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

Gaetan Lesca; Gabrielle Rudolf; Nadine Bruneau; Natalia Lozovaya; Audrey Labalme; Nadia Boutry-Kryza; Manal Salmi; Timur Tsintsadze; Laura Addis; Jacques Motte; Sukhvir Wright; Vera Tsintsadze; Anne Michel; Diane Doummar; Karine Lascelles; Lisa Strug; Patrick Waters; Julitta De Bellescize; Pascal Vrielynck; Anne De Saint Martin; Dorothee Ville; Philippe Ryvlin; Alexis Arzimanoglou; Edouard Hirsch; Angela Vincent; Deb Pal; Nail Burnashev; Damien Sanlaville; Pierre Szepetowski

doi:10.1038/ng.2726

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

Gaetan Lesca
, Gabrielle Rudolf
, Nadine Bruneau
, Natalia Lozovaya
, Audrey Labalme
, Nadia Boutry-Kryza
, Manal Salmi
, Timur Tsintsadze
, Laura Addis
, Jacques Motte
, Sukhvir Wright
, Vera Tsintsadze
, Anne Michel
, Diane Doummar
, Karine Lascelles
, Lisa Strug
, Patrick Waters
, Julitta De Bellescize
, Pascal Vrielynck
, Anne De Saint Martin

Dorothee Ville, Philippe Ryvlin, Alexis Arzimanoglou, Edouard Hirsch, Angela Vincent, Deb Pal, Nail Burnashev, Damien Sanlaville, Pierre Szepetowski^*

^*Corresponding author for this work

College of Health and Life Sciences

University Hospitals of Lyon
CHU-Lyon - UR 5558 CNRS - Université Claude Bernard Lyon
Centre de Recherche en Neurosciences de Lyon
Language and Development (EPILAND) Network
Strasbourg University Hospital
Université Louis Pasteur
Université Mediterranee, Aix-Marseille II Aix-en-Provence
INSERM U632
Mediterranean Institute of Neurobiology (INMED)
UMR S 1138
King's College London
American Memorial Hospital
University Hospital Pontchaillou
French reference centre for platelet disorders
Guy's and St Thomas NHS Foundation Trust
Hospital for Sick Children Research Institute
University of Toronto
University of Oxford
Université catholique de Louvain

Research output: Contribution to journal › Letter, comment/opinion or interview › peer-review

393 Citations (SciVal)

Abstract

Epileptic encephalopathies are severe brain disorders with the epileptic component contributing to the worsening of cognitive and behavioral manifestations. Acquired epileptic aphasia (Landau-Kleffner syndrome, LKS) and continuous spike and waves during slow-wave sleep syndrome (CSWSS) represent rare and closely related childhood focal epileptic encephalopathies of unknown etiology. 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 disorders. Here we demonstrate that about 20% of cases of LKS, CSWSS and electroclinically atypical rolandic epilepsy 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.

Original language	English
Pages (from-to)	1061-1066
Number of pages	6
Journal	Nature Genetics
Volume	45
Issue number	9
DOIs	https://doi.org/10.1038/ng.2726
Publication status	Published - 1 Sept 2013

Funding

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.

Access to Document

10.1038/ng.2726

Cite this

Lesca, G., Rudolf, G., Bruneau, N., Lozovaya, N., Labalme, A., Boutry-Kryza, N., Salmi, M., Tsintsadze, T., Addis, L., Motte, J., Wright, S., Tsintsadze, V., Michel, A., Doummar, D., Lascelles, K., Strug, L., Waters, P., De Bellescize, J., Vrielynck, P., ... Szepetowski, P. (2013). GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction. Nature Genetics, 45(9), 1061-1066. https://doi.org/10.1038/ng.2726

