura, et al (50) found that glucagon enhanced urea excretion in AS deficiency.

Results of therapy in infants with complete or near complete enzyme deficiencies have been less than optimal with delayed death and below normal development. If serious brain swelling and coma are prevented in the neonatal period or if onset of disease expression is delayed, physical growth and mental development are more nearly normal with nutrition and pharmacologic support. If diagnosis is anticipated and treatment is begun during the early neonatal period in affected siblings with citrullinemia or argininosuccinic aciduria (ASA), relatively normal outcome is observed, even in the severe enzyme defects (33, 34, 37, 41, 43). Females heterozygous for OTC deficiency may expire during the neonatal period (19), may develop coma during the postpartum period (15, 55) or if parenteral nutrition is administered (15), or may be developmentally delayed if untreated (17, 33, 42). A female with arginase deficiency was reported to develop coma on the first day of her menstrual period and spontaneously recover 3 days later (22).

A. The Defect 1. Hyperammonemia may result from a defect in any of the following enzymes: a. NAGS (10, 23). b. CPS. c. OTC. d. AS. e. AL. f. Arginase - plasma ammonia may be normal in some instances. B. Diagnostic Studies 1. Diagnostic studies should be conducted in any person with the following symptoms: a. Poor feeding, vomiting, lethargy, hypotonia, spasticity, irritability, twitching, seizures, apnea or coma. b. Plasma ammonia concentration > 150 mol/L in newborn period and > 80 mol/L thereafter (3). 2. See references 3, 4, and 8-10 for methods of diagnosis. 3. Other causes of inherited hyperammonemia must be ruled out, including the following: a. Abnormalities of fatty acid metabolism (Protocol 20). b. Transport defects of urea cycle intermediates - lysinuric protein intolerance (Protocol 11), and hyperornithinemia-hyperammonemia-homocitrullinemia syndrome (Protocol 23). c. Organic acidurias (Protocols 5, 6, 10, 13, 18, 20). 4. Causes of acquired hyperammonemia that must be ruled out include the following: a. Deficient ARG supply. b. Reye's syndrome. c. Transient hyperammonemia of newborn. d. Valproate therapy (31, 38, 45). Warning: Laboratory results MUST be available within 4 to 8 hours when a disorder of urea cycle enzyme is suspected as hyperammonemia is a metabolic emergency.

A. Correct Primary Imbalance in Metabolic Relationships 1. Restrict dietary protein to amount tolerated without causing hyperammonemia (5).
2001 Ross Products Division Urea Cycle Disorders 425
2. Prevent excessive body protein catabolism (5). 3. Restrict dietary tryptophan to that required for growth to prevent excess synthesis of serotonin (25) and quinolinic acid (6). B. Provide Alternate Metabolic Pathways (28) 1. Prescribe L-ARG or L-CIT as indicated. 2. Prescribe sodium benzoate, sodium phenylacetate or sodium phenylbutyrate to help decrease accumulated toxic precursors. C. Supplement "Conditionally Essential" and Essential Nutrients 1. Supply L-ARG (20) (except in arginase deficiency), L-carnitine (39), L-cystine, and L-tyrosine in adequate amounts (30). 2. Administer N-carbamylglutamate to patients with deficiency of NAGS or CPS (29). 3. Use essential amino acid mix to supply approximately 50% of prescribed protein.

A. Plasma Amino Acid Concentrations (53) 1. Maintain 2- to 4-hour postprandial plasma concentrations of selected amino acids in following ranges or within normal range for age established in laboratory used.
Amino Acid ARG Aspartic acid (ASP) CIT Glutamine Glycine (GLY) Serine (SER) mol/L 100 -150 14 - 50 30 - 128 335 - 755 100 - 170 100 - 170 mg/dL 1.75 -2.60 0.18 - 0.67 0.52 - 2.24 4.90 - 11.04 0.75 - 1.28 1.05 - 1.79 Reference 1 36 36 36 36 36
2. In practice, obtaining blood 2 to 4 hours postprandially is not always possible. Acceptable local standards should be developed if plasma amino acids are evaluated at other times (Practical Aspects of Nutrition Support, p viii). B. Plasma Ammonia Concentration (3-5, 53) 1. Maintain plasma ammonia concentration < 35 mol/L or within normal range for age established in laboratory used. C. Growth, Development, and Nutrition Status 1. Support normal growth rate in infants and children and maintain appropriate weight for height in adults. 2. Support normal development. 3. Maintain normal nutrition status. a. Prevent ARG deficiency (20). b. Prevent hyperlipidemia. c. Prevent catabolism. d. Prevent orotic aciduria in deficiencies of AL, AS, and OTC (3-6). D. Behavior and Neurologic Status 1. Prevent anorexia (25). 2. Maintain normal neurologic status. E. Physical Manifestations 1. Prevent liver disease (30).

A. L-ARG 1. Prescribe L-ARG for patients who have deficiency of either AL or AS. Do not prescribe for patients with arginase deficiency. a. Becomes essential amino acid in most disorders of the urea cycle (13) b. Enhances waste nitrogen excretion.
426 Urea Cycle Disorders
2. Requirements vary: a. From patient to patient, depending on age, extent of enzyme defect, and plasma ARG concentration b. In most cases, amount prescribed is between 400 and 700 mg/kg (8, 9). B. L-CIT 1. May be used instead of L-ARG in CPS or OTC deficiencies 2. Initially, prescribe 170 mg/kg (8, 9), 3. Amount to prescribe depends on: a. Age. b. Extent of enzyme defect. c. Plasma CIT concentration C. Citrate 1. Patients with treated AS and AL deficiencies have been found to have very low citrate excretion (3). 2. Some clinicians prescribe 2.2 to 3.0 mmol/kg per 24 hours (3, 26). 3. Greater amounts may be required during periods of illness accompanied by fever. D. Protein (13, 48) 1. Prescribe amount that promotes goals of nutrition support (Table 24-1, p 429). 2. Amount prescribed may need to be increased if sodium benzoate, sodium phenylacetate, or sodium phenylbutyrate is administered daily. Warning: Inadequate protein intake will result in failure to thrive in infants; weight loss, low plasma transthyretin concentration, osteopenia, and hair loss in children and adults; and may result in hyperammonemia (51). E. N-Carbamylglutamate (10, 23) 1. Patients with deficiency of NAGS or CPS may not require protein restriction if N-carbamylglutamate is administered. 2. Administer 80 to 100 mg/kg daily. 3. L-ARG supplements and drugs used to enhance waste nitrogen may be unnecessary when N-carbamylglutamate is administered. F. Energy 1. Prescribe amount greater than Recommended Dietary Allowances (RDAs) (9) to prevent catabolism (3, 4) (Table 24-1, p 429). 2. Requirements will vary widely and may be 5%-10% greater than those listed in Table 24-1, p 429, when infection or hyperammonemia is present. Warning: Inadequate energy intake will result in low plasma transthyretin concentration, poor growth in infants and weight loss in children and adults, decreased dietary protein tolerance, and increased body protein catabolism causing hyperammonemia. G. Fluid 1. Prescribe amount that will supply water requirements (Table 24-1, p 429). Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL fluid to children and adults for each kcal ingested (7). H. Cyanocobalamin, Niacin, Folate, Pantothenic Acid, Pyridoxine 1. Sodium benzoate. a. Enhances waste nitrogen excretion through conjugation of GLY with benzoic acid to form hippuric acid (18). b. GLY biosynthesis and conjugation of GLY with benzoate require adequate cellular concentrations of cyanocobalamin, niacin, folate, pantothenic acid, and pyridoxine (56). c. Prescribe vitamins listed above at 3 to 5 times Recommended Dietary Intakes (RDIs) for age (Appendices 13 and 14, pp A-14 and A-15) when sodium benzoate is administered.
Urea Cycle Disorders 427
2. Sodium phenylacetate and sodium phenylbutyrate. a. Phenylacetic acid conjugates with glutamine in the liver (1) and with glutamine or taurine in kidney (28) and enhances excretion of waste nitrogen as phenylacetylglutamine. b. Cyanocobalamin, niacin, folate, and pantothenic acid are required for conjugation reactions (56). c. Prescribe vitamins listed above at 3 to 5 times RDIs for age (Appendices 13 and 14, pp A-14 and A-15) when phenylacetate or phenylbutyrate is administered.
VII. Fill Prescription (4)

A. L-ARG or L-CIT (Appendix 26, p A-28) 1. Solutions of L-ARG and L-CIT a. Mix weighed amounts of L-ARG and L-CIT with boiled, cooled water to make know volumes of each to yield 100 mg/mL (eg, 100 g of L-ARG or L-CIT with enough water to make 1 liter). b. Measure into Cyclinex mixture with disposable syringe. c. Refrigerate in sterilized, closed containers until used. Discard unused suspensions after 1 week, if not frozen. d. Shake well before using. Warning: Use only ARG-free base. B. Citrate 1. When citrate is prescribed, Polycitra K Oral Solution may be used. 2. May be ordered from: Baker Norton Pharmaceuticals, Inc. 8800 NW 36th St Miami, FL 33178-2404 Phone: 800 735-2315. C. N-Carbamylglutamate 1. Administer 1/4th to 1/8th of prescribed dose before each feed, depending on number of feeds. 2. May be ordered from: Curtin & Warner 19 Phoenix Place Lewis, East Sussex, UK D. Protein 1. Calculate amount of infant formula with iron (use until 1st birthday), beikost, whole cow's milk, or table foods (Table 24-2, p 429) required to fill approximately 50% of the protein prescription. a. See Servings Lists for PHE-Restricted Diets (Protocol 1, pp 13-26) for portion sizes. 2. Subtract amount determined above from total protein prescription. 3. Supply any remaining prescribed protein with Cyclinex (Table 23-2, p 429). a. Cyclinex-1 is for infants and toddlers and Cyclinex-2 is for children, adolescents, and adults. b. Weigh Cyclinex powder on scale that reads in grams because of variability of household measuring equipment (Practical Aspects of Nutrition Support, p vii) and changes in density during shipping. c. See Table 22-4 (p 402, footnote 3) for approximate packed weight of Cyclinex powder in level, dry US standard household measures. E. Energy 1. Calculate energy provided by infant formula, beikost, whole cow's milk, or table foods and Cyclinex (Table 24-2, p 429) required to fill protein prescription. 2. Subtract amount determined above from total energy prescription. 3. Provide any remaining prescribed energy with Polycose Glucose Polymers powder (23 kcal/Tbsp, 3.8 kcal/g) or liquid (2 kcal/mL) (Appendix 9, p A-9); Pro-Phree Protein-Free Energy Module With Iron, Vitamins and Minerals (Appendix 11, p A-10), sugar (48 kcal/Tbsp), or Free Foods B (Table 24-2, p 429), depending on age of patient. a. Do not use corn syrup or table sugar for infants because of osmolarity they yield (35).
b. Do not use honey for infants because it may contain botulinum toxin (49). F. Fluid and Mixing Instructions 1. Add sufficient boiled, cooled water to infant formula, Cyclinex, and carbohydrate (if needed) to yield prescribed volume. Tap water may replace boiled, cooled water when preparing Cyclinex for older infants, children, and adults. 2. Mix with sterilized blender at lowest speed for no longer than 3 to 4 seconds. Excess mixing may destabilize emulsion. May also be mixed in sterilized, tightly closed container by shaking vigorously for 10 to 12 seconds. 3. Refrigerate in sterilized, closed containers until used. Discard unused portion 24 hours after mixing because of nutrient loss. 4. Do not use terminal sterilization or boil because of Maillard reaction (Practical Aspects of Nutrition Support, p viii). 5. Warm or cool medical food mixture to room temperature before feeding to infants. Shake mixture well before feeding. 6. Do not warm medical food mixture for infants in microwave oven. Unevenly heated formula can burn infants, and steam can make bottles explode. 7. Notify parents or caretakers when they may discontinue using aseptic technique in preparing medical food mixture for infants. 8. For children and adults, chill Cyclinex medical food mixture to improve taste. G. Cyanocobalamin, Niacin, Folate, Pantothenic Acid, Pyridoxine (Appendix 26, p A-28) 1. Prescribe daily supplement, if needed. 2. See Appendix 11, p A-10, for composition of supplement. 3. Folate requires prescription. H. Sodium Benzoate, Sodium Phenylacetate, Sodium Phenylbutyrate (Appendix 26, p A-28) 1. Administer appropriate amount with each feed or 1/6th to 1/8th daily dose with each meal, depending on number of meals fed daily. I. Diet Guide 1. Provide parents, caretakers, or patient with completed Diet Guide (Appendix 22, p A-24) with each diet change. 2. Feed young infants 6 to 8 times daily (24, 44). 3. Feed older infants, children, and adults 4 to 6 times daily (24, 44).

A. Nutrient Adequacy 1. Determine if diet provides nutrients in amounts prescribed in Section VI, Establish Prescription, p 420. a. See Table 24-2, p 429, for composition of Cyclinex, infant formulas, beikost, and whole cow's milk. 2. Check diet to determine if it supplies RDIs of minerals and vitamins (Appendices 13 and 14, pp A-14 and A-15). a. See Table 22-4, p 402, for composition of Cyclinex and Appendices 4 through 7, pp A-4 to A-7, for complete nutrient composition of infant formulas. b. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. c. If Cyclinex mixture provides < 100% of RDIs for infants and < 75% for children and adults, supplement diet with needed minerals and vitamins if laboratory tests indicate need (Appendix 11, p A-10, for composition of supplements). B. Osmolarity 1. If concentration of prescribed medical food mixture is > 24 kcal/fl oz, determine if osmolarity is in acceptable range. a. Determine osmolarity by laboratory analysis or use mathematical formula given in Appendix 18, p A-20. b. Osmolarity per gram of Cyclinex is listed in Appendix 19, p A-21.
2. If osmolarity is > 450 mosm/L for infants (32), > 750 mosm/L for children, > 1,000 mosm/L for adults (47), or greater than tolerated by patient, increase water content of prescribed medical food mixture and recalculate its osmolarity. C. Potential Renal Solute Load 1. Dehydration will result if renal solute load is greater than renal-concentrating ability of patient. 2. If concentration of medical food mixture prescribed is > 24 kcal/fl oz, estimate its potential renal solute load. a. This step is important to prevent dehydration of infants who may have renal-concentrating capacity as low as 600 mosm/L. b. Upper limit of renal solute load for neonates is approximately 1,100 mosm/L (46). 3. A method for estimating potential renal solute load is given in Appendix 20, p A-22. 4. If potential renal solute load is excessive, increase water content of medical food mixture and recalculate.

