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

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.