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The Genetics of the Epilepsies

Current Neurology and Neuroscience Reports volume 15, Article number: 39 (2015) Cite this article

Abstract

While genetic causes of epilepsy have been hypothesized from the time of Hippocrates, the advent of new genetic technologies has played a tremendous role in elucidating a growing number of specific genetic causes for the epilepsies. This progress has contributed vastly to our recognition of the epilepsies as a diverse group of disorders, the genetic mechanisms of which are heterogeneous. Genotype-phenotype correlation, however, is not always clear. Nonetheless, the developments in genetic diagnosis raise the promise of a future of personalized medicine. Multiple genetic tests are now available, but there is no one test for all possible genetic mutations, and the balance between cost and benefit must be weighed. A genetic diagnosis, however, can provide valuable information regarding comorbidities, prognosis, and even treatment, as well as allow for genetic counseling. In this review, we will discuss the genetic mechanisms of the epilepsies as well as the specifics of particular genetic epilepsy syndromes. We will include an overview of the available genetic testing methods, the application of clinical knowledge into the selection of genetic testing, genotype-phenotype correlations of epileptic disorders, and therapeutic advances as well as a discussion of the importance of genetic counseling.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Lee BI, Heo K. Epilepsy: new genes, new technologies, new insights. Lancet Neurol. 2014;13(1):7–9.

    PubMed  Google Scholar 

  2. Hauser WA, Kurland LT. The epidemiology of epilepsy in Rochester, Minnesota, 1935 through 1967. Epilepsia. 1975;16(1):1–66.

    CAS  PubMed  Google Scholar 

  3. Thomas RH, Berkovic SF. The hidden genetics of epilepsy-a clinically important new paradigm. Nat Rev Neurol. 2014;10(5):283–92.

    PubMed  Google Scholar 

  4. Buiting K. Prader-Willi syndrome and Angelman syndrome. Am J Med Genet C: Semin Med Genet. 2010;154C(3):365–76.

    CAS  Google Scholar 

  5. Buiting K et al. Inherited microdeletions in the Angelman and Prader-Willi syndromes define an imprinting centre on human chromosome 15. Nat Genet. 1995;9(4):395–400.

    CAS  PubMed  Google Scholar 

  6. Evrony GD et al. Cell lineage analysis in human brain using endogenous retroelements. Neuron. 2015;85(1):49–59.

    CAS  PubMed  Google Scholar 

  7. Lindhout D. Somatic mosaicism as a basic epileptogenic mechanism? Brain. 2008;131(Pt 4):900–1.

    PubMed  Google Scholar 

  8. Shirley MD et al. Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. N Engl J Med. 2013;368(21):1971–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  9. Poduri A et al. Somatic mutation, genomic variation, and neurological disease. Science. 2013;341(6141):1237758.

    PubMed Central  PubMed  Google Scholar 

  10. Riviere JB et al. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat Genet. 2012;44(8):934–40.

    PubMed Central  CAS  PubMed  Google Scholar 

  11. Mirzaa GM, Poduri A. Megalencephaly and hemimegalencephaly: breakthroughs in molecular etiology. Am J Med Genet C: Semin Med Genet. 2014;166C(2):156–72.

    Google Scholar 

  12. Poduri A et al. Somatic activation of AKT3 causes hemispheric developmental brain malformations. Neuron. 2012;74(1):41–8. This study was one of the earliest to demonstrate the role of somatic mutations limited to the brain and involving the AKT3 gene in the development of hemimgalencephaly.

    PubMed Central  CAS  PubMed  Google Scholar 

  13. Gennaro E et al. Somatic and germline mosaicisms in severe myoclonic epilepsy of infancy. Biochem Biophys Res Commun. 2006;341(2):489–93.

    CAS  PubMed  Google Scholar 

  14. Depienne C et al. Mechanisms for variable expressivity of inherited SCN1A mutations causing Dravet syndrome. J Med Genet. 2010;47(6):404–10.

    CAS  PubMed  Google Scholar 

  15. Martin MS et al. The voltage-gated sodium channel Scn8a is a genetic modifier of severe myoclonic epilepsy of infancy. Hum Mol Genet. 2007;16(23):2892–9.

    CAS  PubMed  Google Scholar 

  16. Doty CN. SCN9A: another sodium channel excited to play a role in human epilepsies. Clin Genet. 2010;77(4):326–8.

    CAS  PubMed  Google Scholar 

  17. Meisler MH, O’Brien JE, Sharkey LM. Sodium channel gene family: epilepsy mutations, gene interactions and modifier effects. J Physiol. 2010;588(Pt 11):1841–8.

