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Nocturnal frontal lobe epilepsy and febrile seizures: genetic and molecular aspects

Idiopathic epilepsies are common and devastating neurological disorders in which genetic background and physiopathological mechanisms underlying the clinical phenotype are not fully characterized yet. These diseases are assumed to have a strong genetic component, being monogenic or oligo/polygenic with different recurrence risks in the same family. However, even in monogenic epilepsy, additional genes and environmental factors may modulate its expression, thus resulting in incomplete penetrance and variable phenotype. Ethiology, phenotypic manifestations and prognosis are indeed highly heterogeneous. Idiopathic epilepsies represent about 30-40% of all epilepsies in childhood and 20% in adults. Most of them are complex diseases: patients may shift from one phenotype to another during their lifetime and parents affected by one form may have children suffering from another epileptic syndrome. The identification of genes responsible for distinct epilepsy syndromes or influencing the risk for epilepsy has important implications, for both research and clinical purposes. In this work we studied the genetic bases of two different epilepsies: nocturnal frontal lobe epilepsy (NFLE/ADNFLE) and febrile seizures (FS/GEFS+). In the case of the NFLE/ADNFLE phenotype, we performed a mutational screening of known genes, including CRH and its promoter, in a sample of both sporadic and familial patients. The study allowed the identification of: an already known mutation in the CHRNA4 gene (p.Ser284Leu) originated de novo in one NFLE patient; three unknown variants in the CRH promoter in both sporadic and familial patients which we demonstrated to not cosegregate with the disease; one unknown missense mutation in the coding portion of the CRH gene (p.Pro30Arg) in one ADNFLE patient. By functional in vitro analysis we demonstrated that the p.Pro30Arg causes impairment in the production and release of the CRH hormone. This impairment could be related to an altered capability of patients to respond quickly to stress agents. Finally, by analyzing candidate genes encoding the orexin system we demonstrated an unlikely role of this system in the 2 pathogenesis of ADNFLE: none of the patients has mutations in the three genes. In the study of FS/GEFS+ phenotype, the role of the SCN1A gene was evaluated. Several intronic and exonic polymorphisms were detected. In the case of unknown intronic variants, an in silico analysis revealed that these variations do not introduce or remove any splicing sites. Interestingly, we found in a patient two missense mutations: the already known p.Thr297Ile and the unknown p.Arg1525Gln. These two variants co-segregated with the pathology being present in all …