Genetic architecture of idiopathic generalized epilepsy: clinical genetic analysis of 55 multiplex families

Epilepsia. 2004 May;45(5):467-78. doi: 10.1111/j.0013-9580.2004.46803.x.

Abstract

Purpose: In families with idiopathic generalized epilepsy (IGE), multiple IGE subsyndromes may occur. We performed a genetic study of IGE families to clarify the genetic relation of the IGE subsyndromes and to improve understanding of the mode(s) of inheritance.

Methods: Clinical and genealogic data were obtained on probands with IGE and family members with a history of seizures. Families were grouped according to the probands' IGE subsyndrome: childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and IGE with tonic-clonic seizures only (IGE-TCS). The subsyndromes in the relatives were analyzed. Mutations in genes encoding alpha1 and gamma 2 gamma-aminobutyric acid (GABA)-receptor subunits, alpha1 and beta1 sodium channel subunits, and the chloride channel CLC-2 were sought.

Results: Fifty-five families were studied. 122 (13%) of 937 first- and second-degree relatives had seizures. Phenotypic concordance within families of CAE and JME probands was 28 and 27%, respectively. JAE and IGE-TCS families had a much lower concordance (10 and 13%), and in the JAE group, 31% of relatives had CAE. JME was rare among affected relatives of CAE and JAE probands and vice versa. Mothers were more frequently affected than fathers. No GABA-receptor or sodium or chloride channel gene mutations were identified.

Conclusions: The clinical genetic analysis of this set of families suggests that CAE and JAE share a close genetic relation, whereas JME is a more distinct entity. Febrile seizures and epilepsy with unclassified tonic-clonic seizures were frequent in affected relatives of all IGE individuals, perhaps representing a nonspecific susceptibility to seizures. A maternal effect also was seen. Our findings are consistent with an oligogenic model of inheritance.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Chloride Channels / genetics
  • Epilepsy, Absence / genetics
  • Epilepsy, Generalized / genetics*
  • Family*
  • Female
  • Gene Frequency / genetics
  • Genetic Heterogeneity
  • Genetic Linkage
  • Genetic Predisposition to Disease
  • Genotype
  • Humans
  • Male
  • Models, Genetic
  • Mutation
  • Myoclonic Epilepsy, Juvenile / genetics
  • Pedigree
  • Phenotype
  • Receptors, GABA / genetics
  • Sodium Channels / genetics

Substances

  • Chloride Channels
  • Receptors, GABA
  • Sodium Channels