Researchers Find Heart Arrhythmia Gene Mutations in SUDEP

Sudden unexpected death in epilepsy (SUDEP) is poorly understood. In research presented at the American Epilepsy Society 69^th Annual Meeting in Philadelphia, there is new evidence that genetic variants affecting heart rhythm may explain some cases.

An Australian team from the Universities of Melbourne and Sydney looked at mutations known to cause cardiac sudden death in a cohort of 62 SUDEP cases.

It found six cases had mutations in genes commonly responsible for long QT syndrome, a cardiac rhythm disorder and that in eight cases there were mutations in other cardiac arrhythmia genes. In fifteen cases, they found 16 mutations in known epilepsy genes, including six individuals who had mutations in the focal epilepsy gene DEPDC5.

Though the analysis did not turn up a single gene with “exome-wide significance”, Douglas Crompton, MD, PhD, of the University of Melbourne and colleagues concluded, “analysis of larger SUDEP cohorts holds promise for identifying hitherto unsuspected genes as contributors in SUDEP pathophysiology,” with the ultimate goal of preventing these deaths.

In a second study, NYU Langone Medical Center, New York City, researchers looked at post-mortem brain tissue from eight SUDEP patients. All had had epilepsy surgery. The researchers were looking for genetic and epigenetic factors that may have contributed to these patients SUDEP. The tissues were matched with those from seven living patients with similar histories.

The study found mutations in 607 genes in brain tissue from patients who died from SUDEP that were not seen in controls. Analysis of affected genes revealed possible functional effects from 532 of the mutations.

Three of the patients who had SUDEP had mutations in six genes linked to cardiac arrhythmia. The other five patients who died from SUDEP had mutations in seven genes involved in GABA/glutamate pathways. “Multiplexed genetic testing for these mutations may allow early identification of patients with epilepsy who are in high risk of sudden death,” lead author Daniel Friedman, MD, wrote in an abstract presented at the meeting.

Both studies suggest that if these high-risk patients can be identified, they could be treated with therapies and drugs for people with heart problems—such as beta blockers, pacemakers, and implantable defibrillators” and that anti-epileptics that cause heart-rhythm changes should be avoided.

In a third study, Chad Fraser, PhD and colleagues at the University of Michigan pinpointed a specific mutation that appears to raise the risk of SUDEP in patients with early-infantile epileptic encephalopathy, a condition that is drug-resistant and appears before the babies are three months old.

They duplicated the disorder in mice, breeding a knock-in mouse model carrying a human SCN8A mutation from a patient with this disorder. The team found these genetically altered mice had hearts that were susceptible to arrhythmias.