Pediatric Neurology
Volume 37, Issue 3 , Pages 157-164 , September 2007

Genetic Polymorphisms and Idiopathic Generalized Epilepsies

  • Nazzareno Lucarini, MSc

      Affiliations

    • Department of Molecular, Cellular, and Animal Biology, University of Camerino, Camerino, Italy
    • Corresponding Author InformationCommunications should be addressed to: Dr. Lucarini; Department of Molecular, Cellular and Animal Biology, University of Camerino; Via F. Camerini 2; 62032 Camerino (MC), Italy.
  • ,
  • Alberto Verrotti, MD

      Affiliations

    • Department of Pediatrics, University of Chieti, Chieti, Italy
  • ,
  • Valerio Napolioni, BS

      Affiliations

    • Department of Molecular, Cellular, and Animal Biology, University of Camerino, Camerino, Italy
  • ,
  • Guido Bosco, MD

      Affiliations

    • Department of Pediatrics, University of Chieti, Chieti, Italy
  • ,
  • Paolo Curatolo, MD

      Affiliations

    • Department of Pediatric Neurology and Department of Neurosciences, Tor Vergata University, Rome, Italy.

Received 22 January 2007 ,Accepted 1 June 2007.

References 

  1. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia. 1989;30:389–399
  2. Engel J. A proposed diagnostic scheme for people with epileptic seizures and epilepsy (Report of the ILAE Task Force on Classification and Terminology). Epilepsia. 2001;42:796–803
  3. Picard F, Scheffer IE. Recently defined genetic epilepsy syndromes. In:  Roger J,  Bureau M,  Travet C,  Genton P,  Tassinari CA,  Wolf P editor. Epileptic syndromes in infancy, childhood and adolescence. 4th ed.. Montrouge, France: John Libbey Eurotext, Ltd; 2005;p. 519–535
  4. Zara F, Bianchi A, Avanzini G, et al. Mapping of genes predisposing to idiopathic generalized epilepsy. Hum Mol Genet. 1995;4:1201–1207
  5. Buono RJ, Lohoff FW, Sander T, et al. Association between variation in the human KCNJ10 potassium ion channel gene and seizure susceptibility. Epilepsy Res. 2004;58:175–183
  6. Lenzen KP, Heils A, Lorenz S, et al. Supportive evidence for an allelic association of the human KCNJ10 potassium channel gene with idiopathic generalized epilepsy. Epilepsy Res. 2005;63:113–118
  7. Shang L, Lucchese CJ, Haider S, Tucker SJ. Functional characterisation of missense variations in the Kir4.1 potassium channel (KCNJ10) associated with seizure susceptibility. Brain Res Mol Brain Res. 2005;139:178–183
  8. Chioza B, Osei-Lah A, Wilkie H, et al. Suggestive evidence for association of two potassium channel genes with different idiopathic generalised epilepsy syndromes. Epilepsy Res. 2002;52:107–116
  9. Plouin P, Anderson E. Benign familial and non-familial neonatal seizures. In:  Roger J,  Bureau M,  Travet C,  Genton P,  Tassinari CA,  Wolf P editor. Epileptic syndromes in infancy, childhood and adolescence. 4th ed.. Montrouge, France: John Libbey Eurotext, Ltd; 2005;p. 3–15
  10. North KN, Storey GN, Henderson-Smart DJ. Fifth day fits in the newborn. Aust Paediatr J. 1989;25:284–287
  11. Leppert M, Anderson VE, Quattlebaum T, et al. Benign neonatal convulsions linked to genetic markers on chromosome 20. Nature. 1989;337:647–648
  12. Biervert C, Schroeder BC, Kubisch C, et al. A potassium channel mutation in neonatal human epilepsy. Science. 1998;279:403–406
