Advertisement

The Genetics of the Epilepsies

  • Christelle M. El AchkarEmail author
  • Heather E. Olson
  • Annapurna Poduri
  • Phillip L. Pearl
Pediatric Neurology (P Pearl, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Pediatric Neurology

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.

Keywords

Epilepsy Epileptic encephalopathy Epilepsy syndrome Channelopathies Genetics Channelopathies 

Notes

Compliance with Ethics Guidelines

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.

Human and Animal Rights and Informed Consent

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

References

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

  1. 1.
    Lee BI, Heo K. Epilepsy: new genes, new technologies, new insights. Lancet Neurol. 2014;13(1):7–9.PubMedGoogle Scholar
  2. 2.
    Hauser WA, Kurland LT. The epidemiology of epilepsy in Rochester, Minnesota, 1935 through 1967. Epilepsia. 1975;16(1):1–66.PubMedGoogle Scholar
  3. 3.
    Thomas RH, Berkovic SF. The hidden genetics of epilepsy-a clinically important new paradigm. Nat Rev Neurol. 2014;10(5):283–92.PubMedGoogle Scholar
  4. 4.
    Buiting K. Prader-Willi syndrome and Angelman syndrome. Am J Med Genet C: Semin Med Genet. 2010;154C(3):365–76.Google Scholar
  5. 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.PubMedGoogle Scholar
  6. 6.
    Evrony GD et al. Cell lineage analysis in human brain using endogenous retroelements. Neuron. 2015;85(1):49–59.PubMedGoogle Scholar
  7. 7.
    Lindhout D. Somatic mosaicism as a basic epileptogenic mechanism? Brain. 2008;131(Pt 4):900–1.PubMedGoogle Scholar
  8. 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.PubMedCentralPubMedGoogle Scholar
  9. 9.
    Poduri A et al. Somatic mutation, genomic variation, and neurological disease. Science. 2013;341(6141):1237758.PubMedCentralPubMedGoogle Scholar
  10. 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.PubMedCentralPubMedGoogle Scholar
  11. 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. 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.PubMedCentralPubMedGoogle Scholar
  13. 13.
    Gennaro E et al. Somatic and germline mosaicisms in severe myoclonic epilepsy of infancy. Biochem Biophys Res Commun. 2006;341(2):489–93.PubMedGoogle Scholar
  14. 14.
    Depienne C et al. Mechanisms for variable expressivity of inherited SCN1A mutations causing Dravet syndrome. J Med Genet. 2010;47(6):404–10.PubMedGoogle Scholar
  15. 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.PubMedGoogle Scholar
  16. 16.
    Doty CN. SCN9A: another sodium channel excited to play a role in human epilepsies. Clin Genet. 2010;77(4):326–8.PubMedGoogle Scholar
  17. 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.PubMedCentralPubMedGoogle Scholar
  18. 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.PubMedGoogle Scholar
  19. 19.
    Kato M et al. Clinical spectrum of early onset epileptic encephalopathies caused by KCNQ2 mutation. Epilepsia. 2013;54(7):1282–7.PubMedGoogle Scholar
  20. 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.PubMedGoogle Scholar
  21. 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.PubMedCentralPubMedGoogle Scholar
  22. 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.PubMedGoogle Scholar
  23. 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. 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.PubMedGoogle Scholar
  25. 25.
    Poduri A et al. Homozygous PLCB1 deletion associated with malignant migrating partial seizures in infancy. Epilepsia. 2012;53(8):e146–50.PubMedGoogle Scholar
  26. 26.
    Shen J et al. Mutations in PNKP cause microcephaly, seizures and defects in DNA repair. Nat Genet. 2010;42(3):245–9.PubMedCentralPubMedGoogle Scholar
