New Paradigms of channelopathy in epilepsy syndromes (Interacellular trafficking, HCN and dendritic ion channels)

Some rare idiopathic epilepsies are monogenic, mostly AD, and result from aberrant ion channels dysfunction. More than 600 ion channel genes have been identified and over 1300 sodium channel mutations in CNS and PNS, heart and muscle are present, some of which can cause severe epilepsy. Mutations also occur in genes encoding K+, Cl- and Ca++ channels. For this reason the use of verapamil (a L-type calcium channel antagonist) can be useful in some drug-resistant epilepsies (P. Iannetti, et al, 2017). Although more than100 different mutations of the genes encoding ion channels are known to be associated with about 10 different epilepsy syndromes, but this may be linked to be a more ice cube carved out of a gigantic iceberg. Undoubtedly the imbalance theory can result in epilepsy, but this is not sufficient to delineate the pathogenesis of all epilepsy syndromes of underlying channelopathies. For example, mutations identified in epilepsy, mainly in genes encoding subunits of GABAA receptors, undermine intracellular trafficking of channel molecules, leading to their apoptosis, which is a known pathomechanism of certain disorders, that may interpret differences between generalized epilepsy with febrile seizures plus and Dravet syndrome. It seems that intracellular trafficking results in severe clinical presentations. A third of epilepsies do not respond to current therapies, that may be due to change in HCN channels (particularly increase of HCN2 type), a new factor in the genesis of certain epilepsies. Efforts should be made to develop agents that act selectively on the full-length brain HCN2 channels, while sparing the truncated version found in heart, which provide development of new antiepileptic drugs with limited cardiac impact and better understanding of the pathogenesis of the epilepsy. Dendritic ion channelopathy secondary to brain hypoxia, status epilepticus and cortical malformations is other new approach to better understanding pathogenesis of acquired epilepsy (acquired channelopathy), that offers great hope for development of novel antiepileptic drugs.