Progressive myoclonus epilepsies (PMEs) are a group of rare, inherited disorders manifesting with action myoclonus, tonic-clonic seizures, and ataxia. We exome-sequenced 84 unrelated PME patients of unknown cause and molecularly solved 26 cases (31%). Remarkably, a recurrent de novo mutation c.959G>A (p.Arg320His) in KCNC1 was identified as a novel major cause for PME. Eleven unrelated exome-sequenced (13%) and two patients in a secondary cohort (7%) had this mutation. KCNC1 encodes K V 3.1, a subunit of the K V 3 voltage-gated K + channels, major determinants of high-frequency neuronal firing. Functional analysis of the p.Arg320His mutant channel revealed a dominant-negative loss-of-function effect. Ten patients had pathogenic mutations in known PME-associated genes (NEU1, NHLRC1, AFG3L2, EPM2A, CLN6, SERPINI1). Identification of mutations in PRNP, SACS, and TBC1D24 expand their phenotypic spectrum to PME. These findings provide important insights into the molecular genetic basis of PME and reveal the role of de novo mutations in this disease entity.Correspondence should be addressed to Anna-Elina Lehesjoki (anna-elina.lehesjoki@helsinki.fi). Author Contributions Accession codesMutation nomenclatures correspond to the following canonical Ensembl transcripts: KCNC1, ENST00000265969.6; NEU1, ENST00000375631.4; NHLRC1, ENST00000340650.3; EPM2A, ENST00000367519.3; CLN6, ENST00000249806.5; AFG3L2, ENST00000269143.3; TBC1D24, ENST00000293970.5; SACS, ENST00000382298.3; SERPINI1, ENST00000295777.5; PRNP, ENST00000379440.4; SCN1A, ENST00000303395.4. The raw aligned sequence reads were submitted to the European Genome-phenome Archive (https://www.ebi.ac.uk/ega/home) by Wellcome Trust Sanger Institute under study accession numbers EGAS00001000048 and EGAS00001000386. Competing Financial InterestsAuthors declare no potential competing financial interests. Europe PMC Funders GroupAuthor Manuscript Nat Genet. Author manuscript; available in PMC 2015 July 01. Published in final edited form as:Nat Genet. 5,6 and GOSR2 7 also contribute to cases of PME with preserved cognition. Other PMEs may have additional features, particularly dementia. PME-associated genes encode a variety of proteins, many of them being associated with endosomal and lysosomal function 8,9 , but the associated disease mechanisms are generally poorly understood.The precise clinical diagnosis of specific forms of PME is challenging due to their genetic heterogeneity, phenotypic similarities and overlap of symptoms with other epileptic and neurodegenerative diseases. In many cases, there are no distinguishing clinical features or biomarkers. Consequently, a substantial proportion of PME cases remain without a molecular diagnosis 3 .Here, we aimed to identify the causative genes for unsolved PME cases by employing exome sequencing in unrelated patients assembled from multiple centers in Europe, North America, Asia, and Australia over a 25-year period. The extent of previous molecular studies varied, but all cases were negative for mutations in the ...

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SUMMARYObjective: Seizures may occur in close temporal association with a stroke or after a variable interval. Moreover, epilepsy is often encountered in patients with leukoaraiosis. Although early post-stroke seizures have been studied extensively, less attention has been paid to post-stroke epilepsy (PSE) and to epilepsy associated with leukoaraiosis (EAL). The aim of this paper is to review data concerning pathophysiology, prognosis, and treatment of PSE and EAL. Methods: We performed an extensive literature search to identify experimental and clinical articles on PSE and EAL. We also conducted a systematic review of risk factors for PSE and EAL among eligible studies. Results: PSE is caused by enhanced neuronal excitability within and near the scar. The role played by white matter changes in EAL remains to be elucidated. Meta-analysis showed that cortical involvement (odds ratio [OR]