  27. 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.PubMedCentralPubMedGoogle Scholar
  28. 28.
    Pearl PL, Gospe SM. Pyridoxine or pyridoxal-5′-phosphate for neonatal epilepsy: the distinction just got murkier. Neurology. 2014;82(16):1392–4.PubMedGoogle Scholar
  29. 29.
    Poduri A et al. Genetic testing in the epilepsies-developments and dilemmas. Nat Rev Neurol. 2014;10(5):293–9.PubMedCentralPubMedGoogle Scholar
  30. 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.PubMedGoogle Scholar
  31. 31.
    Veeramah KR et al. Exome sequencing reveals new causal mutations in children with epileptic encephalopathies. Epilepsia. 2013;54(7):1270–81.PubMedCentralPubMedGoogle Scholar
  32. 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.PubMedGoogle Scholar
  33. 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.PubMedCentralPubMedGoogle Scholar
  34. 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.PubMedCentralPubMedGoogle Scholar
  35. 35.
    Scheffer IE et al. Dravet syndrome or genetic (generalized) epilepsy with febrile seizures plus? Brain Dev. 2009;31(5):394–400.PubMedGoogle Scholar
  36. 36.
    Orhan G et al. Dominant-negative effects of KCNQ2 mutations are associated with epileptic encephalopathy. Ann Neurol. 2014;75(3):382–94.PubMedGoogle Scholar
  37. 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.PubMedGoogle Scholar
  38. 38.
    Mastrangelo M, Leuzzi V. Genes of early-onset epileptic encephalopathies: from genotype to phenotype. Pediatr Neurol. 2012;46(1):24–31.PubMedGoogle Scholar
  39. 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.PubMedGoogle Scholar
  40. 40.
    Olson HE et al. Genetic mechanisms of ohtahara syndrome, a cohort study. 2014: Annals of neurology. p. S178-S178.Google Scholar
  41. 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.PubMedGoogle Scholar
  42. 42.
    Saitsu H et al. Whole exome sequencing identifies KCNQ2 mutations in Ohtahara syndrome. Ann Neurol. 2012;72(2):298–300.PubMedGoogle Scholar
  43. 43.
    Nakamura K et al. Clinical spectrum of SCN2A mutations expanding to Ohtahara syndrome. Neurology. 2013;81(11):992–8.PubMedGoogle Scholar
  44. 44.
    Kato M et al. Frameshift mutations of the ARX gene in familial Ohtahara syndrome. Epilepsia. 2010;51(9):1679–84.PubMedGoogle Scholar
  45. 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.PubMedGoogle Scholar
  46. 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.PubMedGoogle Scholar
  47. 47.
    Saitsu H et al. CASK aberrations in male patients with Ohtahara syndrome and cerebellar hypoplasia. Epilepsia. 2012;53(8):1441–9.PubMedGoogle Scholar
  48. 48.
    Kato M et al. PIGA mutations cause early-onset epileptic encephalopathies and distinctive features. Neurology. 2014;82(18):1587–96.PubMedGoogle Scholar
  49. 49.
    Dravet C, Oguni H. Dravet syndrome (severe myoclonic epilepsy in infancy). Handb Clin Neurol. 2013;111:627–33.PubMedGoogle Scholar
  50. 50.
    Patino GA et al. A functional null mutation of SCN1B in a patient with Dravet syndrome. J Neurosci. 2009;29(34):10764–78.PubMedCentralPubMedGoogle Scholar
  51. 51.
    Carvill GL et al. GABRA1 and STXBP1: novel genetic causes of Dravet syndrome. Neurology. 2014;82(14):1245–53.PubMedCentralPubMedGoogle Scholar
  52. 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.PubMedGoogle Scholar
  53. 53.
    Nava C et al. De novo mutations in HCN1 cause early infantile epileptic encephalopathy. Nat Genet. 2014;46(6):640–5.PubMedGoogle Scholar
  54. 54.
    Shi X et al. Mutational analysis of GABRG2 in a Japanese cohort with childhood epilepsies. J Hum Genet. 2010;55(6):375–8.PubMedGoogle Scholar
