The genetics of epilepsies

Lopes-Cendes, Iscia

doi:10.1590/S0021-75572008000500006

Abstracts

OBJECTIVES: To discuss some of the clinical and molecular genetic aspects of new discoveries in the field of the genetics of the epilepsies and relate these with relevant clues for a better understanding of the mechanisms underlying some of the monogenic epilepsy syndromes. SOURCES: Many study designs have been performed over the years and these include family-based studies, genetic-epidemiology surveys. More recently, molecular genetics studies and gene discovery strategies have been used to unravel the molecular and cell mechanisms involved in several Mendelian epilepsy syndromes. SUMMARY OF THE FINDINGS: The importance of genetic factors in the epilepsies has been recognized since the time of Hippocrates. CONCLUSIONS: In the modern era, many studies have demonstrated the existence of an inherited component in the generalized and focal epilepsies and in the last 2 decades a number of families segregating different types of monogenic epilepsy have been described, leading to progresses in the characterization of the molecular defects in these families.

Monogenic disorders; channelopathies; seizures

OBJETIVO: Discutir alguns dos aspectos genéticos clínicos e moleculares de novas descobertas no campo da genética das epilepsias e relacioná-las com indicações importantes para a melhor compreensão dos mecanismos subjacentes a algumas síndromes epilépticas monogênicas. FONTES DOS DADOS: Muitos desenhos de estudo foram usados através dos anos, incluindo estudos familiares e pesquisas genético-epidemiológicas. Mais recentemente, estudos de genética molecular e estratégias de descoberta de genes foram usados para revelar os mecanismos moleculares e celulares envolvidas em diversas síndromes epilépticas mendelianas. SÍNTESE DOS DADOS: A importância dos fatores genéticos em epilepsias é reconhecida desde os tempos de Hipócrates. CONCLUSÕES: Nos tempos modernos, muitos estudos demonstraram a existência de um componente hereditário nas epilepsias generalizadas e focais. Nas últimas duas décadas, diversas famílias segregando diferentes tipos de epilepsia monogência foram descritas, o que levou ao progresso na caracterização dos defeitos moleculares nestas famílias.

Distúrbios monogênicos; canalopatias; convulsões

REVIEW ARTICLE

The genetics of epilepsies

Iscia LopesCendes

Associate professor, School of Medical Sciences, Universidade Estadual de Campinas (Unicamp), Campinas, SP, Brazil

Correspondence

ABSTRACT

OBJECTIVES: To discuss some of the clinical and molecular genetic aspects of new discoveries in the field of the genetics of the epilepsies and relate these with relevant clues for a better understanding of the mechanisms underlying some of the monogenic epilepsy syndromes.

SOURCES: Many study designs have been performed over the years and these include familybased studies, geneticepidemiology surveys. More recently, molecular genetics studies and gene discovery strategies have been used to unravel the molecular and cell mechanisms involved in several Mendelian epilepsy syndromes.

SUMMARY OF THE FINDINGS: The importance of genetic factors in the epilepsies has been recognized since the time of Hippocrates.

CONCLUSIONS: In the modern era, many studies have demonstrated the existence of an inherited component in the generalized and focal epilepsies and in the last 2 decades a number of families segregating different types of monogenic epilepsy have been described leading to progresses in the characterization of the molecular defects in these families.

Keywords: Monogenic disorders, channelopathies, seizures.

Introduction

Epilepsies are one of the most common neurological conditions with a prevalence of approximately 11.5% in the general population and, therefore, are considered a public health problem. The molecular genetics revolution provided new insights into the human idiopathic epilepsies and, more recently, a major role has been suggested for the ligandgated and voltagegated ion channels in the etiology of many epilepsy syndromes.¹ To date, genes encoding for sodium and potassium channel subunits as well as nicotinic cholinergic receptor subunits have been identified for Mendelian idiopathic epilepsies.²In vitro and in vivo studies of mutations demonstrate functional changes, allowing new insights into mechanisms underlying hyperexcitability.³ Progress in this area has been so intense that researchers are now trying to identify genes for the more common forms of epilepsy following complex inheritance.⁴ We believe that once such genes are discovered, the more complex interactions between genes and environment will be better understood making it easier to assess the mechanisms producing specific epilepsy syndromes, as well as determining clinical variability among different patients.

In the 1950's the pioneer studies by Lennox⁵ and Metrakos⁶ were the first to propose scientific evidence for the genetic predisposition to idiopathic generalized epilepsies (IGE). These initial studies reported that the risk of developing epilepsy was 1.5 to 5 times higher in the relatives of patients with epilepsy than that observed in the general population.^5,6 In addition, the risk for relatives of patients with IGE was twice that observed for patients with focal epilepsy.^7,8 These results were confirmed by twin studies in which the concordance rates for monozygotic (MZ) twins were higher as compared to dizygotic (DZ) twins.⁹ By contrast, until recently focal epilepsies were widely believed to be nongenetic. This view probably resulted from the recognition that epilepsy following environmental insults is usually partial; and that a greater proportion of partial than generalized epilepsies are environmental in origin. However, the importance of the genetic contributions to the focal epilepsies is now well established. Evidence for this genetic contribution has come from different study designs, such as a) familial aggregation studies; b) twin studies; c) clinical description of families; and d) the identification of specific genes.¹⁰

