Each year, about one in 150 epileptics, whose seizures are not controled, may die of sudden unexplained death in epilepsy or SUDEP. Though rare in children, SUDEP is the leading cause of death in young adults with uncontroled seizures. Recently, researchers at the University of Texas MD Anderson Cancer Center investigating the genetic basis of cancer accidentally discovered a gene crucial to brain and heart development may be associated with SUDEP.

Their new study reveals how mice bred with a deficiency of a gene highly present in the hippocampus — a key brain region in the genesis of seizures — are more likely to develop spontaneous seizures and sudden death. “Understanding the genetic basis for SUDEP is crucial given that the rate of sudden death in epilepsy patients is 20-fold that of the general population,” said Dr. Edward Yeh, chair of cardiology at MD Anderson.

What does SUDEP look like?

Part of what is so mysterious about SUDEP is casualties are often found dead in their beds with no signs of having suffered a convulsive seizure — in fact, nearly a third of those who die of SUDEP have not suffered a seizure at the time of death. Because fatalities are often found lying face down, some researchers believe they may have suffocated from impaired breathing or fluid in the lungs. What is known from past research is that a seizure may cause irregular heart rhythms, though how this plays into SUDEP deaths remains unclear. Additionally, past studies of epileptics have linked SUDEP to the inactivation of certain genes responsible for potassium channels, which regulate a large variety of functions in many cells.

For the current study, Yeh and his team had bred special mice to study how a deficiency of the gene SENP2 (Sentrin/SUMO-specific protease 2) may be tied to cancer in light of past research connecting SENP2 deficiency to prostate cancer and also congenital heart defect. Their experiments, though, led the team down an entirely different trail. Unexpectedly, Yeh and his colleagues observed how their newly created SENP2-deficient mice appeared normal at birth. However, by six to eight weeks, the mice experienced convulsive seizures and then sudden death. Yeh believes the reason may lie with protein modifiers called SUMO or Small Ubiquitin-like Modifier. SENP2 deficiency results in a process known as hyper-SUMOylation, which dramatically impacts potassium channels in the brain.

"One of the channels, Kv7, is significantly diminished or 'closed' due to the lack of SENP2," Yeh said. "In mice this led to seizures and cardiac arrest."

When SENP2 was deficient in the brain of the mice, the resulting seizures activated a part of the nervous system responsible for regulating the heart's electrical system. In turn this caused atrioventricular conduction block — a disruption of the electrical system — resulting in a slowing down and then stopping of the heart.

It remains unclear, Yeh noted, whether seizure and sudden death are separate manifestations of potassium channel deficiency or whether seizures predispose the heart of an epileptic to cardiac arrhythmias. Still, his team’s findings clearly demonstrate a previously unknown cause of SUDEP, which may open up research into future treatments.

Source:  Yeh E, Qi Y, Wang J, et al. Neuron. 2014.