    PubMed Central  CAS  PubMed  Google Scholar 

  18. Singh NA et al. KCNQ2 and KCNQ3 potassium channel genes in benign familial neonatal convulsions: expansion of the functional and mutation spectrum. Brain. 2003;126(Pt 12):2726–37.

    PubMed  Google Scholar 

  19. Kato M et al. Clinical spectrum of early onset epileptic encephalopathies caused by KCNQ2 mutation. Epilepsia. 2013;54(7):1282–7.

    CAS  PubMed  Google Scholar 

  20. Scheffer IE et al. X-linked myoclonic epilepsy with spasticity and intellectual disability: mutation in the homeobox gene ARX. Neurology. 2002;59(3):348–56.

    CAS  PubMed  Google Scholar 

  21. Depienne C et al. Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females. PLoS Genet. 2009;5(2), e1000381.

    PubMed Central  PubMed  Google Scholar 

  22. Saitsu H et al. De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy. Nat Genet. 2008;40(6):782–8.

    CAS  PubMed  Google Scholar 

  23. Euro, E.-R.E.S.C., P. Epilepsy Phenome/Genome, Epi KC. De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies. Am J Hum Genet. 2014;95(4):360–70.

    Google Scholar 

  24. Mari F et al. CDKL5 belongs to the same molecular pathway of MeCP2 and it is responsible for the early-onset seizure variant of Rett syndrome. Hum Mol Genet. 2005;14(14):1935–46.

    CAS  PubMed  Google Scholar 

  25. Poduri A et al. Homozygous PLCB1 deletion associated with malignant migrating partial seizures in infancy. Epilepsia. 2012;53(8):e146–50.

    CAS  PubMed  Google Scholar 

  26. Shen J et al. Mutations in PNKP cause microcephaly, seizures and defects in DNA repair. Nat Genet. 2010;42(3):245–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  27. Mills PB et al. Epilepsy due to PNPO mutations: genotype, environment and treatment affect presentation and outcome. Brain. 2014;137(Pt 5):1350–60.

    PubMed Central  PubMed  Google Scholar 

  28. Pearl PL, Gospe SM. Pyridoxine or pyridoxal-5′-phosphate for neonatal epilepsy: the distinction just got murkier. Neurology. 2014;82(16):1392–4.

    PubMed  Google Scholar 

  29. Poduri A et al. Genetic testing in the epilepsies-developments and dilemmas. Nat Rev Neurol. 2014;10(5):293–9.

    PubMed Central  PubMed  Google Scholar 

  30. Goto Y, Nonaka I, Horai S. A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature. 1990;348(6302):651–3.

    CAS  PubMed  Google Scholar 

  31. Veeramah KR et al. Exome sequencing reveals new causal mutations in children with epileptic encephalopathies. Epilepsia. 2013;54(7):1270–81.

    PubMed Central  CAS  PubMed  Google Scholar 

  32. Hortopan GA, Dinday MT, Baraban SC. Zebrafish as a model for studying genetic aspects of epilepsy. Dis Model Mech. 2010;3(3–4):144–8.

    CAS  PubMed  Google Scholar 

  33. Olivetti PR, Noebels JL. Interneuron, interrupted: molecular pathogenesis of ARX mutations and X-linked infantile spasms. Curr Opin Neurobiol. 2012;22(5):859–65.

    PubMed Central  CAS  PubMed  Google Scholar 

  34. Liu Y et al. Dravet syndrome patient-derived neurons suggest a novel epilepsy mechanism. Ann Neurol. 2013;74(1):128–39. Data from this study uncovered a potential mechanism for Dravet syndrome that is cell autonomous, which was not described before. This study highlights the role of patient-specific iPSC-derived neurons in the understanding of pathogenesis of certain epilepsies.

    PubMed Central  CAS  PubMed  Google Scholar 

  35. Scheffer IE et al. Dravet syndrome or genetic (generalized) epilepsy with febrile seizures plus? Brain Dev. 2009;31(5):394–400.

    PubMed  Google Scholar 

  36. Orhan G et al. Dominant-negative effects of KCNQ2 mutations are associated with epileptic encephalopathy. Ann Neurol. 2014;75(3):382–94.

    CAS  PubMed  Google Scholar 

  37. Berg AT 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):676–85.

    PubMed  Google Scholar 

  38. Mastrangelo M, Leuzzi V. Genes of early-onset epileptic encephalopathies: from genotype to phenotype. Pediatr Neurol. 2012;46(1):24–31.

    PubMed  Google Scholar 

  39. Allen AS et al. De novo mutations in epileptic encephalopathies. Nature. 2013;501(7466):217–21. This large scale study confirmed and identified multiple new genes causative of epileptic encephalopathies, via exome sequencing of 264 probands and their parents.