  13. Singh NA, Charlier C, Stauffer D, et al. A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nat Genet. 1998;18:25–29
  14. Charlier C, Singh NA, Ryan SG, et al. A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family. Nat Genet. 1998;18:53–55
  15. Singh NA, Westenskow P, Charlier C, et al. KCNQ2 and KCNQ3 potassium channel genes in benign familial neonatal convulsions: Expansion of the functional and mutation spectrum. Brain. 2003;126:2726–2737
  16. Claes LR, Ceulemans B, Audenaert D, et al. De novo KCNQ2 mutations in patients with benign neonatal seizures. Neurology. 2004;63:2155–2158
  17. Schroeder BC, Kubisch C, Stein V, Jentsch TJ. Moderate loss of function of cyclic-AMP-modulated KCNQ2/KCNQ3 K+ channels causes epilepsy. Nature. 1998;396:687–690
  18. Lerche H, Biervert C, Alekov AK, et al. A reduced K+ current due to a novel mutation in KCNQ2 causes neonatal convulsions. Ann Neurol. 1999;46:305–312
  19. Schwake M, Pusch M, Kharkovets T, Jentsch TJ. Surface expression and single channel properties of KCNQ2/KCNQ3, M-type K+ channels involved in epilepsy. J Biol Chem. 2000;275:13343–13348
  20. Dedek K, Fusco L, Teloy N, Steinlein OK. Neonatal convulsions and epileptic encephalopathy in an Italian family with a missense mutation in the fifth transmembrane region of KCNQ2. Epilepsy Res. 2003;54:21–27
  21. Borgatti R, Zucca C, Cavallini A, et al. A novel mutation in KCNQ2 associated with BFNC, drug resistant epilepsy, and mental retardation. Neurology. 2004;63:57–65
  22. Richards MC, Heron SE, Spendlove HE, et al. Novel mutations in the KCNQ2 gene link epilepsy to a dysfunction of the KCNQ2-calmodulin interaction. J Med Genet. 2004;41:35
  23. Bassi MT, Balottin U, Panzeri C, et al. Functional analysis of novel KCNQ2 and KCNQ3 gene variants found in a large pedigree with benign familial neonatal convulsions (BFNC). Neurogenetics. 2005;6:185–193
  24. Fong GCY, Shah PU, Gee MN, et al. Childhood absence epilepsy with tonic-clonic seizures and electroencephalogram 3–4-Hz spike and multispike-slow wave complexes: Linkage to chromosome 8q24. Am J Hum Genet. 1998;63:1117–1129
  25. Wallace RH, Marini C, Petrou S, et al. Mutant GABA(A) receptor gamma-2-subunit in childhood absence epilepsy and febrile seizures. Nat Genet. 2001;28:49–52
  26. Italian League Against Epilepsy Genetic Collaborative Group. Concordance of clinical forms of epilepsy in families with several affected members. Epilepsia. 1993;34:819–826
  27. Sander T, Schulz H, Saar K, et al. Genome search for susceptibility loci of common idiopathic generalised epilepsies. Hum Mol Genet. 2000;9:1465–1472
  28. Haug K, Warnstedt M, Alekov AK, et al. Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies. Nat Genet. 2003;33:527–532
  29. Olsen RW, DeLorey TM, Gordey M, Kang MH. GABA receptor function and epilepsy. Adv Neurol. 1999;79:499–510
  30. Baulac S, Huberfeld G, Gourfinkel-An I, et al. First genetic evidence of GABA(A) receptor dysfunction in epilepsy: A mutation in the gamma-2-subunit gene. Nat Genet. 2001;28:46–48
  31. Brooks-Kayal AR, Pritchett DB. Developmental changes in human γ-aminobutyric acid A receptor subunit composition. Ann Neurol. 1993;34:687–693
  32. Wolf P, Inoue Y. Juvenile absence epilepsy. In:  Roger J,  Bureau M,  Travet C,  Genton P,  Tassinari CA,  Wolf P editor. Epileptic syndromes in infancy, childhood and adolescence. 4th ed.. Montrouge, France: John Libbey Eurotext, Ltd; 2005;p. 363–366
