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What’s new in: “Genetics in childhood epilepsy”

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Abstract

In recent years, different mutations in genes that control the excitability of neurons have been described in idiopathic childhood epilepsies. Most commonly, sodium/potassium channelopathies and GABA-receptor mutations are involved. Major progress has been made in the field of idiopathic generalised epilepsies associated with febrile seizures (GEFS+). It now is becoming clear that mutations should not only be looked for in familial cases, but also in sporadic cases, especially in infants and young children with unexplained severe epileptic encephalopathies. Many studies also define ‘epilepsy susceptibility genes’, which contribute to one’s individual genetic vulnerability to develop epilepsy. It should be realized, however, that in the most common idiopathic benign childhood epilepsies (benign rolandic and occipital epilepsies), major breakthroughs are still awaited. In addition, a better clinical description of the epileptic phenotypes is needed to explain more precisely the genotypic and phenotypic heterogeneity. Genetic studies are nowadays becoming a necessary diagnostic step in the evaluation of idiopathic childhood epilepsies, not only in familial cases, but also in sporadic cases.

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References

  1. Archer HL, Evans J, Edwards S, Colley J, Newbury-Ecob R, O’Callaghan F, Huyton M, O’Regan M, Tolmie J, Sampson J, Clarke A, Osborne J (2006) CDKL5 mutations cause infantile spasms, early onset seizures, and severe mental retardation in female patients. J Med Genet 43(9):729–734

    Article  PubMed  CAS  Google Scholar 

  2. Audenaert D, Claes L, Ceulemans B, Löfgren A, Van Broeckhoven C, De Jonghe P (2003) A deletion in SCN1B is associated with febrile seizures and early-onset absence epilepsy. Neurology 61(6):854–856

    PubMed  CAS  Google Scholar 

  3. Audenaert D, Schwartz E, Claeys KG, Claes L, Deprez L, Suls A, Van Dyck T, Lagae L, Van Broeckhoven C, Macdonald RL, De Jonghe P (2006) A novel GABRG2 mutation associated with febrile seizures. Neurology 67(4):687–690

    Article  PubMed  CAS  Google Scholar 

  4. Audenaert D, Van Broeckhoven C, De Jonghe P (2006) Genes and loci involved in febrile seizures and related epilepsy syndromes. Hum Mutat 27(5):391–401

    Article  PubMed  CAS  Google Scholar 

  5. Baulac S, Huberfeld G, Gourfinkel-An I, Mitropoulou G, Beranger A, Prud’homme JF, Baulac M, Brice A, Bruzzone R, LeGuern E (2001) First genetic evidence of GABA(A) receptor dysfunction in epilepsy: a mutation in the gamma2-subunit gene. Nat Genet 28(1):46–48

    Article  PubMed  CAS  Google Scholar 

  6. Berkovic SF, Harkin L, McMahon JM, Pelekanos JT, Zuberi SM, Wirrell EC, Gill DS, Iona X, Mulley JC, Scheffer IE (2006) De-novo mutations of the sodium channel gene SCN1A in alleged vaccine encephalopathy: a retrospective study. Lancet Neurol 5(6):488–492

    Article  PubMed  CAS  Google Scholar 

  7. Berkovic SF, Heron SE, Giordano L, Marini C, Guerrini R, Kaplan RE, Gambardella A, Steinlein OK, Grinton BE, Dean JT, Bordo L, Hodgson BL, Yamamoto T, Mulley JC, Zara F, Scheffer IE (2004) Benign familial neonatal-infantile seizures: characterization of a new sodium channelopathy. Ann Neurol 55(4):550–557

    Article  PubMed  CAS  Google Scholar 

  8. Berkovic SF, Mulley JC, Scheffer IE, Petrou S (2006) Human epilepsies: interaction of genetic and acquired factors. Trends Neurosci 29(7):391–397

    Article  PubMed  CAS  Google Scholar 

  9. Bisulli F, Tinuper P, Scudellaro E, Naldi I, Bagattin A, Avoni P, Michelucci R, Nobile C (2004) A de novo LGI1 mutation in sporadic partial epilepsy with auditory features. Ann Neurol 56(3):455–456

