Whole exome sequencing revealed that gene variants related to cardiac sudden death, long QT syndrome, and focal epilepsy were more prevalent in people who had died from sudden unexpected death in epilepsy (SUDEP) than in a cohort of control patients, Australian investigators reported on Monday at the annual meeting of the American Epilepsy Society (AES) in Philadelphia.
The findings implicate cardiac rhythm defects in mortality in a percentage of SUDEP cases and suggest that for some patients, SUDEP could be prevented with appropriate drug therapy, Douglas Crompton, MD, PhD, a neurologist at the University of Melbourne, reported at the meeting.
Dr. Crompton and colleagues performed whole exome sequencing to identify genetic variants that were more prevalent in 62 people who had died from SUDEP at two major centers in Australia compared with 2,936 controls.
The researchers reported a higher prevalence of the cardiac sudden death–related gene NOSAP (p=0.00024), the long QT syndrome gene KCNH2 (p=0.0039), and the focal epilepsy gene DEPDC5 (p=0.00016) among the patients with SUDEP. Six SUDEP cases (10 percent) had mutations in genes commonly responsible for long QT syndrome, eight (13 percent) had mutations in other cardiac arrhythmia genes, and 15 (24 percent) had mutations in known epilepsy genes, including six cases (10 percent) with mutations in DEPDC5.
“These findings raise the possibility that SUDEP might be prevented in some cases by avoiding the use of antiepileptic drugs known to alter the heart’s electrical activity, such as prolonging the QT interval,” Dr. Crompton said in an AES news release ahead of the meeting. “In some cases, it may be advisable to recommend beta blockers, pacemakers, or implantable defibrillators.”
Dr. Crompton and colleagues also suggested that, based on their findings, patients with the focal epilepsy mutation DEPDC5 might have a predisposition to SUDEP, perhaps due to subtle cardiorespiratory abnormalities. However, they added, no single gene reached exome-wide significance in the study cohort, and analyses of larger SUDEP cohorts will be needed.
“The findings are definitely intriguing,” said Lara Jehi, MD, director of clinical research at the Cleveland Clinic Epilepsy Center and associate director of the clinic’s Clinical Research Unit, who was not involved with the study. “The idea of looking for a gene that can predict SUDEP is very worthwhile.
“The findings linking [cardiac] genes like the long QT syndrome gene and the cardiac sudden death gene with SUDEP are essentially confirmatory in the sense that it has long been known that patients with epilepsy who have long QT syndrome are at a higher risk for sudden death,” Dr. Jehi added.
However, she cautioned, “before we drive clinical judgment based on these findings or draw any mechanistic conclusions from them, it would be helpful to see how these results compare to [genetic studies] of patients who die from sudden death in general and to patients who have epilepsy but survive,” she said.
That information will be key to determining “whether these genes are critical for the risk of SUDEP in patients with epilepsy in particular, or are a reflection of an increased risk of sudden death in the general population, or are a reflection of epilepsy,” she said.