Familial aggregation studies, which use an epidemiological approach to assess the degree of increased risk in relatives of individuals with partial epilepsy, as compared to other groups (generalized epilepsy or normal controls), are consistent in showing an increased risk of epilepsy in the relatives of patients with partial epilepsies.^11,12 However, this contribution is in a lower magnitude than that of the generalized epilepsies.^12,13 Early studies also provided evidence for a genetic contribution to epilepsy with complex partial seizures (most of which was probably temporal lobe epilepsy).¹² Two recent studies further elucidated the familial aggregation of partial epilepsies. Standardized morbidity ratios (SMR) for unprovoked seizures, a measure of the risk of unprovoked seizures, were determined for a large North American population.¹³ The SMR were very similar for offspring of patients with generalized (SMR = 3.3) and partial epilepsy (SMR = 3.2). However, risk was increased in the offspring of parents with absence seizures (SMR = 9.2), suggesting that the greater genetic contribution to generalized epilepsy may be restricted to specific syndromes.⁸ Another study examined the risk, calculating the relative risk (RR) of epilepsy in first degree relatives of 1,498 patients with cryptogenic epilepsy.⁸ Risk was significantly elevated in both groups, focal and generalized epilepsy, when compared to the controls. In parents and siblings, the RR was lower if the probands epilepsy was focal (RR =2.4 for focal epilepsy and RR = 4.7 for generalized epilepsy). By contrast, in offspring, the risk was actually greater if the probands epilepsy was focal (RR = 4.2 for focal epilepsy and RR = 1.6).¹⁰

However, clustering of disease within families can sometimes result from shared exposure to environmental factors or shared behavioral patterns, rather than from genetic susceptibility.¹⁴ One of the best strategies to confirm that familial aggregation is indeed caused by shared genetic predisposition is twin studies. These have consistently found higher concordance rates of epilepsy in MZ than DZ twins, providing strong evidence for genetic contributions to epilepsy.¹⁵¹⁷ However, very few of these studies have examined focal epilepsies specifically, or compared focal and generalized epilepsies. Berkovic et al.⁸ studied the concordance rates for specific epilepsy syndromes in 253 twin pairs in which one or both twins had epilepsy or febrile convulsions. Concordance rates were significantly higher in MZ than in DZ pairs in both generalized (MZ = 82% vs. DZ = 26%) and focal epilepsies (MZ = 36% vs. DZ = 5%). Interestingly, all of the evidence for a genetic effect in the focal epilepsies came from 30 pairs with cryptogenic epilepsy, in whom the concordance in MZ and DZ pairs was 55% and 0. In the 10 pairs with idiopathic partial epilepsies, most of whom had benign rolandic epilepsy; concordance rates did not differ between MZ and DZ pairs. In addition, none of the 25 pairs with symptomatic focal epilepsy was concordant, excluding the possibility of a major genetic determinant for these types of focal epilepsy.¹⁵

Several studies have described the clinical manifestations of epilepsy in single families, or sets of families. These studies are interesting because they show the full spectrum of symptoms different patients within single families can have, giving a very accurate idea of the clinical variability of specific syndromes. However, prove of the genetic contribution to epileptogenesis is only achieved when the causative genes are localized. To date, familial aggregation has been documented in many epilepsy syndromes. A partial list of these types of epilepsy is presented in Tables 1 to 4. It is important to note that any listing of this type becomes out of date in a short period of time, since new syndromes, loci or genes are identified continuously. In many cases in which the genes have been identified they are voltagegated or receptor genes, except in familial temporal epilepsy with auditory symptoms, in which the leucinerich, gliomainactivated 1 gene (LGI1) has been implicated.¹⁸ The exact functional properties of the LGI1 gene remain unknown.¹⁸ This gene was cloned from the breakpoints of a glioblastoma cell line and its expression is reduced or absent in many highgrade gliomas. This evidence indicates a possible function related to cellular proliferation and tumor suppression.¹⁸ Furthermore, this gene is characterized by a central leucinerich repeat region, which is involved in regulation of cell growth, adhesion, and migration.^18,19 The exact relationship of the LGI1 gene mutation with epilepsy is still unclear. Gu et al.¹⁷ demonstrated the presence of hlgi1 protein in the human brain, particularly in neurons from the frontal and temporal lobes, but no definite pathogenic mechanism was found which could correlate mutations in this gene and epileptogenesis.

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As discussed above, in only a small proportion of epilepsy syndromes a causative gene has been identified. This comprises a very small proportion of all partial epilepsies described.⁷² However, they hold great promise for elucidating the basic mechanisms of epileptogenesis, and in particular the genetic basis for pathology expression in localized brain regions. It is very interesting to note that despite the widespread assumption of a greater genetic effect on generalized epilepsies, more progress has been made to date in localizing genes for focal epilepsies than for generalized epilepsies.⁸

In summary, significant progress has been made in recent years in understanding the genetics of the epilepsies. Research in this area is moving rapidly, and genes that raise risk for new syndromes will undoubtedly be discovered soon. This information will be crucial for elucidating pathogenesis, and also for clarifying definition of syndromes with a major genetic contribution.