    CAS  PubMed  Google Scholar 

  40. Olson HE et al. Genetic mechanisms of ohtahara syndrome, a cohort study. 2014: Annals of neurology. p. S178-S178.

  41. Ohtahara S, Yamatogi Y. Ohtahara syndrome: with special reference to its developmental aspects for differentiating from early myoclonic encephalopathy. Epilepsy Res. 2006;70 Suppl 1:S58–67.

    PubMed  Google Scholar 

  42. Saitsu H et al. Whole exome sequencing identifies KCNQ2 mutations in Ohtahara syndrome. Ann Neurol. 2012;72(2):298–300.

    CAS  PubMed  Google Scholar 

  43. Nakamura K et al. Clinical spectrum of SCN2A mutations expanding to Ohtahara syndrome. Neurology. 2013;81(11):992–8.

    CAS  PubMed  Google Scholar 

  44. Kato M et al. Frameshift mutations of the ARX gene in familial Ohtahara syndrome. Epilepsia. 2010;51(9):1679–84.

    CAS  PubMed  Google Scholar 

  45. Molinari F et al. Mutations in the mitochondrial glutamate carrier SLC25A22 in neonatal epileptic encephalopathy with suppression bursts. Clin Genet. 2009;76(2):188–94.

    CAS  PubMed  Google Scholar 

  46. Saitsu H et al. Compound heterozygous BRAT1 mutations cause familial Ohtahara syndrome with hypertonia and microcephaly. J Hum Genet. 2014;59(12):687–90.

    CAS  PubMed  Google Scholar 

  47. Saitsu H et al. CASK aberrations in male patients with Ohtahara syndrome and cerebellar hypoplasia. Epilepsia. 2012;53(8):1441–9.

    CAS  PubMed  Google Scholar 

  48. Kato M et al. PIGA mutations cause early-onset epileptic encephalopathies and distinctive features. Neurology. 2014;82(18):1587–96.

    CAS  PubMed  Google Scholar 

  49. Dravet C, Oguni H. Dravet syndrome (severe myoclonic epilepsy in infancy). Handb Clin Neurol. 2013;111:627–33.

    PubMed  Google Scholar 

  50. Patino GA et al. A functional null mutation of SCN1B in a patient with Dravet syndrome. J Neurosci. 2009;29(34):10764–78.

    PubMed Central  PubMed  Google Scholar 

  51. Carvill GL et al. GABRA1 and STXBP1: novel genetic causes of Dravet syndrome. Neurology. 2014;82(14):1245–53.

    PubMed Central  CAS  PubMed  Google Scholar 

  52. Carvill GL et al. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat Genet. 2013;45(7):825–30.

    CAS  PubMed  Google Scholar 

  53. Nava C et al. De novo mutations in HCN1 cause early infantile epileptic encephalopathy. Nat Genet. 2014;46(6):640–5.

    CAS  PubMed  Google Scholar 

  54. Shi X et al. Mutational analysis of GABRG2 in a Japanese cohort with childhood epilepsies. J Hum Genet. 2010;55(6):375–8.

    CAS  PubMed  Google Scholar 

  55. Barcia G et al. De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy. Nat Genet. 2012;44(11):1255–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  56. Carranza Rojo D et al. De novo SCN1A mutations in migrating partial seizures of infancy. Neurology. 2011;77(4):380–3.

    PubMed Central  CAS  PubMed  Google Scholar 

  57. Poduri A et al. SLC25A22 is a novel gene for migrating partial seizures in infancy. Ann Neurol. 2013;74(6):873–82.

    PubMed Central  CAS  PubMed  Google Scholar 

  58. Milh M et al. Novel compound heterozygous mutations in TBC1D24 cause familial malignant migrating partial seizures of infancy. Hum Mutat. 2013;34(6):869–72.

    CAS  PubMed  Google Scholar 

  59. Dhamija R et al. Novel de novo SCN2A mutation in a child with migrating focal seizures of infancy. Pediatr Neurol. 2013;49(6):486–8.

    PubMed  Google Scholar 

  60. Zhang X et al. Mutations in QARS, encoding glutaminyl-tRNA synthetase, cause progressive microcephaly, cerebral-cerebellar atrophy, and intractable seizures. Am J Hum Genet. 2014;94(4):547–58.

    PubMed Central  CAS  PubMed  Google Scholar 

  61. Ohba C et al. Early onset epileptic encephalopathy caused by de novo SCN8A mutations. Epilepsia. 2014;55(7):994–1000.

    CAS  PubMed  Google Scholar 

  62. Paciorkowski AR, Thio LL, Dobyns WB. Genetic and biologic classification of infantile spasms. Pediatr Neurol. 2011;45(6):355–67.

