The phenotypic spectrum associated with GABRB3 mutations: from febrile seizures to severe epileptic encephalopathies
Abstract number :
2.361
Submission category :
11. Genetics
Year :
2015
Submission ID :
2327314
Source :
www.aesnet.org
Presentation date :
12/6/2015 12:00:00 AM
Published date :
Nov 13, 2015, 12:43 PM
Authors :
R. S. Møller, G. Rubboli, T. V. Wuttke, M. Nikanorova, E. H. Brilstra, U. Vaher, I. Borggraefe, I. Talvik, T. Talvik, G. Kluger, C. Betzler, J. Lemke, C. Myers, L. Larsen, M. Pendziwiat, Y. Mang, K. Van Gassen, H. Dahl, N. Tommerup, I. Helbig, H. Mefford,
Rationale: Mutations in GABRB3 encoding the β3 subunit of the GABAA receptor have recently been reported in patients with epileptic encephalopathies. We aimed to delineate the clinical spectrum associated with GABRB3 mutations.Methods: We used high-throughput sequence analysis of the GABRB3 gene in 215 patients with a range of epileptic encephalopathies (EEs) and childhood epilepsies. In addition, we ascertained cases with GABRB3 mutations from other centers. A detailed clinical history was obtained together with a review of EEGs. We examined the functional effects of some of the detected sequence alterations using an automated two-microelectrode voltage-clamp Xenopus laevis oocyte testing system.Results: Twelve patients/families with heterozygous mutations of GABRB3 were studied. The phenotypic spectrum of the 12 probands varied from Febrile Seizures Plus (FS+) (2) and MAE (3) to Dravet syndrome (1), West syndrome (1) and unspecified EEs (5). Segregation analysis was performed in eleven cases; eight occurred de novo (3 MAE, 1 West syndrome, 4 EE), whereas the two FS+ associated mutations and the Dravet associated mutation were found to segregate with a GEFS+ phenotype in the affected families. In total, we studied 20 individuals with febrile seizures or epilepsy due to a GABRB3 mutation. Seizure onset ranged from day one to 3 years, however the majority of the probands had seizure onset at around 6-9 months of age. Fourteen of the individuals had febrile seizures, and two of them never developed afebrile seizures. The majority of the patients with epilepsy had multiple seizure types including GTCS, myoclonic seizures, absences, atonic seizures, focal seizures and epileptic spasms; seizures were refractory to antiepileptic therapy in approximately half of them. Twelve had intellectual disability, ranging from mild to severe and seven had neurodevelopmental disorders or behavioral problems including ASD, ADHD or aggressiveness. Electrophysiological analysis revealed a strong loss-of-function effect as the molecular disease mechanism.Conclusions: The present study shows that GABRB3 mutations are associated with a phenotypic spectrum ranging from febrile seizures, FS+ to severe epileptic encephalopathies, defining a novel genetic disease within the GEFS+ spectrum.
Genetics