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GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction

Abstract

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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Figure 1: Inherited and de novo GRIN2A mutations in individuals and families with variable association of LKS, CSWSS, atypical rolandic epilepsy and speech impairment.
Figure 2: GluN2A missense alteration p.Arg518His alters the gating kinetics of the NMDA receptor.
Figure 3: Domain location of nonsense, frameshift and missense alterations found in glutamate receptor subunit GluN2A.

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NCBI Reference Sequence

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Acknowledgements

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.

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G.L. and G.R. coordinated the collection of samples and of clinical information, performed and analyzed genetic data and participated in the study design, with equal contributions. N. Bruneau supervised and carried out the synthesis of the constructs, performed the in vitro assays and the immunocytochemistry experiments and participated in cell-based electrophysiological assays and in study design. N.L., T.T., V.T. and N. Burnashev performed and designed all electrophysiological studies and related data analyses. J.M., A.M., D.D., K.L., J.d.B., P.V., A.S.M., D.V., P.R., A.A., D.P. and E.H. performed phenotyping analysis and clinical data collection. A.L., N.B.-K., M.S., L.A., L.S. and D.P. participated in genetic experiments and analyses. S.W., P.W. and A.V. performed the in vitro immunological assays. D.S. participated in the overall strategy and in genetic data analyses and supervision. P.S. was the project leader. He decided on the overall strategy, directed the follow-up of experiments, supervised data analysis and wrote the manuscript with G.L. and G.R. and with help from N. Bruneau, N.L., N. Burnashev and D.S. All authors contributed to the final version of the manuscript.

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Correspondence to Pierre Szepetowski.

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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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Supplementary Figures 1–6, Supplementary Tables 1 and 2, and Supplementary Note (PDF 3119 kb)

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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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