EPILEPSY AND LONG QT SYNDROME

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 摘要 神经元的兴奋性，从而致癫痫性，是至关重要的电压和配体门控离子通道和离子通道基因的突变的相互作用，现在被认为是一个独立定义的遗传性癫痫综合征和心律失常的重要原因。最近的证据表明，这些基因的一个子集在心脏和大脑中共同表达。大量的临床和实验证据支持癫痫发作和心律失常并存，许多临床报道认为“致痫性癫痫”是癫痫猝死（SUDEP）的病理生理机制。 长QT综合征（LQTS）已被越来越多地认为是特发性心律失常和心源性猝死的原因。已鉴定出7个LQT基因（SCN 5A、KCNQ 1、KCNH 2、KCNE 1、KCNE 2、KCNJ 2和ANKB）。突变改变通道的电生理特性，从而使心脏易于发生致命的心律失常。来自我们实验室的研究数据表明，SCN 5A选择性地在心脏和大脑边缘区共表达，这是一个固有的易致癫痫的网络。KCNH 2、KCNE 2、ANKB和KCNJ 2基因也在脑中表达。此外，我们发现在特发性LQTS患者队列中癫痫发作史的发生率增加。 通道病的临床表型可以根据通道内突变的位置以及根据总突变负荷而广泛变化。LQT基因内部和之间的特定点突变和/或其组合可能导致意想不到的效果。有些可能倾向于心脏表现（如LQTS），有些可能是癫痫表型，有些可能会引发明显的临床癫痫发作和致命的心律失常，并最终导致SUDEP。 因此，我建议增加癫痫和癫痫样异常的发病率与特发性长QT综合征（LQTS）患者和存在两种不同的临床表型（LQTS +癫痫与单一LQTS）与相应的特定LQT基因型。 该项目将通过以下方式扩展我们的初步数据并测试LQT基因在癫痫中的参与：（1）确定LQTS队列中癫痫和癫痫样特征的患病率，（2）定义LQTS患者LQT基因中编码单核苷酸多态性（cSNP）的频率和谱，以及（2）将两种LQTS表型与相应的基因型相关联。 这项研究可能有助于确定LQT基因在癫痫发作和SUDEP病因学中可能发挥的作用。它还可以帮助确定有猝死风险的癫痫人群，这将允许启动挽救生命的预防措施和为受影响的患者设计基因特异性治疗。

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.