DISORDER

ENZYME

NOTES

HEMOGLOBINOPATHIES
Sickle Cell anemia (Hemoglobin S disease)

Glutamate (HbA) replaced with valine (HbS) on beta chain; anemia, pain, dec. circulation, infections

Hemoglobin C disease

Glutamate (HbA) replaced with lysine (HbC) , mild anemia

Hemoglobin SC disease

Hbs + HbC, undiagnosed until childbirth / surgery, can be fatal

Methemoglobinemia

NADH cytochrome b5
reductase

Diminished oxygen-carring capacity of ferric Hb (metHb) headache, lightheadedness, dyspenea and chocolate
cyanosis

THALASSEMIAS
-thalassemia: Silent Carrier

1 defective

No symptoms

Mild Symptoms

2 defective

2 alpha chains missing

Hb B

4 defective

Accumulation of 4 tetramers in newborns, HYDROPS FATALIS

HbH

3 defective

Accumulation of 4 tetramers in newborns, severe anemia

Deletion of both betas

Both chains defective, fatal HEINZ bodies, inability of HbF HbA, manifests around 8 mos old.

Deletion of 1 beta chain

Only 1 chain defective, not fatal

Scurvy

Proly/lysyl hydroxylase

Vit C def. no hydroxylation

Ehlers-Danlos

Lysyl hydroxylase

Stretchy skin, loose joints, aortic aneurysm, ruptured colon,

Osteogenesis Imperfecta

Collagen Type 1 defect

Brittle bones in babies, blue sclera, multiple fractures, slowed healing

Type 1: heterozygous, postnatal, can survive
Type 2: homozygous, perinatal, death in utero

Emphysema

1- anti-trypsin deficiency

Inherited defect in alpha 1 anti-trypsin resulting in emphysema

-thalassemia: major
Minor
COLLAGEN DISEASES

Alports

Affect glomerular basement membrane, hearing loss, ocular defects

Goodpastures

Antibodies destroy basement membrane of pulmonary and glomerular capillaries

2+

Menkes
ETC INHIBITORS
Electron transport blockers

Lysyl oxidase/Cu

Deficient cross linking secondary to functional copper deficiency; depigmented

(steely) hair, arterial tortuosity and rupture, cerebral degeneration, anemia, osteoporosis.

Complex1 NADH
dehydrogenase

Amobarbital, rotenone

Complex III cytochrome

reductase

Antimycin A

Complex IV cytochrome
oxidase

CO,CN

Complex V (ATP
synthase)

Oligomycin

Aconitase

Inhibited

TCA CYCLE
Fluoroacetate

Malonate

Succinate dehydrogenase

Inhibited

Arsenite

-ketogluconate
dehydrogenase

Inhibited

Complex 1 (NADH
dehydrogenase)

Degeneration of optic nerve, blindness in early adult

HEREDITARY MITOCHONDRIAL
DISEASES
Lebers hereditary optic neuropathy
Kearns-Sayre

Ragged red fibers, heart block, retinal pigmentation

MELAS

Mitochondrial myopathy, encephalomyopathy, lactic acidosis, stroke-like episodes

MERRF

Myoclonus epilepsy with ragged red fibers; ataxia, sensorineural deafness

GLUCOSE & PYRUVATE

METABOLISM
Pyruvate dehydrogenase deficiency

Pyruvate dehydrogenase

Lactic acidosis, neurologic defects (Wernicke-Korsakoff)

Pyruvate DH complex deficiency

Pyruvate DH complex

Pyuvate to lactate, neonatal death, infancy death, episodic ataxia after meal

Arsenic poisoning

G3PDH

Lost NADH, pyruvate accumulates

Pyruvate kinase deficiency

Pyruvate kinase

Most common enzyme deficiency in glycolytic pathway; hemolytic anemia, jaundice

GALACTOSE METABOLISM
Classical galactosemia

GALT

Cirrhosis, mental retardation, cataracts, galactosuria

Galactokinase deficiency

Galactokinase

Cataracts, galactosemia, galactosuria

UDP galactose 4-epimerase deficiency

Benign: affects RBCs and WBCs Malignant: similar to GALT def

FRUCTOSE METABOLISM
Hereditary fructose intolerance

Aldolase B

Toxic liver damage, renal disease, hypophosphatemia, gout

Essential fructosuria

Fructokinase

Benign condition, fructosuria

HMP PATHWAY/NADPH RELATED

DISORDERS
Hemolytic Anemia

G6PD

X linked, hemolytic anemia often induced by infections, oxidant drugs & fava beans; inadequate NADPH
production results in reduction in antioxidant activity of glutathione in mature RBCs
Class I: chronic nonspherocytin anemia, most severe
Class II: Mediterranean, normal stability, scarce activity in RBCs
Class III: A-, oldest RBCs removed

