In-depth clinical and genetic study of familial and sporadic patients with Nocturnal Frontal Lobe Epilepsy (NFLE): identification of new genes by WES in 192 cases negative for mutations in the neuronal nicotinic acetylcholine receptor subunits genes

Nocturnal Frontal Lobe Epilepsy (NFLE) is a rare epileptic syndrome characterized by bizarre motor behavior arising exclusively or predominantly from sleep. Seizure onset is usually during adolescence and antiepileptic therapy is effective in most of patients. A familial form of NFLE with autosomal dominant inheritance has been described (ADNFLE). The first gene responsible for ADNFLE, CHRNA4, was identified in 1995. Several years later, mutations two homologous genes,CHRNB2 and CHRNA2 have been reported. However, CHRNA4, CHRNB2 and CHRNA2 account for only the 10% of the families reported, suggesting the presence of other genes involved. Recently, two new genes responsible for this epileptic syndrome have been identified KCNT1 and DEPDC5. KCNT1 is associated with a more severe phenotype, with intellectual disability and psychiatric disorders, while DEPDC5, can be mutated in patients with NFLE and a positive family history for other form of focal epilepsy. In our patients, screening for mutations in CHNRA4, CHNRB2 and CHRNA2 resulted negative. A preliminary analysis of KCNT1 and DEPDC5, identified mutations only in 8/45 patients. The main aim of this study is to disclose new genes underlying NFLE. Secondary aims are: - to establish the frequency of mutations in KCNT1 and DEPDC5; - to assess the frequency of cognitive impairment and psychiatric disorders in this syndrome, in order to verify the association of specific genes with a more severe phenotype and psychiatric disorders. For genetic study, innovative techniques will be used to analyze most of the genetic makeup (Whole Exome Sequencing). Following the acquisition of WES data, we will verify the presence of defects in new and known genes. Cognitive functioning, focused in particular on frontal functions, will be assessed by an extensive neuropsychological battery. The identification of new genes responsible for NFLE will highlight the biological mechanisms underlying this epilepsy, leading to targeted therapies.