PHILADELPHIA—Nearly one-quarter of people who have sudden unexpected death in epilepsy (SUDEP) have genetic mutations known to cause cardiac sudden death, according to a study described at the 69th Annual Meeting of the American Epilepsy Society. Cardiac dysrhythmia thus may contribute to pathophysiology in some instances of SUDEP.
This result “raises the possibility that SUDEP might be preventable in some cases by restricting the use of antiepileptic drugs known to prolong QT interval and, in selected cases, by recommending beta blockers, pacemakers, or implantable cardioverter-defibrillators,” said Douglas Crompton, MD, PhD, a neurologist at the University of Melbourne in Australia.
The researchers collected demographic and clinical information on patients with SUDEP from two major centers in Australia. To identify rare genetic variants in these patients, they performed whole exome sequencing. The investigators’ in silico study of variants included a collapsing analysis to rank genes with an increased prevalence of pathogenic rare variants in the SUDEP cohort, compared with 2,936 control exomes. Dr. Crompton’s group also performed a candidate gene study of cardiac arrhythmia, respiratory control, and epilepsy genes.
Of 61 cases of SUDEP included in the analysis, 53 were considered definite SUDEP, two were definite SUDEP plus (ie, minor pathology might have contributed to death), and six were probable SUDEP. The mean age at epilepsy onset was 10.5, and the mean age at SUDEP was 28. The researchers observed a slight male predominance in the study. The collapsing analysis found the cardiac-related sudden death gene NOSAP1, the long QT syndrome gene KCNH2, and the focal epilepsy gene DEPDC5 to be among the top 30 genes of the whole exome (of 15,294 genes interrogated). Six patients with SUDEP (10%) had mutations in genes commonly responsible for long QT syndrome, and eight patients (13%) had mutations in other cardiac arrhythmia genes. Fifteen patients (24%) had 16 mutations in known epilepsy genes, including six people (10%) with mutations in the focal epilepsy gene DEPDC5.
The high prevalence of DEPDC5 mutations may indicate a predisposition toward SUDEP in patients with this mutation, perhaps because subtle cardiorespiratory abnormalities are comorbid with epilepsy in these individuals, said Dr. Crompton. Although the collapsing analysis identified genes that are biologically plausible as contributors to SUDEP, no single gene reached exome-wide significance. “Analyses of larger SUDEP cohorts holds promise for identifying hitherto unsuspected genes as contributors in SUDEP pathophysiology,” Dr. Crompton concluded.
—Erik Greb
