Autosomal dominant nocturnal frontal lobe epilepsy in a Spanish family with a Ser252Phe mutation in the CHRNA4 gene

Background: A large family with autosomal dominant nocturnal frontal lobe e pilepsy from the south of Spain was studied. The clinical appearance of the disease in this family, which included 28 members, of whom 11 were affecte d and 2 were obligate carriers, was identical to that previously described in an Australian family and a Norwegian family, in which mutations in exon 5 of the CHRNA4 gene were found. Methods: Following DNA extraction, the family was genotyped with 4 fluoresc ent markers flanking the locus to the CHRNA4 gene on chromosome 20q13.3, an d lod score computations were performed. The exon 5 of the CHRNA4 gene was amplified between nucleotides 535 and 825 and polymerase chain reaction pro ducts were purified and sequenced directly. Results: The same missense mutation as that found in the Australian family, C-->T, which causes the replace; ment of a serine with phenylalanine in am ino acid 252 in exon 5, was detected. This mutation segregated with the dis order in all 11 affected members, in the 2 obligate carriers, and in 1 asym ptomatic sibling, and was not found in 1 spouse and 1 daughter. Neither of the 2 polymorphisms associated with this mutation in the Australian family were found, excluding a common ancestral haplotype for the 2 families. Conclusions: These data confirm the clinical homogeneity in the phenotypic expression of autosomal dominant nocturnal frontal lobe epilepsy caused by mutation in the CHRNA4 gene, and the pathogenic role of the Ser252Phe mutat ion in this disorder.