Epilepsy, Childhood Absence, Susceptibility To, 5

A number sign (#) is used with this entry because susceptibility to childhood absence epilepsy-5 (ECA5) can be conferred by heterozygous mutation in the GABRB3 gene (137192) on chromosome 15q.

For a phenotypic description and discussion of genetic heterogeneity of childhood absence epilepsy, see 600131.

Clinical Features

Tanaka et al. (2008) reported 4 unrelated families of Mexican or Honduran origin with childhood absence epilepsy inherited in an autosomal dominant pattern with incomplete penetrance. Age at onset ranged from 2 to 11 years and was characterized by staring, often with eyelid myoclonias and photic sensitivity. Some patients also had generalized tonic-clonic seizures. Absences and accompanying seizures disappeared after 12 years of age in all 4 probands. In 1 family, 2 clinically unaffected family members had epileptiform EEG abnormalities.

Molecular Genetics

Urak et al. (2006) screened 45 childhood absence epilepsy (CAE) patients for sequence variations in the GABRB3 gene. The authors defined 4 haplotypes between the promoter region and intron 3. A transmission disequilibrium test demonstrated significant association of this region and CAE (P = 0.007). Reporter gene assays indicated that the disease-associated haplotype 2 promoter caused significantly lower transcriptional activity than the haplotype 1 promoter, which was overrepresented in the controls. In silico analysis suggested that an exchange from T to C within haplotype 2 may impair binding of the neuron-specific transcriptional activator N-Oct-3 (POU5F1; 164177). Electrophoretic mobility shift assays demonstrated that the respective polymorphism reduced the binding of N-Oct-3. The authors proposed that reduced expression of GABRB3 could be one potential cause for the development of CAE.

In affected members of 4 (8%) of 48 families with childhood absence epilepsy, Tanaka et al. (2008) identified 3 different heterozygous mutations in the GABRB3 gene (137192.0002-137192.0004) Several mutation carriers were unaffected, indicating incomplete penetrance. The authors noted that patients with Angelman syndrome (105830) and deletion of the GABRB3 gene also show absence seizures.