Amyotrophic Lateral Sclerosis

Superoxide dismutase

Degenerated motor neurons in CNS

Chronic granulomatosis

NADPH oxidase

Persistant chronic pyogenic infections; deficiency of enzyme located in leukocyte membrane

Glycogen synthase

Hypoglycemia, death, hyperketonia

GLYCOGEN STORAGE DISEASES

Type 0

VON Gierkes (Type 1)

Glucose 6-phosphate

Hepatosplenomegaly, severe fasting hypoglycemia

Pompes (Type II)

-1-4 glucosidase
(acid maltase)

Infants: mental retardation, cardiomegaly, death by 2 yrs; juvenile myopathy

Adult: gradual skeletal myopathy

Coris (Type III)

-1-6 glucosidase

Mild hypoglycemia, hepatomegaly

Andersens (Type IV)

Glucosyl-4-6-transferase

Hepatosplenomegaly, liver failure, death by 2 yrs

McArdles (Type V)

Muscle glycogen
phosphorylase

Muscle cramping, fatigue, no increase in lactic acid after exercise

Hers (Type VI)

Liver glycogen
phosphorylase

Mild hypoglycemia

Hurlers

-L-iduronidase

Corneal clouding, MR, coarse facial features, early death

Hunters

Iduronate sulfatase

X-linked, physical deformity, MR

Sanfilippos Types A-D

Type-Aheparan sulfate
Type BNacetylglucosaminidase
Type CNacetyltransferase
Type D Nacetylglucosamine

Severe nervous system disorders; mental retardation

Scheies

-L-iduronidase

Like Hurlers but normal life span

Slys

-glucronidase

Hepatosplenomegaly, physical deformity

Lysosomal hydrolytic
enzymes

Deficiency in ability to phosphorylated mannose residuesof potential lysosomal enzymes;

results in incorrect targeting of glycoproteins; death by 8 yrs; elevated N-linked glycoproteins in urine.

Congenital A-beta-lipoproteinemia

Apo B-48

Accum of chylomicrons in enterocytes

Type 1 hyperlipidemia (familial

hyperchylomicronemia)

Apo C-II, Capillary

lipoprotein lipase

Accumulation of chylomicrons in plasma; high plasma TAGs and eruptive xanthomas

(TAG deposits in skin) and pancreatitis.

Mucopolysaccharidoses

Synthesis of glycoproteins
I-cell disease
Metabolism of Dietary Lipids

Type II hyperlipidemia
Type III hyperlipidemia (familial
dysbetalipoproteinemia)

Genetic defect in synthesis, processing or functioning of LDL receptor; elevated LDL levels
Familial hypercholesterolemia
Apolipoprotein E

Accumulation of chylomicron remnants in plasma

Type IV hyperlipidemia

Inc. VLDL due to obesity, alcohol, diabeties

Type V hyperlilidemia

Inc. chylomicrons, TAGs, VLDL, pancreatitis

Wolman disease

Cannot hydrolyze lysosomal cholesteryl esters

Familial LCAT deficiency

Complete absence of LCAT, low HDL

Fish Eye Disease

Partial LCAT absense

Zellweger syndrome

Defective peroxisomal biogenesis, accumulated VLCFAs in blood

X-linked Leukodystrophy

Defective peroxisomal activation of VLCFAs, destroyed myelin

Mobilization of Stored Fats & [FA]

Carnitine deficiency

inability to use long chain FA as fuel, causes: congenital, liver disease

CAT-1 def

Liver cannot synthesize glucose during fast, hypoglycemia, coma, death

CAT-2 def

Cardiomyopathy, muscle weakness following exercise

Medium chain Fattyacyl CoA

dehydrogenase deficiency

Medium chain fatty acyl

CoA

Decreased FA oxidation, severe hypoglycemia; cause of 10% SIDS cases, Reyes syndrome; treat with
high carb diet

Paroxysomal Nocturnal Hemoglobinuria

GPI synthase

In hematopoietic cells

Refsum disease

Fatty acid alphahydroxylase

AR, increased phytanic acid, neurologic symptoms

Vit B12 def

Methylmalonic academia and aciduria, metabolic acidosis

Phospholipid metabolism
Niemann-Pick Type A

Sphingomyelinase

Type B
Type C

Cherry red macula, hepatosplenomegaly, severe mental retardation, death in early childhood
Chronic lung damage, death in early adulthood

Sphingomyelinase

Cannot transport unesterified cholesterol out of lysosomes

Tay-Sachs

-hexoaminidase A

Cherry-red macula inc. GM2, blindness, MR, early death

Gauchers

-glucosidase

Sphingolipidosis, inc. glucocerebrosides, hepatosplenomegaly, MR, frequently fatal

Metachromatic leukodystrophy

Arylsuldatase A

MR, demyelination, fatal in 1st decade

Krabbes

-galactosidase

Inc. galactocerebrosides, MR, almost total absence of myelin, fatal

GM1 gangliosidosis

-galactosidase

GM1 accumulation, MR, skeletal deformities, death

Sandhoffs disease

-hexosaminidase A & B

Inc. globosides; same symptoms as Tay-Sachs with rapid progression.

