Abstracts

Rationale: Glucose transporter type 1 (Glut1) deficiency is associated with increasing phenotypic heterogeneity. Glut1 is coded for by SLC2A1 and is responsible for glucose transport across the blood-brain barrier. Classical Glut1 deficiency is a severe metabolic encephalopathy usually caused by de novo mutations of SLC2A1, whereas dominantly inherited Glut1 deficiency causes paroxysmal exercise-induced dystonia (PED), sometimes with idiopathic epilepsy. We recently showed that 4/34 probands with early-onset absence epilepsy had mutations of SLC2A1; 2 cases had inherited mutations. Here we extend the phenotypic diversity of Glut1 deficiency by studying the families of these probands. Methods: 24 family members of the two probands underwent detailed electroclinical phenotyping including fasting electroencephalogram (EEG) and cerebrospinal fluid (CSF) studies where possible. Family members were sequenced for the proband’s SLC2A1 mutation. Results: Two families segregating SLC2A1 mutations were identified with 14 individuals carrying the familial mutation. Epilepsy occurred in 12 individuals with 6 also having PED. A single individual had PED alone and one had febrile seizures alone. Intellect was normal in 11/14. Of 12 with epilepsy, 8 had idiopathic generalized epilepsy (IGE), two had myoclonic-astatic epilepsy and two focal epilepsy. Mean onset was 10 years (range 3-32 years, median 8 years). Absence was the most frequent seizure type with 4 having childhood absence epilepsy, 2 juvenile absence epilepsy and 1 adult-onset absence epilepsy. Generalized spike-wave on EEG was present in 9/12. Epilepsy responded to medication in all but two cases. PED began in adolescence or later, was mainly mild and universally unrecognized prior to SLC2A1 mutation detection. Comparison of fasting and post-prandial EEG was unhelpful. CSF studies in 3 individuals showed CSF/plasma glucose ratios of 0.38-0.52. Conclusions: Glut1 deficiency is a monogenic cause of IGE and can also cause focal epilepsy. The most striking finding is that Glut1 deficiency can present with easily controlled absence seizures at any age in the setting of normal intellect. Although common forms of IGE usually follow complex inheritance, Glut1 deficiency is an important monogenic cause of IGE.