    PubMed Central  PubMed  Google Scholar 

  63. Mefford HC et al. Rare copy number variants are an important cause of epileptic encephalopathies. Ann Neurol. 2011;70(6):974–85.

    PubMed Central  CAS  PubMed  Google Scholar 

  64. Consortium EK. Epi4K: gene discovery in 4,000 genomes. Epilepsia. 2012;53(8):1457–67.

    Google Scholar 

  65. Chu-Shore CJ et al. The natural history of epilepsy in tuberous sclerosis complex. Epilepsia. 2010;51(7):1236–41.

    PubMed Central  PubMed  Google Scholar 

  66. Guerrini R et al. Nonsyndromic mental retardation and cryptogenic epilepsy in women with doublecortin gene mutations. Ann Neurol. 2003;54(1):30–7.

    PubMed  Google Scholar 

  67. Romaniello R et al. Brain malformations and mutations in α- and β-tubulin genes: a review of the literature and description of two new cases. Dev Med Child Neurol. 2014;56(4):354–60.

    PubMed  Google Scholar 

  68. Dobyns WB. The clinical patterns and molecular genetics of lissencephaly and subcortical band heterotopia. Epilepsia. 2010;51 Suppl 1:5–9.

    PubMed  Google Scholar 

  69. Matalon D et al. Confirming an expanded spectrum of SCN2A mutations: a case series. Epileptic Disord. 2014;16(1):13–8.

    PubMed  Google Scholar 

  70. Allen NM et al. The variable phenotypes of KCNQ-related epilepsy. Epilepsia. 2014;55(9):e99–e105.

    CAS  PubMed  Google Scholar 

  71. Bahi-Buisson N et al. Recurrent mutations in the CDKL5 gene: genotype-phenotype relationships. Am J Med Genet A. 2012;158A(7):1612–9.

    PubMed  Google Scholar 

  72. Mignot C et al. STXBP1-related encephalopathy presenting as infantile spasms and generalized tremor in three patients. Epilepsia. 2011;52(10):1820–7.

    CAS  PubMed  Google Scholar 

  73. Kortüm F et al. The core FOXG1 syndrome phenotype consists of postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and corpus callosum hypogenesis. J Med Genet. 2011;48(6):396–406.

    PubMed  Google Scholar 

  74. Sherr EH. The ARX story (epilepsy, mental retardation, autism, and cerebral malformations): one gene leads to many phenotypes. Curr Opin Pediatr. 2003;15(6):567–71.

    PubMed  Google Scholar 

  75. Hartmann H et al. Agenesis of the corpus callosum, abnormal genitalia and intractable epilepsy due to a novel familial mutation in the Aristaless-related homeobox gene. Neuropediatrics. 2004;35(3):157–60.

    CAS  PubMed  Google Scholar 

  76. Guerrini R et al. Expansion of the first PolyA tract of ARX causes infantile spasms and status dystonicus. Neurology. 2007;69(5):427–33.

    CAS  PubMed  Google Scholar 

  77. Saitsu H et al. Dominant-negative mutations in alpha-II spectrin cause West syndrome with severe cerebral hypomyelination, spastic quadriplegia, and developmental delay. Am J Hum Genet. 2010;86(6):881–91.

    PubMed Central  CAS  PubMed  Google Scholar 

  78. Kurian MA et al. Phospholipase C beta 1 deficiency is associated with early-onset epileptic encephalopathy. Brain. 2010;133(10):2964–70.

    PubMed  Google Scholar 

  79. Ruggieri M et al. Neurofibromatosis type 1 and infantile spasms. Childs Nerv Syst. 2009;25(2):211–6.

    PubMed  Google Scholar 

  80. Bahi-Buisson N et al. Spectrum of epilepsy in terminal 1p36 deletion syndrome. Epilepsia. 2008;49(3):509–15.

    PubMed  Google Scholar 

  81. Saito Y et al. Polymicrogyria and infantile spasms in a patient with 1p36 deletion syndrome. Brain Dev. 2011;33(5):437–41.

    PubMed  Google Scholar 

  82. Verrotti A et al. Electroclinical features and long-term outcome of cryptogenic epilepsy in children with Down syndrome. J Pediatr. 2013;163(6):1754–8.

    PubMed  Google Scholar 

  83. Giordano L et al. Seizures and EEG patterns in Pallister-Killian syndrome: 13 new Italian patients. Eur J Paediatr Neurol. 2012;16(6):636–41.

    PubMed  Google Scholar 

  84. Conant KD et al. A survey of seizures and current treatments in 15q duplication syndrome. Epilepsia. 2014;55(3):396–402.