A. Plasma Amino Acid Concentrations (21) 1. Initial. a. Evaluate twice weekly by quantitative methods until plasma concentrations normalize to prevent deficiency. 2. Ongoing. a. Frequent evaluations help ensure adherence to nutrition support plan. b Evaluate every 2 to 3 months when patients condition is stable. 3. Unacceptable plasma amino acid concentrations. a. If any plasma amino acid concentration is below lower limit of normal noted in Section V, Establish Goals of Nutrition Support, p 420, and patient has ingested full protein prescription: 1) Increase prescribed Cyclinex by 10% and reevaluate plasma concentrations in 3 to 7 days. 2) If any amino acid continues below its lower limit of normal, repeat above process until value is in treatment range. b. If any plasma GLUNH2 concentration is greater than upper limit of normal noted Section V, Establish Goals of Nutrition Support, p 420, and patient has ingested full prescription: 1) Decrease prescribed amount of protein from natural foods by 10% and reevaluate in 3 days. 2) If GLUNH2 concentration continues above its upper limit of normal, repeat above process until value is in treatment range. 4. Elevated plasma GLUNH2 concentrations may indicate impending hyperammonemia. a. Obtain 3-day diet diary. b. Evaluate for infection. c. Obtain plasma ammonia concentration. d. If no infection is present, protein intake is not greater than prescribed, and energy intake is adequate, decrease prescribed protein by 10% and reevaluate plasma glutamine concentrations in 3 days. e. Repeat above process until ammonia and GLUNH2 concentrations are in treatment ranges. B. Plasma Ammonia Concentration (36) 1. Initial. a. Evaluate daily until concentration is in normal range. 2. Ongoing. a. Evaluate weekly until patient is 6 months old, twice monthly until 1 year of age, and monthly thereafter if patient is well. 3. Elevated plasma ammonia concentration (36). a. Obtain 3-day diet diary and evaluate patient for infection. If no infection is found, protein intake is not greater than prescribed, and energy intake is not less than prescribed:
1) Decrease protein from natural foods by 10% or increase prescribed sodium benzoate, sodium phenylacetate, or sodium phenylbutyrate by 10% (if not already at upper limit tolerated) and reevaluate plasma ammonia concentration in 1 to 2 days. 2) If plasma ammonia concentration remains above upper limit of normal, repeat process until normal concentration is achieved. Warning: Over-restriction of protein and/or energy will result in increase in plasma ammonia concentration. C. Protein Status 1. Evaluate plasma transthyretin concentration monthly until patient is 1 year of age and every 3 months thereafter (Appendix 17, p A-18, for standards). a. Plasma transthyretin concentrations provide a more reliable and rapid indication of protein status than plasma albumin concentrations. b. Plasma albumin concentrations may be in the normal range when plasma transthyretin concentrations show a clear deficiency (2). 2. If plasma transthyretin concentration is below standard: a. Increase prescribed protein by 10% and reevaluate plasma transthyretin concentration in 1 month. b. If plasma transthyretin concentration continues below standard, repeat above process until value is in normal range. c. Evaluate plasma ammonia and plasma GLUNH2 concentrations with each increase in prescribed protein. 3. If GLY deficiency is suspected, verify by measuring pyroglutamic acid in urine (27). a. Urinary pyroglutamic acid excretion > 325 mol/mmol creatinine suggests GLY deficiency. 4. If protein catabolism is suspected, verify by measuring 3-methylhistidine in urine. a. Urinary 3-methylhistidine excretion > 25 mol/mol creatinine suggests catabolism. D. Iron Status 1. Plasma ferritin concentration. a. Evaluate at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17, p A-18, for standards). b. If plasma ferritin concentration is below standard: 1) Increase iron intake to 4 mg/kg with supplements (ferrous sulfate). 2) Evaluate plasma ferritin concentration monthly on increased iron intake. 3) Continue iron supplements until plasma ferritin concentration is in normal range. 2. Complete blood count. a. Hemoglobin and hematocrit concentrations should be evaluated at 6, 9, and 12 months of age and every 6 months thereafter (Appendix 17, p A-18, for standards). b. Normal heme synthesis requires adequate GLY. E. Plasma Sodium and Potassium Concentrations 1. Plasma sodium concentration. a. If sodium benzoate, sodium phenylacetate, or sodium phenylbutyrate is prescribed, evaluate after each prescription change. 2. Plasma potassium concentration a. If Polycitra K Oral Solution is used, evaluate on a routine basis. F. Growth Status 1. Length/height and weight. a. Measure monthly to 1 year, every 3 months until prepubertal growth spurt is completed, and every 6 months thereafter. Plot measurements on NCHS growth charts. b. Maintain length/height and weight between 10th and 90th percentiles. Some normal infants, children, and adults will fall above or below these percentiles. 2. If length/height or weight falls below usual growth channel: a. Increase prescribed protein and energy by 5% to 10% and remeasure in 1 month. b. If length/height or weight remains low, repeat above process until usual growth channel is achieved. c. Evaluate plasma ammonia and GLUNH2 concentrations with each increase in prescribed protein.
G. Nutrient Intake 1. Maintain records of food intake for 3 days immediately before each blood test (Appendices 24 and 25, pp A-26 and A-27). 2. Evaluate intakes of protein and energy before each blood test. 3. Evaluate mineral and vitamin intakes after each diet change. a. Appendix 23, p A-25, may be used to check adequacy of nutrients if computer program is not available. b. See Appendix 28, p A-29, for information about ordering software for diet evaluation. H. Clinical Summary 1. A summary record of growth, laboratory, and nutrient intake data is useful for patient management (Table 24-3, p 430).
A. Example 1 Establish and fill prescription for male neonate weighing 3.0 kg who has OTC deficiency using Recommended Daily Nutrient Intakes from Table 24-1, p 429, and approximate nutrient contents from Table 24-2, p 429. 1. Establish prescription.
L-CIT 350 mg Protein 2.2 g/kg Energy 150 kcal/kg Fluid 160 mL/kg Vitamin B supplements, if indicated Citrate X x x x 3.0 kg 3.0 kg 3.0 kg 3.0 kg = = = = 1,050 mg/day 6.6 g 450 kcal 480 mL
Medical Food Mixture Cyclinex-1 Similac With Iron Ready to Feed L-CIT 1 Polycose Liquid Add water to make 480 mL (16 fl oz). Total per day Total per kg 1,050 150 6.6 2.2 450 150 Measure 44 g 236 mL 10.5 mL 33 mL L-CIT (mg) 0 0 1,050 0 3.3 3.3 0.0 0.0 Protein (g) 224 160 0 66 Energy (kcal)
B. Example 2 Establish and fill prescription for 24-month-old child weighing 13.0 kg who AS deficiency using Recommended Daily Nutrient Intakes from Table 24-1, p 429, and approximate nutrient contents from Table 24-2, p 429.
L-ARG 7,150 mg /day Protein 13 g Energy 1,365 kcal Fluid 1,495 mL Vitamin B supplements, if indicated Citrate
Medical Food Mixture Measure ARG (mg) Protein (g) 6.5 0.0 0.0 Energy (kcal) 444 0 129
Cyclinex-1 87 g 0 1 L-ARG 72 mL 7,200 Polycose powder 34 g 0 Add water to make 710 mL (24 fl oz). Offer additional water ad libitum daily. Food List Breads/Cereals Fats Fruits Vegetables Free Foods A Free Foods B Total per day 3 3 4 4
2 2
Servings ------1.8 0.3 2.0 2.0 0.4 0.0 13.0 90 180 240 40 130 110 1,363
7,200
C. Example 3 Establish and fill prescription for 7-year-old girl weighing 25.0 kg who has CPS deficiency using Recommended Daily Nutrient Intakes from Table 24-1, p 429, and approximate nutrient contents from Table 24-2, p 429. 1. Establish prescription.
L-CIT 8,750 mg /day Protein 17 g Energy 1,730 kcal Fluid 2,125 mL Vitamin B supplements, if indicated Citrate
Medical Food Mixture Measure CIT (mg) Protein (g) 8.6 0.0 0.0 Energy (kcal) 51 0 240
Cyclinex-2 57 g 0 1 L-CIT 87.5 mL 8750 Sugar 60 g 0 Add water to make 710 mL (24 fl oz). Offer additional water ad libitum daily. Food List Breads/Cereals Fats Fruits Vegetables Free Foods A Total per day 5 8 7 3
3
Servings 0 0 0 0 0 8,750 3.0 0.8 3.5 1.5 0.3 17.7 150 480 420 30 195 1,766
XI GLY, GLUNH2, Protein, and Nitrogen Deficiencies

A. GLY Deficiency 1. Decreased heme synthesis (27). 2. Decreased glutathione synthesis (27). B. GLUNH2 1. Decreased purine and pyrimidine biosynthesis. C. Protein 1. Kwashiorkor (51). D. Nitrogen 1. No weight gain, decreased weight gain, or weight loss (48). 2. Impaired nitrogen retention (48). 3. Protein malnutrition (48).

A. Rationale 1. In normal persons, febrile illness and trauma are accompanied by catabolism of body protein (54). 2. See references 3, 8, 9, and 13 for management. Warning: Prolonged use (> 2 days) of protein-free or low-energy diet will lead to protein catabolism and rebound hyperammonemia. B. Contraindicated Medication 1. Valproate (31, 38, 45).
TABLE 24-1. Recommended Daily Nutrient Intakes (Ranges) for Infants, Children, and Adults With Urea Cycle Disorders
Age Protein (g/kg) Infants 0 to < 3 mo 3 to < 6 mo 6 to < 9 mo 9 to < 12 mo 2.20 - 1.25 2.00 - 1.80 1.80 - 1.60 1.60 - 1.40 (g/day) Girls and Boys 1 to < 4 yr 4 to < 7 yr 7 to < 11 yr Women 11 to < 15 yr 15 to < 19 yr 19 yr Men 11 to < 15 yr 15 to < 19 yr
1 1-3
Nutrient Energy 1 (kcal/kg) 150 - 125 140 - 120 130 - 115 120 - 110 (kcal/day) 945 - 1,890 1,365 - 2,415 1,730 - 3,465 160 - 130 160 - 130 150 - 125 130 - 120 (mL/day) 945 - 1,890 1,365 - 2,415 1,730 - 3,465 Fluid 4 (mL/kg)
8 - 12 12 - 15 14 - 17
20 - 23 20 - 23 22 - 25
1,575 - 3,150 1,260 - 3,150 1,785 - 2,625
1,575 - 3,150 1,260 - 3,150 1,785 - 2,625
19 yr From references 14, 16. 2 From reference 13, 16. 3 Protein intake may need to be increased if sodium benzoate, sodium phenylacetate, or sodium phenylbutyrate is prescribed. 5 From reference 7. Under normal circumstances, offer minimum of 1.5 mL fluid to neonates and 1.0 mL fluid to children and adults for each kcal ingested.
20 - 23 21 - 24 23 - 32
2,100 - 3,885 2,200 - 4,095 2,625 - 3,465
2,100 - 3,885 2,200 - 4,095 2,625 - 3,465
TABLE 24-2. Serving Lists for Protein-Restricted Diets: Approximate Nutrient Content per Serving
Food List Protein (g) Breads/Cereals 0.6 Fats 0.1 Fruits 0.5 Vegetables 0.5 Free Foods A 0.1 Free Foods B 0.0 1 Alimentum Protein Hydrolysate Formula With Iron, Ready to Feed, 100 mL 1.86 Cyclinex-1 , 100 g 7.50 Cyclinex-2 , 100 g 15.00 1 Isomil Soy Formula With Iron, Ready to Feed, 100 mL 1.66 1 Similac With Iron Infant Formula, Ready to Feed, 100 mL 1.40 2 Whole cow's milk, 100 mL 3.39 1 See Appendices 4 through 7, pp A-4 to A-7, for complete nutrient composition of infant formulas. 2 From reference 40. See Appendix 8, A-8, for complete nutrient composition. 30 60 60 10 65 55 68 510 440 68 68 63 Nutrient Energy (kcal)
TABLE 24.3. Urea Cycle Disorders Clinical Summary Sheet Name: Date of Birth: __________/__________/__________ Mo Day Year
Date Age Physical Data
GLUNH2 (mol/L) GLY (mol/L)
Hospital Number:
Laboratory Data
SER (mol/L) Ammonia (mol/L) Hgb (g/dL) Hct (%) Ferritin (ng/mL) Transthyretin (mg/dL) TAG
1

ARG (mg) CIT (mg) Protein (g) Energy (kcal) (mg/dL)
Length/ Weight Head ARG ASP CIT Height Circum (kg) (cm) (mol/L) (mol/L) (mol/L) (mo/d/yr) (yrs/mo) (cm)
Triacylglycerols
REFERENCES
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. Ambrose AM, Powder FW, Sherwin CP: Further studies on the detoxification of phenylacetic acid. J Biol Chem 1933;101:669-675. Arnold GL, Vladutiu CJ, Kirby RS: Protein insufficiency and impaired growth in children with PKU. J Inher Metab Dis 2000;23 Suppl 1:29A. Bachman C: Urea cycle disorders. In Fernandes J, et al (eds): Inborn Metabolic Diseases: Diagnosis and Treatment. New York: Springer-Verlag, 1990, pp 211-228. Batshaw ML: Inborn errors of urea synthesis. Ann Neurol 1994;35:133-141. Batshaw ML, Monahan PS: Treatment of urea cycle disorders. In Tada K, et al (eds): Recent Advances in Inborn Errors of Metabolism. New York: Karger, 1987, pp 242-250. Batshaw ML, Robinsin MB, Hyland K, et al: Quinolinic acid in children with congenital hyperammonemia. Ann Neurol 1993;34:676-681. Behrman RE, Kleigman RM, Arvin AA (eds): Nelson Textbook of Pediatrics, ed 15. Philadelphia: WB Saunders Co, 1996. Brusilow SW, Horwich AL: Urea cycle enzymes. In Scriver CR, et al (eds): The Metabolic and Molecular Bases of Inherited Disease, ed 8. New York: McGraw-Hill Medical Publishing Division, 2001, pp 1909-1963. Brusilow SW, Maestri NE: Urea cycle disorders: Diagnosis, pathophysiology and therapy. Adv Pediatr 1996;43:127-170. Colombo JP: N-acetylglutamate deficiency: Clinical and biochemical features. Int'l Pediatr 1995;10:109-113. Connelly A, Cross JH, Gadian DG, et al: Magnetic resonance spectroscopy shows increased brain glutamine in ornithine carbamoyl transferase deficiency. Pediatr Res 1993;33:77-81. Demarquoy J: Retroviral-mediated gene therapy for the treatment of citrullinemia: Transfer and expression of argininosuccinate synthetase in human hemopoietic cells. Experientia 1993;49:345-348. Elsas LJ, Acosta PB: Nutrition support of inherited metabolic diseases. In Shils ME, et al (eds): Modern Nutrition in Health and Disease, ed 9. Baltimore: Williams & Wilkins, 1999, pp 1003-1056. FAO/WHO/UNU Expert Consultation: Energy and Protein Requirements. Geneva: World Health Organization, 1985. Felig DM, Brusilow SW, Boyer JL: Hyperammonemic coma due to parenteral nutrition in a woman with heterozygous ornithine transcarbamylase deficiency. Gastroent 1995;109:282-284. Food and Nutrition Board, Committee on Dietary Allowances: Recommended Dietary Allowances, eds 9 and 10. Washington, DC: National Academy of Sciences, 1980 and 1989. Fries MH, Kuller TA, Jurecki E, Packman S: Prenatal counseling in heterozygotes for ornithine transcarbamylase deficiency. Clin Pediatr 1994;Sept:525-529. Gatley SJ, Sherratt HAS: The synthesis of hippurate from benzoate and glycine by rat liver mitochondria. Biochem J 1977;166:39-47. Girgis N, McGravey V, Shah BL, et al: Lethal ornithine transcarbamylase deficiency in a female neonate. J Inher Metab Dis 1987;10;274-275. Goldblum OM, Brusilow SW, Maldonado YA, Farmer ER: Neonatal citrullinemia associated with cutaneous manifestations and arginine deficiency. J Am Acad Dermatol 1986;14:321-326. Gregory DM, Sovetts D, Clow CR: Plasma free amino acid values in normal children and adolescents. Metabolism 1986;35:967-969. Grody WW, Chang RJ, Panagiotis NM, et al: Menstrual cycle and gonadal steroid effects on symptomatic hyperammonaemia of urea-cycle-based and idiopathic aetiologies. J Inher Metab Dis 19994;17:566-574. Guffon N, Vianey-Saban C, Bourgeois J, et al: A new neonatal case of N-acetylglutamate synthase deficiency treated by carbamylglutamate. J Inher Metab Dis 1995;18:61-65. Herrmann ME, Broesicke HG, Keller M, et al: Dependence of the utilization of a phenylalanine-free amino acid mixture on different amounts of single dose ingested. A case report. Eur J Pediatr 1994;153:501-503. Hyman SL, Coyle JT, Parke JC, et al: Anorexia and altered serotonin metabolism in a patient with argininosuccinic aciduria. J Pediatr 1986;108:705-709. Iafolla AK, Gale DS, Roe CR: Citrate therapy in argininosuccinate lyase deficiency. J Pediatr 1990;117:102-105. Jackson AA, Badaloo AV, Forrester T, et al: Urinary excretion of 5-oxoproline (pyroglutamic aciduria) as an index of glycine insufficiency in normal man. Brit J Nutr 1987;58:207-214. James MO, Smith RL, Williams RT, Reidenberg M: The conjugation of phenylacetic acid in man, sub-human primates and some non-primate species. Proc R Soc Lond 1972;182:25-35. Kuchler G, Rabier D, Poggi-Travert F, et al: Therapeutic use of carbamylglutamate in the case of carbamoylphosphate synthetase deficiency. J Inher Metab Dis 1996;19;220-222. LaBrecque DR, Latham PS, Reily CA, et al: Heritable urea cycle enzyme deficiency. Liver disease in 16 patients. J Pediatr 1979;94 (4):587-587. Leao M: Valproate as a cause of hyperammonemia in heterozygotes with ornithine-transcarbamylase deficiency. J Neurol 1995;45:593-594.
32. MacLean W, Graham G: Pediatric Nutrition in Clinical Practice. Menlo Park, Calif: Addison-Wesley Publishing Co, 1982. 33. Maestri NE, Brusilow SW, Clossold DB, Bassett SS: Long-term treatment of girls with ornithine transcarbamylase deficiency. N Engl J Med 1996;335:855-859. 34. Maestri NE, Clissold D, Brusilow SW: Neonatal onset ornithine transcarbamylase deficiency: A retrospective analysis. J Pediatr 1999;134:268-272. 35. Martin SB, Acosta PB: Osmotic behaviors of components of chemically-defined formulas. J Pediatr Perinat Nutr 1987;1:1-17. 36. Meites S (ed): Pediatric Clinical Chemistry: Reference Normal Values, ed 3. Washington, DC: AAAC Press, 1989. 37. Melnyk AR, Matalon R, Henry B, et al: Prospective management of a child with neonatal citrullinemia. J Pediatr 1993;122:96-98. 38. Oechsner M, Steen C, Sturenburg HJ, Kohlschutter A: Hyperammonaemic encephalopathy after initiation of valproate therapy in unrecognized ornithine transcarbamylase deficiency. J Neurol Neurosurg Psychiat 1998;64:680-682. 39. Ohtani Y, Ohyanagi K, Yamamoto S, Matsuda I: Secondary carnitine deficiency in hyperammonemic attacks of ornithine transcarbamylase deficiency. J Pediatr 1988;112:409-414. 40. Posati LP, Orr ML: Composition of Foods: Dairy and Egg Products, Agriculture Handbook No. 8-1. Washington, DC: US Dept of Agriculture, Agricultural Research Service, 1976. 41. Prasad AN, Breen JC, Ampola MG, Rosman P: Argininemia: A treatable genetic cause of progressive spastic diplegia stimulating cerebral palsy. Case reports and literature review. J Child Neurol 1997;12:301-309. 42. Pridmore CL, Clarke JTR, Blaser S: Ornithine transcarbamylase deficiency in females: An often overlooked cause of treatable encephalopathy. J Child Neurol 1995;10:396-374. 43. Sanjurjo P, Rodriguez-Soriano J, Vallo A, Rubio V. Neonatal citrullinemia with satisfactory mental development. Eur J Pediatr 1991;150:730-731. 44. Schoeffer A, Herrmann ME, Broesicke HG, Moench E: Effect of dosage and timing of amino acid mixtures on nitrogen retention in patients with phenylketonuria. J Nutr Med 1994;4 :415-418. 45. Sewell AC, Bohles HJ, Herwig J, Demirkol M: Neurological deterioration in patients with urea cycle disorders under valproate therapy - a cause for concern. Eur J Pediatr 1995;154:593-594. 46. Smith CA, Nelson NM: The Physiology of the Newborn Infant, ed 4. Springfield, IL: Charles C Thomas Publisher, 1976. 47. Smith JL, Heymsfield SB: Enteral nutrition support: Formula preparation from modular ingredients. JPEN 1983;7:280-288. 48. Snyderman SE, Holt LE, Dancis J, et al: "Unessential" nitrogen: A limiting factor for human growth. J Nutr 1962;78:57-52. 49. Spika JS, Shaffer N, Hargrett-Bean N, et al: Risk factors for infant botulism in the United States. Am J Dis Child 1989;143:828-832. 50. Tamura S, Kawata S, Fukuda K, et al: Effects of glucagons on urinary excretion of urea and on plasma ammonia level in argininosuccinate synthetase deficiency. J Gastroenterol 1994;29:31-34. 51. Torun B, Chew F: Protein-energy malnutrition. In Shils ME, et al (eds): Modern Nutrition in Health and Disease, ed 9. Philadelphia: Williams & Wilkins, 1999, pp 963-1001. 52. Tuchman M, Yudkoff M: Blood levels of ammonia and nitrogen scavenging amino acids in patients with inherited hyperammonemia. Mol Genet Metab 1999;66;10-15. 53. Vasudevan S, Qureshi IA, Lambert M, et al: Nucleotide pool imbalances in the livers of patients with urea cycle disorders associated with increased levels of orotic aciduria. Biochem Molec Biol Int'l 1995;35:685-690. 54. Wannemacher RW: Key role of various individual amino acids in host response to infection. Am J Clin Nutr 1977;30:1269-1280. 55. Wong LJC, Craigen WJ, O'Brien WE: Post-partum coma and death due to carbamoyl-phosphate synthetase I deficiency. Ann Int Med 1994;120;216-217. 56. Zeman FJ: Clinical Nutrition and Dietetics, ed 2. New York: MacMillan Publishing Co, 1991.
APPENDICES
Page Nutrient Composition Tables APPENDIX 1. Fatty Acid Profile of Infant/Toddler Metabolic Medical Foods........................................A-2 APPENDIX 2. Fatty Acid Profile of Child/Adult Metabolic Medical Foods ............................................A-2 APPENDIX 3. Density of Metabolic Medical Foods..............................................................................A-3 APPENDIX 4. Nutrient Composition of Alimentum Protein Hydrolysate Formula With Iron...............A-4 APPENDIX 5. Nutrient Composition of Isomil Soy Formula With Iron ..............................................A-5 APPENDIX 6. Nutrient Composition of Similac With Iron Infant Formula .........................................A-6 APPENDIX 7. Nutrient Composition of NeoSure and Similac Lactose Free..................................A-7 APPENDIX 8. Nutrient Composition of Mature Human Milk, Skim Milk, Whole Cow's Milk, and Whole Egg..........................................................................................................A-8 APPENDIX 9. Nutrient Composition of Polycose Glucose Polymers and Pedialyte Oral Electrolyte Maintenance Solution .........................................................................A-9 APPENDIX 10. Nutrient Composition of Selected Vegetable Oils........................................................A-9 APPENDIX 11. Nutrient Composition of Vi-Daylin Multivitamin + Iron Drops and Pro-Phree Protein-Free Energy Module with Iron, Vitamins, and Minerals and ....................A-10 APPENDIX 12. Nutrient Composition of Very-Low-Protein Foods per 100 g. .....................................A-11 Recommended Dietary Intakes APPENDIX 13. Recommended Dietary Intakes (RDIs) for Minerals and Vitamins by Infants .............A-14 APPENDIX 14. Recommended Dietary Intakes (RDIs) for Minerals and Vitamins by Children, Adolescents, and Adults.....................................................................................A-15 Technical Information APPENDIX 15. Mathematical Formula for Interconversion of Plasma Amino Acids Between mol/L and mg/dL ..............................................................................................A-17 APPENDIX 16. Molecular Weights of Amino Acids ...........................................................................A-17 APPENDIX 17. Selected Laboratory Standards.................................................................................A-18 APPENDIX 18. Estimating Osmolarity of a Medical Food Mixture .....................................................A-20 APPENDIX 19. Approximate Osmolarity of Selected Foods ..............................................................A-21 APPENDIX 20. Potential Renal Solute Load of Medical Food Mixture ...............................................A-22 APPENDIX 21. NDC Numbers for Metabolic Medical Foods .............................................................A-23 Clinical Forms APPENDIX 22. Diet Guide ................................................................................................................A-24 APPENDIX 23. Evaluation of Mineral/Vitamin Content of Medical Food Mixture ...............................A-25 APPENDIX 24. Diet Diary .................................................................................................................A-26 APPENDIX 25. Directions for Recording the Diet Diary .....................................................................A-27 Supplier Information APPENDIX 26. Sources of Nutrients and Drugs ................................................................................A-28 APPENDIX 27. Low-Protein Food Suppliers......................................................................................A-29 APPENDIX 28. Products for Prescription Diet Management ..............................................................A-29
A-1
APPENDIX 1. Fatty Acid Profile of Infant/Toddler Metabolic Medical Foods

