Epilepsy, Nocturnal Frontal Lobe, 3

A number sign (#) is used with this entry because of evidence that nocturnal frontal lobe epilepsy-3 (ENFL3) is caused by heterozygous mutation in the gene encoding the beta-2 nicotinic acetylcholine receptor (nAChR) subunit (CHRNB2; 118507) on chromosome 1q21.

Clinical Features

For a general phenotypic description of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE, ENFL), see 600513. Clustered attacks of epileptic episodes originating from the frontal lobe during sleep represent the main manifestation of ADNFLE.

Mapping

Gambardella et al. (2000) reported a large Italian family with ADNFLE. Eight members were affected and 5 were asymptomatic, suggesting incomplete penetrance of the disorder. Linkage to known loci on chromosome 20 (600513) and chromosome 15 (603204) was excluded, and linkage to chromosome 1 was established.

Molecular Genetics

In affected members of the Italian family with ADNFLE reported by Gambardella et al. (2000), De Fusco et al. (2000) identified a heterozygous mutation in the CHRNB2 gene (V287L; 118507.0001).

In affected members of a Scottish family with ADNFL3, Phillips et al. (2001) identified a different heterozygous mutation at the same codon in the CHRNB2 gene (V287M; 118507.0002).

Animal Model

Manfredi et al. (2009) developed and characterized a mouse model of ENFL3 carrying the V287L mutation (118507.0001) of the CHRNB2 gene. Mice expressing mutant receptors showed a spontaneous epileptic phenotype by electroencephalography with very frequent interictal spikes and seizures. Expression of the mutant protein was driven by a neuronal-specific tetracycline-controlled promoter, which allowed reversible planned silencing of transgene expression. Restricted silencing during development was sufficient to prevent the occurrence of epileptic seizures in adulthood. Manfredi et al. (2009) hypothesized that mutant nicotinic receptors are responsible for abnormal formation of neuronal circuits and/or long-lasting alteration of network assembly in the developing brain, thus leading to epilepsy.