    CAS  PubMed  Google Scholar 

  85. Méneret A et al. PRRT2 mutations and paroxysmal disorders. Eur J Neurol. 2013;20(6):872–8.

    PubMed  Google Scholar 

  86. Girard JM et al. Progressive myoclonus epilepsy. Handb Clin Neurol. 2013;113:1731–6.

    PubMed  Google Scholar 

  87. Lalioti MD et al. Dodecamer repeat expansion in cystatin B gene in progressive myoclonus epilepsy. Nature. 1997;386(6627):847–51.

    CAS  PubMed  Google Scholar 

  88. Berkovic SF et al. Array-based gene discovery with three unrelated subjects shows SCARB2/LIMP-2 deficiency causes myoclonus epilepsy and glomerulosclerosis. Am J Hum Genet. 2008;82(3):673–84.

    PubMed Central  CAS  PubMed  Google Scholar 

  89. Corbett MA et al. A mutation in the Golgi Qb-SNARE gene GOSR2 causes progressive myoclonus epilepsy with early ataxia. Am J Hum Genet. 2011;88(5):657–63.

    PubMed Central  CAS  PubMed  Google Scholar 

  90. Trujillo-Tiebas MJ et al. Novel human pathological mutations. Gene symbol: EPM2A. Disease: Lafora progressive myoclonus epilepsy. Hum Genet. 2007;121(5):651.

    CAS  PubMed  Google Scholar 

  91. Chan EM et al. Mutations in NHLRC1 cause progressive myoclonus epilepsy. Nat Genet. 2003;35(2):125–7.

    CAS  PubMed  Google Scholar 

  92. Ferlazzo E, et al. Mild Lafora disease: Clinical, neurophysiologic, and genetic findings. Epilepsia, 2014.

  93. Mink JW et al. Classification and natural history of the neuronal ceroid lipofuscinoses. J Child Neurol. 2013;28(9):1101–5.

    PubMed Central  PubMed  Google Scholar 

  94. Steinfeld R et al. Late infantile neuronal ceroid lipofuscinosis: quantitative description of the clinical course in patients with CLN2 mutations. Am J Med Genet. 2002;112(4):347–54.

    PubMed  Google Scholar 

  95. Steinfeld R et al. Cathepsin D deficiency is associated with a human neurodegenerative disorder. Am J Hum Genet. 2006;78(6):988–98.

    PubMed Central  CAS  PubMed  Google Scholar 

  96. Muona M et al. A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy. Nat Genet, 2014.

  97. Pearson TS et al. Phenotypic spectrum of glucose transporter type 1 deficiency syndrome (Glut1 DS). Curr Neurol Neurosci Rep. 2013;13(4):342.

    PubMed  Google Scholar 

  98. Mefford HC et al. Genome-wide copy number variation in epilepsy: novel susceptibility loci in idiopathic generalized and focal epilepsies. PLoS Genet. 2010;6(5), e1000962.

    PubMed Central  PubMed  Google Scholar 

  99. Olson H et al. Copy number variation plays an important role in clinical epilepsy. Ann Neurol. 2014;75(6):943–58. This study analyzed 323 patients who have CNVs and epilepsy, and concluded that CNVs explained the epilepsy phenotype in at least 5% of the cases. It emphasizes the diagnostic yield of CMA in epilepsy.

    CAS  PubMed  Google Scholar 

  100. Heinzen EL et al. Rare deletions at 16p13.11 predispose to a diverse spectrum of sporadic epilepsy syndromes. Am J Hum Genet. 2010;86(5):707–18.

    PubMed Central  CAS  PubMed  Google Scholar 

  101. Helbig I et al. 15q13.3 microdeletions increase risk of idiopathic generalized epilepsy. Nat Genet. 2009;41(2):160–2.

    PubMed Central  CAS  PubMed  Google Scholar 

  102. de Kovel CG et al. Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies. Brain. 2010;133(Pt 1):23–32.

    PubMed Central  PubMed  Google Scholar 

  103. Mullen SA et al. Copy number variants are frequent in genetic generalized epilepsy with intellectual disability. Neurology. 2013;81(17):1507–14.

    PubMed Central  PubMed  Google Scholar 

  104. Lü JJ et al. T-type calcium channel gene-CACNA1H is a susceptibility gene to childhood absence epilepsy. Zhonghua Er Ke Za Zhi. 2005;43(2):133–6.

    PubMed  Google Scholar 

  105. Escayg A et al. Coding and noncoding variation of the human calcium-channel beta4-subunit gene CACNB4 in patients with idiopathic generalized epilepsy and episodic ataxia. Am J Hum Genet. 2000;66(5):1531–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  106. D’Agostino D et al. Mutations and polymorphisms of the CLCN2 gene in idiopathic epilepsy. Neurology. 2004;63(8):1500–2.