Infant/Toddler Metabolic Medical Foods 1, 2 Pro-Phree Cyclinex-1 Others 3 g/100 g Pwd % of Energy g/100 g Pwd % of Energy g/100 g Pwd % of Energy Caprylic (8:0) 0.78 1.38 0.69 1.22 0.60 1.12 Capric (10:0) 0.57 1.01 0.50 0.88 0.44 0.82 Lauric (12:0) 4.17 7.36 3.66 6.46 3.21 6.02 Myristic (14:0) 1.61 2.84 1.41 2.49 1.24 2.32 Palmitic (16:0) 2.20 3.88 1.93 3.41 1.70 3.19 Palmitoleic (16:1) 0.02 < 0.04 0.02 < 0.04 0.01 < 0.02 Margaric (17:0) 0.01 < 0.02 0.01 < 0.02 0.01 < 0.02 Stearic (18:0) 1.53 2.70 1.34 2.36 1.21 2.27 Oleic (18:1) 9.42 16.62 8.28 14.61 7.30 13.69 Linoleic (18:2) 5.49 9.69 5.08 8.96 4.47 8.38 0.56 0.99 0.51 0.90 0.45 0.84 -Linolenic (18:3) Arachidic (20:0) 0.08 0.14 0.07 0.12 0.06 0.11 Eicosenoic (20:1) 0.05 0.09 0.04 0.07 0.04 0.08 Behenic (22:0) 0.06 0.11 0.06 0.11 0.05 0.09 Lignoceric (24:0) 0.03 0.05 0.03 0.05 0.02 < 0.04 Nervonic (24:1) 0.02 < 0.04 0.02 < 0.04 0.02 < 0.04 Total saturated 11.04 19.48 9.69 17.12 8.54 16.00 Total monounsaturated 9.51 16.78 8.36 14.76 7.37 13.83 Total polyunsaturated 6.05 10.68 5.59 9.86 4.92 9.22 1 Oil blend: 29% soy, 35% coconut, 36% high-oleic safflower oils 2 Analytical data at manufacture. 3 Glutarex-1, Hominex-1, I-Valex-1, Ketonex-1 , Phenex-1, Propimex-1, and Tyrex -1 Amino Acid Modified Medical Foods with Iron. Fatty Acid
APPENDIX 2. Fatty Acid Profile of Child/Adult Metabolic Medical Foods

Child/Adult Metabolic Medical Foods 1, 2 Cyclinex-2 Others 3 Phenex2 Flavored g/100 g Pwd % of Energy g/100 g Pwd % of Energy g/100 g Pwd % of Energy Caprylic (8:0) 0.48 0.98 0.39 0.86 0.38 0.83 Capric (10:0) 0.35 0.72 0.28 0.61 0.27 0.59 Lauric (12:0) 2.53 5.18 2.08 4.57 2.01 4.41 Myristic (14:0) 0.98 2.00 0.80 1.76 0.77 1.69 Palmitic (16:0) 1.33 2.72 1.10 2.41 1.06 2.33 Palmitoleic (16:1) 0.01 0.02 0.01 0.02 < 0.01 0.02 Margaric (17:0) < 0.01 < 0.02 < 0.01 0.02 < 0.01 0.02 Stearic (18:0) 0.93 1.90 0.76 1.67 0.74 1.62 Oleic (18:1) 5.72 11.70 4.71 10.34 4.55 9.99 Linoleic (18:2) 3.33 6.81 2.75 6.04 2.66 5.84 0.34 0.70 0.28 0.61 0.27 0.59 -Linolenic (18:3) Arachidic (20:0) < 0.01 < 0.02 0.04 0.09 0.04 0.09 Eicosenoic (20:1) 0.03 0.06 0.04 0.09 0.04 0.09 Behenic (22:0) 0.04 0.08 0.03 0.07 0.03 0.07 Lignoceric (24:0) 0.02 0.04 0.01 0.02 0.01 0.02 Nervonic (24:1) 0.01 0.02 0.01 0.02 0.01 0.02 Total saturated 6.68 13.66 5.50 12.08 5.32 11.67 Total monounsaturated 5.77 11.80 4.75 10.47 4.61 10.12 Total polyunsaturated 3.67 7.51 3.03 6.65 2.93 6.43 1 Oil blend: 29% soy, 35% coconut, 36% high-oleic safflower oils. 2 Analytical data at manufacture. 3 Glutarex-2; Hominex-2; I-Valex-2; Ketonex-2; Phenex-2, unflavored; Propimex-2; and Tyrex-2 Amino Acid Modified Medical Foods. Fatty Acid
A-2 2001 Ross Products Division
APPENDIX 3. Density of Metabolic Medical Foods
Product Infant/Toddler Calcilo XD Low-Calcium/Vitamin D-Free Infant Formula With Iron Cyclinex -1 Amino Acid Modified Medical Food With Iron Glutarex-1 Amino Acid Modified Medical Food With Iron Hominex-1 Amino Acid Modified Medical Food With Iron I-Valex-1 Amino Acid Modified Medical Food With Iron Ketonex-1 Amino Acid Modified Medical Food With Iron Phenex-1 Amino Acid Modified Medical Food With Iron Pro-Phree Protein-Free Energy Module With Iron, Vitamins & Minerals Propimex-1 Amino Acid Modified Medical Food With Iron ProViMin Protein-Vitamin-Mineral Component With Iron RCF Carbohydrate Free Soy Formula Base With Iron Tyrex-1 Amino Acid Modified Medical Food With Iron Child/Adult Cyclinex-2 Amino Acid Modified Medical Food Glutarex-2 Amino Acid Modified Medical Food Hominex-2 Amino Acid Modified Medical Food I-Valex-2 Amino Acid Modified Medical Food Ketonex 2 Amino Acid Modified Medical Food Phenex-2 Amino Acid Modified Medical Food, flavored Phenex-2 Amino Acid Modified Medical Food, unflavored Propimex -2 Amino Acid Modified Medical Food Tyrex -2 Amino Acid Modified Medical Food
1
g/mL Powder
0.52 0.55 0.59 0.58 0.58 0.56 0.56 0.52 0.57 0.19 1.01/mL1 0.59
0.40 0.52 0.46 0.51 0.54 0.48 0.47 0.54 0.46
Concentrated liquid.
A-3
APPENDIX 4. Nutrient Composition of Alimentum Protein Hydrolysate Formula With Iron

Nutrient Energy, kcal Protein equiv, g 1 Amino acids, g Arginine, mg Cystine, mg Glycine, mg Histidine, mg Isoleucine, mg Leucine, mg Lysine, mg Methionine, mg Phenylalanine, mg Threonine, mg Tryptophan, mg Tyrosine, mg Valine, mg Other Nitrogen-Containing Compounds Carnitine, mg Taurine, mg Carbohydrate, g 2 Fat, g Linoleic acid, g -Linolenic acid, g Minerals Calcium, mg Chloride, mg/mEq Copper, mg Iodine, g Iron, mg Magnesium, mg Manganese, mg Phosphorus, mg Potassium, mg/mEq Selenium, g Sodium, mg/mEq Zinc, mg Vitamins A, g RE D, g E, mg -TE K, g Ascorbic acid, mg Biotin, g B6, mg B12, g Choline, mg Folate, g Inositol, mg Niacin equiv, mg Pantothenic acid, mg Riboflavin, mg Thiamin, mg
1 2
Ready To Feed (per 100 mL) 68 1.86 2.07 77 32 50 53 108 173 163 54 86 88 25 29 140 1.26 5.49 6.9 3.75 1.28 0.066 71 54/1.5 0.05 10 1.22 5.1 0.005 51 80/2.0 1.86 30/1.3 0.51 61 0.76 1.36 10 6.1 3.0 0.04 0.30 5.4 10 3.4 1.33 0.51 0.06 0.04
Mean values. 33% of fat is fractionated coconut oil.
APPENDIX 5. Nutrient Composition of Isomil Soy Formula With Iron

Nutrient Energy, kcal 136 Protein, g 3.32 2 Amino acids, g 3.33 Arginine, mg 244 Cystine, mg 36 Glycine, mg 142 Histidine, mg 84 Isoleucine, mg 148 Leucine, mg 270 Lysine, mg 200 Methionine, mg 84 Phenylalanine, mg 176 Threonine, mg 128 Tryptophan, mg 42 Tyrosine, mg 120 Valine, mg 152 Other Nitrogen-Containing Compounds Carnitine, mg 2.6 Taurine, mg 7.6 Carbohydrate, g 13.9 Fat, g 7.4 Linoleic acid, g 1.36 0.36 -Linolenic acid, g Minerals Calcium, mg 142 Chloride, mg/mEq 84/2.4 Copper, mg 0.10 Iodine, g 20 Iron, mg 2.4 Magnesium, mg 10 Manganese, mg 0.04 Phosphorus, mg 101 Potassium, mg/mEq 146/3.73 Selenium, g 2.66 Sodium, mg/mEq 60/2.6 Zinc, mg 1.02 Vitamins A, g RE 122 D, g 2.0 2.7 E, mg -TE K, g 14.8 Ascorbic acid, mg 12.2 Biotin, g 6 B6, mg 0.08 B12, g 0.6 Choline, mg 10.8 Folate, g 20 Inositol, mg 6.8 Niacin equiv, mg 2.4 Pantothenic acid, mg 1.02 Riboflavin, mg 0.12 Thiamin, mg 0.08
1 2 3
Concentrate (per 100 mL) 516 12.60 12.96 970 154 540 334 578 1,021 754 319 675 493 163 464 582 9.9 28.8 52.8 28.0 5.16 1.37
Powder1 (per 100 g) 68 1.66 1.67 122 18 71 42 74 135 100 42 88 64 21 60 76 1.3 3.8 6.96 3.69 0.68 0.18
3
Ready To Feed (per 100 mL)
539 (697) 319/9.0 0.38 76 9.3 39 0.15 3 387 (464) 554/14.17 10.1 228/9.9 3.87 463 7.6 10.3 56.2 46.3 22.8 0.30 2.27 41 76 25.8 9.1 3.87 0.46 0.30
71 42/1.2 0.05 10 1.2 5.1 0.02 51 73/1.90 1.33 30/1.3 0.51 61 1.0 1.36 7.4 6.1 3.0 0.04 0.30 5.4 10 3.4 1.2 0.51 0.06 0.04
The weight per level unpacked scoop of Isomil Powder is 8.7 g. Mean values. Amount in parentheses is amount present in Isomil 2 powder/100 g.
A-5
APPENDIX 6. Nutrient Composition of Similac With Iron Infant Formula

