Further evidence of genetic heterogeneity in families with autosomal dominant nocturnal frontal lobe epilepsy
ABSTRACT Mutations in the genes encoding the alfa(2), alfa(4) and beta(2) subunits of the neuronal nicotinic acetylcholine receptor (nAChR) play a causative role in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Moreover, variations in the promoter of the corticotropic-releasing hormone gene (CRH) were also associated with ADNFLE. Here, we investigated whether nine brain-expressed genes (CHRNA2, CHRNA3, CHRNA4, CHRNA5, CHRNA6, CHRNA7, CHRNB2, CHRNB3, CHRNB4), encoding distinct nAChR subunits, and CRH are associated with the disease in three distinct ADNFLE families from Southern Italy.
There were 14 living affected individuals (9 women), ranging in age from 14 to 57 years, pertaining to three unrelated families. Age at onset of seizures clustered around 9 years of age (range from 7 and 16 years, mean: 9.1 years+/-3.8). All affected individuals manifested nocturnal partial seizures of frontal lobe origin, which were well controlled by medications. Exon 5 of CHRNA4 and CHRNB2 genes, harboring all the known mutations, was sequenced in the probands. Then, we performed a linkage study on 13 affected and 26 non-affected individuals belonging to the three families with microsatellite markers and an intragenic polymorphisms encompassing the chromosome localization of the nAChR subunit genes and of the CRH gene.
Mutational and linkage analyses allowed us to exclude the involvement of all known nAChR subunit genes and of the CRH gene in ADNFLE in our families.
Our results further illustrate the considerable genetic heterogeneity for such a syndrome, despite the quite homogeneous clinical picture. It is therefore reasonable to hypothesize that at least another gene not belonging to the nAChR gene family, in addition to CRH, is involved in the pathogenesis of ADNFLE.
Heart, Lung and Circulation 12/2000; 9(3). DOI:10.1046/j.1443-9506.2000.07819.x · 1.17 Impact Factor
Article: Nocturnal frontal lobe epilepsy.[Show abstract] [Hide abstract]
ABSTRACT: Nocturnal frontal lobe epilepsy (NFLE) is a syndrome of heterogeneous etiology, characterized by the occurrence of sleep-related seizures with different complexity and duration. Genetic, lesional, and cryptogenetic NFLE forms have been described. NFLE is generally considered a benign clinical entity, although severe, drug-resistant forms do exist. A significant proportion of sleep-related complex motor seizures, hardly distinguishable from NFLE, originate outside the frontal lobe. Moreover, the distinction of NFLE from the non-rapid eye movement arousal parasomnias may be challenging. A correct diagnosis of NFLE should be based on a diagnostic approach that includes the anamnestic, video-polysomnographic, morphological, and genetic aspects. Studies on the relationships between genes, arousal regulatory mechanisms, and epileptogenesis, using both clinical and experimental models of NFLE might provide key insights in the interrelationship between sleep and epilepsy.Current Neurology and Neuroscience Reports 02/2014; 14(2):424. DOI:10.1007/s11910-013-0424-6 · 3.67 Impact Factor
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ABSTRACT: The causes of nocturnal paroxysmal phenomena are numerous including psychiatric disturbances (nocturnal panic attacks for example), epileptic seizures and sleep disorders. Most often, clinical history, context, the description by relatives and the occurrence of daytime episodes allow a diagnostic orientation. Nevertheless, sometimes, the clinical history is atypical and it is difficult to distinguish nocturnal seizure from nonepileptic motor phenomena arising from sleep. This is the case for nocturnal frontal lobe epilepsy seizures, which appear only during sleep. This kind of seizure is characterized by short motor pattern and sometimes violent behaviour, as it is possible to see in some NREM arousal parasomnias or REM behaviour disorders. In this case, the clinician can use the scale Frontal lobe Epilepsy and Parasomnias (FLEP), not yet validated, but nocturnal video-EEG-polysomnography is usually required to make difference.Médecine du Sommeil 04/2009; 6(2). DOI:10.1016/j.msom.2009.05.001