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Stem Cell Reports. 2018 Sep 11;11(3):626-634. doi: 10.1016/j.stemcr.2018.07.012. Epub 2018 Aug 23.

Channelopathy as a SUDEP Biomarker in Dravet Syndrome Patient-Derived Cardiac Myocytes.

Author information

1
Department of Pharmacology, University of Michigan Medical School, 2301E MSRB III, Ann Arbor, MI 48109, USA.
2
Department of Neurology, University of Michigan Medical School, 5021 BSRB, Ann Arbor, MI 48109, USA.
3
Division of Pediatric Neurology, Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
4
Ann Arbor VA Healthcare System, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA.
5
Cellular and Molecular Arrhythmia Research Program, Division of Cardiovascular Medicine, University of Wisconsin, Madison, WI 53705, USA.
6
Cardiology, Electrophysiology Division, Boston Children's Hospital, Boston, MA 02115, USA.
7
Department of Neurology, University of Michigan Medical School, 5021 BSRB, Ann Arbor, MI 48109, USA; Ann Arbor VA Healthcare System, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Electronic address: parent@umich.edu.
8
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. Electronic address: lisom@umich.edu.

Abstract

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 Nav1.1 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 (INa) and spontaneous contraction rates in DS patient iPSC-CMs versus controls. For the subject with the largest increase in INa, cardiac abnormalities were revealed upon clinical evaluation. Generation of a CRISPR gene-edited heterozygous SCN1A deletion in control iPSCs increased INa 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.

KEYWORDS:

SUDEP; cardiac arrhythmia; developmental and epileptic encephalopathy; epilepsy; induced pluripotent stem cell (iPSC); sodium channel

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