    PubMed  Google Scholar 

  107. Chioza B et al. Association between the alpha(1a) calcium channel gene CACNA1A and idiopathic generalized epilepsy. Neurology. 2001;56(9):1245–6.

    CAS  PubMed  Google Scholar 

  108. Bonanni P et al. Generalized epilepsy with febrile seizures plus (GEFS+): clinical spectrum in seven Italian families unrelated to SCN1A, SCN1B, and GABRG2 gene mutations. Epilepsia. 2004;45(2):149–58.

    CAS  PubMed  Google Scholar 

  109. Díaz-Otero F et al. Autosomal dominant nocturnal frontal lobe epilepsy with a mutation in the CHRNB2 gene. Epilepsia. 2008;49(3):516–20.

    PubMed  Google Scholar 

  110. Ottman R et al. Genetic testing in the epilepsies–report of the ILAE Genetics Commission. Epilepsia. 2010;51(4):655–70.

    PubMed Central  PubMed  Google Scholar 

  111. Heron SE et al. Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet. 2012;44(11):1188–90.

    CAS  PubMed  Google Scholar 

  112. Fanciulli M et al. LGI1 microdeletion in autosomal dominant lateral temporal epilepsy. Neurology. 2012;78(17):1299–303.

    PubMed Central  CAS  PubMed  Google Scholar 

  113. Pizzuti A et al. Epilepsy with auditory features: a LGI1 gene mutation suggests a loss-of-function mechanism. Ann Neurol. 2003;53(3):396–9.

    CAS  PubMed  Google Scholar 

  114. Lee JH et al. De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly. Nat Genet. 2012;44(8):941–5.

    PubMed Central  CAS  PubMed  Google Scholar 

  115. Scheffer IE et al. Mutations in mammalian target of rapamycin regulator DEPDC5 cause focal epilepsy with brain malformations. Ann Neurol. 2014;75(5):782–7.

    CAS  PubMed  Google Scholar 

  116. Dibbens LM et al. Mutations in DEPDC5 cause familial focal epilepsy with variable foci. Nat Genet. 2013;45(5):546–51. This study was fundamental in identifying DEPDC5 as a not only a cause, but the most common known cause of familial focal epilepsy, thus substantially improving our understanding of the pathophysiology of epilepsy but also shedding light on treatment strategies and prognosis.

    CAS  PubMed  Google Scholar 

  117. Ishida S et al. Mutations of DEPDC5 cause autosomal dominant focal epilepsies. Nat Genet. 2013;45(5):552–5.

    CAS  PubMed  Google Scholar 

  118. Lal D et al. DEPDC5 mutations in genetic focal epilepsies of childhood. Ann Neurol. 2014;75(5):788–92.

    CAS  PubMed  Google Scholar 

  119. Picard F et al. DEPDC5 mutations in families presenting as autosomal dominant nocturnal frontal lobe epilepsy. Neurology. 2014;82(23):2101–6.

    CAS  PubMed  Google Scholar 

  120. D’Gama AM et al. mTOR pathway mutations cause hemimegalencephaly and focal cortical dysplasia. Ann Neurol, 2015.

  121. Carvill GL et al. GRIN2A mutations cause epilepsy-aphasia spectrum disorders. Nat Genet. 2013;45(9):1073–6.

    CAS  PubMed  Google Scholar 

  122. Endele S et al. Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nat Genet. 2010;42(11):1021–6.

    CAS  PubMed  Google Scholar 

  123. Lemke JR et al. Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes. Nat Genet. 2013;45(9):1067–72.

    CAS  PubMed  Google Scholar 

  124. Lesca G 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):1061–6.

    CAS  PubMed  Google Scholar 

  125. Barba C et al. Co-occurring malformations of cortical development and SCN1A gene mutations. Epilepsia. 2014;55(7):1009–19.

    CAS  PubMed  Google Scholar 

  126. Auerbach DS et al. Altered cardiac electrophysiology and SUDEP in a model of Dravet syndrome. PLoS One. 2013;8(10), e77843.

    PubMed Central  CAS  PubMed  Google Scholar 

  127. Delogu AB et al. Electrical and autonomic cardiac function in patients with Dravet syndrome. Epilepsia. 2011;52 Suppl 2:55–8.

    PubMed  Google Scholar 

  128. Kalume F et al. Sudden unexpected death in a mouse model of Dravet syndrome. J Clin Invest. 2013;123(4):1798–808.

    PubMed Central  CAS  PubMed  Google Scholar 

  129. Le Gal F et al. A case of SUDEP in a patient with Dravet syndrome with SCN1A mutation. Epilepsia. 2010;51(9):1915–8.

