Epilepsy, Juvenile Absence, Susceptibility To, 1

A number sign (#) is used with this entry because of evidence that susceptibility to juvenile absence epilepsy-1 is conferred by variation in the EFHC1 gene (608815) on chromosome 6p12.

Susceptibility to juvenile myoclonic epilepsy-1 (EJM1; 254770) is also conferred by variation in the EFHC1 gene.

See also EJA2 (see 607628), which is conferred by mutation in the CLCN2 gene (600570) on chromosome 3q26.

Clinical Features

Juvenile absence epilepsy is a subtype of idiopathic generalized epilepsy (IGE; see 600669). Manifestations occur around puberty, in contrast to childhood absence epilepsy (CAE; 600131), which begins at age 6 to 7 years. Absence seizures, generalized tonic-clonic seizures (GTCS), GTCS on awakening, and myoclonic seizures are the main features of JAE. (Commission on Classification and Terminology of the International League Against Epilepsy, 1989).

Obeid (1994) described 15 patients, ranging in age from 11 to 25 years, who suffered from juvenile absence epilepsy. Mean age of onset of absence attacks was 11.4 years. Only 3 of the patients had absence seizures as the only seizure type. Twelve had associated tonic-clonic seizures; 3 of these patients also had sporadic myoclonus. Obeid (1994) studied 14 families with an average of 6 sibs per family. Four of the probands had a sib with epilepsy. Of these 4, 2 had juvenile absence epilepsy, whereas the other 2 were diagnosed as having symptomatic epilepsy, one secondary to infantile hemiplegia and the other considered to be idiopathic generalized tonic-clonic seizures.

Inheritance

Winawer et al. (2003) studied 84 persons from 31 families with myoclonic or absence seizures and found that 65% (20 families) were concordant for seizure type (myoclonic, absence, or both). In 2 families, all affected members had myoclonic seizures; in 12 families, all affected members had absence seizures; in 2 families, all affected members had myoclonic and absence seizures. The number of families concordant for juvenile myoclonic epilepsy (see 254770) was greater when compared to JAE and CAE, but not when JAE was compared to CAE. Winawer et al. (2003) concluded that there are distinct genetic effects on absence and myoclonic seizures, and suggested that examining seizure types as opposed to syndromes may be more useful in linkage studies.

Mapping

Sander et al. (2000) used nonparametric multipoint linkage analysis to identify susceptibility loci among 130 IGE-multiplex families ascertained through a proband with childhood or juvenile absence epilepsy or juvenile myoclonic epilepsy, and 1 or more sibs affected by an IGE trait. They obtained evidence for a novel IGE susceptibility locus on chromosome 3q26 with a peak nonparametric linkage (NPL) score of 4.19 at D3S3725 (p = 0.000017).

Associations Pending Confirmation

Sander et al. (1997) used a tetranucleotide repeat polymorphism in the noncoding region of the GRIK1 gene (138245) on chromosome 21q22 to test the hypothesis that allelic variants of this gene confer genetic susceptibility to JAE. Family-based association analysis using the haplotype relative risk statistic revealed an association of JAE with the 9 repeat-containing allele of the GRIK1 tetranucleotide polymorphism. Supportive evidence for linkage to JAE was obtained (maximum lod = 1.67 at GRIK1) under an autosomal dominant mode of inheritance, and significant allele sharing (p less than 0.05) among the affected family members suggested that allelic variants of GRIK1 contribute a major genetic determinant to the pathogenesis of JAE.

Molecular Genetics

Stogmann et al. (2006) identified mutations in the EFHC1 gene (see, e.g., 608815.0006; 608825.0007) in patients with juvenile absence epilepsy.