Journal ArticleDOI
Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes
Johannes R. Lemke,Dennis Lal,Eva M. Reinthaler,Isabelle Steiner,Michael Nothnagel,Michael Alber,Kirsten Geider,Bodo Laube,Michael Schwake,Katrin Finsterwalder,Andre Franke,Markus Schilhabel,Johanna A. Jähn,Hiltrud Muhle,Rainer Boor,Wim Van Paesschen,Roberto Caraballo,Natalio Fejerman,Sarah Weckhuysen,Peter De Jonghe,Jan Larsen,Rikke S. Møller,Helle Hjalgrim,Laura Addis,Shan Tang,Elaine Hughes,Deb K. Pal,Kadi Veri,Ulvi Vaher,Tiina Talvik,Petia Dimova,Rosa Guerrero López,José M. Serratosa,Tarja Linnankivi,Anna-Elina Lehesjoki,Susanne Ruf,Markus Wolff,Sarah E. Buerki,Gabriele Wohlrab,Judith Kroell,Alexandre N. Datta,Barbara Fiedler,Gerhard Kurlemann,Gerhard Kluger,Andreas Hahn,D Edda Haberlandt,Christina Kutzer,Jürgen Sperner,Felicitas Becker,Yvonne G. Weber,Martha Feucht,Hannelore Steinböck,Birgit Neophythou,Gabriel M. Ronen,Ursula Gruber-Sedlmayr,Julia Geldner,Robert J. Harvey,Per Hoffmann,Per Hoffmann,Stefan Herms,Stefan Herms,Janine Altmüller,Mohammad R. Toliat,Holger Thiele,Peter Nürnberg,Christian Wilhelm,Ulrich Stephani,Ingo Helbig,Holger Lerche,Fritz Zimprich,Bernd A. Neubauer,Saskia Biskup,Saskia Biskup,Sarah von Spiczak +73 more
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TLDR
Results establish alterations of the gene encoding the NMDA receptor NR2A subunit as a major genetic risk factor for IFE.Abstract:
Idiopathic focal epilepsy (IFE) with rolandic spikes is the most common childhood epilepsy, comprising a phenotypic spectrum from rolandic epilepsy (also benign epilepsy with centrotemporal spikes, BECTS) to atypical benign partial epilepsy (ABPE), Landau-Kleffner syndrome (LKS) and epileptic encephalopathy with continuous spike and waves during slow-wave sleep (CSWS). The genetic basis is largely unknown. We detected new heterozygous mutations in GRIN2A in 27 of 359 affected individuals from 2 independent cohorts with IFE (7.5%; P = 4.83 × 10(-18), Fisher's exact test). Mutations occurred significantly more frequently in the more severe phenotypes, with mutation detection rates ranging from 12/245 (4.9%) in individuals with BECTS to 9/51 (17.6%) in individuals with CSWS (P = 0.009, Cochran-Armitage test for trend). In addition, exon-disrupting microdeletions were found in 3 of 286 individuals (1.0%; P = 0.004, Fisher's exact test). These results establish alterations of the gene encoding the NMDA receptor NR2A subunit as a major genetic risk factor for IFE.read more
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Journal ArticleDOI
The Clinical Spectrum of Benign Epilepsy with Centro-Temporal Spikes: a Challenge in Categorization and Predictability.
TL;DR: Benign epilepsy with centro-temporal spikes, atypical benign focal epilepsy during childhood, status epilepticus of BECTS, Landau-Kleffner syndrome, and epileptic encephalopathy with continuous spike-and-wave during sleep are all considered different entities, but are part of a single spectrum of disorders.
Journal ArticleDOI
The Genetics of Neuropsychiatric Diseases: Looking In and Beyond the Exome
TL;DR: The recent progress that resulted specifically from exome sequencing is reviewed and the need for rigorous statistical evaluation of the expanding data sets, as well as expanded functional analysis of implicated proteins and mutations is emphasized.
Journal ArticleDOI
Divergent roles of a peripheral transmembrane segment in AMPA and NMDA receptors
Johansen B. Amin,Catherine L. Salussolia,Kelvin Chan,Michael C. Regan,Jian Dai,Huan-Xiang Zhou,Hiro Furukawa,Mark E. Bowen,Lonnie P. Wollmuth +8 more
TL;DR: The findings reveal that the functional roles of the M4 segments in AMPARs and NMDARs have diverged in the course of their evolution and that the M 4 segments in N MDARs may act as a transduction pathway for receptor modulation at synapses.
Journal ArticleDOI
An Epilepsy-Associated GRIN2A Rare Variant Disrupts CaMKIIα Phosphorylation of GluN2A and NMDA Receptor Trafficking.
Marta Vieira,Thien A. Nguyen,Kunwei Wu,John D. Badger,Brett M. Collins,Victor Anggono,Wei Lu,Katherine W. Roche +7 more
TL;DR: Data demonstrate a role for CaMKIIα phosphorylation of GluN2A in receptor targeting and implicate NMDAR trafficking defects as a link to epilepsy.
Journal ArticleDOI
Recent advances in gene therapy for neurodevelopmental disorders with epilepsy.
TL;DR: This review focuses on those neurodevelopmental disorders that are frequently characterized by the presence of epilepsy (NDD + E), and loosely group the genes linked to NDD + E with different neuronal functions: transcriptional regulation, intrinsic excitability and synaptic transmission.
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