Nutrient Energy, kcal 136 Protein, g 2.80 2 Amino acids, g 2.88 Arginine, mg 82 Cystine, mg 38 Glycine, mg 56 Histidine, mg 66 Isoleucine, mg 150 Leucine, mg 288 Lysine, mg 226 Methionine, mg 70 Phenylalanine, mg 118 Threonine, mg 154 Tryptophan, mg 44 Tyrosine, mg 116 Valine, mg 166 Other Nitrogen-Containing Compounds Carnitine, mg 1.4 Taurine, mg 8.0 Carbohydrate, g 14.6 Fat, g 7.30 Linoleic acid, g 1.36 0.14 -Linolenic acid, g Minerals Calcium, mg 106 Chloride, mg/mEq 88/2.4 Copper, mg 0.12 Iodine, g 8.2 Iron, mg 2.4 Magnesium, mg 8.2 Manganese, mg 0.007 Phosphorus, mg 56 Potassium, mg/mEq 142/3.6 Selenium, g 4.2 Sodium, mg/mEq 32.4/1.4 Zinc, mg 1.02 Vitamins A, g RE 122 D, g 2.02 1.5 E, mg -TE K, g 10.8 Ascorbic acid, mg 12.2 Biotin, g 6.0 B6, mg 0.08 B12, g 0.34 Choline, mg 21.6 Folate, g 20.2 Inositol, mg 6.4 Niacin equiv, mg 2.16 Pantothenic acid, mg 0.60 Riboflavin, mg 0.20 Thiamin, mg 0.13
1 2
Concentrate (per 100 mL) 526 10.83 11.05 325 162 217 262 573 1,079 895 273 465 583 174 450 641 5.6 33.0 55.06 28.15 5.13 0.53 400 332/9.4 0.45 30.9 9.2 30.9 0.023 211 536/13.7 15.8 122/5.3 3.85 459 7.62 5.8 41.0 46.0 22.6 0.30 1.28 81.5 76.2 24.1 8.14 2.26 0.75 0.53
Powder (per 100 g) 68 1.40 1.44 41 19 28 33 75 144 113 35 59 77 22 58 83 0.7 4.0 7.3 3.65 0.68 0.07 53 44/1.2 0.06 4.1 1.2 4.1 0.003 28 71/1.8 2.1 16.2/0.7 0.51 61 1.01 0.74 5.4 6.1 3.0 0.04 0.17 10.8 10.1 3.2 1.08 0.30 0.10 0.07
Ready To Feed (per 100 mL)
The weight per level unpacked scoop of Similac With Iron Powder is 8.5 g. Mean values.
APPENDIX 7. Nutrient Composition of Similac NeoSure Powder and Similac Lactose Free Powder
Nutrient Energy, kcal Protein, g 2 Amino acids, g Arginine, mg Cystine, mg Glycine, mg Histidine, mg Isoleucine, mg Leucine, mg Lysine, mg Methionine, mg Phenylalanine, mg Threonine, mg Tryptophan, mg Tyrosine, mg Valine, mg Other Nitrogen-Containing Compounds Carnitine, mg Taurine, mg Carbohydrate, g Fat, g Linoleic acid, g -Linolenic acid, g Minerals Calcium, mg Chloride, mg/mEq Copper, mg Iodine, g Iron, mg Magnesium, mg Manganese, mg Phosphorus, mg Potassium, mg/mEq Selenium, g Sodium, mg/mEq Zinc, mg Vitamins A, g RE D, g E, mg -TE K, g Ascorbic acid, mg Biotin, g B6, mg B12, g Choline, mg Folate, g Inositol, mg Niacin equiv, mg Pantothenic acid, mg Riboflavin, mg Thiamin, mg 1 g/scoop 513 13.3 13.73 389 207 262 299 688 1,335 1,105 336 522 769 217 555 743 34 54 52.9 28.2 4.98 0.54 539 385/10.9 0.62 77 9.2 46 0.05 318 729/18.7 23 170/7.4 6.2 709 8.99 12.4 56 77 46 0.51 2.06 82 128 31 13.63 4.11 0.77 1.13 9.6 NeoSure Powder (100 g)
1
Similac Lactose-Free Powder (100 g) 519 11.1 11.75 384 87 226 298 515 1,128 920 313 549 515 156 580 642 10 42 55.5 28.0 5.61 0.51 436 337/9.5 0.47 47 9.4 31 0.03 291 555/14.2 15 156/6.8 3.9 468 7.80 10.5 42 47 23 0.31 1.30 83 78 22 8.05 2.34 0.78 0.52 8.6
A-7
APPENDIX 8. Nutrient Composition of Mature Human Milk, Skim Milk, Whole Cow's Milk, and Whole Egg
Nutrient Mature Human Milk (per 100 mL) 72 1.07
1
Skim Milk (per 100 mL) 36 3.53 127 33 75 95 213 346 280 89 171 159 50 171 236 NA NA 5.02 0.19 0.005 0.002 127 103/2.90 0.010 1.8 0.04 11 0.002 105 172/4.4 2.17 54/2.3 0.41 63 1.06 0.04 NA 1.01 1.6 0.04 0.39 NA 5.18 NA 0.92 0.34 0.14 0.04
Energy, kcal Protein, g 3 Amino acids, g Arginine, mg 45 Cystine, mg 20 Glycine, mg 27 Histidine, mg 24 Isoleucine, mg 58 Leucine, mg 99 Lysine, mg 71 Methionine, mg 22 Phenylalanine, mg 48 Threonine, mg 48 Tryptophan, mg 18 Tyrosine, mg 55 Valine, mg 66 Other Nitrogen-Containing Compounds 3 Carnitine, mg 1.0 4 Taurine, mg 5.0 Carbohydrate, g 7.18 Fat, g 4.56 Linoleic acid, g 0.39 0.05 -Linolenic acid, g Minerals Calcium, mg 34 Chloride, mg/mEq 42/1.2 Copper, mg 0.05 Iodine, g 11 Iron, mg 0.03 Magnesium, mg 3.5 Manganese, mg 0.027 Phosphorus, mg 14 Potassium, mg/mEq 53/1.36 Selenium, g 1.87 Sodium, mg/mEq 18/0.8 Zinc, mg 0.18 Vitamins A, g RE 67 D, g 0.10 1.00 E, mg -TE K, g 0.21 Ascorbic acid, mg 5.21 Biotin, g 0.4 B6, mg 0.011 B12, g 0.047 Choline, mg 9 Folate, g 5.4 7 Inositol, mg 14.97 Niacin equiv, mg 0.48 Pantothenic acid, mg 0.23 Riboflavin, mg 0.038 Thiamin, mg 0.015
Whole Cow's Milk (per 100 mL) 63 3.39 123 31 72 92 205 332 269 86 164 154 47 164 227 4.0 15.0 4.81 3.46 0.08 0.05 123 105/3.0 0.010 5 37 0.05 13.9 0.004 96 156/4 2.06 50/2.2 0.39 32 1.03 0.103 6.5 0.97 3.65 0.04 0.37 20.5 5.16 7 4.15 0.87 0.32 0.17 0.04
Whole Egg (per 50 g) 74 6.24 375 148 210 147 341 533 449 195 332 300 76 255 380 NA NA 0.61 5.01 0.57 0.02 24 84/2.4 0.007 3 13 0.72 5.0 0.012 89 60.5/1.55 15.4 63/2.74 0.55 96 0.65 0.52 NA 0.0 10.05 0.07 0.50 264.5 24 4.55 1.31 0.63 0.25 0.03
NA = Not available.
References
1. 2. 3. 4. 5. 6. 7. American Academy of Pediatrics Committee on Nutrition: Pediatric Nutrition Handbook, ed 2. Elk Grove Village, IL: American Academy of Pediatrics, 1985. Posati LP, Orr ML: Composition of Foods: Dairy and Egg Products. Agriculture Handbook No. 8-1. US Dept of Agriculture, Agricultural Research Service, 1976. Penn D, Dolderer M, Schmidt-Sommerfeld E: Carnitine concentrations in the milk of different species and infant formulas. Biol Neonat 1987;52:70. Rana SK, Sanders TAB: Taurine concentrations in the diet, plasma, urine, and breast milk of vegans compared with omnivores. Br J Nutr 1986;56:17. Pennington JAT: Food Values of Portions Commonly Used, ed 15. New York: Harper & Row Publishers, 1989. Scherz H, Kloos G: Food Composition and Nutrition Tables 1981/1982. Stuttgart: Wissenschaftliche, Verlagsgesellschaft mbH, 1981. Ogasa K, Kuboyama M, Kiyosawa I, et al: The content of free and bound inositol in human and cow's milk. J Nutr Sci Vitaminol 1975;21:129.
APPENDIX 9. Nutrient Composition of Polycose Glucose Polymers and Pedialyte Oral Electrolyte Maintenance Solution
Nutrient Polycose Powder1 (per 100 g) Polycose Liquid (per 100 mL) Pedialyte (per 100 mL) 10 2.5 0 122/3.5 0 78/2.0 103/4.5
Energy, kcal 380 200 Carbohydrate, g 94 50 Calcium, mg 30 20 Chloride, mg/mEq 223/6.3 140/3.9 Phosphorus, mg 12 3 Potassium, mg/mEq 10/0.3 6/0.15 Sodium, mg/mEq 110/4.8 70/3.0 1 Approximate weights of Polycose Powder in level, dry US standard household measures: 1 Tbsp = 6g 1/4 cup = 25 g 1/3 cup = 33 g 1/2 cup = 50 g 1 cup = 100 g
APPENDIX 10. Nutrient Composition of Selected Vegetable Oils

Nutrient Canola 3, 4 (per 100 mL) 825 93 19 8.7 Coconut (per 100 mL) 807 93 2 0 Vegetable Oils Peanut 4 (per 100 mL) 796 90 29 0
1, 2
Energy, kcal Fat, g Linoleic acid, g
-Linolenic acid, g 1 1 Tbsp = 15 mL. 2 Reeves JB, Weihrauch JL: Composition of Foods: Fats and Oils. Agriculture Handbook No. 8-4. US Dept of Agriculture: Agricultural Research Service, 1979. 3 Available commercially as Puritan Oil, canola oil. 4 Tightly close and refrigerate all oils after opening. Oils containing large amounts of -linolenic acid oxidize rapidly and, after oxidation, are no longer bioactive.
Soybean 4 (per 100 mL) 802 91 46 6
Walnut 4 (per 100 mL) 802 91 48 9.4
A-9
APPENDIX 11. Nutrient Composition of Vi-Daylin Multivitamin + Iron Drops and Pro-Phree Protein-Free Energy Module with Iron, Vitamins, and Minerals
Nutrient Vi-Daylin Pro-Phree1 Multivitamin + Iron Drops (per 100 g) (1 mL) 0 510 0 trace
Energy, kcal Protein Equivalent, g Nitrogen-Containing Compounds 3 Carnitine, mg 0 25 Taurine, mg 0 50 0 65 Carbohydrate, g 0 28 Fat, g Linoleic acid, g 0 2.70 -linolenic acid, g 0 0.48 Minerals Calcium, mg 0 750 Chloride, mg/mEq 0 350/9.9 Copper, mg 0 1.45 Iodine, g 0 80 Iron, mg 10.0 11.9 Magnesium, mg 0 70 Manganese, mg 0 0.70 Phosphorus, mg 0 525 Potassium, mg/mEq 0 875/22.4 Selenium, g 0 30 Sodium, mg/mEq 0 250/10.9 Zinc, mg 0 11 Vitamins A, g RE 450 600 D, g 10 7.5 3.4 12.8 E, mg -TE K, g 0 60 Ascorbic acid, mg 35 70 Biotin, mg 0 0.08 B6, mg 0.4 0.97 B12, g 0 6.5 Choline, mg 0 100.0 Folate, g 0 300.0 Inositol, mg 0 50.0 Niacin,2 mg 8 14.0 Pantothenic acid, mg 0 7.0 Riboflavin, mg 0.6 1.0 Thiamin, mg 0.5 2.1 1 Approximate packed weight of Pro-Phree in level, dry US standard household measures: 1 Tbsp = 7g 1/4 cup = 29 g 1/3 cup = 38 g 1/2 cup = 57 g 1 cup = 107 g 2 Preformed niacin.
2001 Ross Products Division A-11
APPENDIX 12. Nutrient Composition of Very-Low-Protein Foods per 100 g
Food Aproten Foods Cracker toast dp Baking mix, low protein dp Chocolate chip cookies Pasta, uncooked Rusks Wheat Starch Dietary Specialties Breads bread machine mix dinner rolls rye-wheat bread wheat starch bread Cheese imitation sauce mix powder slices Chocolate bon ons Chocolate sauce mix Cookies butterscotch chocolate tea coconut ginger orange Fruit products cassava chips plantain chips Graham cracker Grains, uncooked Porridge Rice, imitation Pasta, uncooked Pizza shells
Protein (g) 1.7 0.3 0.8 0.5 0.8 0.5
Fat (g) 4.4 9.4 22.9 0.9 7.2 0.1
Energy (kcal) 398 410 497 360 420 350
ARG (mg) 100 20 30 30 30 30
CYS (mg) 20 5 10 9 10 9
HIS (mg) 40 6 10 10 10 10
ILE (mg) 50 4 70 10 30 10
LEU (mg) 10 8 10 50 50 50
LYS (mg) 80 8 20 20 40 20
MET (mg) 30 1 2 10 10 10
PHE (mg) 60 5 10 20 30 20
THR (mg) 60 3 20 10 30 10
TRP (mg) 20 3 10 5 10 5
TYR (mg) 30 3 3 10 20 10
VAL (mg) 70 10 10 20 30 20
0.3 0.5 0.8 0.4 2.2 6.0 3.5 2.2 0.2 0.6 0.7 0.8 0.3 0.3 1.7 2.4 0.5 0.3 0.3 0.3 0.7
6.0 3.5 3.0 4.4 20.0 26.0 26.3 11.5 3.0 22.9 19.0 23.0 11.0 20.0 26.7 38.0 20.3 1.0 1.0 1.0 5.3
351 246 200 242 267 482 316 436 375 500 482 503 412 489 520 571 473 360 360 360 368
20 30 40 10 80 170 120 100 10 20 30 60 10 10 160 190 30 10 10 10 30
5 9 10 8 30 110 30 20 4 8 10 10 6 7 30 30 9 6 6 6 9
7 10 10 9 50 110 90 50 3 10 10 20 8 9 20 110 10 8 8 8 10
10 20 30 10 120 190 170 100 4 30 20 30 10 10 30 60 10 9 9 8 20
20 40 50 20 220 320 270 180 6 60 60 90 30 40 40 100 30 20 20 20 40
10 40 40 9 160 460 290 130 6 40 20 20 6 7 50 110 20 8 8 8 20
10 10 10 7 50 90 80 40 2 10 10 10 6 7 10 30 10 3 3 3 9
10 20 30 10 90 150 150 100 4 30 30 40 10 10 30 80 20 10 10 10 20
10 20 30 10 120 370 180 90 4 20 20 20 9 10 30 60 10 8 8 8 10
3 7 9 5 20 90 40 30 3 9 7 4 1 1 20 20 5 2 2 2 5
10 10 20 10 80 120 160 90 2 20 20 20 10 10 20 50 10 10 10 10 10
10 20 40 20 80 260 190 140 5 40 30 40 10 10 40 80 20 10 10 10 30
Food Tomato sauce Ener-G Foods Breads mix rice rice starch wheat starch Cheese, cheddar or mozzarella Cookies lemon sandwich lemon shortbread orange shortbread Egg replacer Flour potato starch rice starch tapioca Gel mix banana chocolate lemon lime orange raspberry strawberry Ice cream cone Pizza shells Potato chips mix Pumpkin donut Waffles Kingsmill Foods Cake base Cookies chocolate chip
Protein Fat (g) (g) 2.8 2.0
Energy ARG CYS HIS ILE LEU LYS MET PHE THR TRP TYR VAL (kcal) (mg) (mg) (mg) (mg) (mg) (mg) (mg) (mg) (mg) (mg) (mg) (mg) 360 270 20 40 40 80 110 20 70 60 20 30 80
0.3 0.3 0.4 0.5 1.9 0.2 0.2 0.4 0.1 0.1 0.8 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.1 1.7 0.7 0.1 0.8 0.2
0.1 8.7 9.5 5.0 20.0 21.0 21.5 19.2 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 2.9 13.6 49.0 0.0 14.0 7.0
376 325 334 257 279 486 476 469 375 320 375 396 372 344 367 383 361 370 372 396 320 641 380 304 248
8 10 10 10 100 10 10 10 4 7 40 10 0 0 0 0 0 0 0 10 3 40 7 40 20
7 5 7 8 10 4 2 10 1 1 7 2 0 0 0 0 0 0 0 2 7 10 1 5 1
4 7 8 8 80 3 2 5 1 2 8 2 0 0 0 0 0 0 0 2 10 10 2 10 8
6 5 10 10 140 4 6 10 1 2 20 2 0 0 0 0 0 0 0 2 10 20 2 20 10
10 10 30 20 280 6 10 10 3 4 40 3 0 0 0 0 0 0 0 3 20 40 4 30 30
9 10 20 20 220 6 6 5 3 5 20 3 0 0 0 0 0 0 0 3 20 20 5 30 10
3 6 4 4 60 2 3 3 1 1 10 1 0 0 0 0 0 0 0 1 9 6 1 10 8
6 10 10 10 150 4 8 10 2 4 30 2 0 0 0 0 0 0 0 2 10 20 3 20 20
6 10 10 10 110 4 5 10 1 2 10 2 0 0 0 0 0 0 0 2 10 10 2 20 10
3 3 4 4 30 3 2 10 1 1 6 2 0 0 0 0 0 0 0 2 4 10 1 9 1
2 6 4 9 120 2 7 5 1 2 20 1 0 0 0 0 0 0 0 2 5 10 2 30 10
9 10 20 10 180 5 8 10 3 4 30 3 0 0 0 0 0 0 0 3 20 20 4 30 20
0.3 0.8
8.8 20.0
353 500
10 30
6 10
6 10
10 20
6 50
5 10
5 10
10 30
7 20
3 9
8 20
10 30
Food orange wheat base Egg replacer Gel dessert, prepared Unimix baking mix Wheat starch LOPROFIN Baking mix Biscuits chocolate sweet Crackers Pasta, uncooked Wafers, cream Wel-Plan Foods Baking Mix Pasta, uncooked Miscellaneous Almond Bark butterscotch chocolate white Prono gel mix Schreiber Cheeses, imitation Cheddar slices Whitehall Cheeses, imitation
Protein (g) 0.6 1.2 0.4 0.0 0.3 0.3
Fat (g) 20.5 17.0 1.0 0.1 4.9 0.2
Energy (kcal) 500 454 350 72 222 356
ARG (mg) 10 40 10 0 10 10
CYS (mg) 10 20 9 0 6 6
HIS (mg) 10 20 10 0 6 6
ILE (mg) 10 30 10 0 10 10
LEU (mg) 30 70 60 1 10 10
LYS (mg) 10 20 8 0 6 6
MET (mg) 8 10 10 0 5 5
PHE (mg) 20 40 20 1 10 10
THR (mg) 10 20 10 0 7 7
TRP (mg) 6 10 2 0 4 3
TYR (mg) 10 30 10 0 10 8
VAL (mg) 10 40 20 0 10 10
0.3 0.5 0.4 0.4 0.4 0.1
0.1 27.0 22.0 14.5 1.0 33.0
355 521 496 444 360 557
10 3 4 8 10 7
5 3 3 4 7 4
5 3 3 4 60 4
7 5 5 8 10 5
10 10 10 20 20 10
10 2 2 6 10 3
4 3 4 4 5 2
9 8 7 10 10 7
8 5 5 7 8 6
4 2 2 1 1 1
6 4 4 7 6 3
10 9 9 10 10 8
0.3 0.4
1.5 0.7
339 360
10 20
5 7
5 10
4 10
8 30
5 10
1 7
50 10
6 10
3 4
30 10
10 10
0.0 1.2 0.0 0.0 1.4 4.2 3.7
28.8 28.9 28.3 0.0 15.7 15.8 26.3
529 518 526 390 275 263 300
0 59 0 0 40 150 140
0 13 0 0 20 100 50
0 18 0 0 30 110 90
0 40 0 0 70 230 200
0 63 0 0 130 410 360
0 52 0 0 100 320 300
0 11 0 0 20 100 90
0 50 0 0 50 180 160
0 41 0 0 70 210 180
0 15 0 0 10 50 40
0 39 0 0 40 170 150
0 62 0 0 80 250 210
APPENDIX 13. Recommended Dietary Intakes (RDIs) for Minerals and Vitamins by Infants
Nutrient Minerals Calcium, mg Chloride, mEq Copper, mg Iodine, g Iron, mg
2
Recommended Intake for Age 0 to <6 mo 400 8 - 20 0.5 - 0.7 40 10 50 0.5 - 0.7 300 9. - 24 15 5 - 15 5 600 11 - 34 0.7 - 1.0 50 15 75 0.7 - 1.0 500 11. - 33 20 11 - 33 5
6 to <12 mo
Magnesium, mg Manganese, mg Phosphorus, mg Potassium, mEq Selenium, g Sodium, mEq Zinc, mg Vitamins A, g RE D, g E, mg -TE K, g Ascorbic acid, mg Biotin, g B6, mg B12, g Choline, mg Folate, g Inositol, mg Niacin equiv, mg Riboflavin, mg
1 3
420 5 4 5 40 35 0.3 0.5 125 65 4.8 6 2 0.4
400 5 6 10 50 50 0.6 1.5 150 80 4.6 8 3 0.6
Pantothenic acid, mg
Thiamin, mg 0.3 0.5 Modified from Food and Nutrition Board: Recommended Dietary Allowances, eds 9 and 10. Washington, DC: National Academy of Sciences, 1980 and 1989 and Monsen ER: Dietary reference intakes for antioxidant nutrients: Vitamin C, vitamin E, selenium, and carotenoids. J Amer Diet Assoc 2000;100:637-640. 2 Iron needs of patients with PKU may be greater than RDAs (Gropper S, Acosta PB, Clarke-Sheehan N, et al: Trace element status of PKU children ingesting an elemental diet. JPEN 1987;11:287). 3 Niacin needs of patients with PKU are greater than RDAs (Lewis JS, Loskill S, Bunker ML, et al: N-Methylnicotinamide excretion of phenylketonuric children and a child with Hartnup disease before and after phenylalanine and tryptophan load. Fed Proc 1974;33:666A).
APPENDIX 14. Recommended Dietary Intakes (RDIs) for Minerals and Vitamins by Children, Adolescents, and Adults
Nutrient Recommended Intake for Age 1 7 to < 11 yr 11 to < 15 yr 15 to < 19 yr
1 to < 4 yr 4 to < 7 yr 19 to < 25 yr > 25 yr Minerals Calcium, mg 800 800 1,300 1,300 1,300 1,200 1,200 Chloride, mEq 14 - 43 20 - 60 26 - 79 40 - 120 40 - 120 49 - 146 49 - 146 Copper, mg 1.0 - 1.5 1.5 - 2.0 2.0 - 2.5 2.0 - 3.0 2.0 - 3.0 2.0 - 3.0 2.0 - 3.0 Iodine, g 70 90 120 150 150 150 150 Iron, mg 2,3 15 10 10 18 18 18 18 Magnesium, mg 150 200 250 410 410 410 420 Manganese, mg 1.0 - 1.5 1.5 - 2.0 2.0 - 3.0 2.5 - 5.0 2.5 - 5.0 2.5 - 5.0 2.5 - 5.0 Phosphorus, mg 800 800 1,250 1,250 1,200 1,200 800 Potassium, mEq 14 - 42 20 - 60 26 - 77 39 - 117 39 - 117 48 - 144 48 - 144 Selenium, g 20 30 40 55 55 55 55 Sodium, mEq 14 - 42 20 - 59 26 - 78 39 - 117 39 - 117 48 - 143 48 - 143 Zinc, mg 10 10 10 15 15 15 15 Vitamins A, g RE 400 500 700 1,000 1,000 1,000 1,000 D, g 5 5 5 5 5 5 5 6 7 11 15 15 15 15 E, mg -TE K, g 15 20 30 45 65 70 80 Ascorbic acid, mg 45 45 45 75 90 90 90 Biotin, g 65 85 120 120 120 120 120 B6, mg 0.9 1.3 1.6 1.8 2.0 2.2 2.2 B12, g 2.0 2.5 3.0 3.0 3.0 3.0 3.0 Choline, mg 200 250 375 550 550 550 550 Folate, g 150 200 300 400 400 400 400 Niacin equiv, mg 4 9 11 16 18 18 19 19 Pantothenic acid, mg 3.0 3.0 4.0 5.0 5.0 5.0 5.0 Riboflavin, mg 0.8 1.0 1.4 1.6 1.7 1.7 1.7 Thiamin, mg 0.7 0.9 1.2 1.4 1.4 1.5 1.5 1 Modified from Food and Nutrition Board: Recommended Dietary Allowances, eds 9 and 10. Washington, DC: National Academy of Sciences, 1980 and 1989 and Monsen ER: Dietary reference intakes for antioxidant nutrients: Vitamin C, vitamin E, selenium, and carotenoids. J Amer Diet Assoc 2000;100:637-640.. 2 Iron needs of patients with PKU may be greater than RDAs (Gropper S, Acosta PB, Clarke-Sheehan N, et al: Trace element status of PKU children ingesting an elemental diet. JPEN 1987;11:287). 3 Recommended iron intake for men 19 years of age is 10 mg/day. 4 Niacin needs of patients with PKU are greater than RDAs (Lewis JS, Loskill S, Bunker ML, et al: N-Methylnicotinamide excretion of phenylketonuric children and a child with Hartnup disease before and after phenylalanine and tryptophan load. Fed Proc 1974;33:666A).
Recommended Daily Intakes (RDIs) Protein requirements are greater than Recommended Dietary Allowances (RDAs) when L-amino acids are the primary protein source (2, 7 ). This increased need is due to rapid amino acid absorption and subsequent oxidation (8, 10), resulting in poor linear growth (5, 16), and lower than normal nitrogen retention (15) and body protein and nitrogen content of patients fed primarily L-amino acids (3). Recommended mineral and vitamin intakes suggested for patients with inherited metabolic disorders are the greatest intakes suggested for each age in the 1980, 1989, and 1998 National Academy of Sciences RDAs and Dietary Reference Intakes (7, 12, 17). Reasons for choosing the greatest recommended intakes include reports of inadequate linear growth (5, 16) and poor bone mineralization (11) with Food and Agriculture Organization/World Health Organization (FAO/WHO) recommended protein intakes (6); greater than normal energy needs when L-amino acids supply the bulk of protein equivalent (13) and depressed plasma concentrations of ferritin (4, 14), selenium (9), and zinc (1) when RDAs were achieved with chemically defined diets.
References
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. Acosta PB, Fernhoff PM, Warshaw HS, et al: Zinc status and growth of children undergoing treatment for phenylketonuria. J Inher Metab Dis 1982;5:107-110. Acosta PB, Yannicelli S: Protein intake affects phenylalanine requirements and growth of infants with phenylketonuria. Acta Paediatr 1994;Suppl 407:66-67. Allen JR, Baur LA, Waters DL, et al: Body protein in prepubertal children with phenylketonuria. Eur J Clin Nutr 1996;50:178-186. Bodley JL, Austin VJ, Hanley WB, et al: Low iron stores in infants and children with treated phenylketonuria: A population at risk for iron-deficiency anaemia and associated cognitive deficits. Eur J Pediatr 1993;152:140-143. Dhondt JL, Largilliere C, Moreno L, Farriaux JP: Physical growth in patients with phenylketonuria. J Inher Metab Dis 1995;18:135-137. FAO/WHO/UNU Expert Consultation: Energy and Protein Requirements. Geneva: World Health Organization, 1985. Food and Nutrition Board, Committee on Dietary Allowances: Recommended Dietary Allowances, eds 9 and 10. Washington, DC: National Academy of Sciences, 1980 and 1989. Gropper S, Acosta PB: Effect of simultaneous ingestion of L-amino acids and whole protein on plasma amino acids and urea nitrogen concentrations in humans. JPEN 1991;15:48-53. Gropper S, Acosta PB, Clarke-Sheehan N, et al: Trace element status of children with PKU and normal children. J Amer Diet Assoc 1988;88:459-464. Herrmann ME, Broesicke HG, Keller M, et al: Dependence of the utilization of a phenylalanine-free amino acid mixture on different amounts of single dose ingested. A case report. Eur J Pediatr 1994;153:501-503. Hillman L, Schlotzhauer C, Lee D, et al: Decreased bone mineralization in children with phenylketonuria under treatment. Eur J Pediatr 1996;155 (Suppl 1):S148-S152. Monsen ER: Dietary reference intakes for antioxidant nutrients: Vitamin C, vitamin E, selenium, and carotenoids. J Amer Diet Assoc 2000;100:637-640. Pratt EL, Snyderman SE, Cheung MW, et al: The threonine requirement of the normal infant. J Nutr 1955;56:231-251. Scaglioni S, Zucotti G, Vedovello M, et al: Study of serum ferritin in 58 children with classic phenylketonuria and persistent hyperphenylalaninemia. J Inher Metab Dis 1985;8:160. Schoeffer A, Herrmann ME, Broesicke HG, Moench E: Effect of dosage and timing of amino acid mixtures on nitrogen retention in patients with phenylketonuria. J Nutr Med 1994;4:415-418. Verkerk PH, van Spronsen JF, Smit GPA, Sengers RCA: Impaired prenatal and postnatal growth in Dutch patients with phenylketonuria. Arch Dis Child 1994;71:114-118. Yates AA, Schlicker SA, Suitor CW: Dietary reference intakes: The new basis for recommendations for calcium and related nutrients, B vitamins, and choline. J Amer Diet Assoc 1998;98;699-706.
APPENDIX 15. Mathematical Formula for Interconversion of Plasma Amino Acids Between mol/L and mg/dL Some laboratories report plasma amino acids in mg/dL while others use mol/L. Converting to either set of units may be accomplished readily using one of the following mathematical formulas:
mol/L
mg/dL x 104 MW
mg/dL
MW x mol/L 104
Where: MW = mol/L = mg/dL =
molecular weight of amino acid micromoles per liter milligrams per deciliter
APPENDIX 16. Molecular Weights of Amino Acids