References

1. Berkovic SF, Steinlein OK. Genetics of partial epilepsies. Adv Neurol. 1999;79:37581.
2. Berkovic SF, Genton P, Hirsch E, Picard F, editors. Genetics of focal epilepsies. Clinical aspects and molecular biology. London: John Libbey; 1999.
3. Ryan SG. Partial epilepsy: chinks in the armour. Nat Genet. 1995;10:46.
4. Ptacek LJ, Fu YH. What's new in epilepsy genetics? Mol Psychiatry. 2003;8:4635.
5. Lennox WG. Heredity of epilepsy as told by relatives and twins. J Am Med Assoc. 1951;146:52936.
6. Metrakos K, Metrakos JD. Genetics of convulsive disorders. II. Genetic and electroencephalographic studies in centrencephalic epilepsy. Neurology. 1961;11:47483.
7. Andermann E. Genetic aspects of the epilepsies. In: Sakai T, Tsuboi T, editors. Genetic aspects of human behavior. Tokyo: IgakuShoin; 1985. p. 12945.
8. Berkovic SF, Howell RA, Hay DA, Hopper JL. Epilepsies in twins: genetics of the major epilepsy syndromes. Ann Neurol. 1998;43:43545.
9. Harper PS. Practical genetic counseling. 4th ed. Cambridge: ButterworthHeinemann; 1993.
10. Vogel F, Motulsky AG, editors. Human genetics: problems and approaches. 3rd ed. Berlin: Springer; 1997.
11. Ottman R. Genetics of the partial epilepsies: a review. Epilepsia 1989;30:10711.
12. Lennox WG, Lennox M. Epilepsy and related disorders. Boston: Little Brown; 1960.
13. Tsuboi T, Endo S. Incidence of seizures and EEG abnormalities among offspring of epileptic patients. Hum Genet. 1997;36:17389.
14. Eisner V, Pauli LL, Livingston S. Hereditary aspects of epilepsy. Bull Johns Hopkins Hosp. 1959;105:24571.
15. Ounted C, Lindsay J, Norman R. Biological factors in temporal lobe epilepsy. London: Heinemann; 1966.
16. Ottman R, Lee JH, Hauser WA, Risch N. Are generalized and localizationrelated epilepsies genetically distinct? Ach Neurol. 1998;55:33944.
17. Lander ES, Schork NJ. Genetic dissection of complex traits. Science. 1994;265:203748.
18. Gu W, Wevers A, Schröder H, Grzeschik KH, Derst C, Brodtkorb E, et al. The LGI1 gene involved in lateral temporal lobe epilepsy belongs to a new subfamily of leucinerich repeat proteins. FEBS Lett. 2002;519:716.
19. Kalachikov S, Evgrafov O, Ross B, Winawer M, BarkerCummings C, Martinelli Boneschi F, et al. Mutations in LGI1 cause autosomaldominant partial epilepsy with auditory features. Nat Genet. 2002;30:33541.
20. Inouye E. Observations on forty twin index cases with chronic epilepsy and their cotwins. J Nerv Ment Dis. 1960;130:40116.
21. Ottman R, Lee JH, Risch N, Hauser WA, Susser M. Clinical indicators of genetic susceptibility to epilepsy. Epilepsia. 1996;37:35361.
22. de Falco FA, Striano P, de Falco A, Striano S, Santangelo R, Perretti A, et al. Benign adult familial myoclonic epilepsy: genetic heterogeneity and allelism with ADCME. Neurology. 2003;60:13815.
23. Hallmann K, Durner M, Sander T, Steinlein OK. Mutation analysis of the inwardly rectifying K(+) channels KCNJ6 (GIRK2) and KCNJ3 (GIRK1) in juvenile myoclonic epilepsy. Am J Med Genet. 2000;96:811.
24. Haug K, Hallmann K, Rebstock J, Dullinger J, Muth S, Haverkamp F, et al. The voltagegated sodium channel gene SCN2A and idiopathic generalized epilepsy. Epilepsy Res. 2001;47:2436.
25. Chioza B, OseiLah A, Wilkie H, Nashef L, McCormick D, Asherson P, et al. Suggestive evidence for association of two potassium channel genes with different idiopathic generalised epilepsy syndromes. Epilepsy Res. 2002;52:10716.
26. Sander T, Berlin W, Gscheidel N, Wendel B, Janz D, Hoehe MR. Genetic variation of the human µopioid receptor and susceptibility to idiopathic absence epilepsy. Epilepsy Res. 2000;39:5761.
27. Sander T, Toliat MR, Heils A, Leschik G, Becker C, Rüschendorf F, et al. Association of the 867Asp variant of the human anion exchanger 3 gene with common subtypes of idiopathic generalized epilepsy. Epilepsy Res. 2002;51:24955.
28. Zara F, Labuda M, Garofalo PG, Durisotti C, Bianchi A, Castellotti B, et al. Unusual EEG pattern linked to chromosome 3p in a family with idiopathic generalized epilepsy. Neurology. 1998;51:4938.
29. Goodwin H, Curran N, Chioza B, Blower J, Nashef L, Asherson P, et al. No association found between polymorphisms in genes enconding mGluR7 and mGluR8 and idiopathic generalised epilepsy in a case control study. Epilepsy Res. 2000;39:2731.
