Abstracts

Rationale: Sudden unexplained death in epilepsy (SUDEP) is a catastrophic complication of idiopathic seizure disorders with unknown cause. Cardiac LQT genes are associated with syncopal episodes and fatal arrhythmias, yet have not been linked to epilepsy. The dysfunction of a cardiac delayed-rectifier potassium channel, KvLQT1, underlies the most common form of inherited long QT syndrome and has not been previously identified in the central nervous system. Methods: We used RT-PCR and immunohistochemistry to localize KCNQ1 (KvLQT1) in human and mouse brain. We simultaneously monitored video EEG/ECG in freely moving mice engineered with human dominant-negative LQT1 mutations. Results: We found that the KCNQ1 gene is expressed in human and mouse brain. Immunohistochemistry revealed strong neuronal staining in cortical, hippocampal and vagal brainstem networks where membrane repolarization defects can produce seizures and dysregulate autonomic control of the heart. Video EEG monitoring revealed frequent electro-clinical seizures while the ECG recordings demonstrated striking cardiac arrhythmias occurring independently of, or in response to, abnormal cortical epileptiform discharges. Conclusions: This novel gene for epilepsy is the first to reveal the dual arrhythmogenic potential of an ion channelopathy co-expressed in heart and brain. The expression of KCNQ1 channel protein in brainstem nuclei of the vagal nerve defines a critical circuit for cardiac dysrhythmia within the central autonomic pathways. The other LQT ion channels are also expressed in brain, suggesting a family of candidate genes for SUDEP. These data validate a combined clinical and genetic diagnostic strategy to improve risk prediction of early mortality in individuals with epilepsy.