    PubMed  Google Scholar 

  130. Nabbout R. Can SCN1A mutations account for SUDEP?–Commentary on Hindocha et al. Epilepsia. 2008;49(2):367–8.

    PubMed  Google Scholar 

  131. Veeramah KR et al. De novo pathogenic SCN8A mutation identified by whole-genome sequencing of a family quartet affected by infantile epileptic encephalopathy and SUDEP. Am J Hum Genet. 2012;90(3):502–10.

    PubMed Central  CAS  PubMed  Google Scholar 

  132. Wagnon JL et al., Convulsive seizures and SUDEP in a mouse model of SCN8A epileptic encephalopathy. Hum Mol Genet. 2014.

  133. Larsen J. et al. The phenotypic spectrum of SCN8A encephalopathy. Neurology, 2015.

  134. Liebrechts-Akkerman G et al. PHOX2B polyalanine repeat length is associated with sudden infant death syndrome and unclassified sudden infant death in the Dutch population. Int J Legal Med. 2014;128(4):621–9.

    PubMed  Google Scholar 

  135. Bagnall RD et al. Genetic analysis of PHOX2B in sudden unexpected death in epilepsy cases. Neurology. 2014;83(11):1018–21. In this study, genetic sequencing of PHOX2B, was performed on 68 patients who succombed to SUDEP, with no mutations found, showing that unlike sudden infant death syndrome, PHOX2B is unlikely to be associated with SUDEP.

    CAS  PubMed  Google Scholar 

  136. Thibert RL et al. Neurologic manifestations of Angelman syndrome. Pediatr Neurol. 2013;48(4):271–9.

    PubMed  Google Scholar 

  137. Pescosolido MF et al. Genetic and phenotypic diversity of NHE6 mutations in Christianson syndrome. Ann Neurol. 2014;76(4):581–93.

    CAS  PubMed  Google Scholar 

  138. Tan WH et al. If not Angelman, what is it? A review of Angelman-like syndromes. Am J Med Genet A. 2014;164A(4):975–92.

    PubMed  Google Scholar 

  139. Cordelli DM et al. Epilepsy in Mowat-Wilson syndrome: delineation of the electroclinical phenotype. Am J Med Genet A. 2013;161A(2):273–84.

    PubMed  Google Scholar 

  140. de Pontual L et al. Mutational, functional, and expression studies of the TCF4 gene in Pitt-Hopkins syndrome. Hum Mutat. 2009;30(4):669–76.

    PubMed  Google Scholar 

  141. Bao X et al. Using a large international sample to investigate epilepsy in Rett syndrome. Dev Med Child Neurol. 2013;55(6):553–8.

    PubMed  Google Scholar 

  142. Neul JL et al. Rett syndrome: revised diagnostic criteria and nomenclature. Ann Neurol. 2010;68(6):944–50.

    PubMed Central  PubMed  Google Scholar 

  143. Nissenkorn A et al. Epilepsy in Rett syndrome–-the experience of a National Rett Center. Epilepsia. 2010;51(7):1252–8.

    PubMed  Google Scholar 

  144. Pintaudi M et al. Epilepsy in Rett syndrome: clinical and genetic features. Epilepsy Behav. 2010;19(3):296–300.

    PubMed  Google Scholar 

  145. Fehr S et al. The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy. Eur J Hum Genet. 2013;21(3):266–73.

    PubMed Central  CAS  PubMed  Google Scholar 

  146. Cardoza B et al. Epilepsy in Rett syndrome: association between phenotype and genotype, and implications for practice. Seizure. 2011;20(8):646–9.

    PubMed  Google Scholar 

  147. Guerrini R, Parrini E. Epilepsy in Rett syndrome, and CDKL5- and FOXG1-gene-related encephalopathies. Epilepsia. 2012;53(12):2067–78.

    CAS  PubMed  Google Scholar 

  148. Klein KM et al. A distinctive seizure type in patients with CDKL5 mutations: Hypermotor-tonic-spasms sequence. Neurology. 2011;76(16):1436–8.

    CAS  PubMed  Google Scholar 

  149. Seltzer LE et al. Epilepsy and outcome in FOXG1-related disorders. Epilepsia. 2014;55(8):1292–300.

    CAS  PubMed  Google Scholar 

  150. Striano P et al. West syndrome associated with 14q12 duplications harboring FOXG1. Neurology. 2011;76(18):1600–2.

    CAS  PubMed  Google Scholar 

  151. Pearl PL, Gospe SM. Pyridoxal phosphate dependency, a newly recognized treatable catastrophic epileptic encephalopathy. J Inherit Metab Dis. 2007;30(1):2–4.