30. Haug K, Warnstedt M, Alekov AK, Sander T, Ramírez A, Poser B, et al. Mutations in CLCN2 encoding a voltagegated chloride channel are associated with idiopathic generalized epilepsies. Nat Genet. 2003;33:52732.
31. Wilkie H, OseiLah A, Chioza B, Nashef L, McCormick D, Asherson P, et al. Association of muopioid receptor subunit gene and idiopathic generalized epilepsy. Neurology. 2002;59:7248.
32. Durner M, Zhou G, Fu D, Abreu P, Shinnar S, Resor SR, et al. Evidence of linkage of adolescenteonset idiopathic generalized epilepsies to chromosome 8 and genetic heterogenity. Am J Hum Genet. 1999;64:14119.
33. Sander T, Windemuth C, Schulz H, Saar K, Gennaro E, Riggio C, et al. Exploration of a putative susceptibility locus for idiopathic generalized epilepsy on chromosome 8p12. Epilepsia. 2003;44:329.
34. Fong GC, Shah PU, Gee MN, Serratosa JM, Castroviejo IP, Khan S, et al. Childhood absence epilepsy with tonicclonic seizures and electroencephalogram 34Hz spike and multispikeslow wave complexes: linkage to chromosome 8q24. Am J Hum Genet. 1998;63:111729.
35. Sander T, Kretz R, Schulz H, Sailer U, Bauer G, Scaramelli A, et al. Replication analysis of a putative susceptibility locus (EGI) for idiopathic generalized epilepsy on chromosome 8q24. Epilepsia. 1998;39:71520.
36. Mikami M, Yasuda T, Terao A, Nakamura M, Ueno S, Tanabe H, et al. Localization of a gene for benign adult familial myoclonic epilepsy to chromosome 8q23.3q24.1. Am J Hum Genet. 1999;65:74551.
37. Sugimoto Y, Morita R, Amano K, Fong CY, Shah PU, Castroviejo IP, et al. Childhood absence epilepsy in 8q24: refinement of candidate region and construction of physical map. Genomics. 2000;68:26472.
38. Haug K, Kremerskothen J, Hallmann K, Sander T, Dulliger J, Raub B, et al. Mutation screening of the chromosome 8q24.3human activityregulated cytoskeletonassociated gene (ARC) in idiopathic generalized epilepsy. Mol Cell Probes. 2000;14:25560.
39. Sugimoto Y, Morita R, Amano K, Shah PU, PascualCastroviejo I, Khan S, et al. TSTAR gene: fine mapping in the candidate region for childhood absence epilepsy on 8q24 and mutational analysis in patients. Epilepsy Res. 2001;46:13944.
40. Sano A, Mikami M, Nakamura M, Ueno S, Tanabe H, Kaneko S. Positional candidate approach for the gene responsible for benign adult familial myoclonic epilepsy. Epilepsia. 2002;43 Suppl 9:2631.
41. Kananura C, Sander T, Rajan S, PreisigMüller R, Grzeschik KH, Daut J, et al. Tandem pore domain K(+)channel TASK3 (KCNK9) and idiopathic absence epilepsies. Am J Med Genet. 2002;114:2279.
42. Elmslie FV, Rees M, Williamson MP, Kerr M, Kjeldsen MJ, Pang KA, et al. Genetic mapping of a major susceptibility locus for juvenile myoclonic epilepsy on chromosome 15q. Hum Mol Genet. 1997;6:132934.
43. Sander T, Hildmann T, Kretz R, Fürst R, Sailer U, Bauer G, et al. Allelic association of juvenile absence epilepsy with a GluR5 kainate receptor gene (GRIK1) polymorphism. Am J Med Genet. 1997;74:41621.
44. Guipponi M, Thomas P, GirardReydet C, Feingold J, BaldyMoulinier M, Malafosse A. Lack of association between juvenile myoclonic epilepsy and GABRA5 and GABRB3 genes. Am J Med Genet. 1997;74:1503.
45. Steinlein OK, Neubauer BA, Sander T, Song L, Stoodt J, Mount DB. Mutation analysis of the potassium chloride cotransporter KCC3 (SLC12A6) in rolandic and idiopathic generalized epilepsy. Epilepsy Res. 2001;44:1915.
46. Taske NL, Williamson MP, Makoff A, Bate L, Curtis D, Kerr M, et al. Evaluation of the positional candidate gene CHRNA7 at the juvenile myoclonic epilepsy locus (EJM2) on chromosome 15q1314. Epilepsy Res. 2002;49:15772.
47. Sander T, Schulz H, VieiraSaeker AM, Bianchi A, Sailer U, Bauer G, et al. Evaluation of a putative major susceptibility locus for juvenile myoclonic epilepsy on chromosome 15q14. Am J Med Genet. 1999;88:1827.
48. Durner M, Keddache MA, Tomasini L, Shinnar S, Resor SR, Cohen J, et al. Genome scan of idiopathic generalized epilepsy: evidence for major susceptibility gene and modifying genes influencing the seizure type. Ann Neurol. 2001;49:32835.
49. Zara F, Gennaro E, Stabile M, Carbone I, Malacarne M, Majello L, et al. Mapping of a locus for a familial autosomal recessive idiopathic myoclonic epilepsy of infancy to chromosome 16p13. Am J Hum Genet. 2000;66:15527.
