Abstracts

Rationale: A variety of epileptic conditions, from mild genetic generalized epilepsies and febrile seizures to severe epileptic encephalopathies (EE) such as Dravet syndrome (DS), have been reported to be associated with mutations in GABRA1, that encodes the alpha subunit of the GABAA receptor. In this study, we aimed to delineate the clinical spectrum associated with GABRA1 mutations.Methods: We investigated 130 patients presenting with a wide range of childhood epilepsies and epileptic encephalopathies by means of high-throughput sequence analysis of the GABRA1 gene. Cases with GABRA1 mutations were ascertained from other centers along with clinical data.Results: Ten patients with heterozygous mutations of GABRA1 were found. The phenotypic spectrum varied from Genetic Generalised Epilepsy (GGE) (in the JME spectrum) (2 patients) to Generalised Epilepsy with Febrile Seizures Plus (1), Dravet Syndrome (1) and Epileptic Encephalopathies (6). Seven patients had de novo mutations (6 EE and the DS patient), while the remaining 3 probands had a epilepsy positive family history, not available for testing. Seizure onset varied between 1 day of life and 17 months (mean 8,3 months) with two outliers with seizure debut at 13 and 16 years respectively. Three had febrile seizures at onset, one experienced febrile seizures at a later point; six developed afebrile seizures. Seven out of ten patients had GTCS, and the majority had multiple seizure types including myoclonic seizures, atypical absence, atonic seizures and focal seizures with/without dyscognitive features. In 7 patients seizures were refractory to antiepileptic therapy; 3 patients became seizure free. Mild to severe developmental delay was reported in 7 patients whereas it was normal in 3. Functional studies in two of the patients with de novo mutations (one with EE the other with familiar GGE) all showed reduced GABA-induced currents.Conclusions: Our study shows that GABRA1 mutations are associated with a wide spectrum of epileptic phenotypes, that range from GEFS+ to severe epileptic encephalopathies. Our results may have important implications for diagnostic testing, clinical management, and genetic counseling.