  33. Janz D, Durner M. Juvenile myoclonic epilepsy. In:  Engel J,  Pedley TA editor. Epilepsy: A comprehensive textbook. Philadelphia: Lippincott-Raven; 1997;p. 2389–2400
  34. Cossette P, Liu L, Brisebois K, et al. Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy. Nat Genet. 2002;31:184–189
  35. Thomas P, Genton P, Gelisse P, Wolf P. Juvenile myoclonic epilepsy. In:  Roger J,  Bureau M,  Travet C,  Genton P,  Tassinari CA,  Wolf P editor. Epileptic syndromes in infancy, childhood and adolescence. 4th ed.. Montrouge, France: John Libbey Eurotext, Ltd; 2005;p. 367–388
  36. Krampfl K, Maljevic S, Cossette P, et al. Molecular analysis of the A322D mutation in the GABA receptor alpha-subunit causing juvenile myoclonic epilepsy. Eur J Neurosci. 2005;22:10–20
  37. Kapoor A, Vijai J, Ravishankar HM, Satishchandra P, Radhakrishnan K, Anand A. Absence of GABRA1 Ala322Asp mutation in juvenile myoclonic epilepsy families from India. J Genet. 2003;82:17–21
  38. Ma S, Blair MA, Abou-Khalil B, Lagrange AH, Gurnett CA, Hedera P. Mutations in the GABRA1 and EFHC1 genes are rare in familial juvenile myoclonic epilepsy. Epilepsy Res. 2006;71:129–134
  39. Gardiner M. Genetics of idiopathic generalized epilepsies. Epilepsia. 2005;46:15–20
  40. 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;19:366–370
  41. 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;68:859–865
  42. Wallace RH, Scheffer IE, Parasivam G, et al. Generalized epilepsy with febrile seizures plus: Mutation of the sodium channel subunit SCN1B. Neurology. 2002;58:1426–1429
  43. Baulac S, Gourfinkel-An I, Picard F, et al. A second locus for familial generalized epilepsy with febrile seizures plus maps to chromosome 2q21-q33. Am J Hum Genet. 1999;65:1078–1085
  44. Moulard B, Guipponi M, Chaigne D, Mouthon D, Buresi C, Malafosse A. Identification of a new locus for generalized epilepsy with febrile seizures plus (GEFS+) on chromosome 2q24-q33. Am J Hum Genet. 1999;65:1396–1400
  45. Lopes-Cendes I, Scheffer IE, Berkovic SF, Rousseau M, Andermann E, Rouleau GA. A new locus for generalized epilepsy with febrile seizures plus maps to chromosome 2. Am J Hum Genet. 2000;66:698–701
  46. 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;24:343–345
  47. Escayg A, Heils A, MacDonald BT, Haug K, Sander T, Meisler MH. A novel SCN1A mutation associated with generalized epilepsy with febrile seizures plus—and prevalence of variants in patients with epilepsy. Am J Hum Genet. 2001;68:866–873
  48. Saccucci P, Verdecchia M, Piciullo A, et al. Convulsive disorder and genetic polymorphism (Association of idiopathic generalized epilepsy with haptoglobin polymorphism). Neurogenetics. 2004;5:245–248
  49. Sadrzadeh SM, Saffari Y, Bozorgmehr J. Haptoglobin phenotypes in epilepsy. Clin Chem. 2004;50:1095–1097
  50. Langlois MR, Delanghe JR. Biological and clinical significance of haptoglobin polymorphism in humans. Clin Chem. 1996;42:1589–1600
  51. Bottini N, Saccucci P, Piciullo A, et al. Convulsive disorder and the genetics of signal transduction: A study of a low molecular weight protein tyrosine phosphatase in a pediatric sample. Neurosci Lett. 2002;333:159–162
