Seminars in Pediatric Neurology
Volume 15, Issue 1 , Pages 32-40 , March 2008

The Hitchhiker’s Guide to the Child Neurologist’s Genetic Evaluation of Epilepsy

  • Marie F. Grill, MD

      Affiliations

    • Department of Neurology, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ.
  • ,
  • Travis E. Losey, MD

      Affiliations

    • Department of Neurology, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ.
  • ,
  • Yu-tze Ng, MD, FRACP

      Affiliations

    • Division of Pediatric Neurology, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ.
    • Corresponding Author InformationAddress reprint requests to Yu-tze Ng, MD, FRACP, 500 West Thomas Road Suite 400, Phoenix, AZ 85013.

References 

  1. Lukasiuk K, Kontula L, Pitkanen A. cDNA profiling of epileptogenesis in the rat brain. Eur J Neurosci. 2003;17:271–279
  2. Lossie AC, Whitney MM, Amidon D, et al. Distinct phenotypes distinguish the molecular classes of Angelman syndrome. Med Genet. 2001;38:834–845
  3. Ptacek LJ, Fu YJ. Channelopathies: Episodic disorders of the nervous system. Epilepsia. 2001;42:35–43
  4. Provini F, Plazzi G, Tinuper P, et al. Nocturnal frontal lobe epilepsy (A clinical and polygraphic overview of 100 consecutive cases). Brain. 1999;122:1017–1031
  5. Scheffer IE, Bhatia KP, Lopes-Cendes I, et al. Autosomal dominant nocturnal frontal lobe epilepsy (A distinctive clinical disorder). Brain. 1995;118:61–73
  6. Phillips HA, Scheffer IE, Berkovic SF, et al. Localization of a gene for autosomal dominant nocturnal frontal lobe epilepsy to chromosome 20q13.2. Nat Genet. 1995;10:117–118
  7. Weiland S, Witzemann V, Villarroel A, et al. An amino acid exchange in the second transmembrane segment of a neuronal nicotinic receptor causes partial epilepsy by altering its desensitization kinetics. FEBS Lett. 1996;399:91–96
  8. Phillips HA, Scheffer IE, Crossland KP, et al. Autosomal dominant nocturnal frontal lobe epilepsy: Genetic heterogeneity and evidence for a second locus at 15q24. Am J Hum Genet. 1998;63:1108–1116
  9. Fusco MD, Beccetti A, Patrignani A, et al. The nicotinic receptor beta2 subunit is mutant in nocturnal frontal lobe epilepsy. Nat Genet. 2000;26:275–276
  10. Autosomal dominant nocturnal frontal lobe epilepsy. www.Genetests.orgAccessed November 4, 2007
  11. Molecular diagnosis of seizure disorders. www.AthenaDiagnostics.orgAccessed November 4, 2007
  12. Vaughn BV, Greenwood RS, Aylsworth AS, et al. Similarities of EEG and seizures in del (1q) and benign Rolandic epilepsy. Pediatr Neurol. 1996;15:261–264
  13. Neubauer BA, Fiedler B, Himmelein B, et al. Centrotemporal spikes in families with Rolandic epilepsy: Linkage to chromosome 15q14. Neurology. 1998;51:1608–1612
  14. Poza JJ, Saenz A, Martinez-Gil A, et al. Autosomal dominant lateral temporal epilepsy: Clinical and genetic study of a large Basque pedigree linked to chromosome 10q. Ann Neurol. 1999;45:182–188
  15. Ottman R, Risch N, Hauser A, et al. Localization of a gene for partial epilepsy to chromosome 10q. Nat Genet. 1995;10:56–60
  16. Scheel H, Tomiuk S, Hofmann K. A common protein interaction domain links two recently identified epilepsy genes. Hum Mol Genet. 2002;11:1757–1762
  17. Autosomal dominant partial epilepsy with auditory features. www.Genetests.orgAccessed November 4, 2007
  18. Flex E, Pizzuti A, Di Bonaventura C, et al. LGI1 gene mutation screening in sporadic partial epilepsy with auditory features. J Neurol. 2005;252:62–66
  19. Bisulli F, Tinuper P, Avoni P, et al. Idiopathic partial epilepsy with auditory features (IPEAF): A clinical and genetic study of 53 sporadic cases. Brain. 2004;127:1343–1352
