Frontal lobe epilepsy and mutations of the corticotropin-releasing hormone gene

• Published in: Annals of neurology 2005-12, Vol.58 (6), p.899-904
• Main Authors: Combi, Romina, Dalprà, Leda, Ferini-Strambi, Luigi, Tenchini, Maria L.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Chromosomes, Human, Pair 8; Corticotropin-Releasing Hormone - genetics; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Electroencephalography; Epilepsy, Frontal Lobe - diagnosis; Epilepsy, Frontal Lobe - genetics; Family Health; Female; Gene Frequency; Genetic Testing; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Humans; Hybrid Cells; Italy; Male; Medical sciences; Mice; Nervous system (semeiology, syndromes); Neuroblastoma; Neurology; Pedigree; Point Mutation; Promoter Regions, Genetic - genetics; Rats; Transfection
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.20660

Nocturnal frontal lobe epilepsy up to now has been considered a channelopathy caused by mutations in the α4 and β2 subunits of the neuronal nicotinic acetylcholine receptor. However, these mutations account for only a minority of patients, and the existence of at least a new locus for the disease has been demonstrated. In one Italian nocturnal frontal lobe epilepsy family, we identified two new putative loci on chromosomes 3 and 8, where several candidate genes are mapped. In particular, on chromosome 8, corticotropin‐releasing hormone gene (CRH) appears to be a good candidate. We therefore searched for CRH mutations in the proband. The study allowed the identification of a nucleotide variation in the promoter that was subsequently detected in all affected and obligate carrier members of the same family, in two sporadic cases, in all affected members of an additional compliant family, and in the proband of a noncompliant family. Moreover, a different mutation in the promoter was detected in a familial case. In vitro experiments showed altered levels of gene expression. CRH alterations could explain several autosomal dominant nocturnal frontal lobe epilepsy clinical features. Ann Neurol 2006