  52. Durner M, Keddache MA, Tomasini L, et al. Genome scan of idiopathic generalized epilepsy: Evidence for major susceptibility gene and modifying genes influencing the seizure type. Ann Neurol. 2001;49:328–335
  53. Greenberg DA, Cayanis E, Strug L, et al. Malic enzyme 2 may underlie susceptibility to adolescent-onset idiopathic generalized epilepsy. Am J Hum Genet. 2005;76:139–146
  54. Lenzen KP, Heils A, Lorenz S, Hempelmann A, Sander T. Association analysis of malic enzyme 2 gene polymorphisms with idiopathic generalized epilepsy. Epilepsia. 2005;46:1637–1641
  55. Gu W, Sander T, Becker T, Steinlein OK. Genotypic association of exonic LGI4 polymorphisms and childhood absence epilepsy. Neurogenetics. 2004;5:41–44
  56. Wang JB, Imai Y, Eppler CM, Gregor P, Spivak CE, Uhl GR. Mu opiate receptor: cDNA cloning and expression. Proc Natl Acad Sci USA. 1993;90:10230–10234
  57. Bergen AW, Kokoszka J, Peterson R, et al. Mu opioid receptor gene variants: Lack of association with alcohol dependence. Mol Psychiatry. 1997;2:490–494
  58. Sander T, Berlin W, Gscheidel N, Wendel B, Janz D, Hoehe MR. Genetic variation of the human mu-opioid receptor and susceptibility to idiopathic absence epilepsy. Epilepsy Res. 2000;39:57–61
  59. Bond C, LaForge KS, Tian M, et al. Single-nucleotide polymorphism in the human mu opioid receptor gene alters beta-endorphin binding and activity: Possible implications for opiate addiction. Proc Natl Acad Sci USA. 1998;95:9608–9613
  60. Wilkie H, Osei-Lah A, Chioza B, et al. Association of mu-opioid receptor subunit gene and idiopathic generalized epilepsy. Neurology. 2002;59:724–728
  61. Makoff A, Asherson P, Nashef L. Authors’ voluntary retraction: H. Wilkie, A. Osei-Lah, B. Chioza, L. Nashef, D. McCormick, P. Asherson, and A.J. Makoff: Association of the mu-opioid receptor subunit gene and idiopathic generalized epilepsy. Neurology. 2002;59:724–728Neurology 2005;64:579
  62. Barratt C, Lai T, Nashef L, et al. No association of single nucleotide polymorphisms in the micro-opioid receptor subunit gene with idiopathic generalized epilepsy. Epilepsia. 2006;47:1728–1731
  63. Sander T, Hildmann T, Kretz R, et al. Allelic association of juvenile absence epilepsy with a GluR5 kainate receptor gene (GRIK1) polymorphism. Am J Med Genet. 1997;74:416–421
  64. Izzi C, Barbon A, Kretz R, Sander T, Barlati S. Sequencing of the GRIK1 gene in patients with juvenile absence epilepsy does not reveal mutations affecting receptor structure. Am J Med Genet. 2002;114:354–359
  65. Durner M, Sander T, Greenberg DA, Johnson K, Beck-Mannagetta G, Janz D. Localization of idiopathic generalized epilepsy on chromosome 6p in families of juvenile myoclonic epilepsy patients. Neurology. 1991;41:1651–1655
  66. Weissbecker KA, Durner M, Janz D, Scaramelli A, Sparkes RS, Spence MA. Confirmation of linkage between juvenile myoclonic epilepsy locus and the HLA region of chromosome 6. Am J Med Genet. 1991;38:32–36
  67. Sander T, Bockenkamp B, Hildmann T, et al. Refined mapping of the epilepsy susceptibility locus EJM1 on chromosome 6. Neurology. 1997;49:842–847
  68. Greenberg DA, Durner M, Keddache M, et al. Reproducibility and complications in gene searches: Linkage on chromosome 6, heterogeneity, association, and maternal inheritance in juvenile myoclonic epilepsy. Am J Hum Genet. 2000;66:508–516
