Abstracts

Autosomal dominant frontal lobe epilepsy is characterized by clusters of sleep-related hypermotor seizures, and has been associated with mutations of the alpha4 and beta2 subunits of the neuronal nicotinic acetylcholine receptor (nAChRs) genes (CHRNA4 and CHRNB2). An Italian family from Sardinia with sleep-related seizures with prominent fear and wandering is presented., Clinical information, EEG studies and blood samples were obtained. A genome-wide linkage analysis was performed, followed by electrophysiological studies of transfected HEK293 cells expressing either the newly identified nAChR alpha2 mutant subunit or the wild type receptor. Expression pattern of the genes coding for the alpha2 and 4, and beta2 nAChRs in areas of autoptic human brain was also performed., Ten family members had clusters of seizures during sleep. Mean age at seizure onset was 10 years. The proband had since 6 years of age, clusters of sleep-related brief episodes with awakening, vocalization, fearful expression and movements of the tongue. The remaining individuals had nocturnal clusters of similar episodes including complex motor behaviors such as walking outside the room. The genome-wide linkage analysis showed a locus on chromosome 8p12.3-8q12.3, and a heterozygous missense mutation in the nAChR alpha2 subunit gene (CHRNA2) was detected in all 10 affected individuals. Whole-cell recordings of transfected HEK293 cells showed that the CHRNA2 mutation markedly increased the receptor sensitivity to acetylcholine. The expression pattern of alpha2 mRNA in autoptic human brain exhibited the highest level in the thalamus, but a diffuse expression was detected in the investigated samples. beta2 and alpha4 mRNA were uniformly distributed throughout the samples., CHRNA2 is the third nAChRs gene to be associated with familial sleep-related epilepsies. CHRNA2 mutation causes a complex ictal behavior with prominent fear and wandering. The alpha2 subunit showed the highest expression in the thalamus, hence confirming that mutations in nAChRs genes are involved in the epileptogenesis related to sleep-arousal mechanisms., (Supported by the Italian Minister of Health; Telethon Foundation; Italian Ministry of Education, University and Research (MIUR).)