    Article  PubMed  Google Scholar 

  10. Borgatti R, Zucca C, Cavallini A, Ferrario M, Panzeri C, Castaldo P, Soldovieri MV, Baschirotto C, Bresolin N, Dalla Bernardina B, Taglialatela M, Bassi MT (2004) A novel mutation in KCNQ2 associated with BFNC, drug resistant epilepsy, and mental retardation. Neurology 63(1):57–65

    PubMed  CAS  Google Scholar 

  11. Brooks-Kayal AR, Pritchett DB (1993) Developmental changes in human gamma-aminobutyric acidA receptor subunit composition. Ann Neurol 34(5):687–693

    Article  PubMed  CAS  Google Scholar 

  12. Cavalleri GL, Walley NM, Soranzo N, Mulley J, Doherty CP, Kapoor A, Depondt C, Lynch JM, Scheffer IE, Heils A, Gehrmann A, Kinirons P, Gandhi S, Satishchandra P, Wood NW, Anand A, Sander T, Berkovic SF, Delanty N, Goldstein DB, Sisodiya SM (2007) A multicenter study of BRD2 as a risk factor for juvenile myoclonic epilepsy. Epilepsia 48(4):706–712

    Article  PubMed  CAS  Google Scholar 

  13. Ceulemans B, Boel M, Claes L, Dom L, Willekens H, Thiry P, Lagae L (2004) Severe myoclonic epilepsy in infancy: toward an optimal treatment. J Child Neurol 19(7):516–521

    Article  PubMed  Google Scholar 

  14. Ceulemans BP, Claes LR, Lagae LG (2004) Clinical correlations of mutations in the SCN1A gene: from febrile seizures to severe myoclonic epilepsy in infancy. Pediatr Neurol 30(4):236–243

    Article  PubMed  Google Scholar 

  15. Chen Y, Lu J, Pan H, Zhang Y, Wu H, Xu K, Liu X, Jiang Y, Bao X, Yao Z, Ding K, Lo WH, Qiang B, Chan P, Shen Y, Wu X (2003) Association between genetic variation of CACNA1H and childhood absence epilepsy. Ann Neurol 54(2):239–243

    Article  PubMed  CAS  Google Scholar 

  16. Chiron C, Marchand MC, Tran A, Rey E, d’Athis P, Vincent J, Dulac O, Pons G (2000) Stiripentol in severe myoclonic epilepsy in infancy: a randomised placebo-controlled syndrome-dedicated trial. STICLO study group. Lancet 356(9242):1638–1642

    Article  PubMed  CAS  Google Scholar 

  17. Chou IC, Lee CC, Tsai CH, Tsai Y, Wan L, Hsu YA, Li TC, Tsai FJ (2007) Association of GABRG2 polymorphisms with idiopathic generalized epilepsy. Pediatr Neurol 36(1):40–44

    Article  PubMed  Google Scholar 

  18. Claes L, Del-Favero J, Ceulemans B, Lagae L, Van Broeckhoven C, De Jonghe P (2001) De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am J Hum Genet 68(6):1327–1332

    Article  PubMed  CAS  Google Scholar 

  19. Claes S, Devriendt K, Lagae L, Ceulemans B, Dom L, Casaer P, Raeymaekers P, Cassiman JJ, Fryns JP (1997) The X-linked infantile spasms syndrome (MIM 308350) maps to Xp11.4-Xpter in two pedigrees. Ann Neurol 42(3):360–364

    Article  PubMed  CAS  Google Scholar 

  20. Commission on Classification and Terminology of the International League Against Epilepsy (1989) Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 30(4):389–399

    Article  Google Scholar 

  21. Cossette P, Liu L, Brisebois K, Dong H, Lortie A, Vanasse M, Saint-Hilaire JM, Carmant L, Verner A, Lu WY, Wang YT, Rouleau GA (2002) Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy. Nat Genet 31(2):184–189

    Article  PubMed  CAS  Google Scholar 

  22. de Ravel TJ, Devriendt K, Fryns JP, Vermeesch JR (2007) What’s new in karyotyping? The move towards array comparative genomic hybridisation (CGH). Eur J Pediatr 166(7):637–643

