EPILEPSY AND LONG QT SYNDROME

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 摘要 神经元的兴奋性，从而致痫，是由电压和配基门控离子通道的相互作用控制的，离子通道基因的突变现在被认为是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“致心律失常性癫痫”是癫痫原因不明猝死的病理生理机制。 QT间期延长综合征(LQTS)是引起特发性心律失常和心脏性猝死的重要原因之一。目前已鉴定出7个LQT基因(SCN5A、KCNQ1、KCNH2、KCNE1、KCNE2、KCNJ2和ANKB)。突变改变了通道的电生理特性，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，SCN5A选择性地在心脏和大脑边缘区域共表达，这是一个天生容易发生癫痫的网络。KCNH2、KCNE2、ANKB和KCNJ2基因在脑中也有表达。此外，我们还发现，在特发性LQTS患者队列中，癫痫史的发生率增加。 通道病的临床表型可以根据通道内突变的位置以及总的突变负荷而有很大的不同。特定的点突变和/或它们在LQT基因内部和之间的组合可能会导致意想不到的效果。有些人可能倾向于心脏表现(如LQTS)，有些人可能是癫痫的表型，有些人可能会同时引发明显的临床癫痫发作和致命性心律失常，最终导致SUDEP。 因此，我建议在特发性长QT综合征(LQTS)患者中癫痫和癫痫样异常的患病率增加，并存在两种不同的临床表型(LQTS+癫痫与单一LQTS)，具有相应的特定LQT基因类型。 该项目将通过(1)确定LQTS队列中癫痫和癫痫样特征的患病率，(2)确定LQT患者LQT基因中编码单核苷酸多态(CSNPs)的频率和谱，以及(2)将LQT基因中有无癫痫的两种表型与相应的基因类型进行关联，从而扩展我们的初步数据和测试涉及癫痫的LQT基因。 这项研究可能有助于确定LQT基因在癫痫和SUDEP的病因中可能发挥的作用。它还可能有助于确定有猝死风险的癫痫人群，这将使受影响的患者能够启动挽救生命的预防措施和设计针对基因的治疗方法。

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.