Department of Pharmacology, University of Michigan Medical School, 2301E MSRB III, Ann Arbor, MI 48109, USA.
Department of Neurology, University of Michigan Medical School, 5021 BSRB, Ann Arbor, MI 48109, USA.
Stem Cell Reports. 2018 Sep 11;11(3):626-634. doi: 10.1016/j.stemcr.2018.07.012. Epub 2018 Aug 23.
Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy with a high incidence of sudden unexpected death in epilepsy (SUDEP). Most DS patients carry de novo variants in SCN1A, resulting in Na1.1 haploinsufficiency. Because SCN1A is expressed in heart and in brain, we proposed that cardiac arrhythmia contributes to SUDEP in DS. We generated DS patient and control induced pluripotent stem cell-derived cardiac myocytes (iPSC-CMs). We observed increased sodium current (I) and spontaneous contraction rates in DS patient iPSC-CMs versus controls. For the subject with the largest increase in I, cardiac abnormalities were revealed upon clinical evaluation. Generation of a CRISPR gene-edited heterozygous SCN1A deletion in control iPSCs increased I density in iPSC-CMs similar to that seen in patient cells. Thus, the high risk of SUDEP in DS may result from a predisposition to cardiac arrhythmias in addition to seizures, reflecting expression of SCN1A in heart and brain.
德拉维特综合征（DS）是一种严重的发育性和癫痫性脑病，癫痫猝死（SUDEP）的发病率很高。大多数 DS 患者携带 SCN1A 的新生变异体，导致 Na1.1 单倍不足。由于 SCN1A 在心脏和大脑中均有表达，我们推测心律失常可能导致 DS 中的 SUDEP。我们生成了 DS 患者和对照诱导多能干细胞衍生的心肌细胞（iPSC-CMs）。与对照相比，我们观察到 DS 患者的 iPSC-CMs 中钠电流（I）增加和自发性收缩率增加。对于 I 增加最大的患者，临床评估显示存在心脏异常。在对照 iPSCs 中生成 CRISPR 基因编辑杂合 SCN1A 缺失会增加 iPSC-CMs 中的 I 密度，类似于患者细胞中的情况。因此，DS 中 SUDEP 的高风险可能不仅源于癫痫发作，还源于心律失常的倾向，反映了 SCN1A 在心脏和大脑中的表达。
