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.

Figure 1

KCNH2 Arg176Trp mutation in SUDEP. A. Sequence chromatograms and B. amino acid conservation of Arg176Trp across species. C. Schematic representation of the linear topology of the KCNH2 protein shows both the location of critical domains and variants identified in cases of SUDEP. PAS = Per‐Arnt‐Sim domain; PAC = PAS‐associated C‐terminal domain; TSR = transmembrane spanning region; cNBD = cyclic nucleotide‐binding domain.

Figure 2

SCN5A Pro1090Leu mutation in SUDEP. A. Sequence chromatograms and B. amino acid conservation of Pro1090Leu across species. C. Linear topology of the SCN5A protein with the location of each variant found in SUDEP. TSR = transmembrane spanning region; IQ = calmodulin binding region; NEDD4 = E3 ubiquitin‐protein ligase NEDD4; NEDD4L = E3 ubiquitin‐protein ligase NEDD4‐like; WWP2 = NEDD4‐like E3 ubiquitin‐protein ligase WWP2.