Post‐Mortem Review and Genetic Analysis of Sudden Unexpected Death in Epilepsy (SUDEP) Cases

Abstract

Sudden unexpected death in epilepsy (SUDEP) is the most frequent epilepsy-related cause of death and is characterized by an absence of any identifiable cause of death at post-mortem, suggesting an underlying arrhythmogenic predisposition. This study sought to identify SUDEP cases in a review of post-mortem records and to undertake genetic studies in key familial long QT syndrome (LQTS) genes. All autopsies performed from 1993-2009 at a forensic centre in Sydney, Australia were reviewed and SUDEP cases identified. DNA was extracted from post-mortem blood and the three most common LQTS genes, ie, KCNQ1, KCNH2 (HERG) and SCN5A, were amplified and analyzed. Sixty-eight SUDEP cases were identified (mean age of 40 ± 16 years). Genetic analysis revealed 6 (13%) non-synonymous (amino acid changing) variants in KCNH2 (n = 2) and SCN5A (n = 4), all previously reported in LQTS patients. Specifically, KCNH2 Arg176Trp and SCN5A Pro1090Leu were identified once in SUDEP cases and absent in control alleles. Both DNA variants have been previously identified in the pathogenesis of LQTS. The cause of SUDEP is currently unknown. Our results indicate that investigation of key ion channel genes should be pursued in the investigation of the relationship between epilepsy and sudden death.

Complex SCN8A DNA-abnormalities in an individual with therapy resistant absence epilepsy

“…SCN8A and SCN5A mutations have both been associated with SUDEP (Larsen et al, 2015;Veeramah et al, 2012;Tu et al, 2011) and SCN5A mutations have been implicated in long QT and Brugada syndrome (Shimizu, 2014). Our case showed fQRS in two contiguous ECG leads.…”

Cardiac and Autonomic Mechanisms Contributing to SUDEP

“…These were found in 13% of SUDEP cases reported in Australia (Tu et al, 2011). KCNH2 encodes for protein Kv11.1 and has been associated with torsade de pointes, syncope, palpitations, and sudden death (Johnson et al, 2009).…”

Genetic investigation of sudden unexpected death in epilepsy cohort by panel target resequencing

“…The predisposition to cardiac arrhythmia can be caused by the prolongation of the QT interval in the electrocardiogram, especially if seizure discharges involve the insular region, hypercapnia and hypoxia, and catecholamine release [4]. Several studies described rare genetic variants in genes associated with long QT syndrome (LQT) (SCN5A, KCNQ1, KCNH2, KCNE1, and KCNE2) in SUDEP cases [5]. Neuronal ion channel pathogenic variants may be responsible for some forms of familial epilepsy.…”