50. Sander T, Windemuth C, Schulz H, Saar K, Gennaro E, Bianchi A, et al. No evidence for a susceptibility locus for idiopathic generalized epilepsy on chromosome 18q21.1. Am J Med Genet 2002;14:6738.
51. Rees M, Curtis D, Parker K, Sundqvist A, Baralle D, Bespalova IN, et al. Linkage analysis of idiopathic generalised epilepsy in families of probands with juvenile myoclonic epilepsy and marker loci in the region of EPM 1 on chromosome 21 q: UnverrichtLundborg disease and JME are not allelic variants. Neuropediatrics. 1994;25:205.
52. 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;114:3549.
53. Sander T, Hildmann T, Janz D, Wienker TF, Bianchi A, Bauer G, et al. Exclusion of linkage between idiopathic generalized epilepsies and the GABAA receptor alpha 1 and gamma 2 subunit gene cluster on chromosome 5. Epilepsy Res. 1996;23:23544.
54. Cossette P, Liu L, Brisebois K, Dong H, Lortie A, Vanasse M, et al. Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy. Nat Genet. 2002;31:1849.
55. Marini C, Harkin LA, Wallace RH, Mulley JC, Scheffer IE, Berkovic SF. Childhood absence epilepsy and febrile seizures: a family with a GABA(A) receptor mutation. Brain. 2003;126:23040.
56. 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;82:1721.
57. Windemuth C, Schulz H, Saar K, Gennaro E, Bianchi A, Zara F, et al. No evidence for a susceptibility locus for idiopathic generalized epilepsy on chromosome 5 in families with typical absence seizures. Epilepsy Res. 2002;51:239.
58. Greenberg DA, DelgadoEscueta AV, Widelitz H, Sparkes RS, Treiman L, Maldonado HM, et al. Juvenile myoclonic epilepsy (JME) may be linked to the BF and HLA loci on human chromosome 6. Am J Med Genet. 1988;31:18592.
59. Durner M, Sander T, Greenberg DA, Johnson K, BeckMannagetta G, Janz D. Localization of idiopathic generalized epilepsy on chromosome 6p in families of juvenile myoclonic epilepsy patients. Neurology. 1991;41:16515.
60. 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;38:326.
61. Obeid T, el Rab MO, Daif AK, Panayiotopoulos CP, Halim K, Bahakim H, et al. Is HLADRW13 (W6) associated with juvenile myoclonic epilepsy in Arab patients? Epilepsia. 1994;35:31921.
62. Liu AW, DelgadoEscueta AV, Serratosa JM, Alonso ME, Medina MT, Gee MN, et al. Juvenile myoclonic epilepsy locus in chromosome 6p21.2p11: linkage to convulsions and electroencephalography trait. Am J Hum Genet. 1995;57:36881.
63. Greenberg DA, Durner M, Shinnar S, Resor S, Rosenbaum D, Klotz I, et al. Association of HLA class II alleles in patients with juvenile myoclonic epilepsy compared with patients with other forms of adolescenteonset generalized epilepsy. Neurology. 1996;47:7505.
64. Serratosa JM, DelgadoEscueta AV, Medina MT, Zhang Q, Iranmanesh R, Sparkes RS. Clinical and genetic analysis of a large pedigree with juvenile myoclonic epilepsy. Ann Neurol. 1996:39:18795.
65. Liu AW, DelgadoEscueta AV, Gee MN, Serratosa JM, Zhang QW, Alonso ME, et al. Juvenile myoclonic epilepsy in chromosome 6p1211: locus heterogeneity and recombinations. Am J Med Genet. 1996;63:43846.
66. Sander T, Bockenkamp B, Hildmann T, Blasczyk R, Kretz R, Wienker TF, et al. Refined mapping of the epilepsy susceptibility locus EJM1 on chromosome 6. Neurology. 1997;49:8427.
67. Le Hellard S, Neidhart E, Thomas P, Feingold J, Malafosse A, Tafti M. Lack of association between juvenile myoclonic epilepsy and HLADR13. Epilepsia. 1999;40:1179.
68. Greenberg DA, Durner M, Keddache M, Shinnar S, Resor SR, Moshe SL, 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;66:50816.
69. Bai D, Alonso ME, Medina MT, Bailey JN, Morita R, Cordova S, et al. Juveline myoclonic epilepsy: linkage to chromosome 6p12 in Mexico families. Am J Med Genet. 2002;113:26874.
70. 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;73:26170.
71. 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;114:3549.
72. Suzuki T, DelgadoEscueta AV, Alonso MA, Morita R, Medina MT, Ganesh S, et al. Juvenile myoclonic epilepsy: mutations and variants in a gene that encodes a protein with EFhand. In: Annual Meeting of the American Academy of Neurology; 21 MarApr 2003; Honolulu. Neurology. 2003;60.

