title: Glucose transporter 1 deficiency in the idiopathic generalized epilepsies.
abstract: OBJECTIVE
  We examined whether glucose transporter 1 (GLUT1) deficiency causes common idiopathic generalized epilepsies (IGEs).
  
  
  METHODS
  The IGEs are common, heritable epilepsies that usually follow complex inheritance; currently little is known about their genetic architecture. Previously considered rare, GLUT1 deficiency, due to mutations in SLC2A1, leads to failure of glucose transport across the blood-brain barrier and inadequate glucose for brain metabolism. GLUT1 deficiency was first associated with an encephalopathy and more recently found in rare dominant families with epilepsy and paroxysmal exertional dyskinesia (PED). Five hundred four probands with IGEs and 470 controls underwent SLC2A1 sequencing. Glucose transport was assayed following expression of SLC2A1 variants in Xenopus oocytes. All available relatives were phenotyped, and SLC2A1 was sequenced.
  
  
  RESULTS
  Functionally validated mutations in SLC2A1 were present in 7 of 504 (1.4%) probands and 0 of 470 controls. PED, undiagnosed prior to study, occurred in 1 proband and 3 of 13 relatives with mutations. The IGEs in probands and relatives were indistinguishable from typical IGE. Three cases (0.6%) had mutations of large functional effect and showed autosomal dominant inheritance or were de novo. Four (0.8%) cases had a subtle functional effect; 2 showed possible dominant inheritance, and 2 did not. These alleles leading to subtle functional impairment may contribute to complex, polygenic inheritance of IGE.
  
  
  CONCLUSIONS
  SLC2A1 mutations contribute to approximately 1% of IGE both as a dominant gene and as a susceptibility allele in complex inheritance. Diagnosis of GLUT1 deficiency has important treatment (ketogenic diet) and genetic counseling implications. The mechanism of restricted glucose delivery differs from the current focus on IGEs as ion channel disorders.
authors.affiliation: Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Melbourne, Australia.
authors.forename: Todor
authors.initials: T
authors.lastname: Arsov
authors.forename: Saul A
authors.initials: SA
authors.lastname: Mullen
authors.forename: Sue
authors.initials: S
authors.lastname: Rogers
authors.forename: A Marie
authors.initials: AM
authors.lastname: Phillips
authors.forename: Kate M
authors.initials: KM
authors.lastname: Lawrence
authors.forename: John A
authors.initials: JA
authors.lastname: Damiano
authors.forename: Hadassa
authors.initials: H
authors.lastname: Goldberg-Stern
authors.forename: Zaid
authors.initials: Z
authors.lastname: Afawi
authors.forename: Sara
authors.initials: S
authors.lastname: Kivity
authors.forename: Chantal
authors.initials: C
authors.lastname: Trager
authors.forename: Steven
authors.initials: S
authors.lastname: Petrou
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Berkovic
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Scheffer
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002239:Carbohydrate Metabolism, Inborn Errors / Q000150:complications* / Q000235:genetics*; D004252:DNA Mutational Analysis; D004829:Epilepsy, Generalized / Q000209:etiology* / Q000235:genetics*; D019143:Evolution, Molecular; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D051272:Glucose Transporter Type 1 / Q000172:deficiency / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009004:Monosaccharide Transport Proteins / Q000172:deficiency / Q000235:genetics; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D055815:Young Adult
chemical_list: D051272:Glucose Transporter Type 1; D009004:Monosaccharide Transport Proteins; C495677:SLC2A1 protein, human