  20. Hedera P, Blair MA, Andermann E, et al. Familial mesial temporal lobe epilepsy maps to chromosome 4q13.2-q21.3. Neurology. 2007;68:2107–2112
  21. Berkovic SF, Izzillo P, Mcahon JM, et al. LGI1 mutations in temporal lobe epilepsies. Neurology. 2004;62:1115–1119
  22. Xiong L, Labuda , Li DS, et al. Mapping of a gene determining familial partial epilepsy with variable foci to chromosome 22q11-q12. Am J Hum Genet. 1999;65:1698–1710
  23. ILAE. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia. 1989;30:389–399
  24. Aanegers JF, Hauser WA, Elveback LR, et al. The risk of epilepsy following febrile convulsions. Neurology. 1979;29:297–303
  25. Wallace RH, Berkovic SF, Howell RA, et al. Suggestion of a major gene for familial febrile convulsions mapping to 8q13-21. J Med Genet. 1996;33:308–312
  26. Johson EW, O’Donovan C, Anderson VE, et al. Narrowing the candidate intervals for the familial febrile convulsion genes. Epilepsia. 1997;38(suppl 3):201;(abstr)
  27. Peiffer A, Thompson J, Charlier C, et al. A locus for febrile seizures to chromosome 2q23-24. Ann Neurol. 1999;46:671–677
  28. Nakayama J, Hamano K, Iwasaki N, et al. Significant evidence for linkage of febrile seizures to chromosome 5q14-15. Hum Mol Genet. 2000;9:87–91
  29. Nakayama J, Yamamoto N, Hamano K, et al. Linkage and association of febrile seizures to the IMPA2 gene on human chromosome 18. Neurology. 2004;63:1803–1807
  30. Hedera P, Ma S, Blair MA, et al. Identification of a novel locus for febrile seizures and epilepsy on chromosome 21q22. Epilepsia. 2006;47:1622–1628
  31. Iwasaki N, Nakayama J, Hamano K, et al. Symposium I: Molecular genetics of febrile seizures. Epilepsia. 2002;43:32–35
  32. Gerard F, Pereira S, Robaglia-Schlupp A, et al. Clinical and genetic analysis of a new multigenerational pedigree with GEFS+ (generalized epilepsy with febrile seizures plus). Epilepsia. 2002;43:581–586
  33. 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
  34. Moulard B, Guipponi , Chaigne D, et al. Identification of a new locus for generalized epilepsy with febrile seizures plus on chromosome 2q24-q33. Am J Hum Genet. 1999;46:671–678
  35. Baulac S, Huberfeld G, Gourfinkel-An I, et al. First genetic evidence of GABA A receptor dysfunction in epilepsy: A mutation in the gamma2-subunit gene. Nat Genet. 2001;28:46–48
  36. Nakayama J, Hamano K, Iwasaki N, et al. Significant evidence for linkage of febrile seizures to chromosome 5q14-q15. Hum Mol Genet. 2000;9:87–91
  37. Escayg A, MacDonald B, Meisler M, et al. Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2. Nature Genet. 2000;24:343–345
  38. Harkin LA, Bowser DN, Dibbens LM, et al. Truncation of the GABAA-receptor gamma2 subunit in a family with generalized epilepsy with febrile seizures plus. Am J Hum Genet. 2002;70:530–536
  39. Sugwara T, Tsurubuchi Y, Argwala KL, et al. A missense mutation of the Na+ channel alpha II subunit gene Na (v) 1.2 in a patient with febrile and afebrile seizures causes channel dysfunction. Proc Natl Acad Sci U S A. 2001;98:6384–6389
  40. Audenaert D, Claes L, Claeys KG, et al. A novel susceptibility locus at 2p24 for generalized epilepsy with febrile seizures plus. J Med Genet. 2005;42:947–952
  41. Baulac S, Gourfinkel-An I, Picard F, et al. A second locus for familial generalized epilepsy with febrile seizures maps to chromosome 2q21-q33. Am J Hum Genet. 1999;65:1078–1085
  42. GABRG-2-related generalized epilepsy with febrile seizures plus. www.Genetests.orgAccessed November 4, 2007