Amino Acid Alanine Arginine Asparagine Aspartic acid Citrulline Cystine Glutamic acid Glutamine Glycine Histidine Homocystine Hydroxyproline Isoleucine Leucine Lysine Methionine Ornithine Phenylalanine Proline Serine Threonine Tryptophan Tyrosine Valine Molecular Weight 89.1 174.2 132.1 133.1 175.2 240.3 147.1 146.2 75.1 155.2 268.4 131.1 131.2 131.2 146.2 149.2 132.2 165.2 115.1 105.1 119.1 204.2 181.2 117.2
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APPENDIX 17. Selected Laboratory Standards

Parameter Albumin, plasma (g/dL) Infants and children Age of Patient Normal < 1 yr 1 to < 9 yr > 9 yr Trimester 1 Trimester 2 Trimester 3 All ages and during pregnancy All ages and during pregnancy 0 < 20 yr Trimester 1 Trimester 2 Trimester 3 6 mo to < 2 yr 2 to < 6 yr 6 to < 12 yr > 12 yr Trimester 1 Trimester 2 Trimester 3 All ages and during pregnancy 0 to < 5 yr 5 to < 8 yr 8 to < 12 yr > 12 yr Trimester 1 Trimester 2 Trimester 3 12 to < 15 yr 15 to < 18 yr >18 yr 4.00 - 5.00 3.50 - 5.00 3.50 - 5.00 > 4.00 > 3.75 > 3.50 22 > 300 150 - 200 150 - 250 150 - 350 200 - 400 > 30 > 40 > 50 > 50 > 50 > 40 > 30 > 200 < 300 > 11.0 > 11.5 > 12.0 > 12.0 > 12.0 > 12.0 > 12.0 > 12.5 > 13.0 > 14.0 Status 1 Marginal < 3.50 < 3.50 < 3.50 < 3.50 < 3.25 < 3.00 < 20 < 260 < 150 < 150 < 150 < 200 < 20 < 20 < 20 < 20 < 20 < 20 < 20 < 160 < 11.0 < 11.5 < 12.0 < 12.0 < 12.0 < 12.0 < 12.0 < 12.5 < 13.0 < 14.0
Deficient 3.00 3.00 3.00 < 3.00 < 2.75 < 2.50 < 15 < 200 < 120 < 120 < 120 < 150 < 12 < 12 < 12 < 12 < 12 < 12 < 12 < 120 < 10.0 < 10.5 < 11.0 < 11.0 < 11.0 < 11.0 < 11.0 < 11.5 < 12.0 < 13.0
Pregnant women
Transthyretin (mg/dL) B12, serum, (pg/mL) Cholesterol (mg/dL) Infants, children, young adults Pregnant women
Ferritin, plasma (ng/mL) Infants and children
Pregnant women
Folate, erythrocyte (ng/mL) Hemoglobin (Hgb) (g/dL) Infants and children
Girls and women Pregnant women
Boys and men
Hematocrit (Hct) (%) Infants and children
0 to < 2 yr < 33 < 30 > 33 2 to < 5 yr < 34 < 32 > 34 5 to < 8 yr < 35 < 33 > 35 8 to < 12 yr < 36 < 33 > 36 Girls and women 12 to < 18 yr < 36 < 33 > 36 < 37 < 33 >18 yr > 37 Pregnant women Trimester 1 < 36 < 33 > 36 Trimester 2 < 36 < 33 > 36 Trimester 3 < 36 < 33 > 36 Boys and men 12 to < 15 yr < 37 < 34 > 37 15 to < 18 yr < 38 < 36 > 38 < 40 < 39 > 18 yr > 40 1 Laboratory values vary based on method(s) of sample preparation and analyses. The above standards are considered guides. Local laboratory standards based on age, gender, and state of health should be developed.
REFERENCES
Ances G, Granados J, Baltazar M: Serum ferritin as an early determinant of decreased iron stores in pregnant women. South Med J 1979;72:591. Behrman RE, Kleigman RM, Arvin AA (eds): Nelson Textbook of Pediatrics, ed 12. Philadelphia: WB Saunders Co, 1996. Deinard AS, Schwartz S, Yip R: Developmental changes in serum ferritin and erythrocyte protoporphyrin in normal (nonanemic) children. Am J Clin Nutr 1983;38:71. Fredrickson DS, Goldstein JL, Brown MS: The familial hyperlipoproteinemias. In Stanbury JB, et al (eds): The Metabolic Basis of Inherited Disease, ed 4. New York: McGraw-Hill Book Co, 1978. Herbert VD: Folic acid. In Shils ME, et al (eds): Modern Nutrition in Health and Disease, ed 9. Baltimore: Williams & Wilkins, 1999. Ingenbleek Y, VanDenSchrieck VD, DeNayer P, DeVisscher M: Albumin, transferrin, and thyroxine binding prealbumin/retinol binding protein complex in assessment of malnutrition. Clin Chim Acta 1975;63:61. Lockitch G (ed): Handbook of Diagnosistic Biochemistry and Hematology in Normal Pregnancy. Boca Raton: CRC Press, 1993. Ongushina SO, Hussein MA: Plasma thyroxine binding prealbumin as an index of mild protein-energy malnutrition in Nigerian children. Am J Clin Nutr 1980;33:794. Soldin SJ, Brugnara C, Hicks JM: Pediatric Reference Ranges, ed 3. Washington, DC: AACC Press, 1999.
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APPENDIX 18. Estimating Osmolarity of a Medical Food Mixture Osmolarity (mosm/L) E A B C = = = = A+B+C+D
g Medical food x osmolarity/g (Appendix 19, p A-21). mL Infant formula or whole cow's milk x osmolarity/mL (Appendix 19, p A-21). mL or g Polycose Glucose Polymers or sugar x osmolarity/mL or osmolarity/g (Appendix 19, p A-21). g Supplemental amino acids x osmolarity/g (mosm/g amino acids = 1.25). mL Total volume of medical food mixture x 0.001 (1 fl oz = 29.57 mL).
D E
= =
Example
Formula 39 g Phenex-1 305 mL Similac With Iron RTF 16 mL Polycose Liquid Add water to make 540 mL Osmolarity B C A = = = 39 x 2.70 mosm/g 305 mL Similac x 0.274 mosm/mL 16 mL Polycose x 0.82 mosm/mL = = = = 0.54 201.99 0.54 = 374 mosm/L 105.30 83.57 13.12 201.99
Total of A + B + C E = 540 mL x 0.001 = =
Osmolarity
Estimated osmolarity
APPENDIX 19. Approximate Osmolarity of Selected Foods
Food
Approximate Osmolality (mosm/g)
Kcal/fl oz 20 24
27
(mosm/kg H O) 2
30
Infant/Toddler Alimentum, Ready to Feed Calcilo XD Cyclinex-1 Glutarex-1 Hominex-1 I-Valex-1 Ketonex-1 Phenex-1 Pro-Phree Propimex-1 ProViMin RCF, Concentrated Liquid Similac With Iron, Ready to Feed Similac With Iron, Concentrated Liquid Similac With Iron, Powder Isomil, Ready to Feed Isomil, Concentrated Liquid Isomil, Powder Tyrex-1 Child/Adult Cyclinex-2 Glutarex-2 Hominex-2 I-Valex-2 Ketonex-2 Phenex-2, flavored Phenex-2, unflavored Propimex-2 Tyrex-2 Whole Cow's Milk Polycose Liquid Polycose Powder Sugar 1 Mixed only with water.
0.339/mL 2.02 2.21 2.84 2.75 2.80 2.70 2.70 1.54 2.76 2.74 0.08/mL 0.274/mL 0.75/mL 2.84 0.218/mL 0.60/mL 2.46 2.74
--275 389 373 378 366 371 205 371 --------380
--352 476 463 470 451 453 247 470 --------461
--408 541 527 543 517 516 275 525 --------521
--452 616 601 608 588 587 305 606 --------593
4.24 5.28 5.18 5.36 5.10 4.78 4.98 5.23 5.13 0.30/mL 0.82/mL 1.60 2.90
615 830 813 847 805 775 782 834 809 -----
784 1032 1018 1038 999 938 965 1018 1001 -----
895 1201 1162 1216 1153 1070 1134 1172 1157 -----
1013 1360 1354 1395 1315 1216 1293 1354 1332 -----
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APPENDIX 20. Potential Renal Solute Load of Medical Food Mixture Because of the limited ability of infants to concentrate urine, fluid may not be retained when an infant is fed a formula with a high renal solute load; has a restricted water intake; or is suffering from a disease accompanied by an excessively high temperature. Any of these conditions may result in hypertonic dehydration if the renal solute load of the infant's formula is not changed. Approximate the renal solute load of a medical food mixture from its protein, sodium, potassium, phosphorus and chloride content. Nitrogen (as urea), sodium, chloride, potassium, and phosphorus not retained for growth or maintenance contribute most of the renal solute load that is excreted with water via the kidneys. Each gram of protein yields 5.7 mosm. Sodium, potassium, and chloride each yield 1 mosm/mEq. Each milligram of phosphorus yields 0.0323 mosm (mg P 31). The milliosmoles in the medical food mixture are estimated as follows: mosm Potential Renal Solute Load (PRSL) = (mg dietary protein 175) + mosm (Na + K + Cl + P) Consider the effect of both insensible and fecal water losses when calculating the effect of renal solute load on urine concentration. Fever and/or diarrhea may considerably increase these water losses. Approximate water losses by infants are 10 mL/kg/day in feces and 60 mL/kg/day of insensible loss. Estimate the urinary concentration by dividing the PRSL contributed to the diet by the water available for urine formation using the following formula:
mosm RSL/L
mosm in medical food mixture mL medical food mixture - (mL insensible + fecal water losses)
1,000
Reference
Fomon SJ, Ziegler EE: Water and renal solute load. In Fomon SJ (ed): Nutrition of Normal Infants. St. Louis: Mosby, 1993.
APPENDIX 21. NDC Numbers for Metabolic Medical Foods Pseudo-NDC Number 70074-0037-80 70074-0511-45 70074-0511-47 70074-0511-41 70074-0511-43 70074-0511-17 70074-0511-19 70074-0511-37 70074-0511-39 70074-0511-13 70074-0511-15 70074-0511-21 70074-0557-56 70074-0511-23 70074-0511-49 70074-0511-33 70074-0511-35 70074-0502-60 70074-0401-08 70074-0511-29 70074-0511-27
Product Calcilo XD Powder Cyclinex-1 Powder Cyclinex-2 Powder Glutarex-1 Powder Glutarex-2 Powder Hominex-1 Powder Hominex-2 Powder I-Valex-1 Powder I-Valex-2 Powder Ketonex-1 Powder Ketonex-2 Powder Phenex-1 Powder Phenex-2 Powder, flavored Phenex-2 Powder, unflavored Pro-Phree Powder Propimex-1 Powder Propimex-2 Powder ProViMin Powder RCF (Concentrate) Tyrex-1 Powder Tyrex-2 Powder Can Size 400 g 400 g 400 g 400 g 400 g 400 g 400 g 400 g 400 g 400 g 400 g 400 g 400 g 400 g 400 g 400 g 400 g 150 g 13 fl oz 400 g 400 g
A-23
APPENDIX 22. Diet Guide
Date: _________/_________/__________
Mo Day Year
Name:_______________________________________________________ Birthdate: __________/__________/__________