Publication Dates

Publication in this collection
24 Oct 2008
Date of issue
Aug 2008

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

[1] 1. Berkovic SF, Steinlein OK. Genetics of partial epilepsies. Adv Neurol. 1999;79:37581.

[2] 2. Berkovic SF, Genton P, Hirsch E, Picard F, editors. Genetics of focal epilepsies. Clinical aspects and molecular biology. London: John Libbey; 1999.

[3] 3. Ryan SG. Partial epilepsy: chinks in the armour. Nat Genet. 1995;10:46.

[4] 4. Ptacek LJ, Fu YH. What's new in epilepsy genetics? Mol Psychiatry. 2003;8:4635.

[5] 5. Lennox WG. Heredity of epilepsy as told by relatives and twins. J Am Med Assoc. 1951;146:52936.

[6] 6. Metrakos K, Metrakos JD. Genetics of convulsive disorders. II. Genetic and electroencephalographic studies in centrencephalic epilepsy. Neurology. 1961;11:47483.

[7] 7. Andermann E. Genetic aspects of the epilepsies. In: Sakai T, Tsuboi T, editors. Genetic aspects of human behavior. Tokyo: IgakuShoin; 1985. p. 12945.

[8] 8. Berkovic SF, Howell RA, Hay DA, Hopper JL. Epilepsies in twins: genetics of the major epilepsy syndromes. Ann Neurol. 1998;43:43545.

[9] 9. Harper PS. Practical genetic counseling. 4th ed. Cambridge: ButterworthHeinemann; 1993.

[10] 10. Vogel F, Motulsky AG, editors. Human genetics: problems and approaches. 3rd ed. Berlin: Springer; 1997.

[11] 11. Ottman R. Genetics of the partial epilepsies: a review. Epilepsia 1989;30:10711.

[12] 12. Lennox WG, Lennox M. Epilepsy and related disorders. Boston: Little Brown; 1960.

[13] 13. Tsuboi T, Endo S. Incidence of seizures and EEG abnormalities among offspring of epileptic patients. Hum Genet. 1997;36:17389.

[14] 14. Eisner V, Pauli LL, Livingston S. Hereditary aspects of epilepsy. Bull Johns Hopkins Hosp. 1959;105:24571.

[15] 15. Ounted C, Lindsay J, Norman R. Biological factors in temporal lobe epilepsy. London: Heinemann; 1966.

[16] 16. Ottman R, Lee JH, Hauser WA, Risch N. Are generalized and localizationrelated epilepsies genetically distinct? Ach Neurol. 1998;55:33944.

[17] 17. Lander ES, Schork NJ. Genetic dissection of complex traits. Science. 1994;265:203748.

[18] 18. Gu W, Wevers A, Schröder H, Grzeschik KH, Derst C, Brodtkorb E, et al. The LGI1 gene involved in lateral temporal lobe epilepsy belongs to a new subfamily of leucinerich repeat proteins. FEBS Lett. 2002;519:716.

[19] 19. Kalachikov S, Evgrafov O, Ross B, Winawer M, BarkerCummings C, Martinelli Boneschi F, et al. Mutations in LGI1 cause autosomaldominant partial epilepsy with auditory features. Nat Genet. 2002;30:33541.

[20] 20. Inouye E. Observations on forty twin index cases with chronic epilepsy and their cotwins. J Nerv Ment Dis. 1960;130:40116.

[21] 21. Ottman R, Lee JH, Risch N, Hauser WA, Susser M. Clinical indicators of genetic susceptibility to epilepsy. Epilepsia. 1996;37:35361.

[22] 22. de Falco FA, Striano P, de Falco A, Striano S, Santangelo R, Perretti A, et al. Benign adult familial myoclonic epilepsy: genetic heterogeneity and allelism with ADCME. Neurology. 2003;60:13815.

[23] 23. Hallmann K, Durner M, Sander T, Steinlein OK. Mutation analysis of the inwardly rectifying K(+) channels KCNJ6 (GIRK2) and KCNJ3 (GIRK1) in juvenile myoclonic epilepsy. Am J Med Genet. 2000;96:811.

[24] 24. Haug K, Hallmann K, Rebstock J, Dullinger J, Muth S, Haverkamp F, et al. The voltagegated sodium channel gene SCN2A and idiopathic generalized epilepsy. Epilepsy Res. 2001;47:2436.

[25] 25. Chioza B, OseiLah A, Wilkie H, Nashef L, McCormick D, Asherson P, et al. Suggestive evidence for association of two potassium channel genes with different idiopathic generalised epilepsy syndromes. Epilepsy Res. 2002;52:10716.

[26] 26. Sander T, Berlin W, Gscheidel N, Wendel B, Janz D, Hoehe MR. Genetic variation of the human µopioid receptor and susceptibility to idiopathic absence epilepsy. Epilepsy Res. 2000;39:5761.

[27] 27. Sander T, Toliat MR, Heils A, Leschik G, Becker C, Rüschendorf F, et al. Association of the 867Asp variant of the human anion exchanger 3 gene with common subtypes of idiopathic generalized epilepsy. Epilepsy Res. 2002;51:24955.

[28] 28. Zara F, Labuda M, Garofalo PG, Durisotti C, Bianchi A, Castellotti B, et al. Unusual EEG pattern linked to chromosome 3p in a family with idiopathic generalized epilepsy. Neurology. 1998;51:4938.

[29] 29. Goodwin H, Curran N, Chioza B, Blower J, Nashef L, Asherson P, et al. No association found between polymorphisms in genes enconding mGluR7 and mGluR8 and idiopathic generalised epilepsy in a case control study. Epilepsy Res. 2000;39:2731.

