Genotype-phenotype correlations, novel pathogenetic mechanisms, and pilot clinical studies in neonatal epilepsies associated to mutations in the KCNQ2/3 potassium channel genes

Epilepsy affects 0.5-1% of the general population. Although most epilepsies are idiopathic, as they do not recognize a specific triggering mechanism or hereditary transmission, about 1-2% of epilepsies are genetically-determined in a Mendelian fashion. Among the latter forms, mutations in KCNQ2 (and more rarely, KCNQ3) genes encoding for voltage-dependent K+ channel subunits cause neonatal epilepsies with wide phenotypic heterogeneity. On the benign end of the spectrum is Benign Familial Neonatal Seizures (BFNS), a rare, autosomal-dominant epilepsy of newborns, characterized by recurrent seizures that begin in the very first days of life and remit after a few weeks or months; BFNS-affected individuals mostly display normal interictal EEG, neuroimaging, and psychomotor development. More recently, KCNQ2 mutations have been described in neonates affected with pharmacoresistant seizures with psychomotor retardation, suppression-burst pattern at the EEG, and distinct neuroradiological features, thus defining a so-called "KCNQ2 encephalopathy". The molecular basis for this striking phenotypic heterogeneity is largely unknown. The present research project will pursue two main objective: on one hand, it will expand the range of molecular mechanisms potentially involved in disease pathogenesis to attempt to establish novel correlation between the severity of the disease and the underlying genetic alteration. On the other hand, in genotyped patients with the most severe conditions and in whom a specific defect in channel function is the likely determinant for disease pathogenesis, it will test the novel hypothesis that a KCNQ opener might improve seizure severity and developmental outcome in a clinical setting. The present project will be of interest not only to those patients affected with KCNQ-related epilepsies, but also impact on the large population of pediatric patients suffering from idiopathic epilepsy, for whom optimal pharmacological treatments are still missing.