Mo Day Year
Age: __________ Weight: _______________ (kg or lb)
Length/Height: __________ (cm or in)

Medical Food Mixture Amount _____ (mg) _____________________ _____________________ _____________________ _____________________ _____________________ _____________________ _______ g _______ g _______ g/Tbsp _______ g/Tbsp _______ mL _______ mL ______ ______ ______ ______ ______ ______
_____ (mg) ______ ______ ______ ______ ______ ______
_____ (mg) ______ ______ ______ ______ ______ ______
_____ (mg) ______ ______ ______ ______ ______ ______
Protein (g) _______ _______ _______ _______ _______ _______
Energy (kcal) _______ _______ _______ _______ _______ _______
(_____________ mg/mL) Add water to make _______________________ mL (__________________ fl oz).
Food List
Servings
Breads/Cereals Fats Fruits Vegetables Free Foods A Free Foods B Total per day Total per kg
_______ _______ _______ _______ _______ _______
______ ______ ______ ______ ______ ______ ______ ______
______ ______ ______ ______ ______ ______ ______ ______
______ ______ ______ ______ ______ ______ ______ ______
______ ______ ______ ______ ______ ______ ______ ______
_______ _______ _______ _______ _______ _______ _______ _______
_______ _______ _______ _______ _______ _______ _______ _______
Comments:
__________________________________________ Nutritionist
APPENDIX 23. Evaluation of Mineral/Vitamin Content of Medical Food Mixture

Nutrient Name of Product(s) Amount of Product(s) Minerals Calcium, mg Chloride, mEq Copper, mg Iodine, g Iron, mg Magnesium, mg Manganese, mg Phosphorus, mg Potassium, mEq Selenium, g Sodium, mEq Zinc, mg g g mL Medical Food(s) Total Amount % RDI RDI
Vitamins A, g RE D, g E, mg -TE K, g Biotin, g B6, mg B12, g Ascorbic acid (C), mg Choline, mg Folacin, g Inositol, mg Niacin, mg NE Pantothenic acid, mg Riboflavin, mg Thiamin, mg Carnitine, mg Taurine, mg
A-25
APPENDIX 24. Diet Diary Name:________________________________________________________________________________ Date of Specimen: _______/_______/_______ Time of Specimen: ________1 Time of Last Meal: _________1
Mo Day Year
Date of Birth: _______/_______/_______ Weight: _______/_______ (lb/oz) Height: __________ (in)

Mo Day Year
Recorded By: ____________________________________________________ Please record below the food eaten for 3 consecutive days before obtaining a blood specimen. Medical Food Amount Mineral and/or Vitamin Supplements g g mL mL Tbsp Kind: Amount:
Add water to make ____________________ mL (_______________ fl oz).
Spaces Below for Clinic Use Time

1
Foods or Liquids Eaten (mg) (mg) (mg) (mg)
Protein (g)
Energy (kcal)
Totals
Remarks: Patient's appetite today was: Better Than Usual Usual Poor Patient was ill today: Yes No If yes, describe:_______________________________ If ill, was medication required? Yes No If ill, what was thermometer reading?________________ If yes, name and amount of medication prescribed:________________________________________________________ Did patient regurgitate food or formula? Yes No Does patient have diarrhea? Yes No 1 Record in 24-hour clock (1:00 PM = 13:00)
APPENDIX 25. Directions for Recording the Diet Diary
For greatest accuracy, weigh food on a scale that reads in grams. All measures are level. 1. Use US Bureau of Standards approved measuring cups and spoons for all servings. All measurements should be level. 2. Measuring utensils needed: a. 1 set standard measuring spoons b. 1 set standard measuring cups for nonliquid foods c. 1 standard glass measuring cup for liquids d. 1 quart measuring pitcher e. 1 standard ruler Equivalent measures are: 3 tsp = 16 Tbsp 1 fl oz = 1 jar 1st Fruits and Vegetables 1 jar 2nd and 3rd Fruits and Vegetables
3.
1 Tbsp = 1 cup 2 Tbsp = 4 1/2 oz = 7 1/2 oz
= =
9 Tbsp 15 Tbsp
4. At the time it is eaten, record the exact amount of all medical food mixture and beikost or table foods for 3 days before obtaining a blood specimen. 5. Record the following on the Diet Diary form: a. Prescription for the medical food mixture. b. Medical food mixture. 1) Amount consumed in mL or fl oz. c. Beikost (Baby foods). 1) Amount of fruit juice consumed in fluid ounces; the amount of baby fruits in level tablespoon or teaspoons. 2) Vegetables in level tablespoons or teaspoons. 3) Dry cereals in tablespoons; cooked or jarred cereals in tablespoons. 4) Brand name of foods used. d. Table foods. 1) Dry and cooked cereals in level cups or tablespoons. List brand name of cereal. 2) Amount of raw fruit consumed as number and size - small, medium, or large - with approximate measurements such as 2-1/2" x 2". 3) Canned or frozen fruits in cup portions. 4) Cooked vegetables in cup portions or number and length of spears (broccoli and asparagus). 5) Raw vegetables consumed as number and size, such as 2, 4" carrot sticks. 6) Fats in level teaspoons or tablespoons, including those used in cooking. Be sure to use the correct label, that is butter for butter, margarine, corn oil, etc. 7) Size of portion of desserts and recipes used. 8) List exact number or amount of Free Foods eaten. 9) List amount of each ingredient in mixed dishes unless a standard recipe has been given previously. Contact your nutritionist before using any food not included on the food list provided.
6.
A-27
APPENDIX 26. Sources of Nutrients and Drugs

