Abstracts

Rationale: The genetic generalized epilepsies (GGEs) are common, heritable epilepsies which 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). Methods: We examined whether GLUT1-deficiency causes common GGEs. 504 probands with GGEs 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 sequenced Results: Functionally validated mutations in SLC2A1were present in 7/504 (1.4%) probands and 0/470 controls. PED, undiagnosed prior to study, occurred in one proband and 3/13 relatives with mutations. The GGEs in probands and relatives were indistinguishable from typical GGE. 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; two showed possible dominant inheritance, two did not. These alleles leading to subtle functional impairment may contribute to complex, polygenic inheritance of GGE. Conclusions: SLC2A1 mutations contribute to approximately 1% of GGE both as a dominant gene and as a susceptibility allele in complex inheritance. Diagnosis of GLUT1-deficiency has important treatment (ketogenic diet) and genetic counselling implications. The mechanism of restricted glucose delivery differs from the current focus on GGEs as ion channels disorders.