  55. 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.PubMedCentralPubMedGoogle Scholar
  56. 56.
    Carranza Rojo D et al. De novo SCN1A mutations in migrating partial seizures of infancy. Neurology. 2011;77(4):380–3.PubMedCentralPubMedGoogle Scholar
  57. 57.
    Poduri A et al. SLC25A22 is a novel gene for migrating partial seizures in infancy. Ann Neurol. 2013;74(6):873–82.PubMedCentralPubMedGoogle Scholar
  58. 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.PubMedGoogle Scholar
  59. 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.PubMedGoogle Scholar
  60. 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.PubMedCentralPubMedGoogle Scholar
  61. 61.
    Ohba C et al. Early onset epileptic encephalopathy caused by de novo SCN8A mutations. Epilepsia. 2014;55(7):994–1000.PubMedGoogle Scholar
  62. 62.
    Paciorkowski AR, Thio LL, Dobyns WB. Genetic and biologic classification of infantile spasms. Pediatr Neurol. 2011;45(6):355–67.PubMedCentralPubMedGoogle Scholar
  63. 63.
    Mefford HC et al. Rare copy number variants are an important cause of epileptic encephalopathies. Ann Neurol. 2011;70(6):974–85.PubMedCentralPubMedGoogle Scholar
  64. 64.
    Consortium EK. Epi4K: gene discovery in 4,000 genomes. Epilepsia. 2012;53(8):1457–67.Google Scholar
  65. 65.
    Chu-Shore CJ et al. The natural history of epilepsy in tuberous sclerosis complex. Epilepsia. 2010;51(7):1236–41.PubMedCentralPubMedGoogle Scholar
  66. 66.
    Guerrini R et al. Nonsyndromic mental retardation and cryptogenic epilepsy in women with doublecortin gene mutations. Ann Neurol. 2003;54(1):30–7.PubMedGoogle Scholar
  67. 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.PubMedGoogle Scholar
  68. 68.
    Dobyns WB. The clinical patterns and molecular genetics of lissencephaly and subcortical band heterotopia. Epilepsia. 2010;51 Suppl 1:5–9.PubMedGoogle Scholar
  69. 69.
    Matalon D et al. Confirming an expanded spectrum of SCN2A mutations: a case series. Epileptic Disord. 2014;16(1):13–8.PubMedGoogle Scholar
  70. 70.
    Allen NM et al. The variable phenotypes of KCNQ-related epilepsy. Epilepsia. 2014;55(9):e99–e105.PubMedGoogle Scholar
  71. 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.PubMedGoogle Scholar
  72. 72.
    Mignot C et al. STXBP1-related encephalopathy presenting as infantile spasms and generalized tremor in three patients. Epilepsia. 2011;52(10):1820–7.PubMedGoogle Scholar
  73. 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.PubMedGoogle Scholar
  74. 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.PubMedGoogle Scholar
  75. 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.PubMedGoogle Scholar
  76. 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.PubMedGoogle Scholar
  77. 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.PubMedCentralPubMedGoogle Scholar
  78. 78.
    Kurian MA et al. Phospholipase C beta 1 deficiency is associated with early-onset epileptic encephalopathy. Brain. 2010;133(10):2964–70.PubMedGoogle Scholar
  79. 79.
    Ruggieri M et al. Neurofibromatosis type 1 and infantile spasms. Childs Nerv Syst. 2009;25(2):211–6.PubMedGoogle Scholar
  80. 80.
    Bahi-Buisson N et al. Spectrum of epilepsy in terminal 1p36 deletion syndrome. Epilepsia. 2008;49(3):509–15.PubMedGoogle Scholar
  81. 81.
    Saito Y et al. Polymicrogyria and infantile spasms in a patient with 1p36 deletion syndrome. Brain Dev. 2011;33(5):437–41.PubMedGoogle Scholar
  82. 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.PubMedGoogle Scholar
  83. 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.PubMedGoogle Scholar
  84. 84.
