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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Past and present definitions of epileptogenesis and its biomarkers.
Asla Pitkänen,Jerome Engel +1 more
TL;DR: A high priority is currently being placed on investigations to elucidate fundamental mechanisms of epileptogenesis and identify biomarkers for specific models of human epilepsy, such as mesial temporal lobe epilepsy with hippocampal sclerosis, traumatic brain injury, and a variety of pediatric diseases, including tuberous sclerosis and West syndrome.
Journal ArticleDOI
Ion Channels in Genetic Epilepsy: From Genes and Mechanisms to Disease-Targeted Therapies.
Julia Oyrer,Snezana Maljevic,Ingrid E. Scheffer,Samuel F. Berkovic,Steven Petrou,Christopher A. Reid +5 more
TL;DR: The genetic, molecular, and physiologic evidence supporting the pathogenic role of a number of different voltage- and ligand-activated ion channels in genetic epilepsy is reviewed and proposed disease mechanisms for each ion channel are reviewed.
Journal ArticleDOI
GRIN2B mutations in West syndrome and intellectual disability with focal epilepsy.
Johannes R. Lemke,Rik Hendrickx,Kirsten Geider,Bodo Laube,Michael Schwake,Robert J. Harvey,Victoria M. James,Alex Pepler,Isabelle Steiner,Konstanze Hörtnagel,John Neidhardt,Susanne Ruf,Markus Wolff,Deborah Bartholdi,Roberto Caraballo,Konrad Platzer,Arvid Suls,Peter De Jonghe,Saskia Biskup,Sarah Weckhuysen +19 more
TL;DR: To identify novel epilepsy genes using a panel approach and describe the functional consequences of mutations, a large number of mutations are identified using a single gene-based approach.
Journal ArticleDOI
Zinc Dynamics and Action at Excitatory Synapses
Angela Maria Vergnano,Nelson Rebola,Leonid P. Savtchenko,Paulo S. Pinheiro,Paulo S. Pinheiro,Mariano Casado,Mariano Casado,Mariano Casado,Brigitte L. Kieffer,Dmitri A. Rusakov,Christophe Mulle,Christophe Mulle,Pierre Paoletti,Pierre Paoletti,Pierre Paoletti +14 more
TL;DR: This work establishes the rules of zinc action and reveals that zinc modulation extends beyond hippocampal mossy fibers to excitatory SC-CA1 synapses and acts as a widespread activity-dependent regulator of neuronal circuits.
Journal ArticleDOI
Advancing epilepsy genetics in the genomic era
TL;DR: The rapid pace of gene discovery in epilepsy, as facilitated by genomic technologies, is discussed, and several novel genes and potential therapies are highlighted.
References
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