  43. 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
  44. Hirose S, Zenri F, Akiyoshi H, et al. A novel mutation of KCNQ3 is a Japanese family with benign neonatal familiar convulsion (BFNC2). Ann Neurol. 2000;47:822–836
  45. Wang HS, Pan Z, Shi W, et al. KCNQ2 and KCNQ3 potassium channel subunits: Molecular correlates of the M-channel. Science. 1998;282:1890–1893
  46. Heron SE, Crossland KM, Andermann E, et al. Sodium-channel defects in benign familial neonatal-infantile seizures. Lancet. 2002;360:851–852
  47. Guipponi M, Rivier F, Vigevano F, et al. Linkage mapping of benign familial infantile convulsions (BIFC) to chromosome 19q. Hum Mol Genet. 1997;6:473–477
  48. Benign familial neonatal epilepsy. www.Genetests.orgAccessed November 4, 2007
  49. 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 Med Genet. 1988;31:185–192
  50. Elmslie FV, Rees M, Williamson MP, et al. Genetic mapping of a major susceptibility locus for juvenile myoclonic epilepsy on chromosome 15q. Hum Mol Genet. 1997;6:1329–1334
  51. Suzuki T, Delgado-Escueta AV, Aguan K, et al. Mutations in EFHC1 cause juvenile myoclonic epilepsy. Nat Genet. 2004;36:842–849
  52. Elmslie FV, Rees M, Williamson MP, et al. Genetic mapping of a major susceptibility locus for juvenile myoclonic epilepsy on chromosome 15q. Hum Mol Genet. 1997;6:1329–1334
  53. Bate L, Mitchell W, Williamson M, et al. Molecular genetic analysis of juvenile myoclonic epilepsy in the Saudi Arabian population. Epilepsia. 2000;41:72;(abstr)
  54. Puranam RS, Jain S, Kleindienst AM, et al. A locus for generalized tonic-clonic seizure susceptibility maps to chromosome 10q25-q26. Ann Neurol. 2005;58:449–458
  55. Claes L, Del-Favero J, Cueulemans B, et al. De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am J Hum Genet. 2001;68:1327–1332
  56. Kanai K, Hirose S, Oguni H, et al. Effect of localization of missense mutations in SCN1A on epilepsy phenotype severity. Neurology. 2004;63:329–334
  57. Marini C, Mei D, Temudo T, et al. Idiopathic epilepsies with seizures precipitated by fever and SCN1A abnormalities. Epilepsia. 2007;48:1678–1685
  58. Korff C, Laux L, Kelley K, et al. Dravet syndrome (severe myoclonic epilepsy in infancy): A retrospective study of 16 patients. J Child Neurol. 2007;22:185–194
  59. Sankar R, Wheless JW, Dravet C, et al. Treatment of myoclonic epilepsies in infancy and early childhood. Adv Neurol. 2005;9:289–298
  60. Fejerman N, Carabello R, Cerososimo R. Ketogenic diet patients with Dravet syndrome and myoclonic epilepsies in infancy and early childhood. Adv Neurol. 2005;95:299–305
  61. Chen Y, Lu J, Pan H, et al. Association between genetic variation of CACNA1H and childhood absence epilepsy. Ann Neurol. 2003;54:239–243
  62. Steinlein OK, Sander T, Stoodt J, et al. Possible association of a silent polymorphism in the neuronal nicotinic acetylcholine receptor subunit alpha 4 with common idiopathic generalized epilepsies. Am J Med Genet. 1997;74:445–449
  63. Fong CYG, Shah PU, Hung Y, et al. Childhood absence epilepsy in an Indian (Bombay) family maps to chromosome 8q24. Neurology. 1998;50:A357;(abstr)
  64. Marini C, Harkin LA, Wallace RH, et al. Childhood absence epilepsy and febrile seizures: A family with a GABA(A) receptor mutation. Brain. 2003;126:230–240
  65. Wallace RH, Marini C, Petrou S, et al. Mutant GABA(A) receptor gamma2-subunit in childhood absence epilepsy and febrile seizures. Nat Genet. 2001;28:49–52
  66. Koskiniemi M, Toivakka E, Donner M. Progressive myoclonus epilepsy (Electroencephalographical findings). Acta Neurol Scand. 1974;50:333–359
