Epilepsy, Childhood Absence, Susceptibility To, 6

A number sign (#) is used with this entry because of evidence that susceptibility to childhood absence epilepsy-6 (ECA6) and idiopathic generalized epilepsy-6 (EIG6) can be conferred by variation in the CACNA1H gene (607904) on chromosome 16p.

Description

Childhood absence epilepsy is a subtype of idiopathic generalized epilepsy. For a general phenotypic description and a discussion of genetic heterogeneity of childhood absence epilepsy and idiopathic generalized epilepsy, see ECA1 (600131) and (600669), respectively.

Clinical Features

Heron et al. (2004) observed associations between variants in the CACNA1H gene and idiopathic generalized epilepsy in 2 unrelated families. In 1 family, 3 affected individuals had a heterozygous P618L variant (607904.0005), 2 affected patients did not have the variant, and 1 unaffected member carried the variant. In the second family, only 1 of 2 affected individuals carried the P618L variant. The phenotypes were variable and included febrile seizures and myoclonic/astatic epilepsy. Although the variant was not identified in 96 controls, it did not segregate perfectly with seizures in either family.

Heron et al. (2007) identified a different heterozygous variant in the CACNA1H gene (A876T; 607904.0006) in 4 affected members of a family with idiopathic generalized epilepsy. The specific phenotypes were variable and included childhood absence epilepsy, febrile seizures, temporal lobe epilepsy, and generalized epilepsy.

Molecular Genetics

Chen et al. (2003) identified heterozygous variants in the CACNA1H gene (see, e.g., 607904.0001-607904.0004) in Chinese Han children with childhood absence epilepsy. The variants were all inherited from an unaffected parent but were not identified in 230 control individuals. Chen et al. (2003) concluded that the CACNA1H variants represented susceptibility alleles involved in the pathogenesis of a multifactorial disorder.

Heron et al. (2007) identified more than 100 heterozygous variants, including 19 novel variants, in the CACNA1H gene (see, e.g., 607904.0006) among 240 patients with idiopathic generalized epilepsy. Only 2 of the variants clearly segregated with the phenotype in the identified families; the rest showed partial or lack of segregation. Electrophysiologic studies showed that 9 of 11 variants altered channel properties in a gain-of-function manner consistent with increased channel activity. Heron et al. (2007) concluded that these variants contributed to susceptibility to epilepsy, but were not sufficient to induce epilepsy on their own. The findings were consistent with a polygenic and multifactorial etiology of various subtypes of idiopathic generalized epilepsy.