@article{5ceba23e1dab40d8b79621a56aa476dc,

title = "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 manifestations. Acquired epileptic aphasia (Landau-Kleffner syndrome, LKS) and continuous spike and waves during slow-wave sleep syndrome (CSWSS) represent rare and closely related childhood focal epileptic encephalopathies of unknown etiology. 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 disorders. Here we demonstrate that about 20\% of cases of LKS, CSWSS and electroclinically atypical rolandic epilepsy 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.",

author = "Gaetan Lesca and Gabrielle Rudolf and Nadine Bruneau and Natalia Lozovaya and Audrey Labalme and Nadia Boutry-Kryza and Manal Salmi and Timur Tsintsadze and Laura Addis and Jacques Motte and Sukhvir Wright and Vera Tsintsadze and Anne Michel and Diane Doummar and Karine Lascelles and Lisa Strug and Patrick Waters and \{De Bellescize\}, Julitta and Pascal Vrielynck and \{De Saint Martin\}, Anne and Dorothee Ville and Philippe Ryvlin and Alexis Arzimanoglou and Edouard Hirsch and Angela Vincent and Deb Pal and Nail Burnashev and Damien Sanlaville and Pierre Szepetowski",

year = "2013",

month = sep,

day = "1",

doi = "10.1038/ng.2726",

language = "English",

volume = "45",

pages = "1061--1066",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "9",

}

Lesca, G, Rudolf, G, Bruneau, N, Lozovaya, N, Labalme, A, Boutry-Kryza, N, Salmi, M, Tsintsadze, T, Addis, L, Motte, J, Wright, S, Tsintsadze, V, Michel, A, Doummar, D, Lascelles, K, Strug, L, Waters, P, De Bellescize, J, Vrielynck, P, De Saint Martin, A, Ville, D, Ryvlin, P, Arzimanoglou, A, Hirsch, E, Vincent, A, Pal, D, Burnashev, N, Sanlaville, D & Szepetowski, P 2013, 'GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction', Nature Genetics, vol. 45, no. 9, pp. 1061-1066. https://doi.org/10.1038/ng.2726

TY - JOUR

T1 - GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction

AU - Lesca, Gaetan

AU - Rudolf, Gabrielle

AU - Bruneau, Nadine

AU - Lozovaya, Natalia

AU - Labalme, Audrey

AU - Boutry-Kryza, Nadia

AU - Salmi, Manal

AU - Tsintsadze, Timur

AU - Addis, Laura

AU - Motte, Jacques

AU - Wright, Sukhvir

AU - Tsintsadze, Vera

AU - Michel, Anne

AU - Doummar, Diane

AU - Lascelles, Karine

AU - Strug, Lisa

AU - Waters, Patrick

AU - De Bellescize, Julitta

AU - Vrielynck, Pascal

AU - De Saint Martin, Anne

AU - Ville, Dorothee

AU - Ryvlin, Philippe

AU - Arzimanoglou, Alexis

AU - Hirsch, Edouard

AU - Vincent, Angela

AU - Pal, Deb

AU - Burnashev, Nail

AU - Sanlaville, Damien

AU - Szepetowski, Pierre

PY - 2013/9/1

Y1 - 2013/9/1

N2 - Epileptic encephalopathies are severe brain disorders with the epileptic component contributing to the worsening of cognitive and behavioral manifestations. Acquired epileptic aphasia (Landau-Kleffner syndrome, LKS) and continuous spike and waves during slow-wave sleep syndrome (CSWSS) represent rare and closely related childhood focal epileptic encephalopathies of unknown etiology. 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 disorders. Here we demonstrate that about 20% of cases of LKS, CSWSS and electroclinically atypical rolandic epilepsy 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.

AB - Epileptic encephalopathies are severe brain disorders with the epileptic component contributing to the worsening of cognitive and behavioral manifestations. Acquired epileptic aphasia (Landau-Kleffner syndrome, LKS) and continuous spike and waves during slow-wave sleep syndrome (CSWSS) represent rare and closely related childhood focal epileptic encephalopathies of unknown etiology. 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 disorders. Here we demonstrate that about 20% of cases of LKS, CSWSS and electroclinically atypical rolandic epilepsy 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.

UR - https://www.scopus.com/pages/publications/84883462975

UR - https://www.nature.com/articles/ng.2726

U2 - 10.1038/ng.2726

DO - 10.1038/ng.2726

M3 - Letter, comment/opinion or interview

C2 - 23933820

AN - SCOPUS:84883462975

SN - 1061-4036

VL - 45

SP - 1061

EP - 1066

JO - Nature Genetics

JF - Nature Genetics

IS - 9

ER -

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

Abstract

Funding

Access to Document

Other files and links

Fingerprint

Cite this