[30] 30. Haug K, Warnstedt M, Alekov AK, Sander T, Ramírez A, Poser B, et al. Mutations in CLCN2 encoding a voltagegated chloride channel are associated with idiopathic generalized epilepsies. Nat Genet. 2003;33:52732.

[31] 31. Wilkie H, OseiLah A, Chioza B, Nashef L, McCormick D, Asherson P, et al. Association of muopioid receptor subunit gene and idiopathic generalized epilepsy. Neurology. 2002;59:7248.

[32] 32. Durner M, Zhou G, Fu D, Abreu P, Shinnar S, Resor SR, et al. Evidence of linkage of adolescenteonset idiopathic generalized epilepsies to chromosome 8 and genetic heterogenity. Am J Hum Genet. 1999;64:14119.

[33] 33. Sander T, Windemuth C, Schulz H, Saar K, Gennaro E, Riggio C, et al. Exploration of a putative susceptibility locus for idiopathic generalized epilepsy on chromosome 8p12. Epilepsia. 2003;44:329.

[34] 34. Fong GC, Shah PU, Gee MN, Serratosa JM, Castroviejo IP, Khan S, et al. Childhood absence epilepsy with tonicclonic seizures and electroencephalogram 34Hz spike and multispikeslow wave complexes: linkage to chromosome 8q24. Am J Hum Genet. 1998;63:111729.

[35] 35. Sander T, Kretz R, Schulz H, Sailer U, Bauer G, Scaramelli A, et al. Replication analysis of a putative susceptibility locus (EGI) for idiopathic generalized epilepsy on chromosome 8q24. Epilepsia. 1998;39:71520.

[36] 36. Mikami M, Yasuda T, Terao A, Nakamura M, Ueno S, Tanabe H, et al. Localization of a gene for benign adult familial myoclonic epilepsy to chromosome 8q23.3q24.1. Am J Hum Genet. 1999;65:74551.

[37] 37. Sugimoto Y, Morita R, Amano K, Fong CY, Shah PU, Castroviejo IP, et al. Childhood absence epilepsy in 8q24: refinement of candidate region and construction of physical map. Genomics. 2000;68:26472.

[38] 38. Haug K, Kremerskothen J, Hallmann K, Sander T, Dulliger J, Raub B, et al. Mutation screening of the chromosome 8q24.3human activityregulated cytoskeletonassociated gene (ARC) in idiopathic generalized epilepsy. Mol Cell Probes. 2000;14:25560.

[39] 39. Sugimoto Y, Morita R, Amano K, Shah PU, PascualCastroviejo I, Khan S, et al. TSTAR gene: fine mapping in the candidate region for childhood absence epilepsy on 8q24 and mutational analysis in patients. Epilepsy Res. 2001;46:13944.

[40] 40. Sano A, Mikami M, Nakamura M, Ueno S, Tanabe H, Kaneko S. Positional candidate approach for the gene responsible for benign adult familial myoclonic epilepsy. Epilepsia. 2002;43 Suppl 9:2631.

[41] 41. Kananura C, Sander T, Rajan S, PreisigMüller R, Grzeschik KH, Daut J, et al. Tandem pore domain K(+)channel TASK3 (KCNK9) and idiopathic absence epilepsies. Am J Med Genet. 2002;114:2279.

[42] 42. Elmslie FV, Rees M, Williamson MP, Kerr M, Kjeldsen MJ, Pang KA, et al. Genetic mapping of a major susceptibility locus for juvenile myoclonic epilepsy on chromosome 15q. Hum Mol Genet. 1997;6:132934.

[43] 43. Sander T, Hildmann T, Kretz R, Fürst R, Sailer U, Bauer G, et al. Allelic association of juvenile absence epilepsy with a GluR5 kainate receptor gene (GRIK1) polymorphism. Am J Med Genet. 1997;74:41621.

[44] 44. Guipponi M, Thomas P, GirardReydet C, Feingold J, BaldyMoulinier M, Malafosse A. Lack of association between juvenile myoclonic epilepsy and GABRA5 and GABRB3 genes. Am J Med Genet. 1997;74:1503.

[45] 45. Steinlein OK, Neubauer BA, Sander T, Song L, Stoodt J, Mount DB. Mutation analysis of the potassium chloride cotransporter KCC3 (SLC12A6) in rolandic and idiopathic generalized epilepsy. Epilepsy Res. 2001;44:1915.

[46] 46. Taske NL, Williamson MP, Makoff A, Bate L, Curtis D, Kerr M, et al. Evaluation of the positional candidate gene CHRNA7 at the juvenile myoclonic epilepsy locus (EJM2) on chromosome 15q1314. Epilepsy Res. 2002;49:15772.

[47] 47. Sander T, Schulz H, VieiraSaeker AM, Bianchi A, Sailer U, Bauer G, et al. Evaluation of a putative major susceptibility locus for juvenile myoclonic epilepsy on chromosome 15q14. Am J Med Genet. 1999;88:1827.

[48] 48. Durner M, Keddache MA, Tomasini L, Shinnar S, Resor SR, Cohen J, et al. Genome scan of idiopathic generalized epilepsy: evidence for major susceptibility gene and modifying genes influencing the seizure type. Ann Neurol. 2001;49:32835.

