Cardiac Mechanisms of Sudden Unexpected Death in Epilepsy

癫痫猝死（SUDEP）是癫痫患者死亡的主要原因。SUDEP 机制尚不清楚，尽管有证据表明呼吸暂停，自主神经功能障碍， 心律失常我们将利用遗传学中SUDEP风险的最新进展， 癫痫病研究心律失常的作用。SUDEP风险以基因特异性方式变化。损失- 电压门控钠通道（VGSC）基因SCN 1A或SCN 1B的功能变体在 Dravet综合征（DS）患者和VGSC SCN 8A中的功能获得性变体见于 早期婴儿癫痫性脑病13（EIEE 13）。DS和EIEE 13患者的SUDEP风险最高， 到20%。相比之下，染色体结构域解旋酶DNA结合蛋白2（CHD 2）的变体也与 早发性EE，但该人群中尚未报告SUDEP。SCN 1A-、SCN 1B-、SCN 8A-和CHD 2- 连锁癫痫是发育性和癫痫性脑病（DEE），严重的儿童癫痫 与认知和行为障碍有关。家族性局灶性癫痫，归因于致病性 DEPDC 5的变体，编码mTOR途径中GATOR复合物的一个成员。SUDEP报告于 10%的患者。由于VGSC基因在心脏和大脑中都有表达，我们提出， 心律失常是与通道病变相关的遗传性癫痫中SUDEP的机制。我们 总体目标是了解遗传性癫痫中SUDEP的机制。我们的目标是利用 患者来源的或转基因小鼠心肌细胞（CM），以了解癫痫VGSC基因突变如何 改变CM功能和致瘤潜力，并确定在非离子型细胞中是否发现类似的变化。 在心脏中表达的癫痫基因。我们的中心假设是，离子通道和非离子通道都是一种生物学机制。 具有高SUDEP风险但不低SUDEP风险离子通道遗传性癫痫在患者中表现出促癫痫发生的变化， 衍生的CM和小鼠模型。探讨CM兴奋性异常是否也发生在非离子通道中 因此，我们将研究DEPDC 5变体iPSC-CM和Depdc 5-/-小鼠。 最后，我们将检查具有CHD 2变体的Chd 2-/-小鼠和人iPSC-CM，CHD 2是一种非离子通道基因， 低SUDEP风险，以测试CM兴奋性的改变是否特异于具有高SUDEP率的遗传性癫痫。 与VGSC一样，DEPDC 5和CHD 2在大脑和心脏中表达。我们的具体目标是：1。以确定 使用源自患者的iPSC-CM，研究SCN 1A、SCN 1B和SCN 8A癫痫变体对CM兴奋性的影响。 2.为了确定来自DEPDC 5患者或Depdc 5 +/-小鼠的CM是否表现出异常兴奋性，以及是否 Depdc 5 +/-小鼠具有心律失常。3.为了确定来自CHD 2患者或Chd 2 +/-小鼠的CM是否表现出 异常兴奋性和Chd 2 +/-小鼠是否有心律失常。目前还没有有效的治疗方法 遗传性癫痫和SUDEP风险没有可靠的生物标志物。这项工作可能会导致诊断的发现 未来SUDEP风险的生物标志物。

Sudden Unexpected Death in EPilepsy, or SUDEP, is a leading cause of death in patients with epilepsy. SUDEP mechanisms are not understood, although there is evidence to implicate apnea, autonomic dysfunction, and cardiac arrhythmias. We will take advantage of recent progress in the understanding of SUDEP risk in the genetic epilepsies to investigate the role of cardiac arrhythmias. SUDEP risk varies in a gene-specific manner. Loss-of- function variants in the voltage-gated sodium channel (VGSC) genes, SCN1A or SCN1B, are identified in patients with Dravet syndrome (DS) and gain-of-function variants in the VGSC SCN8A are found in patients with Early Infantile Epileptic Encephalopathy 13 (EIEE13). DS and EIEE13 patients have the highest SUDEP risk, up to 20%. In contrast, variants in chromodomain helicase DNA binding protein 2 (CHD2) are also associated with early onset EE, but SUDEP has not been reported in this population. SCN1A-, SCN1B-, SCN8A-, and CHD2- linked epilepsies are developmental and epileptic encephalopathies (DEEs), severe childhood epilepsies associated with cognitive and behavioral impairments. The familial focal epilepsies, are attributed to pathogenic variants in DEPDC5, encoding a member of the GATOR complex in the mTOR pathway. SUDEP is reported in 10% of these patients. Because VGSC genes are expressed in both heart and brain, we have proposed that cardiac arrhythmias contribute to the mechanism of SUDEP in channelopathy-linked genetic epilepsies. Our overall goal is to understand the mechanisms of SUDEP in the genetic epilepsies. Our objectives are to use patient-derived or transgenic mouse cardiac myocytes (CMs) to understand how epileptic VGSC gene mutations alter CM function and arrhythmogenic potential, and to determine whether similar changes are found in non-ion channel epilepsy genes that are expressed in the heart. Our central hypothesis is that both ion channel and non- ion channel genetic epilepsies with high, but not low, SUDEP risk exhibit pro-arrhythmogenic changes in patient- derived CMs and mouse models. To ask whether abnormal CM excitability also occurs in a non-ion channel genetic epilepsy with high SUDEP risk, we will investigate DEPDC5 variant iPSC-CMs and Depdc5-/- mice. Finally, we will examine Chd2-/- mice and human iPSC-CMs with variants in CHD2, a non-ion channel gene with a low SUDEP risk, to test whether altered CM excitability is specific to genetic epilepsies with high SUDEP rates. Like the VGSCs, DEPDC5 and CHD2 are expressed in brain and heart. Our Specific Aims are: 1. To determine the effects of SCN1A, SCN1B, and SCN8A epilepsy variants on CM excitability using patient-derived iPSC-CMs. 2. To ascertain whether CMs from DEPDC5 patients or Depdc5+/- mice display abnormal excitability and whether Depdc5+/- mice have arrhythmia. 3. To determine whether CMs from CHD2 patients or Chd2+/- mice display abnormal excitability and whether Chd2+/- mice have arrhythmia. There are no effective therapies for any of the genetic epilepsies and no reliable biomarkers for SUDEP risk. This work may lead to the discovery of diagnostic biomarkers for SUDEP risk in the future.