L-Amino Acids Ajinomoto, USA, Inc. Amino Acid division 4020 Ajinomoto Drive Raleigh, NC 27610 (919) 325-1400; 1404 FAX (919) 325-1420 Jo Mar Laboratories 251-B E Hacienda Avenue Campbell, CA 95008-6622 (800) 538-4545 D-Biotin Mericon Industries, Inc. 8819 North Pioneer Road Peoria, IL 61615 (309) 693-2150 FAX: (309) 693-2158 Betaine (Cystadane) Chronimed, Inc. 13911 Ridgedale Drive Minnetonka, MN 55305 (800) 900-4267 NTBC Rare Disease Therapeutics, Inc. 1101 Kermit Drive Suite 608 Nashville, TN 37217-2126 (615) 399-0700 FAX (615) 399-1217 Parenteral Amino Acid Solutions. Designed for specific inherited metabolic disorders. Eastern Region Pharmacy Manager Coram Health Care (610) 296-4446 Western Region Pharmacy Manager Coram Health Care (651) 452-5600 PharmaThera 1785 Nonconnah Blvd Suite 118 Memphis, TN 88132 (901) 348-8200 (800) 767-6714 Oral Riboflavin, Oral Thiamin Nature's Bounty, Inc. 90 Orville Drive Bohemia, NY 11716 (516) 567-9500 (800) 645-5412 Sodium Phenylacetate, Sodium Phenylbutyrate (Ucyclyd) Ucyclyd Pharma 8125 North Hayden Road Scottsdale, AZ 85258-2463 (602) 667-3914 (888) 829-2593 (24 hours, 7 days week)
L-Carnitine Sigma Tau Pharmaceuticals, Inc. 800 South Frederick Avenue Suite 300 Gaithersburg, MD 20877 (800) 447-0169 Liposyn II Abbott Laboratories North Chicago, IL 60064 (800) 633-9110 MCT Oil (Fractionated Coconut Oil) Mead Johnson Nutritionals Evansville, IN 47721-0001 (812) 429-6399
APPENDIX 27. Low-Protein Food Suppliers Low-Protein Breads, Baking Mixes, Crackers, Cookies, and Pastas Ener-G Foods, Inc 6901 Fox Ave, S PO Box 24723 Seattle, WA 98124 (206) 767-6660 Kingsmill Foods Co, Ltd 1399 Kennedy Rd, Unit 17 Scarborough, Ontario Canada M1P 2L6 (416) 755-1124 Med-Diet Laboratories Inc 3050 Ranchview Ln Plymouth, MN 55447 (612) 550-2020 (800) 633-3438 (out of state)
APPENDIX 28. Products for Prescription Diet Management Computer Software Amino Acid Analyzer Metabolic Diseases, RP3-2 Ross Products Division Abbott Laboratories 625 Cleveland Avenue Columbus, OH 43215 (614) 624-7648; (614) 624-7516 (800) 986-8755 Scales That Read in Grams Pelouze Scales Co PO Box 1058 Evanston, IL 60204 (800) 654-8330 (708) 328-8330 Order Digital Scale Model RD 5 Current List price: $99.00 (battery operated)
This software contains data for approximately 2,000 foods, including Ross medical foods for inherited metabolic disorders and low-protein foods. Data were derived from the US Department of Agriculture and other sources. Nutrient intakes are compared to RDIs for age where available. The software can be used to calculate the following nutrients: protein; fat; carbohydrate; cholesterol; energy; the amino acids arginine, cystine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, tyrosine, and valine; the minerals calcium, copper, iron, magnesium, phosphorus, potassium, and zinc; and the vitamins A, B6, B12, C, folacin, niacin, pantothenic acid, riboflavin, and thiamin. Metanova Metabolic Diet Planner is software that helps plan diets and evaluate nutrients in the medical food mixture for patients with PKU. Order from: Metabolic Diseases Ross Products Division, RP3-2 Abbott Laboratories Columbus, OH 43215 (614) 624-7648; (614) 624-7516 (800) 986-8755
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INDEX
A Abdominal pain, 338 Abetalipoproteinemia, xv Abnormal electroencephalograms, 2 Abnormal metabolites, 233, 351, 352 Acetoacetic acid, 103, 111, 326, 350 Acetoacetyl-CoA thiolase, 124, 125 Acetoacetyl-CoA, 123 Acetyl-CoA, 103, 123, 279, 325, 350, 418 N-Acetylglutamate synthetase, 418-420 N-Acetylglutamate synthetase deficiency, xvi, 421 N-Acetylglutamine, 418 N-Acetyllysine, 210 N-Acetyltyrosine, 63, 65, 68 Acylcarnitine, xv, 166, 356 Acyl-CoA dehydrogenase, 350 Acylglycine, 351 Adenosylcobalamin, xi, 230 S-Adenosylmethionine, 137 Adenosyltransferase, xiii Adipic acid, 197 Alanine, xiv, 77, 80, 210, 279-282, 325, 326, 406, 407 Alanine aminotransferase, 325 Albumin, 8, 38, 55, 68, 78, 81, 111, 126, 129, 144, 172, 173, 201, 214, 224, 234, 237, 266, 285, 302, 316, 329, 341, 350, 356, 370, 384, 411, 425 Albuminuria, 262 Aldolase B, xiv, 313, 314 Alimentum, xiii, 12, 58, 70, 87, 117, 133, 148, 178, 216, 226, 243, 332, 373, 387, 414, 429, A-4 Alkaline phosphatase, 370 Alloisoleucine, 75, 77, 80, 104 Alopecia, 104, 107 -1, 4-Glucan -1, 4-glucan 6-glucosyltransferase, xiv -Galactosidase, 264 -Ketobutyrate, 138 -Ketoisocaproic acid, x -Ketoisovaleric acid, x -Keto--methylvaleric acid, x -Methylacetoacetic acid, 124 -Methylacetoacetyl-CoA, 123 -Methyl--hyroxybutyric acid, 124 Alveolar proteinosis, 209 Amino Acid Analyzer, ix Aminoaciduria, 4 2-Aminoadipic acid, 166, 168 Amylo-1, 6-glucosidase, xiv Anemia, 4, 75, 78, 231, 238, 314, 371 Anorexia, 52, 65, 104, 169, 231, 238, 280, 326, 366, 407, 420 Antiepileptic medication, 283 Apnea, x, 74, 75, 220, 231, 281, 406, 419 Apo B, xv Apo E2, xvi Apolipoprotein C-II, xv, 338 Apolipoprotein C-II deficiency, 338 Arabinogalactans, 263 Areflexia, 231 Arginase, xvi, 418, 419 Arginase deficiency, 419, 420
I-1 2001 Ross Products Division
Arginine, xi, xvi, 209-211, 213-215, 326, 327, 379-387, 406, 418-422, 427 Arginine deficiency, 419, 420 Argininemia, xvi Argininosuccinate, 419 Argininosuccinic acid, 418 Argininosuccinic acid lyase, xvi, 418, 419 Argininosuccinic acid lyase deficiency, 419-421 Argininosuccinic acid synthase, xvi, 210, 418, 419 Argininosuccinic acid synthase deficiency, 418, 420, 421, 426 Argininosuccinic aciduria, xvi, 419 Arrhythmia, 351 Arteriosclerosis, 296 Ascites, 313, 314 Asparagine, xv, 325, 327 Aspartic acid, xv, 325-327, 418, 420 Ataxia, 63, 64, 123, 166, 281, 406 Atherosclerosis, 296, 338 Attention deficit disorder, 351 B Benzoic acid, 114, 421 -1-4-linkages, 263 -Adrenergic blocking agents, 343 -Galactosidase, 264 -Hydroxybutyric acid, 111, 326, 350 -Ketoacyl-CoA, 123 -Ketothiolase, 123 -Ketothiolase deficiency, xii, 123, 134 Betaine, xiii, 137-139, 141, 142, 145, 146 Betaine-homocysteine methyltransferase, 137 Biopterin, 2 Biopterin synthetic defects, xi Biotin, xi, xiv, 230, 231, 234, 325, 327 Biotinidase deficiency, xi, 325 Bleeding diatheses, 419 Bleeding tendency, 140, 313, 314 Brain swelling, 419 Branched-chain amino acids, xii, 74-82, 85, 87, 88, 91, 125, 128, 130, 172 Branched-chain--ketoacid dehydrogenase complex, xi, xii, 74-77, 103 Branched-chain--ketoacid dehydrogenase complex deficiency, 103 Branched-chain--ketoacids, x, 75, 77, 78 Butanone, 124 C Calcilo XD, xvi, 366, 368-370, 372, 374, A-3 Calcitriol, 367, 368 Calcium, xvi, 263, 265, 367, 368, 370, 372, 373 Calcium propionate, 234 N-Carbamylglutamate, xvi, 420-422 Carbamylphosphate, 418 Carbamylphosphate synthetase, 406, 418-420 Carbamylphosphate synthetase deficiency, xvi, 421, 427 Carbidopa, 1
Cardiac arrest, 103 Cardiac defect, 33 Cardiomyopathy, 123, 197, 231, 351 Carnitine, xi, xii, xiii, xiv, xv, xvi, 104-109, 111-114, 123, 124, 126, 127, 129, 168-175, 196-199, 201, 202, 221, 222, 224, 232, 234, 235, 238-240, 281283, 285, 286, 351-354, 356-358, 407, 420 Carnitine-acylcarnitine translocase deficiency, xv Carnitine palmitoyl transferase type I, 350 Carnitine palmitoyl transferase type II, 350 Cataracts, 262, 263, 264, 379, 380 Central nervous system hemorrhage, 103 Cerebral atrophy, 280 Cerebral palsy, 351 Cholesterol, xv, xvi, 78, 125, 140, 169, 233, 234, 297, 302 Cholesterol granulomas, 209, 210 Choline, 138, 220 Chordee, 197 Choreoathetosis, 166, 167, 169, 406 Chylomicronemia, 338, 339, 343-345 Cirrhosis, xiv, 49, 207, 314 Citric acid, xv, 282, 325-328, 336, 421, 422, 426, 427 Citrulline, xiii, xvi, 209-213, 215, 326, 387, 407, 408, 411-413, 418, 420-422, 426-428 Citrullinemia, xvi, 325, 419 Coagulation factors, 314, 315, 406 Coagulopathy, 314 Cobalamin, 230 Cobalamin reductase, xiii Cognitive delay, 281 Cognitive impairment, 279 Coma, x, 104, 105, 123, 167, 221, 231, 314, 326, 350, 351, 406, 419 Congenital anomalies, 33 Constipation, 40, 174, 280, 281, 282 Convulsions, 105, 167, 314, 419 Corneal de-epithelialization, 233 Cornstarch, xiv, 202, 298-304, 327, 328, 331, 353, 358 Cortical atrophy, 221 Creatine, 137, 379, 406 Cyanocobalamin, 408, 409, 421-423 Cyanosis, 105 Cyclinex, xvi, 379, 382-386, 402, 406-410, 412, 413, 418, 422-424, 426-428, A-3 Cystathionase, 138 Cystathionine -synthase, xi, xiii, 138-140 Cystathionine -synthase deficiency, 138, 139 Cystathioninuria, 138 Cysteine, 138 2-L-Cysteinyl 5-1,4-dihydroxycyclohexenyl-5, 1-acetic acid, 63 Cystine, xi, xiii, 139-142, 144-147, 420 D Dehydration, 7, 54, 67, 80, 104, 105, 110, 128, 143, 172, 174, 200, 213, 223, 230, 231, 236, 266, 280, 282, 285, 301, 329, 341, 355, 370, 383, 410, 424, A-22 Delayed neurologic development, 326 -Aminolevulinic acid, x, xi, 49, 51 -Aminolevulinic acid dehydratase, x, 49, 51
Developmental delay, 107, 167, 231, 279, 351, 366, 406, 419 Dextromethorphan, 220, 221 Diarrhea, 49, 50, 78, 103, 200, 262, 263, 298, 299, 313, 314, 328, 331, 350, 353, 354 Diazepam, 220, 221 Dicarboxylic aciduria, 351, 355 Dichloroacetate, 280-283 Diet Diary, 26, 27 Diet Guide, 6, 37, 44, 53, 66, 80, 109, 128, 143, 171, 200, 205, 212, 222, 235, 265, 284, 291, 301, 309, 316, 322, 328, 334, 340, 346, 347, 354, 361, 369, 375, 383, 409, 423, A-24 Dietary Reference Intakes, vii Dihydropteridine reductase, xii, 2 Dinitrophenylhydrazine, 81 Dislocated lenses, 138 Diuretics, 343 Dizziness, 286, 314 Dodecanedioic acid, 197 DOPA, 1 Dysarthria, 174 Dysmorphia, 33, 197, 281 Dysphagia, 174 Dysplasia, 196 Dyspnea, 105 Dystonia, 140, 231 E Eczema, 2, 3 Edema, 313, 314 Electron transfer flavoprotein, 196, 197 Electron transfer flavoprotein deficiency, 196 Electron transfer flavoprotein ubiquinone oxidoreductase, 197 Electron transfer flavoprotein ubiquinone oxidoreductase deficiency, 196 Encephalopathy, 105, 167 Enoyl-CoA hydratase, 350 Epimerase, xiv Epimerase deficiency, xiv Epinephrine, 137 Eruptive xanthomas, 338 Essential fatty acid deficiency, 352, 355 Essential fatty acids, xv, 198, 299, 327, 339, 352, 353, 355, 358 Estrogen, 343 Ethylmalonic acid, 197 Ethylmalonic-adipic aciduria, 197 Extrahepatic lipoprotein lipase, xv Eye lenses, 262 F Failure to thrive, 3-5, 50, 52, 63, 65, 75, 78, 123, 126, 140, 141, 169, 174, 209-211, 222, 230, 231, 233, 234, 262, 263, 281, 282, 313, 314, 351, 381, 408, 421 Fanconi syndrome, 49, 50 Fasting chylomicronemia, 338, 345-348 Fatty acid metabolism, 406 Fatty acid oxidation, 123 Fatty acid oxidation defects, 351, 353, 358 Fatty acids, 202, 330, 342, 350, 355, 356, 358
I-2
Febrile illness, 11, 57, 69, 75, 84, 114, 132, 147, 169, 175, 202, 215, 225, 240, 267, 330, 343, 358, 413, 428 Ferritin, vii, 8, 38, 55, 68, 81, 111, 129, 130, 144, 173, 201, 210, 212, 214, 224, 238, 266, 267, 286, 302, 316, 329, 341, 356, 370, 371, 384, 411, 425 Ferrous sulfate, 8, 38, 55, 68, 81 111, 129, 144, 173, 201, 224, 238, 266, 286, 302, 316, 329, 341, 356, 371, 384, 411, 425 Fetal damage, 33 Fibrosis, 314 Fishy odor, 169, 234 Fissures at corners of mouth, 78, 125, 233 Folate, xiii, 8, 35, 37, 38, 75, 138, 139, 141, 142, 144146, 220, 223, 316, 317, 408, 409, 421-423 Fractionated coconut oil, xv, 351 Fructoaldolase, 314 Fructoaldolase B deficiency, 313 Fructose, xiv, 298, 299, 306, 313-320 Fructose intolerance, 314 Fructose-1-phosphate, 313 Fructose-1-phosphate aldolase, 313 Fumarate, 418 Fumarylacetoacetate, 49 Fumarylacetoacetate hydrolyase, xii, 49-51, 64 G Galactans, 263 Galactitol, 262, 264, 266 Galactokinase, 262-264, 266 Galactokinase deficiency, xiv, 262, 263, 266 Galactolipids, 263 Galactonate, 262 Galactoproteins, 263 Galactose, xiv, 262-268, 270, 273, 298, 299, 306 Galactose-1-phosphate, 262-264, 266 Galactose-1-phosphate uridyltransferase, 262, 263 Galactose-1-phosphate uridyltransferase deficiency, xiv, 262-264, 266 Galactose toxicity, 262, 263 Galactosemia, 262, 263, 265, 268-270, 274, 275 Aminobutyric acid, 166 Gastrostomy tube feeding, 174, 237, 238 Glossitis, 234 Glucagon, 313, 419 Gluconeogenesis, 313, 325 Glucose, viii, xi, 76, 77, 105, 106, 123-125, 168, 198, 200, 202, 231, 232, 268, 279, 281, 286, 296, 297, 298, 299, 301-304, 314, 315, 326, 331, 352, 353, 358 Glucose-6-phosphatase deficiency, 297 Glucose-6-phosphatase, xiv, 296, 297 Glucose-6-phosphate, 297 Glucose-6-phosphate translocase, 296, 297 Glucose-6-phosphate transport, xiv Glucose-6-phosphate-6-phosphate, 298 Glucose transport protein, 279, 281 Glucose transport protein deficiency, xiv, 279, 281, 283, 284 Glucosuria, 314 GLUT7 transport protein, 297 Glutaconic acid, 166, 168 Glutamate, 220, 379, 406, 418
Glutamic acid, xv, 327 Glutamine, xv, 325-327, 379, 384, 406-408, 410-412, 422, 424, 425, 428 Glutarex, xiii, 166, 168, 170-173, 175, 177, A-2, A-3 Glutaric acid, 166-169, 173, 197 Glutaric aciduria type I, xiii, 166, 167, 169, 170, 174176, 192 Glutaric aciduria type II, xiii, 196, 197, 202, 204-206 Glutarylcarnitine, 167 Glutaryl-CoA dehydrogenase, xiii, 166, 167 Glutaryl-CoA dehydrogenase complex, 166 Glutathione synthesis, 428 Glycine, xi, xii, xiii, 104-109, 112, 113, 173, 197-199, 210, 220, 221, 223, 232, 233, 236, 351, 353, 354, 357, 358, 420, 421, 425 Glycine deficiency, 428 Glycine-N-transacylase, xi Glycogen storage disease type I, 296-298, 301-303, 305, 309, 310 Glycogen storage disease type Ia, xiv, 296 Glycogen storage disease type Ib, xiv, 296, 297, 303 Glycogen storage disease type Ic, 296, 297 Glycogen storage disease type Id, 296, 297 Glycogen storage disease type III, xiv Glycogen storage disease type IV, xiv Glycogen storage disease type V, xiv Glycogenolysis, 313 Glycoproteins, 279 Gout, 296 Growth failure, 198, 223, 327, 339, 352 Gyrate atrophy of the choroid and retina, xvi, 379-381, 403 H H4 biopterin, 2 H4 biopterin deficiency, 1 Hair loss, 4, 52, 65, 78, 107, 126, 141, 169, 211, 222, 233, 282, 381, 408, 421 Hawkinsinuria, 50, 63 Hematemesis, 123, 124 Hematologic abnormalities, 104, 209 Hematophagocytic lymphohistiocytosis, 209 Hepatic adenomas, 296 Hepatic glycogen metabolism, 296 Hepatic lipoprotein lipase, xvi Hepatoma, 50, 51, 56 Hepatomegaly, 105, 167, 197, 209, 263, 296, 297, 313, 314, 326, 338, 351 Hepatosplenomegaly, 50, 210, 338 Hereditary fructose intolerance, xiv, 313, 314, 317, 321-323 Herpetiform dendritic ulcers, 64 Hippuric acid, 421 Hominex, xiii, 137, 140, 142-147, 162, A-2, A-3 Homoargininuria, 210 Homocitrulline, 406 Homocitrullinuria, 210 Homocysteine, 137-139, 141, 144 Homocystine, 137, 139-141, 144 Homocystinemia, 138 Homocystinuria, xi, xiii, 137-139, 147, 148, 163 3-Hydroxy-3-methylglutaric acid, 111
3-Hydroxy-3-methylglutaric aciduria, xiii, 105, 106, 111, 113 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency, 103, 105-109, 112 3-Hydroxyacyl-CoA dehydrogenase, 350 3-Hydroxyacyl-CoA dehydrogenase deficiency, 351 2-Hydroxyadipic acid, 166, 168 3-Hydroxy-CoA dehydrogenase, 350 Hydroxycobalamin, xiii, 230, 231 2-Hydroxyglutaric acid, 197 3-Hydroxyglutaric acid, 166, 168 5-Hydroxyhexanoic acid, 197 3-Hydroxyisobutyric acid dehydrogenase, xii 3-Hydroxyisobutyric aciduria, xii 3-Hydroxyisovaleric acid, 103, 110, 111, 197 p-Hydroxyphenyl, 68, 71 p-Hydroxyphenylpyruvic acid dioxygenase, 49, 63-65 3-Hydroxypropionate, 231, 233 Hyperactivity, 2 Hyperaminoaciduria, 262, 314 Hyperammonemia, 103-105, 114, 197, 198, 209-211, 213, 215, 230, 231, 325, 381, 384, 406, 408, 410, 413, 418, 419, 421, 424, 428 Hyperbilirubinemia, 314 Hypercalcemia, 366, 367, 373, 375, 376 Hypercholesterolemia, 296, 297 Hyperglycinemia, 124, 172, 226, 230, 231 Hyperkeratosis, 64 Hyperlacticacidemia, 231, 297 Hyperlipidemia, 296, 420 Hyperlipoproteinemia type I, xv Hyperlipoproteinemia type IIa, xvi Hyperlipoproteinemia type IIb, xvi Hyperlipoproteinemia type III, xvi Hyperlysinemia, 325 Hypermethioninemia, xiii, 137, 138 Hypernornithinemia - hyperammonemia homocitrullinuria syndrome, xvi, 406, 41-415, 419 Hyperornithinuria, 380, 381, 406 Hyperphenylalaninemia, 1, 2 Hyperpnea, 105 Hypertonia, 75, 231 Hypertriacylglycerolemia, 280, 296-298 Hyperuricemia, 296, 297 Hyperventilation, 231 Hypoalbuminemia, 173, 280, 282, 314 Hypobetalipoproteinemia, xv Hypocalcemia, 104 Hypocarnitinemia, 281 Hypocholesterolemia, 314 Hypodensity of myelin, 221 Hypoglycemia, 105, 167, 197, 230, 286, 296, 297, 301, 302, 313, 326, 328, 353 Hypogonadism, 263 Hypogonadotropic hypogonadism, 263 Hypokalemia, 262 Hypoketotic hypoglycemia, 196, 351 Hypophosphatemia, 262 Hypoproteinemia, 4 Hyporeflexia, 281 Hypospadias, 197
Hypotonia, 52, 65, 75, 103, 105, 166, 167, 197, 209, 210, 220, 230, 279, 281, 326, 406, 419 I Idiopathic hypercalcemia, xvi, 366, 367 Imipramine, 220, 221 Infection, viii, 11, 57, 62, 69, 78, 84, 104, 108, 114, 115, 123, 126, 147, 175, 196, 202, 211, 213, 215, 222, 230, 231, 240, 268, 303, 317, 330, 343, 350, 352, 358, 408, 410, 411, 413, 419, 421, 424 Infertility, 263 Inflammatory bowel disease, 296 Interstitial lung disease, 210 Intracranial pressure, 262 Intractable seizures, 220, 279-284, 286 Intragastric infusion, 300, 301 Intravascular thromboses, 138 Irregular respiration, 75 Irritability, 78, 107, 126, 169, 234, 314, 326, 366, 406, 419 Isobutrylglycine, 197 Isobutyric acid, 197 Isoleucine, x, xi, xii, xiii, xiv, 74, 76-79, 81-83, 85, 104, 107, 123-127, 129-131, 133, 197, 198, 230-239, 243, 244, 247 Isomil, vii, xiii, xiv, xvi, 12, 58, 70, 87, 117, 133, 148, 178, 213, 216, 223, 226, 243, 262, 263, 265, 267, 268, 274, 332, 373, 387, 414, 429, A-5 Isoretinoin, 343 Isovaleric acid, xi, 103, 104, 111, 197 Isovaleric acidemia, xi, xii, 103, 104, 110, 112, 119 Isovaleryl-CoA dehydrogenase, xii, 103 Isovaleryl-CoA dehydrogenase deficiency, 103, 104 Isovalerylglycine, xi, 103, 110, 197 I-Valex, xii, xiii, 103, 105, 106, 108-114, 116, A-2, A-3 J Jaundice, 50, 262, 263, 313, 314 K Ketamine, 220 Ketoacidosis, 231 Ketoacids, 81, 111, 129, 133, 237 3-Ketoacyl-CoA thiolase, 350 2-Ketoadipic acid, 166, 168 2-Ketoadipic aciduria, xiii, 166, 167, 176, 178, 192 2-Ketoadipic dehydrogenase, xiii, 166, 167 Ketogenesis, 282, 283 Ketogenic diet, xiv, xv, 279-282, 286, 287, 291, 292 Ketones, 125, 234, 240, 280, 281, 285, 350 Ketonex, xii, 74, 76, 77, 79-84, 86, 124, 125, 127-132, A-2, A-3 Ketonuria, 105, 197 Ketosis, 123, 124, 167, 221, 233, 281-285 L Lactate dehydrogenase, 279, 325 Lactic acid, 197, 279-282, 285, 297, 298, 300, 302, 314, 315, 325, 326 Lactic acidemia, 280, 282, 296 Lactic acidosis, 279-281, 283, 301
I-4
Lactose, xiv, 262-264, 266, 267, 298, 299 LDL receptor, xvi Lecithin:cholesterol acyltransferase deficiency, xv Lethargy, 52, 65, 75, 103, 105, 174, 220, 221, 231, 314, 326, 351, 366, 406, 419 Leucine, x, xi, xii, xiii, 74-79, 81-83, 85, 103-115, 117, 124-127, 129-131, 197, 198 Leucine catabolism, 103 Leukopenia, 104 Lipemia retinalis, 280, 338 Lipoamide dehydrogenase deficiency, 281 Lipoic acid, 74, 281 Lipoprotein lipase, 338 Lipoprotein lipase deficiency, 338, 339 Lipoprotein lipase inhibitor, xv Liposyn II, 76, 77, 105, 106, 124, 125, 232 Liver failure, 49, 314 Liver parenchymal cells, 196 Liver transplantation, 231 Long-chain-CoA dehydrogenase, 350 Long-chain-acyl-CoA dehydrogenase deficiency, xv, 351 Long-chain-fatty acid oxidation defects, 351-353 Long-chain-fatty acids, xv, 351 Long-chain-hydroxyacyl-CoA dehydrogenase deficiency, xv, 350, 352, 357 Long-chain-unsaturated fatty acids, xiii, xiv Low blood pH, 231 Lysine, xiii, 78, 125, 166-170, 172-175, 178, 197, 198, 209, 210, 213, 214, 233, 326, 379, 384, 406 Lysinuric protein intolerance, xiii, 209, 214, 215, 217, 406, 419 M Macrocephaly, 166, 167 Maillard reaction, viii, 6, 37, 53, 66, 80, 109, 127, 143, 171, 212, 235, 382, 409, 423 Malar flushing, 138 Maleylacetoacetate, 49 Maleylacetoacetic acid isomerase, xii, 49, 50, 64 Maple syrup odor, 75 Maple syrup urine disease, x, xi, xii, 74, 75, 84, 85, 100, 103, 104 Maternal phenylketonuria, 33, 46 Medium-chain-acyl-CoA dehydrogenase, 350 Medium-chain-acyl-CoA dehydrogenase deficiency, xv, 350, 351, 357 Medium-chain-fatty acid oxidation defects, 352, 353 Medium-chain-triglycerides, xv, 351-353, 355, 357-359 Melena, 123, 124 Mental aberrations, 2 Mental retardation, x, 2-4, 33, 63, 64, 105, 107, 137, 138, 209, 264, 326, 419 Metabolic acidosis, 63, 75, 78, 103-105, 108, 115, 123, 124, 126, 166-168, 196-198, 230, 314, 326, 351 Methionine, xiii, xiv, xvi, 78, 107, 126, 137-142, 144149, 152, 161, 220, 230, 231-239, 243, 244, 247, 314, 315, 339 Methionine-S-adenosyltransferase, xiii, 137 2-Methylbutyric acid, 197 2-Methylbutyrylglycine, 197 Methylcitrate, 231, 233 Methylcobalamin, 137, 138
3-Methylcrotonyl-CoA carboxylase, xii 3-Methylcrotonyl-CoA carboxylase deficiency, 103, 105 3-Methylcrotonylglycine, 111 3-Methylcrotonylglycinuria, xii, 105, 111, 113 N-Methyl--aspartate, 220 5, 10-Methylenetetrahydrofolate reductase deficiency, 138 Methylenetetrahydrofolate reductase, 139 3-Methylglutaconic acid, 111 3-Methylglutaconic aciduria, xii, 105, 108, 111 3-Methylglutaconyl-CoA hydratase, xii 3-Methylglutaconyl-CoA hydratase deficiency, 103, 105 3-Methylglutaric acid, 111 3-Methylhistidine, 411, 425 Methylmalonic acid, 230, 231, 233, 237 Methylmalonic acidemia, xi, xiii, 230, 231, 233, 236, 237, 240, 258 Methylmalonic aciduria, xi, 139 Methylmalonyl-CoA, 138 Methylmalonyl-CoA mutase, 230, 231 Methylmalonyl-CoA mutase , xiii, 230 Methylmalonyl-CoA mutase , xiii, 230, 231 N5-Methyltetrahydrofolate, 137 5-Methyltetrahydrofolate, 139 5-Methyltetrahydrofolate-homocysteine methyltransferase, 137-139 Metronidazole, 237 Microcephaly, 2, 33, 281 Microsomal 7-dehydrocholesterol reductase, xv Microsomal phosphate transport, 297 Mitochondrial acetoacetyl-CoA thiolase, 123, 124 Mitochondrial acetoacetyl-CoA thiolase deficiency, 123 Mitochondrial fatty acid oxidation defects, 350, 351, 359-362 Mitochondrial ornithine transport protein, 406 Mitochondrial transport defect, 406 Mitochondrial trifunctional protein, 350 Mitochondrial trifunctional protein deficiency, 351 Motor delay, 279 Multiple acyl-CoA dehydrogenase, xiii Multiple acyl-CoA dehydrogenase deficiency, 196 Muscle phosphorylase, xiv Muscle weakness, 350, 351 Musty odor, 2 Myocardium, 196 Myoclonic jerks, 105 Myoclonic seizures, 166, 221, 279, 280 Myoglobinuria, 351 N + NAD , 74, 196 Nasogastric feeding, 76, 77, 105, 106, 124, 125, 168, 174, 232, 237, 238 Nausea, 285, 286, 314 Neocalglucon, 267, 268 Neonatal hyperparathyroidism, 366, 367 NeoSure, A-7 Nephrocalcinosis, 367 Nephropathy, 50 Neurologic abnormalities, 2, 63, 64 Neurologic crises, 51, 52, 167, 169 Neurologic damage, 220 Neurologic deterioration, 2, 3, 166-168, 221, 264
Neurologic dysfunction, 75 Neurologic impairment, 75, 167, 170, 174, 231, 263 Neutropenia, 104, 231, 296, 297, 303 Niacin, 162, 170, 408, 409, 421-423 Nicotinamide adenine dinucleotide, 196 2 (2-Nitro-4-trifluoromethylbenzoyl)-1, 3-cyclohexanedione, 49-52 Nonketotic hyperglycinemia, xiii, 220, 221, 225, 227 Nonketotic hypoglycemia, 196 Normoglycemia, 281, 285, 298-300 O Oculocutaneous lesions, 65 Odd-chain-fatty acids, xiii, xiv, 230, 231, 234, 240 Offspring, 2, 33, 35, 196 Opisthotonos, 75, 105 Organic acidemias, xi, 221 Organic acids, 51, 55, 65, 68, 71, 75, 105, 107, 110, 121, 124-126, 166, 168, 173, 197, 198, 201, 221, 231, 237, 240, 355 Organic acidurias, 196, 406, 419 Ornithine transcarbamylase, 418, 419 Ornithine transcarbamylase deficiency, xvi, 418-421, 426 Ornithine transport defect, xvi Ornithine, xvi, 209-211, 213-215, 379-381, 383, 384, 406-408, 411-413, 418 Ornithine--aminotransferase, xvi, 379-381, 406 Ornithinuria, 381 Orotic acid, 210, 381, 406 Orotic aciduria, 407, 418, 420 Osmolarity, viii, 6, 7, 10, 11, 37, 39, 40, 53, 54, 56, 57, 67, 69, 79, 80, 83, 84, 109, 110, 112-114, 127, 128, 130-132, 142, 143, 145-147, 170-172, 175, 199, 200, 202, 212, 213, 215, 222, 223, 225, 232, 235, 236, 239, 240, 265-267, 283, 285, 287, 301, 317, 328-330, 341, 342, 354, 355, 357, 358, 369, 370, 372, 382, 383, 385, 409, 410, 412, 413, 422- 424, 426-428, A-20, A-21 Osteopenia, 3, 4, 52, 65, 78, 106, 125, 126, 141, 169, 233, 282, 381, 408, 421 Osteopetrosis, xvi, 366-368, 370, 371 Osteoporosis, 112, 138, 209, 211, 296 Ovarian failure, 264 Oxaloacetate, 279, 325-327 P Palmo-plantar lesions, 65 Pancreatic amylase, 298, 299, 304 Pancreatitis, 140, 231, 280, 296, 338, 339 Pancytopenia, 104, 197, 231 Pantothenic acid, xii, 108, 408, 409, 421-423 Parahydroxyphenyl, 51, 55, 65 Parahydroxyphenylpyruvic acid dioxygenase, 50 Parathyroid hormone, 366 Parathyroid hyperplasia, 366 Pathophysiologic changes in the brain, 231 Pedialyte, 11, 57, 69, 147, 202, 268, 318, 331, 343, 358, A-9 Peripheral neuropathy, x, xiii, 138, 350, 351, 381 Phenex, xii, 1, 4-11, 27, 33, 36-40, 43, A-2, A-3 Phenylacetic acid, x, 408, 422
Phenylacetylglutamine, 408, 422 Phenylalanine, x-xii, 1-12, 33-40, 42, 49-58, 63-70, 78, 108, 126, 140, 233, 234 Phenylalanine hydroxylase, x, xii, 1-3, 34 Phenylalanine hydroxylase deficiency, 34 Phenylketonuria, x-xii, 1-3, 8, 9, 11, 12, 29, 33, 41 Phenyllactic acid, x Phenylpyruvic acid, x Phosphoenolpyruvate, 325 Phosphoenolpyruvate carboxykinase, 325 Photophobia, 64 Pigmentary retinopathy, 350, 351 Pin-point pupils, 221 Platelet dysfunction, 296 Polycitra, 411, 422, 425 Polycose, xiv-xvi, 6, 11, 36, 53, 57, 66, 67, 69, 79, 83, 109, 127, 142, 143, 147, 168, 170, 171, 199, 200, 202, 232, 235, 236, 268, 283, 284, 287, 299-301, 304, 318, 328, 330, 331, 340, 342, 343, 354, 357, 358, 360, 369, 382, 383, 408, 412, 422, 426, 427, A-9 Polyunsaturated fatty acids, xvi, 231, 234 Poor appetite, 210, 220, 221 Poor feeding, 103, 104, 230, 313, 314, 406, 419 Poor growth, 4, 5, 75, 78, 126, 141, 169, 211, 222, 233, 234, 314, 381, 408, 421 Poor suck, 75 Potential renal solute load, viii, 7, 9, 54, 56, 67, 80, 82, 110, 112, 128, 130, 143, 145, 172, 175, 200, 202, 213, 223, 225, 236, 239, 266, 267, 285, 287, 301, 317, 329, 330, 341, 342, 355, 357, 358, 370, 372, 383, 385, 410, 412, 424, 426, 427, A-22 Pregnancy, 33-35, 39, 41, 196, 221, 350 Proline, 140, 234, 326, 406 Pro-Phree, xiii, xiv, xvi, 6, 11, 53, 57, 66, 67, 79, 109, 127, 142, 143, 147, 168, 170, 171, 209, 212, 213, 215, 216, 220, 222, 223, 225, 226, 235, 236, 268, 317, 318, 382, 383, 385, 386, 387, 408, 422, A-3, A-10 Propimex, xiii, xiv, 230, 232, 234-237, 239, 240, 242, A-2, A-3 Propionic acid, 231, 233, 237, 240, 243 Propionic acidemia, xiv, 230, 231, 234, 236, 240, 258 Propionylcarnitine, 231, 233 Propionyl-CoA, 123, 138 Propionyl-CoA carboxylase, xiv, 230, 231, 234 Propionylglycine, 231 Proteinuria, 314 ProViMin, xiii, xiv, xv, xvi, 106, 108, 114, 118, 199, 200, 202, 203, 279, 283-285, 287, 289, 296, 299301, 304, 308, 325, 328-332, 338, 340-345, 353355, 357-359, A-3 Proximal myopathy, 197 Psychomotor retardation, 50, 167, 280, 281, 366 Pyridoxal phosphate, 74, 138 Pyridoxine, xi, xiii, xvi, 138, 223, 379, 380-382, 408, 409, 421, 423 Pyroglutamic acid, 425 Pyrophosphate transport, 297 Pyruvate, 138, 279-282, 285, 325, 326 Pyruvate carboxylase, 279, 325-327 Pyruvate carboxylase apoenzyme, 325
I-6
Pyruvate carboxylase apoprotein, 325 Pyruvate carboxylase deficiency, xv, 325, 326, 332-335 Pyruvate dehydrogenase complex, 279-281, 325 Pyruvate dehydrogenase complex defect, xv, 279-282, 284, 288 Pyruvate dehydrogenase kinase, 280, 283 Pyruvate kinase, 325 Pyruvic acid, 281 Q Quinolinic acid, 166, 420 R Rachitic changes, 368 RCF, xiv, xv, xvi, 279, 283-285, 287, 289, 296, 299301, 304, 308, A-3 Recommended Dietary Allowances, vii, xii-xvi, 4, 35, 52, 65, 75, 78, 107, 126, 139, 141, 169, 170, 211, 222, 233, 265, 282, 298, 316, 408, 421, A16 Recommended Dietary Intakes, vii, 6, 37, 45, 53, 54, 67, 80, 109, 110, 128, 143, 171, 200, 212, 223, 236, 265, 284, 301, 315-317, 329, 341, 355, 369, 383, 409, 421, 422, 423, A-14, A-15 Redness of buccal mucosa, 78, 126, 233, 234 Reduced bone mass, 280 Remnant receptor defect, xvi Renal abnormalities, 352 Renal calculi, 280, 282 Renal cysts, 167, 197 Renal failure, 231 Renal insufficiency, 296 Renal proximal tubular dysfunction, 314 Renal solute load, 7, 54, 67, 80, 110, 128, 143, 172, 200, 213, 223, 236, 266, 285, 301, 329, 341, 355, 370, 383, 410, 424, A-22 Renal tubular disease, 210 Renal tubular dysfunction, 50, 314 Respiratory insufficiency, 221 Reye's syndrome, 105, 166, 197, 351, 406, 419 Rhabdomyolysis, 138, 351 Riboflavin, xiii, 166, 167, 170, 171, 173-175, 196, 198200, 351-354, 357, 363 Rickets, 50 Rocaltrol, 52 S Salicylate toxicity, 123 Salicylate, 114, 123 Sarcosine, 197 Sarcosinuria, 196 Sebacic acid, 197 Seizures, 2, 63, 74, 75, 104, 105, 138, 167, 169, 209, 221, 279, 280, 281, 283, 284, 285, 313, 350, 351, 406, 419 Sepsis, 103, 262, 263, 366 Serine, 78, 107, 126, 138, 140, 210, 233, 234, 420 Serotonin, 104, 420 Shock, 313, 419 Short-chain-acyl-CoA dehydrogenase, 350 Short-chain-acyl-CoA dehydrogenase deficiency, xv, 351 Short-chain-fatty acid oxidation defects, 352, 353
Short-chain-hydroxyacyl-CoA dehydrogenase, 350 Short-chain-hydroxyacyl-CoA dehydrogenase deficiency, xv, 351 Similac, vii, xiii, xiv, 9, 12, 56, 58, 70, 82, 87, 106, 112, 117, 130, 133, 145, 148, 168, 175, 178, 213, 215, 216, 225, 226, 239, 243, 316-318, 321, 330, 332, 373, 385, 387, 412, 414, 426, 429, A-6 Similac Lactose Free, A-7 Skeletal abnormalities, 210 Skeletal changes, 138 Skin desquamation, 78, 107, 126, 233 Smith-Lemli-Opitz syndrome, xv Sodium benzoate, 114, 211, 216, 220, 221, 224, 226, 232, 407-409, 411, 414, 420, 421, 423, 425, 429 Sodium bicarbonate, 126, 326 Sodium phenylacetate, 211, 216, 232, 408, 420-423, 425, 429 Sodium phenylbutyrate, 211, 216, 407-409, 411, 414, 420-423, 425, 429 Sodium propionate, 234 Sorbitol, 313-318, 320 Spasticity, 167, 406, 419 Speech delay, 279 Speech disabilities, 351 Splenomegaly, 338 Steatosis, 314 Stem cell differentiation, 238 Strychnine, 220 Stupor, x, 104, 419 Suberic acid, 197 Succinylacetone, x, 49-51, 55 Succinyl-CoA, 138 Sucrose, xiv, 298, 299, 306, 313-318, 320 Sudden infant death syndrome, 351 Sulphite oxidase deficiency, xvi Supravalvular aortic stenosis, xvi Sweaty-feet odor, 103, 104, 197 T Tachypnea, 103, 104, 197 Tetrahydrobiopterin, xi, xii Tetrahydrobiopterin deficiency, 1 Thiamin, xi, xii, xv, 74-76, 280-282, 284, 325-327 Thiamin pyrophosphate, xi, 74 Threonine, xiii, xiv, 78, 107, 126, 140, 230-239, 243, 244, 247 Thrombocytopenia, 104, 231, 314, 371 Thymic hypoplasia, 209 Thyroxin-binding globulin, 210 Tiglic acid, 231 Tiglylglycine, 124 Transient hyperammonemia, 406, 419 Transport protein defect, 407 Transsulfuration pathway, 137 Transthyretin, viii, 4, 5, 8, 38, 52, 55, 65, 68, 78, 81, 111, 126, 129, 139, 141, 144, 169, 173, 201, 211, 214, 222, 224, 233, 237, 282, 285, 302, 356, 381, 384, 408, 411, 421, 425 Trauma, viii, 11, 57, 69, 84, 108, 114, 115, 132, 147, 175, 202, 215, 225, 240, 267, 268, 317, 330, 343, 358, 413, 428 Trembling, 314 Tremors, 78, 103, 126, 233
Triacylglycerols, 297, 298, 302, 338, 339, 341 Trimethylamines, 234 Tryptophan, xiii, 104, 162, 166-170, 172-175, 178, 194, 197, 198, 220, 420 Tryptophan hydroxylase, x, 1 Twitching, 406, 419 Tyramine, 63 p-Tyramine, 65, 68 Tyrex, xii, 49, 53-57, 59, 63, 66-69, A-2, A-3 Tyrosine, x-xii, 1-11, 34-36, 38-40, 49-58, 63-70, 78, 126, 127, 140, 233, 234, 314, 315, 420 Tyrosine aminotransferase, xii, 50, 63, 64, 65 Tyrosine hydroxylase, x, 1 Tyrosinemia, 50, 64 Tyrosinemia type I, 60 Tyrosinemia type Ia, x-xii, 49-51, 58 Tyrosinemia type Ib, xii, 49-51, 58 Tyrosinemia type II, xii, 50, 63, 64, 69-71 Tyrosinemia type III, xii, 50, 63, 64, 69-71 Tyrosinemia type IIIa, 63 Tyrosinemia type IIIb, 63 U Ubiquinone, 196 Urate, 314, 315, 351 Urea cycle disorders, 418, 429, 430 Urea cycle enzyme defects, 406, 419 Urea cycle function, 209 Uric acid, 297, 302 Uridine diphosphate-galactose-4-epimerase, 262, 263 Uridine diphosphate-galactose-4-epimerase deficiency, 263 Uridine therapy, 263 V Valine, x-xiv, 74, 76-79, 81-83, 85, 107, 124-127, 129131, 197, 198, 230-239, 243, 244, 247 Valproate, 172, 406, 419, 428 Very-long-chain-acyl-CoA dehydrogenase, 350 Very-long-chain-acyl-CoA dehydrogenase deficiency, xv, 351 Very-long-chain-fatty acid oxidation defects, 352, 353 Vi-Daylin Multivitamin + Iron, A-10 Vitamin A, 37, 38, 139 Vitamin B12, xi, 8, 35, 37, 38, 138, 231 Vitamin B6, 138, 139, 379, 381 Vomiting, 49, 50, 75, 103-105, 166, 167, 197, 200, 210, 220, 221, 230, 231, 262, 263, 280, 285, 313, 314, 328, 350, 351, 353, 354, 406, 419 Von Gierke's disease, 296 W Williams syndrome, xvi, 366, 367, 370
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Nutrition Support Protocols

