Epileptic encephalopathies of the Landau-Kleffner and continuous spike and waves during slow-wave sleep types: Genomic dissection makes the link with autism

被引:128
作者
Lesca, Gaetan [2 ,3 ,4 ]
Rudolf, Gabrielle [5 ,6 ]
Labalme, Audrey [2 ]
Hirsch, Edouard [5 ,6 ]
Arzimanoglou, Alexis [4 ,7 ]
Genton, Pierre [8 ]
Motte, Jacques [9 ]
de Saint Martin, Anne [10 ]
Valenti, Maria-Paola [5 ]
Boulay, Clotilde [5 ]
De Bellescize, Julitta [7 ]
Keo-Kosal, Pascale [7 ]
Boutry-Kryza, Nadia [3 ,4 ,11 ]
Edery, Patrick [2 ,3 ,4 ]
Sanlaville, Damien [2 ,3 ,4 ]
Szepetowski, Pierre [1 ,12 ]
机构
[1] Genet Epilepsies Isolees & Associees GEIA Grp, Inst Neurobiolo Mediterranee INMED, INSERM, UMR901, F-13273 Marseille 09, France
[2] Lyon Hosp Civils, Dept Constitut Cytogenet, Lyon, France
[3] Univ Lyon 1, F-69365 Lyon, France
[4] CNRS, CRNL, UMR 5292, INSERM,U1028, Lyon, France
[5] Strasbourg Univ Hosp, Dept Neurol, Strasbourg, France
[6] Strasbourg Univ, Strasbourg, France
[7] Lyon Hosp Civils, Dept Pediat Epileptol, Lyon, France
[8] Henri Gastaut Hosp, Marseille, France
[9] Amer Mem Hosp, Pediat Dept A, Reims, France
[10] Strasbourg Univ Hosp, Dept Pediat 1, Strasbourg, France
[11] Lyon Hosp Civils, Mol Genet Lab, Lyon, France
[12] Aix Marseille Univ, Marseille, France
关键词
Epilepsy; Slow-wave sleep; Landau-Kleffner; Autism; Gene; COPY NUMBER VARIANTS; ELECTRICAL STATUS EPILEPTICUS; IDIOPATHIC ROLANDIC EPILEPSY; WIDE ASSOCIATION; SPECTRUM; GENE; DISORDERS; MUTATIONS; SPEECH; EEG;
D O I
10.1111/j.1528-1167.2012.03559.x
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Purpose: The continuous spike and waves during slow-wave sleep syndrome (CSWSS) and the Landau-Kleffner (LKS) syndrome are two rare epileptic encephalopathies sharing common clinical features including seizures and regression. Both CSWSS and LKS can be associated with the electroencephalography pattern of electrical status epilepticus during slow-wave sleep and are part of a clinical continuum that at its benign end also includes rolandic epilepsy (RE) with centrotemporal spikes. The CSWSS and LKS patients can also have behavioral manifestations that overlap the spectrum of autism disorders (ASD). An impairment of brain development and/or maturation with complex interplay between genetic predisposition and nongenetic factors has been suspected. A role for autoimmunity has been proposed but the pathophysiology of CSWSS and of LKS remains uncharacterized. Methods: In recent years, the participation of rare genomic alterations in the susceptibility to epileptic and autistic disorders has been demonstrated. The involvement of copy number variations (CNVs) in 61 CSWSS and LKS patients was questioned using comparative genomic hybridization assays coupled with validation by quantitative polymerase chain reaction (PCR). Key Findings: Whereas the patients showed highly heterogeneous in genomic architecture, several potentially pathogenic alterations were detected. A large number of these corresponded to genomic regions or genes (ATP13A4, CDH9, CDH13, CNTNAP2, CTNNA3, DIAPH3, GRIN2A, MDGA2, SHANK3) that have been either associated with ASD for most of them, or involved in speech or language impairment, or in RE. Particularly, CNVs encoding cell adhesion proteins (cadherins, protocadherins, contactins, catenins) were detected with high frequency (approximate to 20% of the patients) and significant enrichment (cell adhesion: p = 0.027; cell adhesion molecule binding: p = 9.27 x 10-7). Significance: Overall our data bring the first insights into the possible molecular pathophysiology of CSWSS and LKS. The overrepresentation of cell adhesion genes and the strong overlap with the genetic, genomic and molecular ASD networks, provide an exciting and unifying view on the clinical links among CSWSS, LKS, and ASD.
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收藏
页码:1526 / 1538
页数:13
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