Genetics Studies in Idiopathic Focal Epilepsies in Childhood

Abstract

Numerous “epilepsy genes” have been identified in the recent years, thanks to the recent progress in massive parallel sequencing and genome analysis. Among the formerly called “idiopathic” childhood focal epilepsies, a first and major gene responsible for focal epilepsies and epileptic encephalopathies with speech and language dysfunction (the epilepsy–aphasia spectrum, EAS), GRIN2A, has been identified. GRIN2A encodes the GluN2A subunit of N-methyl-D-aspartate receptors, which are gated by the excitatory neurotransmitter glutamate. More than 60 mutations of various types and with various functional consequences in vitro have been reported. Several rare genetic variants that may influence EAS have been reported in a few other genes. The identification of GRIN2A as a first cause of EAS represents a first key point that will help in deciphering the underlying pathophysiology and in understanding the clinical heterogeneity and variability seen in the patients and families.

Keywords

focal epilepsies - Rolandic - epilepsy–aphasia - GRIN2A - gene

• References

• 1 Myers CT, Mefford HC. Advancing epilepsy genetics in the genomic era. Genome Med 2015; 7 (1) 91
• 2 Berg AT, Berkovic SF, Brodie MJ , et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia 2010; 51 (4) 676-685
• 3 De Tiège X, Goldman S, Verheulpen D, Aeby A, Poznanski N, Van Bogaert P. Coexistence of idiopathic rolandic epilepsy and CSWS in two families. Epilepsia 2006; 47 (10) 1723-1727
• 4 Vears DF, Tsai MH, Sadleir LG , et al. Clinical genetic studies in benign childhood epilepsy with centrotemporal spikes. Epilepsia 2012; 53 (2) 319-324
• 5 Dimassi S, Labalme A, Lesca G , et al. A subset of genomic alterations detected in rolandic epilepsies contains candidate or known epilepsy genes including GRIN2A and PRRT2. Epilepsia 2014; 55 (2) 370-378
• 6 Scheffer IE, Jones L, Pozzebon M, Howell RA, Saling MM, Berkovic SF. Autosomal dominant rolandic epilepsy and speech dyspraxia: a new syndrome with anticipation. Ann Neurol 1995; 38 (4) 633-642
• 7 Roll P, Rudolf G, Pereira S , et al. SRPX2 mutations in disorders of language cortex and cognition. Hum Mol Genet 2006; 15 (7) 1195-1207
• 8 Kugler SL, Bali B, Lieberman P , et al. An autosomal dominant genetically heterogeneous variant of rolandic epilepsy and speech disorder. Epilepsia 2008; 49 (6) 1086-1090
• 9 Nieuwenhuis L, Nicolai J. The pathophysiological mechanisms of cognitive and behavioral disturbances in children with Landau-Kleffner syndrome or epilepsy with continuous spike-and-waves during slow-wave sleep. Seizure 2006; 15 (4) 249-258
• 10 Lesca G, Rudolf G, Labalme A , et al. Epileptic encephalopathies of the Landau-Kleffner and continuous spike and waves during slow-wave sleep types: genomic dissection makes the link with autism. Epilepsia 2012; 53 (9) 1526-1538
• 11 Endele S, Rosenberger G, Geider K , et al. Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nat Genet 2010; 42 (11) 1021-1026
• 12 Reutlinger C, Helbig I, Gawelczyk B , et al. Deletions in 16p13 including GRIN2A in patients with intellectual disability, various dysmorphic features, and seizure disorders of the rolandic region. Epilepsia 2010; 51 (9) 1870-1873
• 13 Carvill GL, Regan BM, Yendle SC , et al. GRIN2A mutations cause epilepsy-aphasia spectrum disorders. Nat Genet 2013; 45 (9) 1073-1076
• 14 Lemke JR, Lal D, Reinthaler EM , et al. Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes. Nat Genet 2013; 45 (9) 1067-1072
• 15 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 2013; 45 (9) 1061-1066
