Clinical characteristics: The phenotypic spectrum of glucose transporter type 1 deficiency syndrome (Glut1 DS) is now known to be a continuum that includes the classic phenotype as well as paroxysmal exercise-induced dyskinesia and epilepsy (previously known as dystonia 18 [DYT18]) and paroxysmal choreoathetosis with spasticity (previously known as dystonia 9 [DYT9]), atypical childhood absence epilepsy, myoclonic astatic epilepsy, and paroxysmal non-epileptic findings including intermittent ataxia, choreoathetosis, dystonia, and alternating hemiplegia. The classic phenotype is characterized by infantile-onset seizures, delayed neurologic development, acquired microcephaly, and complex movement disorders. Seizures in classic early-onset Glut1 DS begin before age six months. Several seizure types occur: generalized tonic or clonic, focal, myoclonic, atypical absence, atonic, and unclassified. In some infants, apneic episodes and abnormal episodic eye-head movements similar to opsoclonus may precede the onset of seizures. 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 continual with fluctuations in severity influenced by environmental factors such as fasting or with infectious stress. Symptoms often improve substantially when a ketogenic diet is started.
Diagnosis/testing: The diagnosis of Glut1 DS is established in a proband with suggestive clinical findings, normal blood glucose concentration, CSF glucose concentration <60 mg/dL, and the identification of a heterozygous pathogenic variant (or rarely, biallelic pathogenic variants) in SLC2A1 by molecular genetic testing. If no pathogenic variant is identified, 3-O-methyl-D-glucose uptake in erythrocytes can be performed; results between 35% and 74% of controls are diagnostic.
Management: Treatment of manifestations: The ketogenic diet is highly effective in controlling the seizures and improving gait disturbance and is generally well tolerated. Affected individuals treated effectively at a younger age have a better outcome The ketogenic diet is deficient in L-carnitine necessitating dietary supplementation.
Prevention of primary manifestations: Early diagnosis and treatment with a ketogenic diet is associated with improved neurologic outcome.
Prevention of secondary complications: For those on a ketogenic diet: L-carnitine supplementation; proper hydration and avoidance of carbonic anhydrase inhibitors; avoidance of carbohydrate-containing foods, intravenous fluids, and medications that interrupt the state of ketosis; avoidance of valproic acid because it increases the risk of a Reye-like illness.
Surveillance: Periodic measurement of blood ketone concentration with a target beta-hydroxybutyrate concentration of 3-5 mmol/L.
Agents to avoid: Barbiturates (e.g., phenobarbital, the antiepileptic drug most commonly used in treating infants), methylxanthines (e.g., caffeine), valproic acid.
Evaluation of relatives at risk: If the pathogenic variant has been identified in an affected family member, it is appropriate to test at-risk newborns, infants, and other relatives at risk in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures.
Genetic counseling: Glut1 DS is most commonly inherited in an autosomal dominant (AD) manner. About 90% of individuals with AD Glut1 DS have the disorder as the result of a de novo heterozygous pathogenic variant; about 10% have a clinically affected parent. Parents who are heterozygous for the pathogenic variant may have a mild phenotype or be asymptomatic, findings that can suggest mosaicism in the parent. Offspring of an individual with AD Glut1 DS have a 50% chance of inheriting the pathogenic variant and being clinically affected.
Rarely, Glut1 DS is inherited in an autosomal recessive (AR) manner. Heterozygotes (carriers) in families with AR Glut1 DS are asymptomatic.
Once the SLC2A1 pathogenic variant(s) have been identified in an affected family member, prenatal diagnosis for a pregnancy at increased risk and preimplantation genetic testing for Glut1 DS are possible.
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