    CAS  PubMed  Google Scholar 

  152. Giovannini S et al. Epilepsy in ring 14 syndrome: a clinical and EEG study of 22 patients. Epilepsia. 2013;54(12):2204–13.

    PubMed  Google Scholar 

  153. Elens I et al. Ring chromosome 20 syndrome: electroclinical description of six patients and review of the literature. Epilepsy Behav. 2012;23(4):409–14.

    PubMed  Google Scholar 

  154. Battaglia A. The inv dup (15) or idic (15) syndrome (Tetrasomy 15q). Orphanet J Rare Dis. 2008;3:30.

    PubMed Central  PubMed  Google Scholar 

  155. Scheffer IE. Epilepsy genetics revolutionizes clinical practice. Neuropediatrics. 2014;45(2):70–4.

    PubMed  Google Scholar 

  156. Leuzzi V et al. Inborn errors of creatine metabolism and epilepsy. Epilepsia. 2013;54(2):217–27.

    CAS  PubMed  Google Scholar 

  157. Mikati AG et al. Epileptic and electroencephalographic manifestations of guanidinoacetate-methyltransferase deficiency. Epileptic Disord. 2013;15(4):407–16.

    PubMed  Google Scholar 

  158. Leen WG et al. Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder. Brain. 2010;133(Pt 3):655–70.

    PubMed  Google Scholar 

  159. Mills PB et al. Genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy (ALDH7A1 deficiency). Brain. 2010;133(Pt 7):2148–59.

    PubMed Central  PubMed  Google Scholar 

  160. Elterman RD et al. Randomized trial of vigabatrin in patients with infantile spasms. Neurology. 2001;57(8):1416–21.

    CAS  PubMed  Google Scholar 

  161. Krueger DA et al. Everolimus long-term safety and efficacy in subependymal giant cell astrocytoma. Neurology. 2013;80(6):574–80.

    PubMed Central  CAS  PubMed  Google Scholar 

  162. Guerrini R et al. Lamotrigine and seizure aggravation in severe myoclonic epilepsy. Epilepsia. 1998;39(5):508–12.

    CAS  PubMed  Google Scholar 

  163. Chiron C, Dulac O. The pharmacologic treatment of Dravet syndrome. Epilepsia. 2011;52 Suppl 2:72–5.

    PubMed  Google Scholar 

  164. Touma M et al. Whole genome sequencing identifies SCN2A mutation in monozygotic twins with Ohtahara syndrome and unique neuropathologic findings. Epilepsia. 2013;54(5):e81–5.

    PubMed Central  PubMed  Google Scholar 

  165. Walleigh DJ, Legido A, Valencia I. Ring chromosome 20: a pediatric potassium channelopathy responsive to treatment with ezogabine. Pediatr Neurol. 2013;49(5):368–9.

    PubMed  Google Scholar 

  166. Pierson TM et al. Mutation and early-onset epileptic encephalopathy: personalized therapy with memantine. Ann Clin Transl Neurol. 2014;1(3):190–8. This study provides a remarkable example of targeted therapy based on the knowledge of the genetic mutation causing epilepsy and its functional consequences.

    PubMed Central  CAS  PubMed  Google Scholar 

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Conflict of Interest

Christelle M. El Achkar and Phillip L. Pearl declare that they have no conflict of interest. Heather E. Olson has received a grant from the NINDS (5K12 NS079414-02). Annapurna Poduri has received a K23 grant from the NINDS.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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Affiliations

  1. Division of Epilepsy, Department of Neurology, Boston Children’s Hospital, and Harvard Medical School, Fegan 9, 300 Longwood Ave, Boston, MA, 02115, USA

    Christelle M. El Achkar & Phillip L. Pearl

  2. Epilepsy Genetics Program, Division of Epilepsy, Department of Neurology, Boston Children’s Hospital, and Harvard Medical School, Boston, MA, USA

    Heather E. Olson & Annapurna Poduri

Authors
  1. Christelle M. El Achkar
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  2. Heather E. Olson
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  3. Annapurna Poduri
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  4. Phillip L. Pearl
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Correspondence to Christelle M. El Achkar.

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Thank you to Dr. Carl Bazil for taking the time to review this manuscript.

This article is part of the Topical Collection on Pediatric Neurology

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El Achkar, C.M., Olson, H.E., Poduri, A. et al. The Genetics of the Epilepsies. Curr Neurol Neurosci Rep 15, 39 (2015). https://doi.org/10.1007/s11910-015-0559-8

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  • DOI: https://doi.org/10.1007/s11910-015-0559-8

Keywords

  • Epilepsy
  • Epileptic encephalopathy
  • Epilepsy syndrome
  • Channelopathies
  • Genetics
  • Channelopathies