This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT Neuronal excitability, and thus epileptogenicity, is critically governed by the interaction of voltage- and ligand-gated ion channels and mutations of ion channel genes are now recognized as an important cause of independently defined inherited epilepsy syndromes and cardiac arrhythmias. Recent evidence indicates that a subset of these genes is co-expressed in heart and brain. There is extensive clinical and experimental evidence supporting coexistence of seizures and cardiac arrhythmias, and many clinical reports suggest that """"""""arrhythmogenic epilepsy"""""""" is the pathophysiological mechanism of sudden unexplained death in epilepsy (SUDEP). Long QT syndrome (LQTS) has been increasingly recognized as a cause for idiopathic cardiac arrhythmia and sudden cardiac death. Seven LQT genes (SCN5A, KCNQ1, KCNH2, KCNE1, KCNE2, KCNJ2, and ANKB) have been identified. Mutations alter electrophysiological properties of a channel thus predisposing the heart towards fatal arrhythmias. Research data originating from our laboratory demonstrated that SCN5A is selectively co-expressed in heart and the brain limbic region, a network inherently prone towards epileptogenesis. KCNH2, KCNE2, ANKB, and KCNJ2 genes are also expressed in brain. Moreover, we found an increased incidence of seizure history in the cohort of patients with an idiopathic LQTS. The clinical phenotype of channelopathies can vary widely according to the position of the mutation within the channel as well as according to the total mutational load. Specific point mutations and/or their combinations within and between LQT genes can lead to unexpected effects. Some might favor a cardiac presentation (such as LQTS), some an epileptic phenotype, some may trigger both overt clinical seizures and fatal cardiac arrhythmias and ultimately lead to SUDEP. I therefore propose an increased prevalence of epilepsy and epileptiform abnormalities in patients with idiopathic long QT syndrome (LQTS) and the existence of two distinct clinical phenotypes (LQTS + epilepsy vs. sole LQTS) with corresponding specific LQT genotypes. This project will extend our preliminary data and test involvement of LQT genes in epilepsy by (1) determining the prevalence of epilepsy and epileptiform traits in the LQTS cohort, (2) defining the frequency and the spectrum of coding single nucleotide polymorphisms (cSNPs) in LQT genes of the LQTS patients, and by (2) correlating the two LQTS phenotypes with and without epilepsy with a corresponding genotypes. This research may help to determine the roles that LQT genes may play in the etiology of seizures and SUDEP. It may also assist in defining an epilepsy population at risk for sudden death, which would allow initiation of life-saving preventative measures and the design of gene-specific therapy for the affected patients.
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