Epileptic encephalopathies are severe brain disorders with the epileptic component contributing to the worsening of cognitive and behavioral manifestations1. Acquired epileptic aphasia (Landau-Kleffner syndrome, LKS)2 and continuous spike and waves during slow-wave sleep syndrome (CSWSS)3 represent rare and closely related childhood focal epileptic encephalopathies of unknown etiology4,5. They show electroclinical overlap with rolandic epilepsy (the most frequent childhood focal epilepsy) and can be viewed as different clinical expressions of a single pathological entity situated at the crossroads of epileptic, speech, language, cognitive and behavioral disorders6,7,8,9,10. Here we demonstrate that about 20% of cases of LKS, CSWSS and electroclinically atypical rolandic epilepsy11,12,13 often associated with speech impairment can have a genetic origin sustained by de novo or inherited mutations in the GRIN2A gene (encoding the N-methyl-D-aspartate (NMDA) glutamate receptor α2 subunit, GluN2A). The identification of GRIN2A as a major gene for these epileptic encephalopathies provides crucial insights into the underlying pathophysiology.
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We thank all the subjects and families who participated in the study. Written informed consent was obtained from parents for their children and for themselves, according to the appropriate bioethics laws and ethical committees (no. 05/78, CPP Strasbourg, Alsace 1). We thank C. Boulay, M. Lim, E. Panagiotakaki, C. Seegmuller and M.-P. Valenti-Hirsch for their valuable participation in clinical analyses, R. Lamy for expert technical assistance, F. Michel at inMAGIC (INMED Imaging Centre) and all the administrative staff at INMED. Assistance from the Biological Resource Centre, Hospices Civils (Lyon, France) and from the Banque de Génome, Hôpital de Brabois (Vandoeuvre-les-Nancy, France) was greatly appreciated. S.W. is supported by the Wellcome Trust. P.W. and A.V. are partly supported by the NIHR Oxford Biomedical Research Centre. This work was supported by ANR (Agence Nationale de la Recherche) grant EPILAND (ANR-2010-BLAN-1405 01) with EuroBiomed label, by National PHRC (Projet Hospitalier de Recherche Clinique) grant 2010 03-08 and by INSERM.
A.V. and the University of Oxford hold patents and receive royalties and payments for antibody assays for the diagnosis of neurological diseases such as myasthenia gravis and different forms of autoimmune encephalitis.
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Lesca, G., Rudolf, G., Bruneau, N. et al. GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction. Nat Genet 45, 1061–1066 (2013). https://doi.org/10.1038/ng.2726
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