    Conant KD et al. A survey of seizures and current treatments in 15q duplication syndrome. Epilepsia. 2014;55(3):396–402.PubMedGoogle Scholar
  85. 85.
    Méneret A et al. PRRT2 mutations and paroxysmal disorders. Eur J Neurol. 2013;20(6):872–8.PubMedGoogle Scholar
  86. 86.
    Girard JM et al. Progressive myoclonus epilepsy. Handb Clin Neurol. 2013;113:1731–6.PubMedGoogle Scholar
  87. 87.
    Lalioti MD et al. Dodecamer repeat expansion in cystatin B gene in progressive myoclonus epilepsy. Nature. 1997;386(6627):847–51.PubMedGoogle Scholar
  88. 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.PubMedCentralPubMedGoogle Scholar
  89. 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.PubMedCentralPubMedGoogle Scholar
  90. 90.
    Trujillo-Tiebas MJ et al. Novel human pathological mutations. Gene symbol: EPM2A. Disease: Lafora progressive myoclonus epilepsy. Hum Genet. 2007;121(5):651.PubMedGoogle Scholar
  91. 91.
    Chan EM et al. Mutations in NHLRC1 cause progressive myoclonus epilepsy. Nat Genet. 2003;35(2):125–7.PubMedGoogle Scholar
  92. 92.
    Ferlazzo E, et al. Mild Lafora disease: Clinical, neurophysiologic, and genetic findings. Epilepsia, 2014.Google Scholar
  93. 93.
    Mink JW et al. Classification and natural history of the neuronal ceroid lipofuscinoses. J Child Neurol. 2013;28(9):1101–5.PubMedCentralPubMedGoogle Scholar
  94. 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.PubMedGoogle Scholar
  95. 95.
    Steinfeld R et al. Cathepsin D deficiency is associated with a human neurodegenerative disorder. Am J Hum Genet. 2006;78(6):988–98.PubMedCentralPubMedGoogle Scholar
  96. 96.
    Muona M et al. A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy. Nat Genet, 2014.Google Scholar
  97. 97.
    Pearson TS et al. Phenotypic spectrum of glucose transporter type 1 deficiency syndrome (Glut1 DS). Curr Neurol Neurosci Rep. 2013;13(4):342.PubMedGoogle Scholar
  98. 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.PubMedCentralPubMedGoogle Scholar
  99. 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.PubMedGoogle Scholar
  100. 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.PubMedCentralPubMedGoogle Scholar
  101. 101.
    Helbig I et al. 15q13.3 microdeletions increase risk of idiopathic generalized epilepsy. Nat Genet. 2009;41(2):160–2.PubMedCentralPubMedGoogle Scholar
  102. 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.PubMedCentralPubMedGoogle Scholar
  103. 103.
    Mullen SA et al. Copy number variants are frequent in genetic generalized epilepsy with intellectual disability. Neurology. 2013;81(17):1507–14.PubMedCentralPubMedGoogle Scholar
  104. 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.PubMedGoogle Scholar
  105. 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.PubMedCentralPubMedGoogle Scholar
  106. 106.
    D’Agostino D et al. Mutations and polymorphisms of the CLCN2 gene in idiopathic epilepsy. Neurology. 2004;63(8):1500–2.PubMedGoogle Scholar
  107. 107.
    Chioza B et al. Association between the alpha(1a) calcium channel gene CACNA1A and idiopathic generalized epilepsy. Neurology. 2001;56(9):1245–6.PubMedGoogle Scholar
  108. 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.PubMedGoogle Scholar
  109. 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.PubMedGoogle Scholar
  110. 110.
    Ottman R et al. Genetic testing in the epilepsies–report of the ILAE Genetics Commission. Epilepsia. 2010;51(4):655–70.PubMedCentralPubMedGoogle Scholar
  111. 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.PubMedGoogle Scholar
  112. 112.
    Fanciulli M et al. LGI1 microdeletion in autosomal dominant lateral temporal epilepsy. Neurology. 2012;78(17):1299–303.PubMedCentralPubMedGoogle Scholar
