AUTOSOMAL-DOMINANT NOCTURNAL FRONTAL-LOBE EPILEPSY - A VIDEO-POLYSOMNOGRAPHIC AND GENETIC APPRAISAL OF 40 PATIENTS AND DELINEATION OF THE EPILEPTIC SYNDROME

A number of clinical and aetiological studies have been performed duri ng the last 30 years, on patients with abnormal nocturnal motor and be havioural phenomena. The aetiological conclusions of these studies wer e often conflicting, suggesting either an epileptic or a non-epileptic origin. Among the clinical characteristics of these patients, the fam ilial clustering was one thoroughly accepted. A nocturnal familial for m of frontal lobe epilepsy (autosomal dominant nocturnal frontal lobe epilepsy, ADNFLE), often misdiagnosed as parasomnia, has been recently described in some families. In one large Australian kindred, a missen se in the second transmembrane domain of the nicotinic acetylcholine r eceptor alpha 4 subunit (CHRNA4) gene, located on chromosome 20 q13.2- 13.3, has been reported to be associated with nocturnal frontal lobe e pilepsy. We performed an extensive clinical and video-polysomnographic study in 40 patients complaining of repeated abnormal nocturnal motor and/or behavioural phenomena, from 30 unrelated Italian families. Thi rty-eight patients had an electroclinical picture strongly suggesting the diagnosis of ADNFLE. They had a wide clinical spectrum, ranging fr om nocturnal enuresis to sleep-related violent behaviour thus includin g all the main features of the so-called 'typical' parasomnias. The vi deo-polysomnographic recording confirmed the wide spectrum of abnormal manifestations including sudden awakenings with dystonic/dyskinetic m ovements (in 42.1% of patients), complex behaviours (13.2%) and sleep- related violent behaviour (5.3%). The EEG findings showed ictal epilep tiform abnormalities predominantly over frontal areas in 31.6% of pati ents. In another 47.4% of patients the EEG showed ictal rhythmic slow activity over anterior areas. Only 18.4% of the patients had already r eceived a correct diagnosis of epilepsy In 73.3% of the patients treat ed with anti-epileptic drugs the seizures were readily controlled. Ped igree analysis on 28 of the families was consistent with autosomal dom inant transmission with reduced penetrance (81%). DNAs from 20 represe ntative affected individuals were sequenced in order to check for the presence of the missense mutation in the CHRNA4 gene found in the Aust ralian kindred affected by ADNFLE. Nucleotide sequence analysis did no t reveal the presence of this mutation, but it did confirm the presenc e of two other base substitutions, not leading to amino acid changes. These two intragenic polymorphisms, together with a closely linked res triction fragment length polymorphism at the D20S20 locus, have been u sed for linkage analysis of ADNFLE to the terminal region of the long ann of chromosome 20 in five compliant families. The results allowed u s to exclude linkage of ADNFLE to this chromosomal region in these fam ilies, thus confirming the locus heterogeneity of the disorder: Large and fill video-polysomnographical studies are of the utmost importance in order to clarify the real prevalence of both nocturnal frontal lob e epilepsy and parasomnias, and to provide a correct therapy.