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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The genetic landscape of the epileptic encephalopathies of infancy and childhood
Amy McTague,Amy McTague,Katherine B. Howell,Katherine B. Howell,J. Helen Cross,J. Helen Cross,Manju A. Kurian,Manju A. Kurian,Ingrid E. Scheffer +8 more
TL;DR: Gene discovery provides the basis for neurobiological insights, often showing convergence of mechanistic pathways that underpin the development of targeted therapies, which are essential to improve the outcome of these devastating disorders.
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References
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Journal ArticleDOI
Centrotemporal spikes in families with rolandic epilepsy: linkage to chromosome 15q14.
Bernd A. Neubauer,B. Fiedler,B. Himmelein,F. Kampfer,Uta Lässker,G. Schwabe,I. Spanier,D. Tams,C. Bretscher,K. Moldenhauer,Gerhard Kurlemann,S. Weise,Kristina Tedroff,Orvar Eeg-Olofsson,C. Wadelius,Ulrich Stephani +15 more
TL;DR: Evidence for linkage of BECTS to a region on chromosome 15q14 is found and either the alpha 7 AChR subunit gene or a closely linked gene are implicated in pedigrees with BEC TS, which is genetically heterogeneous.
Journal ArticleDOI
Centrotemporal sharp wave EEG trait in rolandic epilepsy maps to Elongator Protein Complex 4 (ELP4)
Lisa J. Strug,Tara Clarke,Theodore Chiang,Minchen Chien,Zeynep Baskurt,Weili Li,Ruslan Dorfman,Bhavna Bali,Elaine C. Wirrell,Steven L. Kugler,David E. Mandelbaum,Steven M Wolf,Patricia McGoldrick,Huntley Hardison,Edward J. Novotny,Jingyue Ju,David A. Greenberg,David A. Greenberg,James J. Russo,Deb K. Pal,Deb K. Pal +20 more
TL;DR: It is hypothesized that a non-coding mutation in ELP4 impairs brain-specific Elongator-mediated interaction of genes implicated in brain development, resulting in susceptibility to seizures and neurodevelopmental disorders.
Journal ArticleDOI
Idiopathic epilepsies with seizures precipitated by fever and SCN1A abnormalities
Carla Marini,Davide Mei,Teresa Temudo,Anna Rita Ferrari,Daniela Buti,Charlotte Dravet,Ana I. Dias,Ana Lucila Moreira,Eulália Calado,Stefano Seri,Brian G. R. Neville,Juan Narbona,Evan Reid,Roberto Michelucci,Federico Sicca,Helen Cross,Renzo Guerrini +16 more
TL;DR: SCN1A is the most clinically relevant epilepsy gene, most mutations lead to severe myoclonic epilepsy of infancy (SMEI) and generalized epilepsy with febrile seizures plus (GEFS+).
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The NMDA receptor complex as a therapeutic target in epilepsy: a review
TL;DR: The evidence for the involvement of N MDARs in the pathophysiology of epilepsy is described and an overview of NMDAR antagonists that have been investigated in clinical trials and animal models of epilepsy are provided.
Journal ArticleDOI
Analysis of Donor Splice Sites in Different Eukaryotic Organisms
Igor B. Rogozin,Luciano Milanesi +1 more
TL;DR: The analysis demonstrated that accuracy of the functional site prediction could be improved if one takes into account correlations between the site positions, and the accuracy of prediction by using human consensus sequences was tested on sequences from different organisms.
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