    Article  PubMed  Google Scholar 

  23. Dibbens LM, Ekberg J, Taylor I, Hodgson BL, Conroy SJ, Lensink IL, Kumar S, Zielinski MA, Harkin LA, Sutherland GR, Adams DJ, Berkovic SF, Scheffer IE, Mulley JC, Poronnik P (2007) NEDD4–2 as a potential candidate susceptibility gene for epileptic photosensitivity. Genes Brain Behav 6(8):750–755

    Article  PubMed  CAS  Google Scholar 

  24. Dibbens LM, Feng HJ, Richards MC, Harkin LA, Hodgson BL, Scott D, Jenkins M, Petrou S, Sutherland GR, Scheffer IE, Berkovic SF, Macdonald RL, Mulley JC (2004) GABRD encoding a protein for extra- or peri-synaptic GABAA receptors is a susceptibility locus for generalized epilepsies. Hum Mol Genet 13(13):1315–1319

    Article  PubMed  CAS  Google Scholar 

  25. Engel J Jr (2001) A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE task force on classification and terminology. Epilepsia 42:796–803

    Article  PubMed  Google Scholar 

  26. Harkin LA, Bowser DN, Dibbens LM, Singh R, Phillips F, Wallace RH, Richards MC, Williams DA, Mulley JC, Berkovic SF, Scheffer IE, Petrou S (2002) Truncation of the GABA(A)-receptor gamma2 subunit in a family with generalized epilepsy with febrile seizures plus. Am J Hum Genet 70(2):530–536

    Article  PubMed  CAS  Google Scholar 

  27. Harkin LA, McMahon JM, Iona X, Dibbens L, Pelekanos JT, Zuberi SM, Sadleir LG, Andermann E, Gill D, Farrell K, Connolly M, Stanley T, Harbord M, Andermann F, Wang J, Batish SD, Jones JG, Seltzer WK, Gardner A; Infantile Epileptic Encephalopathy Referral Consortium, Sutherland G, Berkovic SF, Mulley JC, Scheffer IE (2007) The spectrum of SCN1A-related infantile epileptic encephalopathies. Brain 130:843–852

    Google Scholar 

  28. Haug K, Warnstedt M, Alekov AK, Sander T, Ramírez A, Poser B, Maljevic S, Hebeisen S, Kubisch C, Rebstock J, Horvath S, Hallmann K, Dullinger JS, Rau B, Haverkamp F, Beyenburg S, Schulz H, Janz D, Giese B, Müller-Newen G, Propping P, Elger CE, Fahlke C, Lerche H, Heils A (2003) Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies. Nat Genet 33(4):527–532

    Article  PubMed  CAS  Google Scholar 

  29. Heron SE, Crossland KM, Andermann E, Phillips HA, Hall AJ, Bleasel A, Shevell M, Mercho S, Seni MH, Guiot MC, Mulley JC, Berkovic SF, Scheffer IE (2002) Sodium-channel defects in benign familial neonatal-infantile seizures. Lancet 360(9336):851–852

    Article  PubMed  CAS  Google Scholar 

  30. Heron SE, Phillips HA, Mulley JC, Mazarib A, Neufeld MY, Berkovic SF, Scheffer IE (2004) Genetic variation of CACNA1H in idiopathic generalized epilepsy. Ann Neurol 55(4):595–596

    Article  PubMed  CAS  Google Scholar 

  31. Heron SE, Scheffer IE, Berkovic SF, Dibbens LM, Mulley JC (2007) Channelopathies in idiopathic epilepsy. Neurotherapeutics 4(2):295–304

    Article  PubMed  CAS  Google Scholar 

  32. Kahane P, Arzimanoglou A (2007) Vaccine encephalopathy: a myth collapses? Presse Med 36(10 Pt 1):1339–1340

    Article  PubMed  Google Scholar 

  33. Kalachikov S, Evgrafov O, Ross B, Winawer M, Barker-Cummings C, Martinelli Boneschi F, Choi C, Morozov P, Das K, Teplitskaya E, Yu A, Cayanis E, Penchaszadeh G, Kottmann AH, Pedley TA, Hauser WA, Ottman R, Gilliam TC (2002) Mutations in LGI1 cause autosomal-dominant partial epilepsy with auditory features. Nat Genet 30(3):335–341

