Download PDF
Semin Neurol 2015; 35(03): 288-292
DOI: 10.1055/s-0035-1552922
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Genetic Causes of Generalized Epilepsies

Ingo Helbig
1   Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
2   Department of Neuropediatrics, Christian-Albrechts-Univerisity of Kiel and University Medical Center Schleswig-Holstein (UKSH), Kiel, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
10 June 2015 (online)

   Permissions and Reprints

Abstract

Generalized epilepsies, particularly the idiopathic or genetic generalized epilepsies (GGEs), represent some of the most common epilepsies. Clinical genetic data including family studies and twin studies provide compelling evidence for a prominent genetic impact. The first decade of the 21st century was marked by progress in understanding the basic biology of generalized epilepsies including generalized/genetic epilepsies with febrile seizures plus (GEFS+) and GGE through studies of large families, discovering causative mutations in SCN1A, SCN1B, GABRG2, and GABRA1. Subsequently, recurrent microdeletions at 15q13.3, 16p13.11, and 15q11.2 were found to be relevant risk factors for nonfamilial GGE. Genes for epileptic encephalopathies such as SLC2A1 were rediscovered in GGE, highlighting the biological continuum between different epilepsies. Genome-wide studies examining common genetic risk factors identified common variants in SCN1A, indicating a convergence of shared pathophysiological pathways in various types of epilepsies. In the era of next-generation sequencing, however, the GGEs appear more complex than expected, and small or moderately sized studies give only a limited genetic perspective. Thus, there is a strong impetus for large collaborative investigations on an international level.

