A new paradigm of channelopathy in epilepsy syndromes: intracellular trafficking abnormality of channel molecules.

Mutations in genes encoding ion channels in brain neurons have been identified in various epilepsy syndromes. In neuronal networks, "gain-of-function" of channels in excitatory neurotransmission could lead to hyper-excitation while "loss-of-function" in inhibitory transmission impairs neuronal inhibitory system, both of which can result in epilepsy. A working hypothesis to view epilepsy as a disorder of channel or "channelopathy" seems rational to explore the pathogenesis of epilepsy. However, the imbalance resulting from channel dysfunction is not sufficient to delineate the pathogenesis of all epilepsy syndromes of which the underlying channel abnormalities have been verified. Mutations identified in epilepsy, mainly in genes encoding subunits of GABA(A) receptors, undermine intracellular trafficking, thus leading to retention of channel molecules in the endoplasmic reticulum (ER). This process may cause ER stress followed by apoptosis, which is a known pathomechanism of certain neurodegenerative disorders. Thus, the pathomechanism of "channel trafficking abnormality" may provide a new paradigm to channelopathy to unsolved questions underlying epilepsy, such as differences between generalized epilepsy with febrile seizures plus and severe myoclonic epilepsy in infancy, which share the causative genetic abnormalities in the same genes and hence are so far considered to be within the spectrum of one disease entity or allelic variants.