    Article  PubMed  Google Scholar 

  34. Lagae L (2000) Cortical malformations: a frequent cause of epilepsy in children. Eur J Pediatr 159(8):555–562

    Article  PubMed  CAS  Google Scholar 

  35. Lian G, Sheen V (2006) Cerebral developmental disorders. Curr Opin Pediatr 18(6):614–620

    Article  PubMed  Google Scholar 

  36. Lucarini N, Verrotti A, Napolioni V, Bosco G, Curatolo P (2007) Genetic polymorphisms and idiopathic generalized epilepsies. Pediatr Neurol 37(3):157–164

    Article  PubMed  Google Scholar 

  37. Maljevic S, Krampfl K, Cobilanschi J, Tilgen N, Beyer S, Weber YG, Schlesinger F, Ursu D, Melzer W, Cossette P, Bufler J, Lerche H, Heils A (2006) A mutation in the GABA(A) receptor alpha(1)-subunit is associated with absence epilepsy. Ann Neurol 59(6):983–987

    Article  PubMed  CAS  Google Scholar 

  38. Marini C, Guerrini R (2007) The role of the nicotinic acetylcholine receptors in sleep-related epilepsy. Biochem Pharmacol 74(8):1308–1314

    Article  PubMed  CAS  Google Scholar 

  39. Mulley JC, Scheffer IE, Petrou S, Dibbens LM, Berkovic SF, Harkin LA (2005) SCN1A mutations and epilepsy. Hum Mutat 25(6):535–542

    Article  PubMed  CAS  Google Scholar 

  40. Nakayama J, Arinami T (2006) Molecular genetics of febrile seizures. Epilepsy Res 70(Suppl 1):S190–S198

    Article  PubMed  CAS  Google Scholar 

  41. Noebels JL (2006) The Judith Hoyer Lecture: genes, pixels, patterns, and prevention. Epilepsy Behav 9(3):379–385

    Article  PubMed  Google Scholar 

  42. Pinto D, Louwaars S, Westland B, Volkers L, de Haan GJ, Trenité DG, Lindhout D, Koeleman BP (2006) Heterogeneity at the JME 6p11–12 locus: absence of mutations in the EFHC1 gene in linked Dutch families. Epilepsia 47(10):1743–1746

    Article  PubMed  CAS  Google Scholar 

  43. Rosas-Vargas H, Bahi-Buisson N, Philippe C, Nectoux J, Girard B, N’guyen Morel MA, Gitiaux C, Lazzaro L, Odent S, Jonveaux P, Chelly J, Bienvenu T (2007) Impairment of CDKL5 nuclear localization as a cause for severe infantile encephalopathy. J Med Genet 44:1–20

    Google Scholar 

  44. Scheffer IE, Berkovic SF (1997) Generalized epilepsy with febrile seizures plus. A genetic disorder with heterogeneous clinical phenotypes. Brain 120(Pt 3):479–490

    Article  PubMed  Google Scholar 

  45. Sherr EH (2003) The ARX story (epilepsy, mental retardation, autism, and cerebral malformations): one gene leads to many phenotypes. Curr Opin Pediatr 15(6):567–571

    Article  PubMed  Google Scholar 

  46. Singh NA, Charlier C, Stauffer D, DuPont BR, Leach RJ, Melis R, Ronen GM, Bjerre I, Quattlebaum T, Murphy JV, McHarg ML, Gagnon D, Rosales TO, Peiffer A, Anderson VE, Leppert M (1998) A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nat Genet 18(1):25–29

    Article  PubMed  CAS  Google Scholar 

  47. Singh NA, Westenskow P, Charlier C, Pappas C, Leslie J, Dillon J, Anderson VE, Sanguinetti MC, Leppert MF, BFNC Physician Consortium (2003) KCNQ2 and KCNQ3 potassium channel genes in benign familial neonatal convulsions: expansion of the functional and mutation spectrum. Brain 126(Pt 12):2726–2737