Fabrys

-galactosidase

Inc. globosides; X linked, kidney & heart failure, redish purple skin rash

Farbers

Ceraminidase

Inc. ceramide, painful and progressively deformed joints; granulomas, fatal early in life

Cholesterol & steroid metabolism

CAH Congenital
Adrenal

Hyperplasia

SPHINGOLIPIDOSES

Smith-Lemli-Opitz Syndrome

7-hydrocholesterol-7reductase

AR, double bond migration (Lanosterol to Cholesterol)

Fatty Liver

Imbalanced TG synthesis
and VLDL secretion

Causes: obesity, diabetes mellitus, alcoholism

Cholelithiasis

Cholesterol gallstones

Malabsorption, obstructed biliary tract, hepatic dysfunction; treat: laparoscopic cholecystectomy

3--hydroxysteroid dehydrogenase def

3--hydroxysteroid
dehydrogenase

Inc. pregnenolone, No glucocorticoids, mineralocorticoids, androgens, or estrogen; early death

17- -hydroxylase deficiency

17- -hydroxylase

Sex hormones & cortisol not produced inc. production of aldosterone gives HTN, phenotypically female
but unable to mature

21- -hydroxylase deficiency

21- -hydroxylase

Most common CAH; ACTH levels inc. gives inc. sex hormones & masculinization

11--hydroxylase deficiency

11- -hydroxylase

Dec. cortisol & aldesterone; masculization

Classic PKU

Phenylalanine hydroxylase

MR, dec. melanin synthesis; fair skin, mousy odor, congenital pyloric stenosis, screen after 1st
exposure to phenylalanine in breat milk, restrict phenylalanine intake, increase tyrosine

Malignant PKU

Dihydrobiopterin
reductase/ synthase

Similar to classic PKU, melatonin and serotonin synthesis also compromised., restrict phenylalanine,
add tyrosine, L-dopa, 5-hydroxytryptophan

Maternal PKU

Mother with either classic

or malignant

Developmental abnormalities, microcephaly, MR, mother didnt stay within dietary restrictions during
pregnancy

Alcaptonuria

Homogentisate oxidase

Benign; homogentisate accumulation forms polymers which darkens standing urine. Ochronosis;
darkening of articular cartilage

Maple Syrup Urine Disease

Branched chain ketoacid dehydrogenase

Elevated levels of amino acids and their keto analogues in plasma and urine; high mortality rate;
neurologic problems

Propionyl CoA Carboxylase Deficiency

Elevated propionate in blood; accumulation of odd chain FA in liver; developmental problems

Cystathioninuria

Propionyl CoA
Carboxylase
Cystathionase

Homocystinuria

Cystathionine synthetase

Accumulation of homocysteine in urine, elevated methionine & metabolites in blood, MR, osteoporosis

Histidinemia

Histidase

Elevated histadine in blood and urine, sometimes MR

Albinism

Tyrosinase

Inability to convert tyrosine to melanin

Tyrosinosis

Eumarylacetoacetate
hydrolase

Liver & kidney damage

Nonketogenic hyperglycinemia

Glycine cleavage complex

Severe mental deficiencies & low survival rate past infancy, inc. glycine in blood.

Carbamoylphosphate
synthetase I

Within 24-48 hrs after birth infant becomes increasingly lethargic, needs stimulation to feed, vomiting,
hypothermia, & hyperventilation; without appropriate intervention death occurs; treat with arginine which

AMINO ACID METABOLISM

Accumulation of cystathionine and metabolites, no clinical symptoms

UREA CYCLE
Type I Hyperammonemia

activates N-acetylglutamate synthetase

N-acetylglutamate synthetase deficiency

N-acetylglutamate
synthetase

Severe/mild hyperammonemia associated wuth deep coma, acidosis, recurrent diarrhea, ataxia, hypoglycemia,
hyperornithinemia; treatment includes administration of carbamoyl glutamate which activates CPS I

Type 2 hyperammonemia

Ornithine
transcarbmoylase

Most commonly occurring UCD, only X linked, increased ammonia and aa in serum, increased serum
orotic acid due to mitochondrial carbamoylphosphate entering cytosoland incorporating in pyrimidine
nucleotides leading to excess productin and excess catabolic products; treat with high carb, low protein diet,
and sodium phenylacetate/benzoate for ammonia detox

Classic Citrullinemia

Argininosuccunate
synthetase

Episodic hyperammonemia, vomiting, lethargy, ataxia, seizures, coma; treat with arginine to increase
citruline excertion and sodium benzoate to detox ammonia

Argininosuccinate Aciduria

Argininosuccinate lyase
(argininosuccinase)

Episodic symptoms similar to classic citrullinemia, elevated plasma and CSF argininosuccunate;
treat with argentine and sodium benzoate.

