The molecular basis of KCNH1-related epileptic encephalopathy and the challenge of developing targeted therapeutics

Epilepsy is a common but heterogeneous neurological disorder characterized by recurrent seizures resulting from aberrant hypersynchronous electrical discharges in all or part of the brain. While there are numerous potential causes, such as traumatic brain injury, stroke and infection, many epilepsies have a genetic basis. Here we review the molecular basis, clinical phenotype and treatment options for KCNH1 epilepsy, which is caused by gain-of-function mutations in the gene KCNH1, encoding the voltage-gated potassium channel Kv10.1. Although first discovered in patients with Temple-Baraitser syndrome and Zimmermann-Laband syndrome, these genetic disorders are now recognized as belonging to a broad spectrum of KCNH1-related encephalopathies characterized by developmental delay, intellectual disability, facial dysmorphism and infantile-onset seizures. A major challenge in developing disease-specific anti-seizure medications for KCNH1 epilepsy is selectivity over Kv11.1 (hERG), a closely related channel that plays a fundamental role in repolarization of the cardiac action potential and which is uniquely susceptible to inhibition by a diverse range of drugs. We argue that allosteric modulators of Kv10.1 that induce a depolarizing shift in the channel's activation threshold are more likely to provide seizure control in KCNH1 epilepsy patients than pore blockers that annihilate channel function.