Epilepsy, Childhood Absence, Susceptibility To, 1

Description

Childhood absence epilepsy (CAE, ECA), a subtype of idiopathic generalized epilepsy (EIG; 600669), is characterized by a sudden and brief impairment of consciousness that is accompanied by a generalized, synchronous, bilateral, 2.5- to 4-Hz spike and slow-wave discharge (SWD) on EEG. Seizure onset occurs between 3 and 8 years of age and seizures generally occur multiple times per day. About 70% of patients experience spontaneous remission of seizures, often around adolescence. There are no structural neuropathologic findings in patients with ECA (Crunelli and Leresche, 2002).

Genetic Heterogeneity of Susceptibility to Childhood Absence Epilepsy

The ECA1 locus has been mapped to chromosome 8q24; see also EIG1 (see 600669), which also maps to 8q24.

Susceptibility to the development of childhood absence epilepsy may be conferred by variation in several genes: ECA2 (see 607681), conferred by variation in the GABRG2 gene (137164) on chromosome 5q31.1; ECA4 (611136), conferred by variation in the GABRA1 gene (137160) on chromosome 5q34; ECA5 (612269), conferred by variation in the GABRB3 gene (137192) on chromosome 15q12; and ECA6 (see 611942), conferred by variation in the CACNA1H gene (607904) on chromosome 16p13.

See EIG11 (607628) for discussion of a locus previously designated ECA3 on chromosome 3q26.

Clinical Features

Childhood absence epilepsy accounts for 5 to 15% of childhood epilepsies (Fong et al., 1998).

Manifestations begin at age 6 to 7 years, in contrast to juvenile absence epilepsy (JAE; 607631), which begins around puberty. The main features are frequent absence seizures (several per day) and bilateral, synchronous, symmetric 3-Hz spike waves on EEG. Generalized tonic-clonic seizures (GTCS) often develop during adolescence. Otherwise, absence seizures may either remit or persist into adulthood (Commission on Classification and Terminology of the International League Against Epilepsy, 1989).

Fong et al. (1998) defined 3 subsyndromes of ECA. The first subsyndrome, which accounts for approximately 40 to 60% of ECA patients, is characterized by absence seizures as the sole phenotype and remits spontaneously during adolescence. The second subsyndrome, which accounts for another 40% of ECA patients, persists into adolescence and adulthood, during which patients develop tonic-clonic seizures. The third subsyndrome accounts for a smaller percentage (possibly 10 to 12%) of ECA patients and is characterized by the development of tonic-clonic and myoclonic seizures during adolescence, after the onset of absences in childhood.

Wallace et al. (2001) stated that febrile seizures (121210) occur in about 3% of children and that 10 to 15% of persons with childhood absence epilepsy have febrile seizures before the onset of epilepsy. Febrile convulsions are a common seizure type in relatives of childhood absence epilepsy probands (Italian League Against Epilepsy Genetic Collaborative Group, 1993).

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 (JME; 606904) 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.

Population Genetics

Overall, the annual incidence of childhood absence epilepsy is 2 to 8 per 100,000 children under the age of 15 to 16 years, with a prevalence of 2 to 10% among children with any type of epilepsy (Crunelli and Leresche, 2002).

Mapping

Fong et al. (1998) studied clinical and electroencephalographic traits of 78 members of a 5-generation family in Bombay, India, with childhood absence epilepsy. The model-free affected-pedigree member method was used during initial screening, and only individuals with absence seizures and/or EEG 3-4-Hz spike- and multispike-slow wave complexes were considered to be affected. Significant P values were obtained for several markers on 8q. Two-point linkage analysis assuming autosomal dominant inheritance with 50% penetrance, yielded a maximum lod score of 3.6 for D8S502. For 5 smaller multiplex families, the summed maximum lod score was 2.4 for D8S537 and 1.7 for D8S1761. Haplotypes composed of the same 8q24 microsatellites segregated with affected members of the large family from India and with all 5 smaller families. Recombinations positioned the ECA1 locus to a 3.2-cM interval.

Using YACs and BACs, Sugimoto et al. (2000) constructed a physical map of the ECA1 region on 8q24. By accurate ordering of STS markers within the physical map, they narrowed the locus to 1.5 Mb flanked by D8S554 and D8S502, which was confirmed by pairwise linkage analysis in 6 families (lod score of 4.1 at theta = 0 for D8S534).

Molecular Genetics

Exclusion Studies

In 2 families with childhood absence epilepsy mapping to chromosome 8q24 (ECA1), Morita et al. (1999) did not identify mutations in the JRK gene (603210).

Associations Pending Confirmation

See 608146 for discussion of a possible association of childhood absence epilepsy with variation in the NIPA2 gene on chromosome 15q11.

Animal Model

The activation of peri- or extrasynaptic GABA receptors by ambient GABA causes a persistently active, or tonic, inhibitory current. Extrasynaptic GABA-A receptors in thalamocortical neurons contain the delta subunit (GABRD; 137163). In an established rat model of absence epilepsy with spontaneous spike-wave discharges called GAERS (genetic absence epilepsy rats from Strasbourg), Cope et al. (2009) found increased tonic current amplitude at thalamocortical GABA-A receptors beginning at postnatal day 17 compared to controls. Similarly increased tonic GABA-A receptor activation was observed in other mouse strains of absence epilepsy, including stargazer and lethargic, but not in tottering mice. In addition, pharmacologic spike-wave discharge-inducing agents were found to enhance the tonic GABA-A receptor current in thalamocortical neurons. Increased tonic inhibition was due to compromised GABA uptake by the GABA transporter GAT1 (SLC6A1; 137165) in the thalamus. Blockade or knockout of GAT1 in normal animals induced absence-like seizures. Finally, mice without thalamic GABA-A receptors were resistant to pharmacologically induced seizures. Overall, these results showed that enhanced extrasynaptic GABA-A receptor activation in the thalamus may underlie absence seizures.