Activation of specific cortical territories by sensory stimuli or of less restricted areas of the brain by cognitive stimuli is known to induce apparently generalized seizures in predisposed patients; this is clinically and electroencephalographically distinct from reflex triggering of partial seizures. Photosensitive patients may have seizures when exposed to environmental stimuli producing appropriate flickering light or geometric patterns. Some children with benign myoclonic epilepsy in infancy have seizures triggered by unexpected touch or noise. Seizures induced by thinking have been reported in response to non-verbal higher mental activity such as mental arithmetic. Praxis-induced seizures are triggered by similar mental activities accompanied by the use of the hands. Language-induced seizures are usually triggered by verbal higher mental activity. Functional imaging and other methods have contributed to understanding how these seizures arise. Patients with these generalized reflex seizures appear to have regions of cortical hyperexcitability overlapping or coinciding with areas physiologically activated during specific sensory stimulations and cognitive or motor activities. When these areas receive appropriate afferent volleys and a critical mass of cortex is activated, an epileptic activity is produced that ultimately involves cortico-reticular or cortico-cortical pathways resulting in a generalized or bilateral epileptic event.

In this review we assess our currently available knowledge about reflex seizures with special emphasis on the difference between "generalized" reflex seizures induced by visual stimuli, thinking, praxis and language tasks, and "focal" seizures induced by startle, eating, music, hot water, somatosensory stimuli and orgasm. We discuss in particular evidence from animal, clinical, neurophysiological and neuroimaging studies supporting the concept that "generalized" reflex seizures, usually occurring in the setting of IGE, should be considered as focal seizures with quick secondary generalization. We also review recent advances in genetic and therapeutic approach of reflex seizures.

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).

SUMMARYPurpose: Absence status epilepticus (AS) is a prolonged, generalized, and nonconvulsive seizure that may occur in various circumstances. We report a series of patients in whom recurrent, unprovoked, typical AS was the main clinical feature. Method: We retrospectively reviewed consecutive patients referred to our epileptic centers, on the following criteria: (1) recurrent, unprovoked episodes of typical AS representing the unique or the predominant seizure type, (2) at least one episode of AS recorded by video-EEG or by EEG only, and (3) clinical and EEG features fulfilling the criteria of idiopathic epilepsy. We excluded patients with situation-related AS. Results: We found 11 such cases (5F, 6M). The onset of AS was after puberty or in early adulthood in most; no clear triggering factor could account for the recurrence of AS episodes; infrequent generalized tonic-clonic seizures, and, rarely, absences, could also occur. These patients had no family history of epilepsy, normal neurological evaluation, normal neuroimaging, interictal EEG showing generalized spike-and polyspike-wave discharges on a normal background, no photoparoxysmal response, variable response of AS to intravenous benzodiazepines, and usually good seizure control with valproate. This peculiar condition was misdiagnosed in most because of the unusual clinical presentation and of some atypical interictal EEG findings, often leading to the use of inappropriate drugs. Conclusion: Although there is some overlap with previously described epilepsy syndromes, specific and shared features point to the existence of a distinct epilepsy entity that we propose to name "absence status epilepsy." This syndrome expands the spectrum of idiopathic generalized epilepsies. KEY WORDS: Absence status, Idiopathic generalized epilepsy, Valproate.Absence status epilepticus (AS) is a prolonged, generalized, and nonconvulsive seizure characterized by more or less severe impairment of consciousness at times associated with other clinical manifestations such as automatisms or subtle myoclonic, tonic, atonic, or autonomic phenomena . The current proposed ILAE diagnostic scheme (Engel, 2001) considers AS as a subtype of generalized status epilepticus. AS can occur in various clinical contexts although ictal manifestations significantly overlap. On this ground, some authors distinguish typical AS, occurring in the setting of idiopathic generalized epilepsies (IGEs), from atypical AS,

Summary:Purpose: To assess the long-term evolution of Unverricht-Lundborg disease (ULD), especially concerning myoclonus, seizures, and EEG characteristics.Methods: We retrospectively evaluated 20 patients (six women, 14 men; mean age, 37.9 years; range, 26-53 years) with ULD who had been closely followed up since the onset of the disease (mean age, 12.3 years; range, 6-17 years) for an average of 25.6 years (range, 13-41 years). ULD was confirmed by genetic tests in all. We used simplified myoclonus and seizure rating scales.