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Aim: Pharmacoresistance is a major burden in epilepsy treatment. We aimed to identify genetic biomarkers in response to specific antiepileptic drugs (AEDs) in genetic generalized epilepsies (GGE). Materials & methods: We conducted a genome-wide association study (GWAS) of 3.3 million autosomal SNPs in 893 European subjects with GGE - responsive or nonresponsive to lamotrigine, levetiracetam and valproic acid. Results: Our GWAS of AED response revealed suggestive evidence for association at 29 genomic loci (p <10 -5 ) but no significant association reflecting its limited power. The suggestive associations highlight candidate genes that are implicated in epileptogenesis and neurodevelopment. Conclusion: This first GWAS of AED response in GGE provides a comprehensive reference of SNP associations for hypothesis-driven candidate gene analyses in upcoming pharmacogenetic studies.

Background: Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We aimed to investigate the burden of rare genetic variants in genetic generalised epilepsy., Methods: For this exome-based case-control study, we used three different genetic generalised epilepsy case cohorts and three independent control cohorts, all of European descent. Cases included in the study were clinically evaluated for genetic generalised epilepsy. Whole-exome sequencing was done for the discovery case cohort, a validation case cohort, and two independent control cohorts. The replication case cohort underwent targeted next-generation sequencing of the 19 known genes encoding subunits of GABA A receptors and was compared to the respective GABA A receptor variants of a third independent control cohort. Functional investigations were done with automated two-microelectrode voltage clamping in Xenopus laevis oocytes., Findings: Statistical comparison of 152 familial index cases with genetic generalised epilepsy in the discovery cohort to 549 ethnically matched controls suggested an enrichment of rare missense (Nonsyn) variants in the ensemble of 19 genes encoding GABA A receptors in cases (odds ratio [OR] 2·40 [95% CI 1·41-4·10]; p Nonsyn =0·0014, adjusted p Nonsyn =0·019). Enrichment for these genes was validated in a whole-exome sequencing cohort of 357 sporadic and familial genetic generalised epilepsy cases and 1485 independent controls (OR 1·46 [95% CI 1·05-2·03]; p Nonsyn =0·0081, adjusted p Nonsyn =0·016). Comparison of genes encoding GABA A receptors in the independent replication cohort of 583 familial and sporadic genetic generalised epilepsy index cases, based on candidate-gene panel sequencing, with a third independent control cohort of 635 controls confirmed the overall enrichment of rare missense variants for 15 GABA A receptor genes in cases compared with controls (OR 1·46 [95% CI 1·02-2·08]; p Nonsyn =0·013, adjusted p Nonsyn =0·027). Functional studies for two selected genes (GABRB2 and GABRA5) showed significant loss-of-function effects with reduced current amplitudes in four of seven tested variants compared with wild-type receptors., Interpretation: Functionally relevant variants in genes encoding GABA A receptor subunits constitute a significant risk factor for genetic generalised epilepsy. Examination of the role of specific gene groups and pathways can disentangle the complex genetic architecture of genetic generalised epilepsy., Funding: EuroEPINOMICS (European Science Foundation through national funding organisations), Epicure and EpiPGX (Sixth Framework Programme and Seventh Framework Programme of the European Commission), Research Unit FOR2715 (German Research Foundation and Luxembourg National Research Fund)., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: Rufinamide is approved for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients aged ≥4years. The objective of this study was to provide real-world, long-term data on patients with LGS initiating rufinamide as add-on therapy and patients with LGS receiving other antiepileptic drugs (AEDs)., Methods: A Phase IV, noninterventional, multicenter registry study was conducted in patients with LGS aged ≥4years requiring modification to any AED treatment, including initiation of add-on rufinamide therapy. Safety/tolerability was assessed by evaluating treatment-emergent adverse events (TEAEs), and efficacy was assessed using a generic seizure frequency scale., Results: A total of 111 patients from 64 sites in 8 European countries were included, of whom 64 initiated rufinamide ("rufinamide" group) and 21 did not receive rufinamide at any time during the study ("no-rufinamide" group). Mean ages were 16.1years (rufinamide) and 15.0years (no rufinamide). The median duration of follow-up was >2years (range: 1.3-46.4months). Antiepileptic drug-related TEAEs were reported for 40.6% (rufinamide) and 33.3% (no rufinamide) of patients and led to discontinuation of 7.8% and 4.8%, respectively. The most frequently reported rufinamide-related TEAEs (≥5% patients) were somnolence (7.8%) and decreased appetite (6.3%). There were no unexpected safety/tolerability findings. At month 12, the proportion of patients with improvement in all seizures ("much improved" or "very much improved") was 28.6% (12/42) for the rufinamide group and 14.3% (2/14) for the no-rufinamide group., Conclusion: The study provided valuable information on LGS and its management, and evidence that rufinamide has a consistent and generally favorable safety/tolerability profile when used in routine clinical practice. CLINICALTRIALS., Gov Identifier: NCT01991041., (Copyright © 2017 Elsevier Inc. All rights reserved.)