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To order products in the Ross Metabolic Formula System, call: 1-800-551-5838 8:30 AM - 5:00 PM EST, Monday - Friday, except

The Ross Metabolic Formula System

Nutrition Support Protocols 4th Edition

Vice President, Medical and Regulatory Affairs William C. MacLean, MD

Manuscript Processor: Christine K. Downs

Ross Products Division Division of Abbott Laboratories Columbus, Ohio 43216

A6224/(500)/June, 2001 LITHO IN USA

Steven Yannicelli, PhD, RD

Ross Products Division/Abbott Laboratories P O Box 1317 Columbus, OH 43216-1317

2001 Ross Products Division

2001 Ross Products Division

2001 Ross Products Division

2001 Ross Products Division

Practical Aspects of Nutrition Support of Inborn Errors of Metabolism

2001 Ross Products Division

2001 Ross Products Division

2001 Ross Products Division

2001 Ross Products Division

2001 Ross Products Division

xii 2001 Ross Products Division

TABLE A. Nutrition Support of Selected Inborn Errors of Metabolism

No No Yes; tetrahydrobiopterin, 2 mg/kg/day.

3-Hydroxyisobutyric aciduria (3-Hydroxyisobutyric acid dehydrogenase)

2001 Ross Products Division xiii

Ross Metabolic Formula/Other I-Valex-1 I-Valex-2

Pro-Phree ProViMin Glutarex-1 Glutarex-2 Pro-Phree

Propimex-1 Propimex-2 Pro-Phree Similac Isomil Alimentum

xiv 2001 Ross Products Division

Inborn Error and Defect Propionic acidemia (propionyl-CoA carboxylase)

Ross Metabolic Formula/Other Propimex-1 Propimex-2

Health Source Isomil Powder

GSD Type III (amylo-1, 6-glucosidase)

GSD Type IV (-1, 4-Glucan -1, 4-glucan 6glucosyltransferase)

2001 Ross Products Division xv

Vitamin-Responsive Yes? Thiamin. No

Ross Metabolic Formula/Other ProViMin RCF ProViMin

ProViMin Polycose ProViMin Polycose

xvi 2001 Ross Products Division

2001 Ross Products Division

GTP GTP cyclohydrolase Dihydroneopterin triphosphate NAD Dihydrobiopterin synthetase

Dihydropteridine reductase (N) Dietary protein

H2 biopterin Tissue protein CO2 + H2O Melanin

Tyrosine (N) (N)

Epinephrine O2 Phenylalanine hydroxylase H2O Thyroxine

Phenylethylamine * Accumulates in untreated PKU (N) = several steps

Phenylacetate* Indicates sites of possible enzyme defects

Figure A. Phenylalanine metabolism in phenylketonuria

2001 Ross Products Division

II. Screening for PKU

III. Outcome of Nutrition Support

IV. Establish Diagnosis

V. Rationale for Nutrition Support

VI. Establish Goals of Nutrition Support (19, 58)

VII. Establish Prescription

Dietary PHE (mg/kg) 70 55 45 35 25

VIII. Fill Prescription

2001 Ross Products Division

IX. Evaluate Adequacy and Safety of Planned Nutrition Support

X. Suggested Evaluation of Nutrition Support

2001 Ross Products Division

XI. Sample Prescriptions

2001 Ross Products Division

1.8 0.2 1.0 2.5 0.0 30.1

90 120 120 50 110 1,309