  113. 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.PubMedGoogle Scholar
  114. 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.PubMedCentralPubMedGoogle Scholar
  115. 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.PubMedGoogle Scholar
  116. 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.PubMedGoogle Scholar
  117. 117.
    Ishida S et al. Mutations of DEPDC5 cause autosomal dominant focal epilepsies. Nat Genet. 2013;45(5):552–5.PubMedGoogle Scholar
  118. 118.
    Lal D et al. DEPDC5 mutations in genetic focal epilepsies of childhood. Ann Neurol. 2014;75(5):788–92.PubMedGoogle Scholar
  119. 119.
    Picard F et al. DEPDC5 mutations in families presenting as autosomal dominant nocturnal frontal lobe epilepsy. Neurology. 2014;82(23):2101–6.PubMedGoogle Scholar
  120. 120.
    D’Gama AM et al. mTOR pathway mutations cause hemimegalencephaly and focal cortical dysplasia. Ann Neurol, 2015.Google Scholar
  121. 121.
    Carvill GL et al. GRIN2A mutations cause epilepsy-aphasia spectrum disorders. Nat Genet. 2013;45(9):1073–6.PubMedGoogle Scholar
  122. 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.PubMedGoogle Scholar
  123. 123.
    Lemke JR et al. Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes. Nat Genet. 2013;45(9):1067–72.PubMedGoogle Scholar
  124. 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.PubMedGoogle Scholar
  125. 125.
    Barba C et al. Co-occurring malformations of cortical development and SCN1A gene mutations. Epilepsia. 2014;55(7):1009–19.PubMedGoogle Scholar
  126. 126.
    Auerbach DS et al. Altered cardiac electrophysiology and SUDEP in a model of Dravet syndrome. PLoS One. 2013;8(10), e77843.PubMedCentralPubMedGoogle Scholar
  127. 127.
    Delogu AB et al. Electrical and autonomic cardiac function in patients with Dravet syndrome. Epilepsia. 2011;52 Suppl 2:55–8.PubMedGoogle Scholar
  128. 128.
    Kalume F et al. Sudden unexpected death in a mouse model of Dravet syndrome. J Clin Invest. 2013;123(4):1798–808.PubMedCentralPubMedGoogle Scholar
  129. 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.PubMedGoogle Scholar
  130. 130.
    Nabbout R. Can SCN1A mutations account for SUDEP?–Commentary on Hindocha et al. Epilepsia. 2008;49(2):367–8.PubMedGoogle Scholar
  131. 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.PubMedCentralPubMedGoogle Scholar
  132. 132.
    Wagnon JL et al., Convulsive seizures and SUDEP in a mouse model of SCN8A epileptic encephalopathy. Hum Mol Genet. 2014.Google Scholar
  133. 133.
    Larsen J. et al. The phenotypic spectrum of SCN8A encephalopathy. Neurology, 2015.Google Scholar
  134. 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.PubMedGoogle Scholar
  135. 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.PubMedGoogle Scholar
  136. 136.
    Thibert RL et al. Neurologic manifestations of Angelman syndrome. Pediatr Neurol. 2013;48(4):271–9.PubMedGoogle Scholar
  137. 137.
    Pescosolido MF et al. Genetic and phenotypic diversity of NHE6 mutations in Christianson syndrome. Ann Neurol. 2014;76(4):581–93.PubMedGoogle Scholar
  138. 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.PubMedGoogle Scholar
  139. 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.PubMedGoogle Scholar
  140. 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.PubMedGoogle Scholar
  141. 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.PubMedGoogle Scholar
  142. 142.
    Neul JL et al. Rett syndrome: revised diagnostic criteria and nomenclature. Ann Neurol. 2010;68(6):944–50.PubMedCentralPubMedGoogle Scholar
  143. 143.
    Nissenkorn A et al. Epilepsy in Rett syndrome–-the experience of a National Rett Center. Epilepsia. 2010;51(7):1252–8.PubMedGoogle Scholar
