Independent occurrence of the CHRNA4 Ser248Phe mutation in a Norwegian family with nocturnal frontal lobe epilepsy

Purpose: To describe the clinical features of a family from Northern Norway in which autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is as sociated with a Ser248Phe amino acid exchange in the second transmembrane d omain of the neuronal nicotinic acetylcholine receptor alpha 4 subunit (CHR NA4). We also tested for evidence of a de novo mutation or founder effect b y comparing haplotypes with the original Australian family where the Ser248 Phe mutation was first described. Methods: Clinical details were obtained from 19 family members. Personal in terviews and genetic analysis were carried out in 17. Parts of the coding r egion of CHRNA4 were sequenced, and two known polymorphisms (bp555/FokI, bp 594/ CfoI) were typed by restriction analysis. Results: Eleven individuals had ADNFLE. The haplotypes of the mutation-carr ying alleles of affected individuals from the Northern Norwegian and the Au stralian ADNFLE family are different. The phenotypic expressions are remark ably similar. Conclusions: The Ser248Phe mutation occurred independently in both families . Given the rarity of the disease, this suggests that not only the position of a mutation in the coding sequence but also the type of an amino acid ex change is important for the etiology of ADNFLE. The phenotypic similarity o f these two families with different genetic backgrounds suggests that the S er248Phe mutation largely determines the phenotype, with relatively little influence of other background genes.