Keywords

genetic generalized epilepsy - copy number variation - exome sequencing
 

  • References

  • 1 Jallon P, Loiseau P, Loiseau J. Newly diagnosed unprovoked epileptic seizures: presentation at diagnosis in CAROLE study. Coordination Active du Réseau Observatoire Longitudinal de l' Epilepsie. Epilepsia 2001; 42 (4) 464-475
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 3 Peljto AL, Barker-Cummings C, Vasoli VM , et al. Familial risk of epilepsy: a population-based study. Brain 2014; 137 (Pt 3) 795-805
    CrossrefPubMedGoogle Scholar
  • 4 Scheffer IE, Berkovic SF. Generalized epilepsy with febrile seizures plus. A genetic disorder with heterogeneous clinical phenotypes. Brain 1997; 120 (Pt 3) 479-490
    CrossrefPubMedGoogle Scholar
  • 5 Berkovic SF, Howell RA, Hay DA, Hopper JL. Epilepsies in twins: genetics of the major epilepsy syndromes. Ann Neurol 1998; 43 (4) 435-445
    CrossrefPubMedGoogle Scholar
  • 6 Kjeldsen MJ, Kyvik KO, Christensen K, Friis ML. Genetic and environmental factors in epilepsy: a population-based study of 11900 Danish twin pairs. Epilepsy Res 2001; 44 (2-3) 167-178
    CrossrefPubMedGoogle Scholar
  • 7 Escayg A, MacDonald BT, Meisler MH , et al. Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2. Nat Genet 2000; 24 (4) 343-345
    CrossrefPubMedGoogle Scholar
  • 8 Wallace RH, Wang DW, Singh R , et al. Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B. Nat Genet 1998; 19 (4) 366-370
    CrossrefPubMedGoogle Scholar
  • 9 Wallace RH, Scheffer IE, Barnett S , et al. Neuronal sodium-channel alpha1-subunit mutations in generalized epilepsy with febrile seizures plus. Am J Hum Genet 2001; 68 (4) 859-865
    CrossrefPubMedGoogle Scholar
  • 10 Harkin LA, Bowser DN, Dibbens LM , et al. Truncation of the GABA(A)-receptor gamma2 subunit in a family with generalized epilepsy with febrile seizures plus. Am J Hum Genet 2002; 70 (2) 530-536
    CrossrefPubMedGoogle Scholar
  • 11 Baulac S, Huberfeld G, Gourfinkel-An I , et al. First genetic evidence of GABA(A) receptor dysfunction in epilepsy: a mutation in the gamma2-subunit gene. Nat Genet 2001; 28 (1) 46-48
    PubMedGoogle Scholar
  • 12 Wallace RH, Marini C, Petrou S , et al. Mutant GABA(A) receptor gamma2-subunit in childhood absence epilepsy and febrile seizures. Nat Genet 2001; 28 (1) 49-52
    PubMedGoogle Scholar
  • 13 Berkovic SF, Mulley JC, Scheffer IE, Petrou S. Human epilepsies: interaction of genetic and acquired factors. Trends Neurosci 2006; 29 (7) 391-397
    CrossrefPubMedGoogle Scholar
  • 14 Schubert J, Siekierska A, Langlois M , et al; EuroEPINOMICS RES Consortium. Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes. Nat Genet 2014; 46 (12) 1327-1332
    CrossrefPubMedGoogle Scholar
  • 15 Cossette P, Liu L, Brisebois K , et al. Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy. Nat Genet 2002; 31 (2) 184-189
    CrossrefPubMedGoogle Scholar
  • 16 Suzuki T, Delgado-Escueta AV, Aguan K , et al. Mutations in EFHC1 cause juvenile myoclonic epilepsy. Nat Genet 2004; 36 (8) 842-849
    CrossrefPubMedGoogle Scholar
  • 17 Subaran RL, Conte JM, Stewart WC, Greenberg DA. Pathogenic EFHC1 mutations are tolerated in healthy individuals dependent on reported ancestry. Epilepsia 2015; 56 (2) 188-194
    CrossrefPubMedGoogle Scholar
  • 18 Cherepanova NS, Leslie E, Ferguson PJ, Bamshad MJ, Bassuk AG. Presence of epilepsy-associated variants in large exome databases. J Neurogenet 2013; 27 (1-2) 1-4
    CrossrefPubMedGoogle Scholar
  • 19 Chen Y, Lu J, Pan H , et al. Association between genetic variation of CACNA1H and childhood absence epilepsy. Ann Neurol 2003; 54 (2) 239-243
    CrossrefPubMedGoogle Scholar
  • 20 Suls A, Mullen SA, Weber YG , et al. Early-onset absence epilepsy caused by mutations in the glucose transporter GLUT1. Ann Neurol 2009; 66 (3) 415-419
    CrossrefPubMedGoogle Scholar
  • 21 Mullen SA, Marini C, Suls A , et al. Glucose transporter 1 deficiency as a treatable cause of myoclonic astatic epilepsy. Arch Neurol 2011; 68 (9) 1152-1155
    CrossrefPubMedGoogle Scholar
  • 22 Seidner G, Alvarez MG, Yeh JI , et al. GLUT-1 deficiency syndrome caused by haploinsufficiency of the blood-brain barrier hexose carrier. Nat Genet 1998; 18 (2) 188-191
    CrossrefPubMedGoogle Scholar
  • 23 Suls A, Dedeken P, Goffin K , et al. Paroxysmal exercise-induced dyskinesia and epilepsy is due to mutations in SLC2A1, encoding the glucose transporter GLUT1. Brain 2008; 131 (Pt 7) 1831-1844
    CrossrefPubMedGoogle Scholar
  • 24 Striano P, Weber YG, Toliat MR , et al; EPICURE Consortium. GLUT1 mutations are a rare cause of familial idiopathic generalized epilepsy. Neurology 2012; 78 (8) 557-562
    CrossrefPubMedGoogle Scholar
  • 25 Mefford HC, Eichler EE. Duplication hotspots, rare genomic disorders, and common disease. Curr Opin Genet Dev 2009; 19 (3) 196-204
    CrossrefPubMedGoogle Scholar
  • 26 Redon R, Ishikawa S, Fitch KR , et al. Global variation in copy number in the human genome. Nature 2006; 444 (7118) 444-454
    Google Scholar
  • 27 Helbig I, Mefford HC, Sharp AJ , et al. 15q13.3 microdeletions increase risk of idiopathic generalized epilepsy. Nat Genet 2009; 41 (2) 160-162
    CrossrefPubMedGoogle Scholar
  • 28 Dibbens LM, Mullen S, Helbig I , et al; EPICURE Consortium. Familial and sporadic 15q13.3 microdeletions in idiopathic generalized epilepsy: precedent for disorders with complex inheritance. Hum Mol Genet 2009; 18 (19) 3626-3631
    CrossrefPubMedGoogle Scholar
  • 29 de Kovel CG, Trucks H, Helbig I , et al. Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies. Brain 2010; 133 (Pt 1) 23-32
    CrossrefPubMedGoogle Scholar
  • 30 Boone PM, Wiszniewski W, Lupski JR. Genomic medicine and neurological disease. Hum Genet 2011; 130 (1) 103-121
    CrossrefPubMedGoogle Scholar
  • 31 Sharp AJ. Emerging themes and new challenges in defining the role of structural variation in human disease. Hum Mutat 2009; 30 (2) 135-144
    CrossrefPubMedGoogle Scholar
  • 32 Mullen SA, Carvill GL, Bellows S , et al. Copy number variants are frequent in genetic generalized epilepsy with intellectual disability. Neurology 2013; 81 (17) 1507-1514
    CrossrefPubMedGoogle Scholar
  • 33 Carvill GL, Mefford HC. Microdeletion syndromes. Curr Opin Genet Dev 2013; 23 (3) 232-239
    CrossrefPubMedGoogle Scholar
  • 34 Helbig I, Lowenstein DH. Genetics of the epilepsies: where are we and where are we going?. Curr Opin Neurol 2013; 26 (2) 179-185
    CrossrefPubMedGoogle Scholar
  • 35 Helbig I, Hodge SE, Ottman R. Familial cosegregation of rare genetic variants with disease in complex disorders. Eur J Hum Genet 2013; 21 (4) 444-450
    CrossrefPubMedGoogle Scholar
  • 36 Manolio TA, Collins FS, Cox NJ , et al. Finding the missing heritability of complex diseases. Nature 2009; 461 (7265) 747-753
    CrossrefPubMedGoogle Scholar
  • 37 Steffens M, Leu C, Ruppert AK , et al; EPICURE Consortium; EMINet Consortium. Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32. Hum Mol Genet 2012; 21 (24) 5359-5372
    CrossrefPubMedGoogle Scholar
  • 38 International League Against Epilepsy Consortium on Complex Epilepsies. Electronic address: epilepsy-austin@unimelb.edu.au. Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies. Lancet Neurol 2014; 13 (9) 893-903
    CrossrefPubMedGoogle Scholar
  • 39 Heinzen EL, Depondt C, Cavalleri GL , et al. Exome sequencing followed by large-scale genotyping fails to identify single rare variants of large effect in idiopathic generalized epilepsy. Am J Hum Genet 2012; 91 (2) 293-302
    CrossrefPubMedGoogle Scholar