  144. 144.
    Pintaudi M et al. Epilepsy in Rett syndrome: clinical and genetic features. Epilepsy Behav. 2010;19(3):296–300.PubMedGoogle Scholar
  145. 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.PubMedCentralPubMedGoogle Scholar
  146. 146.
    Cardoza B et al. Epilepsy in Rett syndrome: association between phenotype and genotype, and implications for practice. Seizure. 2011;20(8):646–9.PubMedGoogle Scholar
  147. 147.
    Guerrini R, Parrini E. Epilepsy in Rett syndrome, and CDKL5- and FOXG1-gene-related encephalopathies. Epilepsia. 2012;53(12):2067–78.PubMedGoogle Scholar
  148. 148.
    Klein KM et al. A distinctive seizure type in patients with CDKL5 mutations: Hypermotor-tonic-spasms sequence. Neurology. 2011;76(16):1436–8.PubMedGoogle Scholar
  149. 149.
    Seltzer LE et al. Epilepsy and outcome in FOXG1-related disorders. Epilepsia. 2014;55(8):1292–300.PubMedGoogle Scholar
  150. 150.
    Striano P et al. West syndrome associated with 14q12 duplications harboring FOXG1. Neurology. 2011;76(18):1600–2.PubMedGoogle Scholar
  151. 151.
    Pearl PL, Gospe SM. Pyridoxal phosphate dependency, a newly recognized treatable catastrophic epileptic encephalopathy. J Inherit Metab Dis. 2007;30(1):2–4.PubMedGoogle Scholar
  152. 152.
    Giovannini S et al. Epilepsy in ring 14 syndrome: a clinical and EEG study of 22 patients. Epilepsia. 2013;54(12):2204–13.PubMedGoogle Scholar
  153. 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.PubMedGoogle Scholar
  154. 154.
    Battaglia A. The inv dup (15) or idic (15) syndrome (Tetrasomy 15q). Orphanet J Rare Dis. 2008;3:30.PubMedCentralPubMedGoogle Scholar
  155. 155.
    Scheffer IE. Epilepsy genetics revolutionizes clinical practice. Neuropediatrics. 2014;45(2):70–4.PubMedGoogle Scholar
  156. 156.
    Leuzzi V et al. Inborn errors of creatine metabolism and epilepsy. Epilepsia. 2013;54(2):217–27.PubMedGoogle Scholar
  157. 157.
    Mikati AG et al. Epileptic and electroencephalographic manifestations of guanidinoacetate-methyltransferase deficiency. Epileptic Disord. 2013;15(4):407–16.PubMedGoogle Scholar
  158. 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.PubMedGoogle Scholar
  159. 159.
    Mills PB et al. Genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy (ALDH7A1 deficiency). Brain. 2010;133(Pt 7):2148–59.PubMedCentralPubMedGoogle Scholar
  160. 160.
    Elterman RD et al. Randomized trial of vigabatrin in patients with infantile spasms. Neurology. 2001;57(8):1416–21.PubMedGoogle Scholar
  161. 161.
    Krueger DA et al. Everolimus long-term safety and efficacy in subependymal giant cell astrocytoma. Neurology. 2013;80(6):574–80.PubMedCentralPubMedGoogle Scholar
  162. 162.
    Guerrini R et al. Lamotrigine and seizure aggravation in severe myoclonic epilepsy. Epilepsia. 1998;39(5):508–12.PubMedGoogle Scholar
  163. 163.
    Chiron C, Dulac O. The pharmacologic treatment of Dravet syndrome. Epilepsia. 2011;52 Suppl 2:72–5.PubMedGoogle Scholar
  164. 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.PubMedCentralPubMedGoogle Scholar
  165. 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.PubMedGoogle Scholar
  166. 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.PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Christelle M. El Achkar
    • 1
    Email author
  • Heather E. Olson
    • 2
  • Annapurna Poduri
    • 2
  • Phillip L. Pearl
    • 1
  1. 1.Division of Epilepsy, Department of NeurologyBoston Children’s Hospital, and Harvard Medical SchoolBostonUSA
  2. 2.Epilepsy Genetics Program, Division of Epilepsy, Department of NeurologyBoston Children’s Hospital, and Harvard Medical SchoolBostonUSA

Personalised recommendations