• 16 Burnashev N, Szepetowski P. NMDA receptor subunit mutations in neurodevelopmental disorders. Curr Opin Pharmacol 2015; 20: 73-82
• 17 Yuan H, Hansen KB, Zhang J , et al. Functional analysis of a de novo GRIN2A missense mutation associated with early-onset epileptic encephalopathy. Nat Commun 2014; 5: 3251
• 18 Pierson TM, Yuan H, Marsh ED , et al; PhD for the NISC Comparative Sequencing Program. GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine. Ann Clin Transl Neurol 2014; 1 (3) 190-198
• 19 Reinthaler EM, Lal D, Lebon S , et al; 16p11.2 European Consortium; EPICURE Consortium; EuroEPINOMICS Consortium. 16p11.2 600 kb duplications confer risk for typical and atypical rolandic epilepsy. Hum Mol Genet 2014; 23 (22) 6069-6080
• 20 Cloarec R, Bruneau N, Rudolf G , et al. PRRT2 links infantile convulsions and paroxysmal dyskinesia with migraine. Neurology 2012; 79 (21) 2097-2103
• 21 Lee HY, Huang Y, Bruneau N , et al. Mutations in the gene PRRT2 cause paroxysmal kinesigenic dyskinesia with infantile convulsions. Cell Reports 2012; 1 (1) 2-12
• 22 Golzio C, Willer J, Talkowski ME , et al. KCTD13 is a major driver of mirrored neuroanatomical phenotypes of the 16p11.2 copy number variant. Nature 2012; 485 (7398) 363-367
• 23 Piton A, Redin C, Mandel JL. XLID-causing mutations and associated genes challenged in light of data from large-scale human exome sequencing. Am J Hum Genet 2013; 93 (2) 368-383
• 24 Redin C, Gérard B, Lauer J , et al. Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing. J Med Genet 2014; 51 (11) 724-736
• 25 Reinthaler EM, Lal D, Jurkowski W , et al; EuroEPINOMICS Consortium. Analysis of ELP4, SRPX2, and interacting genes in typical and atypical rolandic epilepsy. Epilepsia 2014; 55 (8) e89-e93
• 26 Salmi M, Bruneau N, Cillario J , et al. Tubacin prevents neuronal migration defects and epileptic activity caused by rat Srpx2 silencing in utero. Brain 2013; 136 (Pt 8): 2457-2473
• 27 Sia GM, Clem RL, Huganir RL. The human language-associated gene SRPX2 regulates synapse formation and vocalization in mice. Science 2013; 342 (6161) 987-991
• 28 Strug LJ, Clarke T, Chiang T , et al. Centrotemporal sharp wave EEG trait in rolandic epilepsy maps to Elongator protein complex 4 (ELP4). Eur J Hum Genet 2009; 17 (9) 1171-1181
• 29 Gkampeta A, Fidani L, Clarimón J , et al. Association of brain-derived neurotrophic factor (BDNF) and elongator protein complex 4 (ELP4) polymorphisms with benign epilepsy with centrotemporal spikes in a Greek population. Epilepsy Res 2014; 108 (10) 1734-1739
• 30 Singh NA, Westenskow P, Charlier C , et al; BFNC Physician Consortium. KCNQ2 and KCNQ3 potassium channel genes in benign familial neonatal convulsions: expansion of the functional and mutation spectrum. Brain 2003; 126 (Pt 12): 2726-2737
• 31 Neubauer BA, Waldegger S, Heinzinger J , et al. KCNQ2 and KCNQ3 mutations contribute to different idiopathic epilepsy syndromes. Neurology 2008; 71 (3) 177-183
• 32 Syrbe S, Hedrich UB, Riesch E , et al; EuroEPINOMICS RES. De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy. Nat Genet 2015; 47 (4) 393-399
• 33 Lal D, Reinthaler EM, Altmüller J , et al. RBFOX1 and RBFOX3 mutations in rolandic epilepsy. PLoS ONE 2013; 8 (9) e73323
• 34 Lal D, Reinthaler EM, Schubert J , et al. DEPDC5 mutations in genetic focal epilepsies of childhood. Ann Neurol 2014; 75 (5) 788-792
• 35 Vaags AK, Bowdin S, Smith ML , et al. Absent CNKSR2 causes seizures and intellectual, attention, and language deficits. Ann Neurol 2014; 76 (5) 758-764
• 36 Reinthaler EM, Dejanovic B, Lal D , et al; Euro EPINOMICS Consortium. Rare variants in γ-aminobutyric acid type A receptor genes in rolandic epilepsy and related syndromes. Ann Neurol 2015; 77 (6) 972-986