[49] 49. Zara F, Gennaro E, Stabile M, Carbone I, Malacarne M, Majello L, et al. Mapping of a locus for a familial autosomal recessive idiopathic myoclonic epilepsy of infancy to chromosome 16p13. Am J Hum Genet. 2000;66:15527.

[50] 50. Sander T, Windemuth C, Schulz H, Saar K, Gennaro E, Bianchi A, et al. No evidence for a susceptibility locus for idiopathic generalized epilepsy on chromosome 18q21.1. Am J Med Genet 2002;14:6738.

[51] 51. Rees M, Curtis D, Parker K, Sundqvist A, Baralle D, Bespalova IN, et al. Linkage analysis of idiopathic generalised epilepsy in families of probands with juvenile myoclonic epilepsy and marker loci in the region of EPM 1 on chromosome 21 q: UnverrichtLundborg disease and JME are not allelic variants. Neuropediatrics. 1994;25:205.

[52] 52. 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;114:3549.

[53] 53. Sander T, Hildmann T, Janz D, Wienker TF, Bianchi A, Bauer G, et al. Exclusion of linkage between idiopathic generalized epilepsies and the GABAA receptor alpha 1 and gamma 2 subunit gene cluster on chromosome 5. Epilepsy Res. 1996;23:23544.

[54] 54. Cossette P, Liu L, Brisebois K, Dong H, Lortie A, Vanasse M, et al. Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy. Nat Genet. 2002;31:1849.

[55] 55. Marini C, Harkin LA, Wallace RH, Mulley JC, Scheffer IE, Berkovic SF. Childhood absence epilepsy and febrile seizures: a family with a GABA(A) receptor mutation. Brain. 2003;126:23040.

[56] 56. 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;82:1721.

[57] 57. Windemuth C, Schulz H, Saar K, Gennaro E, Bianchi A, Zara F, et al. No evidence for a susceptibility locus for idiopathic generalized epilepsy on chromosome 5 in families with typical absence seizures. Epilepsy Res. 2002;51:239.

[58] 58. Greenberg DA, DelgadoEscueta AV, Widelitz H, Sparkes RS, Treiman L, Maldonado HM, et al. Juvenile myoclonic epilepsy (JME) may be linked to the BF and HLA loci on human chromosome 6. Am J Med Genet. 1988;31:18592.

[59] 59. Durner M, Sander T, Greenberg DA, Johnson K, BeckMannagetta G, Janz D. Localization of idiopathic generalized epilepsy on chromosome 6p in families of juvenile myoclonic epilepsy patients. Neurology. 1991;41:16515.

[60] 60. 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;38:326.

[61] 61. Obeid T, el Rab MO, Daif AK, Panayiotopoulos CP, Halim K, Bahakim H, et al. Is HLADRW13 (W6) associated with juvenile myoclonic epilepsy in Arab patients? Epilepsia. 1994;35:31921.

[62] 62. Liu AW, DelgadoEscueta AV, Serratosa JM, Alonso ME, Medina MT, Gee MN, et al. Juvenile myoclonic epilepsy locus in chromosome 6p21.2p11: linkage to convulsions and electroencephalography trait. Am J Hum Genet. 1995;57:36881.

[63] 63. Greenberg DA, Durner M, Shinnar S, Resor S, Rosenbaum D, Klotz I, et al. Association of HLA class II alleles in patients with juvenile myoclonic epilepsy compared with patients with other forms of adolescenteonset generalized epilepsy. Neurology. 1996;47:7505.

[64] 64. Serratosa JM, DelgadoEscueta AV, Medina MT, Zhang Q, Iranmanesh R, Sparkes RS. Clinical and genetic analysis of a large pedigree with juvenile myoclonic epilepsy. Ann Neurol. 1996:39:18795.

[65] 65. Liu AW, DelgadoEscueta AV, Gee MN, Serratosa JM, Zhang QW, Alonso ME, et al. Juvenile myoclonic epilepsy in chromosome 6p1211: locus heterogeneity and recombinations. Am J Med Genet. 1996;63:43846.

[66] 66. Sander T, Bockenkamp B, Hildmann T, Blasczyk R, Kretz R, Wienker TF, et al. Refined mapping of the epilepsy susceptibility locus EJM1 on chromosome 6. Neurology. 1997;49:8427.

[67] 67. Le Hellard S, Neidhart E, Thomas P, Feingold J, Malafosse A, Tafti M. Lack of association between juvenile myoclonic epilepsy and HLADR13. Epilepsia. 1999;40:1179.

[68] 68. Greenberg DA, Durner M, Keddache M, Shinnar S, Resor SR, Moshe SL, 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;66:50816.

[69] 69. Bai D, Alonso ME, Medina MT, Bailey JN, Morita R, Cordova S, et al. Juveline myoclonic epilepsy: linkage to chromosome 6p12 in Mexico families. Am J Med Genet. 2002;113:26874.

[70] 70. 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;73:26170.

[71] 71. 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;114:3549.

[72] 72. Suzuki T, DelgadoEscueta AV, Alonso MA, Morita R, Medina MT, Ganesh S, et al. Juvenile myoclonic epilepsy: mutations and variants in a gene that encodes a protein with EFhand. In: Annual Meeting of the American Academy of Neurology; 21 MarApr 2003; Honolulu. Neurology. 2003;60.

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The genetics of epilepsies

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