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.

Author information

Author notes

    • Gaetan Lesca
    •  & Gabrielle Rudolf

    These authors contributed equally to this work.


  1. Department of Genetics, University Hospitals of Lyon, Lyon, France.

    • Gaetan Lesca
    • , Audrey Labalme
    •  & Damien Sanlaville
  2. Claude Bernard Lyon I University, Lyon, France.

    • Gaetan Lesca
    •  & Damien Sanlaville
  3. Centre de Recherche en Neurosciences de Lyon, Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 5292, Institut National de la Santé et de la Recherche Médicale (INSERM) U1028, Lyon, France.

    • Gaetan Lesca
    • , Nadia Boutry-Kryza
    • , Philippe Ryvlin
    • , Alexis Arzimanoglou
    •  & Damien Sanlaville
  4. French Epilepsy, Language and Development (EPILAND) Network, Marseille, France.

    • Gaetan Lesca
    • , Gabrielle Rudolf
    • , Nadine Bruneau
    • , Audrey Labalme
    • , Nadia Boutry-Kryza
    • , Manal Salmi
    • , Timur Tsintsadze
    • , Jacques Motte
    • , Julitta de Bellescize
    • , Anne de Saint Martin
    • , Dorothee Ville
    • , Philippe Ryvlin
    • , Alexis Arzimanoglou
    • , Edouard Hirsch
    • , Nail Burnashev
    • , Damien Sanlaville
    •  & Pierre Szepetowski
  5. Department of Neurology, Strasbourg University Hospital, Strasbourg, France.

    • Gabrielle Rudolf
    •  & Edouard Hirsch
  6. Strasbourg University, Strasbourg, France.

    • Gabrielle Rudolf
    •  & Edouard Hirsch
  7. Aix-Marseille University, Marseille, France.

    • Nadine Bruneau
    • , Natalia Lozovaya
    • , Manal Salmi
    • , Timur Tsintsadze
    • , Vera Tsintsadze
    • , Nail Burnashev
    •  & Pierre Szepetowski
  8. INSERM UMRS 901, Marseille, France.

    • Nadine Bruneau
    • , Natalia Lozovaya
    • , Manal Salmi
    • , Timur Tsintsadze
    • , Vera Tsintsadze
    • , Nail Burnashev
    •  & Pierre Szepetowski
  9. Mediterranean Institute of Neurobiology (INMED), Marseille, France.

    • Nadine Bruneau
    • , Natalia Lozovaya
    • , Manal Salmi
    • , Timur Tsintsadze
    • , Vera Tsintsadze
    • , Nail Burnashev
    •  & Pierre Szepetowski
  10. INSERM UMRS 663, Paris Descartes University, Paris, France.

    • Natalia Lozovaya
  11. Laboratory of Medical Genetics, University Hospitals of Lyon, Lyon, France.

    • Nadia Boutry-Kryza
  12. Department of Clinical Neurosciences, Institute of Psychiatry, King's College London, London, UK.

    • Laura Addis
    •  & Deb Pal
  13. Department of Pediatrics A, American Memorial Hospital, Reims, France.

    • Jacques Motte
  14. Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, UK.

    • Sukhvir Wright
    • , Patrick Waters
    •  & Angela Vincent
  15. Department of Neurology, University Hospital Pontchaillou, Rennes, France.

    • Anne Michel
  16. Department of Neuropediatrics, Armand-Trousseau Hospital, Paris, France.

    • Diane Doummar
  17. Department of Paediatric Neurology, Evelina Children's Hospital, London, UK.

    • Karine Lascelles
  18. The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada.

    • Lisa Strug
  19. The University of Toronto, Toronto, Ontario, Canada.

    • Lisa Strug
  20. Epilepsy, Sleep and Pediatric Neurophysiology Department, University Hospitals of Lyon, Lyon, France.

    • Julitta de Bellescize
    • , Philippe Ryvlin
    •  & Alexis Arzimanoglou
  21. William Lennox Neurology Centre, Université Catholique de Louvain, Ottignies, Belgium.

    • Pascal Vrielynck
  22. Pediatric Department I, Strasbourg University Hospital, Strasbourg, France.

    • Anne de Saint Martin
  23. Department of Neuropediatrics, University Hospitals of Lyon, Lyon, France.

    • Dorothee Ville


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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.

Competing interests

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.

Corresponding author

Correspondence to Pierre Szepetowski.

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