Hyperargininemia

Arginase

Rare UCD progressive spastic quadriplegia and MR high ammonia & arginine in CSF & serum, high arginine,
lysine, and ornithine in urine; treat with low protein diet including essential AA but no arginine

Acute Intermittent porphyria

Uroporphyrinogen
synthase

Autosomal dominant, inc. porphobilinogen & ALA in urine, attacks precipitated by drugs that induce
cytochrome P450 in liver

Congenital erythropoietic porphyria

Uroporphyeinogen III
synthase

Inc. uroporphyrinogen I & uroporphyninI

Prophyria Cutanea Tarda

Uroporphyrinogen
decarboxylase

Inc. uroporphyrinogen III which converts to uroporphyrinogen I & coproporphyrinogen I

Hereditary Coproporphyria

Coproporphyrinogen
oxidase

Inc. coproporphyrinogen III

Varigate Porphyria

Protoporphyrin oxidase

Accumulation of protoporphyrinogen IX

Erythropoietic Protoporphyria

Ferrochelatase

Accumulation of protoporphyrin IX

Sideroblastic Anemia

ALA synthase

X-linked

Crigler-Najjar syndrome

Bilirubin glucuronyl
transferase

In newborns: newborn jaundice, treat with blue light

Lead poisoning

ferrochelatase/
ALA dehydratase

Inc. ALA and protoporphyrin XI, DEC. heme

HEME BIOSYNTHESIS/DEGREDATION

CONGENITAL ADRENAL HYPERPLASIA

3--hydroxysteroid DH def.

No glucocorticoids, mineralocorticoids, androgens/estrogens, hyponatremia, feminine genitalia,

early death

17--hydroxylase def.

No sex hormones, cortisol, inc. mineralocorticoids, hypernatremia, HTN, feminine genitalia,

early death

21--hydroxylase def.

Greater than 90% CAH, no mineralo/glucocorticoids, inc. androgens, masculinization

11--hydroxylase def.

Dec. cortisol, aldesterone, and corticosterone, inc. deoxycorticosterone; fluid retention, HTN,

masculinization

LETTER

NAME

COENZYME/
ACTIVE FORM

DEFICIENCY

REACTIONS

TYPE

B1

Thiamine

TPP

Beri-beri; Wernicke-Korsakoff

Transketolase, PDC and -KG

Dehydrogenase

Oxidative, decaeboxyl
ation, transfer of -ketols

B2

Riboflavin

FAD, FMN

Dermatitis, cheilosis, glossitis

Succinate DH

Redox

B3

Niacin

NAD, NADP

Pellagra; 3 Ds,

B6

Biotin

Biotin

Adivin; dermatitis, glossitis, anorexia, nausea

Acetyl carboxylase,propionyl
carboxulase, pyruvate
carboxylase

Carboxylation

B6

Pantothenic acid

CoA

Not significant

Citrate & FA synthase

Acyl carrier

Folic Acid

THF

Megaloblastic anemia, neural tube defects, PABA

analogues, dihydrofolate inhibitors

Purine & thymine sntesis, Met,

Ser, Gly, Cys

1 C metabolism

B12

Cobalamin

5deoxyadenosyl
cobalamin,
methylcobalamin

Pernicious anemia, CNS symotoms, folate trap

Synth of Met & isomerization

of methylmalonyl CoA
succinyl CoA

B6

Pyridoxine,
pyridoxal

Pyridoxal PO4

Rare, isoniazid can induce deficiency

AST,ALT

Transamination,
deamination

Ascorbic acid

Ascorbic acid

Scurvey

Hydroxylation of praline in
collagen

Antioxidant, hydrox of
Praline & lysine

Retinol

Retinol in vision,
retinoic acid in
epithelial cells

Blindness, sterility, skin problems

Visual cycle

Cholecalciferol

1,25-diOH D3

Children: rickets, adults: osteomalacia

Calcium levels in plasma

Phyllo/menaquinones

Same

Hypothrombinemia

Formation of gcarboxyglutamate

Tocopherols

-tocopherol

Abnormal cell membranes

Redox

Carboxylation of
certain Glu residues
Anti-oxidant