Potassium Channel Gain of Function in Epilepsy: An Unresolved Paradox

Exome and targeted sequencing have revolutionized clinical diagnosis. This has been particularly striking in epilepsy and neurodevelopmental disorders, for which new genes or new variants of preexisting candidate genes are being continuously identified at increasing rates every year. A surprising finding of these efforts is the recognition that gain of function potassium channel variants are actually associated with certain types of epilepsy, such as malignant migrating partial seizures of infancy or early-onset epileptic encephalopathy. This development has been difficult to understand as traditionally potassium channel loss-of-function, not gain-of-function, has been associated with hyperexcitability disorders. In this article, we describe the current state of the field regarding the gain-of-function potassium channel variants associated with epilepsy (KCNA2, KCNB1, KCND2, KCNH1, KCNH5, KCNJ10, KCNMA1, KCNQ2, KCNQ3, and KCNT1) and speculate on the possible cellular mechanisms behind the development of seizures and epilepsy in these patients. Understanding how potassium channel gain-of-function leads to epilepsy will provide new insights into the inner working of neural circuits and aid in developing new therapies.