  67. Lieuallen K, Pennacchio LA, Park M, et al. Cystatin B-deficient mice have increased expression of apoptosis and glial activation genes. Hum Mol Gent. 2001;10:1867–1871
  68. Unverricht-Lundborg disease. www.Genetests.orgAccessed November 4, 2007
  69. Minnassian BA, Lee JR, Herbrick JA, et al. Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy. Nat Genet. 1998;20:171–174
  70. Ganesh S, Agarwala KL, Ueda K, et al. Laforin, defective in the progressive myoclonus epilepsy of lafora type, is a dual-specificity phosphatase associated with polyribosomes. Hum Mol Genet. 2000;9:2251–2261
  71. Lafora disease. www.Genetests.orgAccessed November 4, 2007
  72. Lombes A, Mendell JR, Nakase H, et al. Myoclonic epilepsy and ragged-red fibers with cytochrome oxidase deficiency: Neuropathology, biochemistry, and molecular genetics. Ann Neurol. 1989;26:20–33
  73. Myoclonic epilepsy associated with ragged-red fibers. www.Genetests.orgAccessed November 4, 2007
  74. Howell N, Kubacka I, Smith R, et al. Association of the mitochondrial 8344 MERRF mutation with maternally inherited spinocerebellar degeneration and Leigh disease. Neurology. 1996;46:219–222
  75. Shoffner JM, Lott MT, Lezza AM, et al. Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNA(Lys) mutation. Cell. 1990;61:931–937
  76. Zeviani M, Muntoni F, Savarese N, et al. A MERRF/MELAS overlap syndrome associated with a new point mutation in the mitochondrial DNA tRNA (Lys) gene. Eur J Hum Genet. 1993;1:80–87
  77. Santorelli FM, Mak SC, El-Schahawi M, et al. Maternally inherited cardiomyopathy and hearing loss associated with a novel mutation in the mitochondrial tRNA (Lys) gene (G8363A). Am J Hum Genet. 1996;58:933–939
  78. Shtilbans A, Shanske S, Goodman S, et al. G8363A mutation in the mitochondrial DNA transfer ribonucleic acid Lys gene: Another cause of Leigh syndrome. J Child Neurol. 2000;15:759–761
  79. Narayanan V. Tuberous sclerosis complex: Genetics to pathogenesis. Pediatr Neurol. 2003;29:404–409
  80. Reiner O, Carrozzo R, Shen Y, et al. Isolatio of a Miller-Dicker lissencephaly gene containing G protein beta-subunit-like repeats. Nature. 1993;364:717–721
  81. Toyo-oka K, Shionoya A, Ganbello MJ, et al. 14-3-3epsilon is important for neuronal migration by binding to NUDEL: A molecular explanation for Miller-Dieker syndrome. Nat Genet. 2003;34:274–285
  82. Hong SE, Shugart YY, Huang DT, et al. Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Nat Genet. 2000;26:93–96
  83. des Portes V, Pinard J, Billuart P, et al. A novel CNS gene required for neuronal migration and involved in X-linked subcortical laminar heterotopia and lissencephaly syndrome. Cell. 1998;92:51–61
  84. Sherr EH. The ARX story (epilepsy, mental retardation, autism, and cerebral malformations): One gene leads to many phenotypes. Curr Opin Pediatr. 2003;15:567–571
  85. Mills PB, Struys E, Jakobs C, et al. Mutations in antiquitin in individuals with pyridoxine-dependent seizures. Nat Med. 2006;12:30730–30739
  86. Cormier-Daire V, Dagoneau N, Nabbout R, et al. A gene for pyridoxine-dependent epilepsy maps to chromosome 5q31. Am J Hum Genet. 2000;67:991–993
  87. Epilepsy genetics. www.Genetests.orgAccessed November 4, 2007
  88. Steinlein OK, Sander T, Stoodt J, et al. Possible association of a silent polymorphism in the neuronal nicotinic acetylcholine receptor subunit alpha 4 with common idiopathic generalized epilepsies. Am J Med Genet. 1997;74:44544–44549

PII: S1071-9091(08)00007-7

doi: 10.1016/j.spen.2008.01.006

Seminars in Pediatric Neurology
Volume 15, Issue 1 , Pages 32-40 , March 2008