  69. Pal DK, Evgrafov OV, Tabares P, Zhang F, Durner M, Greenberg DA. BRD2 (RING3) is a probable major susceptibility gene for common juvenile myoclonic epilepsy. Am J Hum Genet. 2003;73:261–270
  70. Lorenz S, Taylor KP, Gehrmann A, et al. Association of BRD2 polymorphisms with photoparoxysmal response. Neurosci Lett. 2006;400:135–139
  71. Guerrini R, Genton P. Epileptic syndromes and visually induced seizures. Epilepsia. 2004;45:14–18
  72. Kasteleijn-Nolst Trenite D. Reflex seizures induced by intermittent light stimulation. Adv Neurol. 1998;75:99–121
  73. Greenberg DA, Delgado-Escueta AV, Widelitz H, et al. Juvenile myoclonic epilepsy (JME) may be linked to the BF and HLA loci on human chromosome 6. Am J Hum Genet. 1988;31:185–192
  74. Greenberg DA, Durner M, Resor S, Rosenbaum D, Shinnar S. The genetics of idiopathic generalized epilepsies of adolescent onset: Differences between juvenile myoclonic epilepsy and epilepsy with random grand mal and with awakening grand mal. Neurology. 1995;45:942–946
  75. Sander T, Hildmann T, Janz D, et al. The phenotypic spectrum related to the human epilepsy susceptibility gene “EJM1”. Ann Neurol. 1995;38:210–217
  76. Tauer U, Lorenz S, Lenzen KP, et al. Genetic dissection of photosensivity and its relation to idiopathic generalized epilepsy. Ann Neurol. 2005;57:866–873
  77. Suzuki T, Delgado-Escueta AV, Aguan K, et al. Mutations in EFHC1 cause juvenile myoclonic epilepsy. Nat Genet. 2004;36:842–849
  78. Braunewell KH, Gundelfinger ED. Intracellular neuronal calcium sensor proteins: A family of EF-hand calcium-binding proteins in search of a function. Cell Tissue Res. 1999;295:1–12
  79. Suzuki T, Delgado-Escueta AV, Alonso ME, et al. Mutation analyses of genes on 6p12-p11 in patients with juvenile myoclonic epilepsy. Neurosci Lett. 2006;405:126–131
  80. Stogmann E, Lichtner P, Baumgartner C, et al. Idiopathic generalized epilepsy phenotypes associated with different EFHC1 mutations. Neurology. 2006;67:2029–2031
  81. Kretsinger RH, Nockolds CE. Carp muscle calcium-binding protein. J Biol Chem. 1973;248:3313–3326
  82. Mori Y, Hara Y, Aguan K, et al. Molecular and functional interaction of the juvenile myoclonic epilepsy-related gene EFHC1 with the redox-sensitive TRPM2 channel. Washington, DC: Society for Neuroscience; 2005;
  83. Pinto D, Louwaars S, Westland B, et al. Heterogeneity at the JME 6p11-12 locus: Absence of mutations in the EFHC1 gene in linked Dutch families. Epilepsia. 2006;47:1743–1746
  84. Gu W, Sander T, Heils A, Lenzen KP, Steinlein OK. A new EF-hand containing gene EFHC2 on Xp11.4: Tentative evidence for association with juvenile myoclonic epilepsy. Epilepsy Res. 2005;66:91–98
  85. Page GP, George V, Go RC, Page PZ, Allison DB. “Are we there yet?”: Deciding when one has demonstrated specific genetic causation in complex diseases and quantitative traits. Am J Hum Genet. 2003;73:711–719
  86. Cardon LR, Palmer LJ. Population stratification and spurious allelic association. Lancet. 2003;361:598–604
  87. Colhoun HM, McKeigue PM, Davey Smith G. Problems of reporting genetic associations with complex outcomes. Lancet. 2003;361:865–872

PII: S0887-8994(07)00262-7

doi: 10.1016/j.pediatrneurol.2007.06.001

Pediatric Neurology
Volume 37, Issue 3 , Pages 157-164 , September 2007