RARE GENETIC DISORDER: GLUT 1 DEFICIENCY INTRODUCTION Glucose transporter deficiency syndrome (Glut1 DS) is a pediatric brain energy

metabolic syndrome. The affected child's cells do not pick up and transport glucose to the brain properly. Glucose is the principal source of fuel to the brain. Children with this disorder have a myriad of physical and mental disabilities, ranging from mild to so severe. Glut1 DS was first discovered in 1991 by Dr. Darryl DeVivo INCIDENCE GLUT1 deficiency syndrome is a rare disorder. Fewer than 100 cases have been reported since the disorder was first identified in 1991. GENES RELATED TO GLUT1 DEFICIENCY SYNDROME The SLC2A1 gene provides instructions for producing a protein called the glucose transporter protein type 1 (GLUT1). This protein is part of the membranes of cells, where it transports glucose from the blood into the cells for use as fuel.Glucose transporter protein type 1 is involved in moving glucose across the blood-brain barrier, Glucose is the brain's main energy source under normal conditions SLC2A1 mutations reduce or eliminate the function of the glucose transporter protein type 1 produced from one copy of the gene in each cell. Reduced transporter function lessens the availability of glucose, resulting in the signs and symptoms of GLUT1 deficiency syndrome. MODE OF INHERITACE This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Most cases of this disorder result from new mutations in the gene. These cases occur in people with no history of the disorder in their family. In some cases, an affected person inherits the mutation from an affected parent. DISEASE CHARACTERISTICS. It is characterized by infantile-onset seizures, delayed neurologic development, acquired microcephaly, and complex movement disorders. Seizures begin before age two years in approximately 90% and later in approximately 10%. Five seizure types occur: generalized tonic or clonic, myoclonic, atypical absence, atonic, and unclassified. The frequency, severity, and type of seizures vary among affected individuals and are not related to disease severity. Cognitive impairment, ranging from learning disabilities to severe intellectual disability, is typical. The complex movement disorder, characterized by ataxia, dystonia, and chorea, may

occur in any combination and may be continuous, paroxysmal, or continuous with fluctuations in severity influenced by environmental factors such as fasting, fever, and intercurrent infection. Symptoms often improve substantially when a ketogenic diet is started. DIAGNOSIS Low-normal or low CSF lactate concentration, normal blood glucose concentration, and low CSF glucose concentration (<60 mg/dL ) Detection of a heterozygous disease causing mutation in SLC2A1 confirms the diagnosis. Decreased 3-O-methyl-D-glucose uptake in erythrocytes confirms the diagnosis of Glut1-DS. TREATMENT FOR GLUT1 DS The only known treatment is a very restrictive diet called the ketogenic diet which is usually used for children with seizure disorders that do not benefit from conventional drugs. For children with Glut1 DS, it is the only treatment that may help control the seizures and providing energy to the brain. However, it is currently unknown how effective this treatment may be. KETOGENIC DIET The ketogenic diet is a very restrictive, calorie-limited, high fat diet. All food consumed is based on a ratio of fat to protein and carbohydrate combined, usually a 4:1 or 3:1 ratio, (3 or 4 grams of fat to 1 gram of protein and carbohydrate combined). No sugar is allowed and minimal carbohydrate is included. Each meal or snack is measured in grams and typically includes a small amount of protein, a little amount of a lower carbohydrate fruit or vegetable and a large amount of oil, butter, mayonnaise or heavy cream as the fat source. Strict compliance with this diet causes the body to produce ketones. Ketones are used by the brain as an alternate fuel source. The ketogenic diet usually helps with seizure control. But, it is currently unknown how much this diet may benefit the other symptoms of Glut1 DS deficiency syndrome. Every child on this diet must be monitored to measure for adequate ketones. If ketones are too low, the child may have seizures or other symptoms of Glut1 DS deficiency syndrome, and if ketones are too high, acidosis or other side effects can occur. ANTIEPILEPTIC DRUGS are generally ineffective or afford only limited improvement in the absence of a ketogenic diet. GENETIC COUNSELING Most commonly Glut1-DS is inherited in an autosomal dominant manner. About 90% of individuals with Glut1-DS have the disorder as the result of a de novo heterozygous mutation; about 10% have a clinically affected parent. Parents who are heterozygous for the diseasecausing mutation may have a mild phenotype or be asymptomatic. Offspring of an individual with Glut1-DS have a 50% chance of inheriting the mutation and being clinically affected.

Rarely, Glut1-DS is inherited in an autosomal recessive manner. Carriers in families with Glut1DS are asymptomatic. Prenatal testing for pregnancies at increased risk is possible if the diseasecausing mutation has been identified in families with autosomal dominance inheritance or both disease-causing mutations have been identified in families with autosomal recessive inheritance. PRENATAL TESTING Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. REFERENCES Dong Wang, MD, Juan M Pascual, MD, PhD, and Darryl De Vivo, MD. http://www.ncbi.nlm.nih.gov/books/NBK1430/ http://ghr.nlm.nih.gov/condition/glut1-deficiency-syndrome http://www.milestonesforchildren.org/glut1.html