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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Dendritic Structural Plasticity and Neuropsychiatric Disease
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GRIN2A mutation and early‐onset epileptic encephalopathy: personalized therapy with memantine
Tyler Mark Pierson,Hongjie Yuan,Eric D. Marsh,Karin Fuentes-Fajardo,David R. Adams,Thomas C. Markello,Gretchen Golas,Dimitre R. Simeonov,Conisha Holloman,Anel Tankovic,Manish M. Karamchandani,John M. Schreiber,James C. Mullikin,Cynthia J. Tifft,Camilo Toro,Cornelius F. Boerkoel,Stephen F. Traynelis,William A Gahl +17 more
TL;DR: Techniques of modern translational medicine are employed to identify a disease‐causing mutation, analyze its altered behavior, and screen for therapeutic compounds to treat the proband.
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Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis
Giles E. Hardingham,Kim Q. Do +1 more
TL;DR: These factors have been separately linked to schizophrenia pathogenesis, but evidence now suggests that they are mechanistically interdependent and contribute to a common schizophrenia-associated pathology.
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The hidden genetics of epilepsy—a clinically important new paradigm
TL;DR: Improved understanding of the genetics of the epilepsies is confirmed by the positive outcomes, in terms of treatment selection and counselling, of receiving a genetic diagnosis, and a new paradigm for use in the clinic is suggested.
References
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Journal ArticleDOI
The tower of Babel: Survey on concepts and terminology in electrical status epilepticus in sleep and continuous spikes and waves during sleep in North America
Iván Sánchez Fernández,Kevin E. Chapman,Jurriaan M. Peters,Sanjeev V. Kothare,Douglas R. Nordli,Frances E. Jensen,Anne T. Berg,Tobias Loddenkemper +7 more
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TL;DR: Centrotemporal sharp (CTS) waves, the electroencephalogram (EEG) hallmark of rolandic epilepsy, are found in approximately 4% of the childhood population and the inheritance of CTS is presumed autosomal dominant but this is controversial.
Journal ArticleDOI
A review of the relationships between Landau-Kleffner syndrome, electrical status epilepticus during sleep, and continuous spike-waves during sleep.
TL;DR: The goal of this report is to review the relationships between Landau-Kleffner syndrome, electrical status epilepticus duringsleep (ESES), and continuous spike-waves during sleep (CSWS), and CSWS, which are likely equivalent terms.
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Genetic deletion of NR3A accelerates glutamatergic synapse maturation.
Maile A. Henson,Rylan S. Larsen,Shelikha N. Lawson,Isabel Pérez-Otaño,Nobuki Nakanishi,Stuart A. Lipton,Benjamin D. Philpot +6 more
TL;DR: The data support a model whereby NR3A negatively regulates the developmental stabilization of glutamate receptors involved in excitatory neurotransmission, synaptogenesis, and spine growth, as measured by AMPAR-mediated postsynaptic currents recorded in hippocampal CA1.
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