    Article  PubMed  Google Scholar 

  48. Specchio N, Vigevano F (2006) The spectrum of benign infantile seizures. Epilepsy Res 70(Suppl 1):S156–S167

    Article  PubMed  Google Scholar 

  49. Suzuki T, Delgado-Escueta AV, Aguan K, Alonso ME, Shi J, Hara Y, Nishida M, Numata T, Medina MT, Takeuchi T, Morita R, Bai D, Ganesh S, Sugimoto Y, Inazawa J, Bailey JN, Ochoa A, Jara-Prado A, Rasmussen A, Ramos-Peek J, Cordova S, Rubio-Donnadieu F, Inoue Y, Osawa M, Kaneko S, Oguni H, Mori Y, Yamakawa K (2004) Mutations in EFHC1 cause juvenile myoclonic epilepsy. Nat Genet 36(8):842–849

    Article  PubMed  CAS  Google Scholar 

  50. Terwindt GM, Ophoff RA, Lindhout D, Haan J, Halley DJ, Sandkuijl LA, Brouwer OF, Frants RR, Ferrari MD (1997) Partial cosegregation of familial hemiplegic migraine and a benign familial infantile epileptic syndrome. Epilepsia 38(8):915–921

    Article  PubMed  CAS  Google Scholar 

  51. Van Bogaert P, Azizieh R, Désir J, Aeby A, De Meirleir L, Laes JF, Christiaens F, Abramowicz MJ (2007) Mutation of a potassium channel-related gene in progressive myoclonic epilepsy. Ann Neurol 61(6):579–586

    Article  PubMed  Google Scholar 

  52. Vanmolkot KR, Kors EE, Hottenga JJ, Terwindt GM, Haan J, Hoefnagels WA, Black DF, Sandkuijl LA, Frants RR, Ferrari MD, van den Maagdenberg AM (2003) Novel mutations in the Na+ , K+ -ATPase pump gene ATP1A2 associated with familial hemiplegic migraine and benign familial infantile convulsions. Ann Neurol 54(3):360–366

    Article  PubMed  CAS  Google Scholar 

  53. Vigevano F (2005) Benign familial infantile seizures. Brain Dev 27(3):172–177

    Article  PubMed  Google Scholar 

  54. Wallace RH, Marini C, Petrou S, Harkin LA, Bowser DN, Panchal RG, Williams DA, Sutherland GR, Mulley JC, Scheffer IE, Berkovic SF (2001) Mutant GABA(A) receptor gamma2-subunit in childhood absence epilepsy and febrile seizures. Nat Genet 28(1):49–52

    Article  PubMed  CAS  Google Scholar 

  55. Wallace RH, Scheffer IE, Barnett S, Richards M, Dibbens L, Desai RR, Lerman-Sagie T, Lev D, Mazarib A, Brand N, Ben-Zeev B, Goikhman I, Singh R, Kremmidiotis G, Gardner A, Sutherland GR, George AL Jr, Mulley JC, Berkovic SF (2001) Neuronal sodium-channel alpha1-subunit mutations in generalized epilepsy with febrile seizures plus. Am J Hum Genet 68(4):859–865

    Article  PubMed  CAS  Google Scholar 

  56. Wallace RH, Scheffer IE, Parasivam G, Barnett S, Wallace GB, Sutherland GR, Berkovic SF, Mulley JC (2002) Generalized epilepsy with febrile seizures plus: mutation of the sodium channel subunit SCN1B. Neurology 58(9):1426–1429

    PubMed  CAS  Google Scholar 

  57. Wallace RH, Wang DW, Singh R, Scheffer IE, George AL Jr, Phillips HA, Saar K, Reis A, Johnson EW, Sutherland GR, Berkovic SF, Mulley JC (1998) Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B. Nat Genet 19(4):366–370

    Article  PubMed  CAS  Google Scholar 

  58. Yu ZL, Jiang JM, Wu DH, Xie HJ, Jiang JJ, Zhou L, Peng L, Bao GS (2007) Febrile seizures are associated with mutation of seizure-related (SEZ) 6, a brain-specific gene. J Neurosci Res 85(1):166–172

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Paediatric Neurology, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium

    Lieven Lagae

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Lagae, L. What’s new in: “Genetics in childhood epilepsy”. Eur J Pediatr 167, 715–722 (2008). https://doi.org/10.1007/s00431-008-0690-5

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