Although many genes that predispose for epilepsy in humans have been determined, those that underlie the classical syndromes of idiopathic generalized epilepsy (IGE) have yet to be identified. We report that an Ala322Asp mutation in GABRA1, encoding the alpha1 subunit of the gamma-aminobutyric acid receptor subtype A (GABA(A)), is found in affected individuals of a large French Canadian family with juvenile myoclonic epilepsy. Compared with wildtype receptors, GABA(A) receptors that contain the mutant subunit show a lesser amplitude of GABA-activated currents in vitro, indicating that seizures may result from loss of function of this inhibitory ligand-gated channel. Our results confirm that mutation of GABRA1 predisposes towards a common idiopathic generalized epilepsy syndrome in humans.

Epilepsy is one of the most common and disabling neurologic conditions, yet we have an incomplete understanding of the detailed pathophysiology and, thus, treatment rationale for much of epilepsy. This article reviews the clinical aspects of seizures and epilepsy with the goal of providing neuroscientists an introduction to aspects that might be amenable to scientific investigation. Seizures and epilepsy are defined, diagnostic methods are reviewed, various clinical syndromes are discussed, and aspects of differential diagnosis, treatment, and prognosis are considered to enable neuroscientists to formulate basic and translational research questions.T his article provides an overview of seizures and epilepsy for neuroscientists. We focus on broad concepts, rather than clinical details, and raise questions related to mechanisms, epileptogenesis, and therapeutic approaches that might generate interest among basic researchers. Further information about differential diagnosis, drug doses, and clinical management are available from numerous resources (Engel and Pedley 2008;Duchowny et al. 2012;Engel 2013).We first define seizures and epilepsy and summarize their classification, pathophysiology, and genetics. Diagnostic methods are then considered, including the importance of an accurate historical description of an event suspected to be a seizure and the appropriate use of ancillary/confirmative tests, such as electroencephalogram (EEG), neuroimaging, and genetic studies. These modalities enable the clinician to differentiate epilepsy from numerous clinical conditions that mimic seizures, but have a nonepileptic pathophysiological basis. Examples of epilepsy syndromes are then described, selected based on their frequency in the population or because they embody scientific questions that warrant elucidation. Finally, we provide an overview of treatment options and prognosis, including a consideration of conditions that accompany epilepsy (comorbidities) and complicate the daily lives of people with epilepsy. Subsequent articles in this collection explore the scientific basis of many of the clinical concepts introduced here. DEFINITIONS AND EPIDEMIOLOGYA "seizure" is a paroxysmal alteration of neurologic function caused by the excessive, hyper-

Developmental and epileptic encephalopathy (DEE) is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability (ID), typically with developmental plateauing or regression associated with frequent epileptiform activity. The cause of DEE remains unknown in the majority of cases. We performed whole-genome sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant seizures and in their unaffected parents. We focused our attention on de novo mutations (DNMs) and identified candidate genes containing such variants. We sought to identify additional subjects with DNMs in these genes by performing targeted sequencing in another series of individuals with DEE and by mining various sequencing datasets. We also performed meta-analyses to document enrichment of DNMs in candidate genes by leveraging our WGS dataset with those of several DEE and ID series. By combining these strategies, we were able to provide a causal link between DEE and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25. Overall, we established a molecular diagnosis in 63/197 (32%) individuals in our WGS series. The main cause of DEE in these individuals was de novo point mutations (53/63 solved cases), followed by inherited mutations (6/63 solved cases) and de novo CNVs (4/63 solved cases). De novo missense variants explained a larger proportion of individuals in our series than in other series that were primarily ascertained because of ID. Moreover, these DNMs were more frequently recurrent than those identified in ID series. These observations indicate that the genetic landscape of DEE might be different from that of ID without epilepsy.