CURE Epilepsy Discovery: Heart Dysfunction Is a Risk Factor for SUDEP

Key Points:

• CURE Epilepsy Award grantee Dr. Christopher Reid and his team sought to understand the genetic connection between sudden expected death in epilepsy (SUDEP) and cardiac arrhythmia with the goal of improving treatment for people with epilepsy and reducing the risk of SUDEP.
• The team focused on KCNH2, a gene whose loss-of-function mutations are linked to cardiac arrhythmias and increased SUDEP risk in humans.
• Currently, the team is generating laboratory models with genetic mutations comparable to those found in humans, to explore the link between cardiac abnormalities and SUDEP risk with greater precision than is feasible with humans.

Deep Dive:

SUDEP is the most common cause of death among people with treatment-resistant epilepsy [1], but its underlying biological cause remains obscure. There is strong evidence of the association of breathing problems with SUDEP [2,3], but there is also equally strong, if not more so, data for cardiac abnormalities, particularly cardiac arrhythmias (irregular heartbeat). In fact, studies have found mutations in genes associated with cardiac arrhythmias in SUDEP patients [4].

Dr. Christopher Reid and his team at the Florey Institute of Neuroscience & Mental Health at the University of Melbourne sought to build upon the known relationship between cardiac abnormalities and SUDEP risk by identifying specific genes involved in proper cardiac function. With the assistance of a CURE Epilepsy Award, they chose to focus on a gene known as KCNH2, which affects the spread of electrical signals in the heart. KCNH2 variants that result in a loss of cardiac function are a well-known cause of long QT syndrome [5], a potentially fatal condition that affects heart function and which has as a distinct pattern on an electrocardiogram.

 Prior research revealed that KCNH2 was one of thirty genes found in an analysis of rare genetic variants in SUDEP patients when compared to controls [6]. Following up on that work and as part of this study, the team characterized the variants, finding that about 8% of SUDEP cases carry a KCNH2 variant that causes the gene to not function (7). As a result of these findings, the team proposed that the risk of SUDEP is significantly higher for a person who experiences seizures and carries a KCNH2 loss-of-function variant than for a person who has seizures but does not carry a loss-of-function variant. This suggests that the presence of loss-of-function mutations of KCNH2 may serve as valuable biomarkers for SUDEP risk [7].

To probe this relationship with greater precision than is possible in humans, Dr. Reid and his team are currently generating laboratory models with mutations in genes that are involved in cardiac arrhythmias and development of epilepsy, comparing their SUDEP risk to those models with either arrhythmia alone or epilepsy alone. Based on the human studies, the expectation is that the combination of cardiac- and epilepsy-related genetic mutations will result in a much greater propensity for sudden death. The eventual goal is to use these data to help understand how cardiac function and epilepsy might intersect and inform clinical guidelines for the treatment of epilepsy patients, hopefully reducing SUDEP risk in the process.

Literature Cited

1. Thurman, D.J. et al. The burden of premature mortality of epilepsy in high-income countries: a systematic review from the Mortality Task Force of the International League against Epilepsy. Seizure 2017; 58(1): 17-26.
2. Ryvlin, P. et al. Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study. Lancet Neurol. 2013; 12(10): 966-977.
3. Wenker, I.C. et al. Postictal death is associated with tonic phase apnea in a mouse model of sudden expected death in epilepsy. Neurol. 2021; 89: 1023-1035.
4. Bagnall, R.D., Crompton, D.E., and Semsarian, C. Genetic basis of sudden unexpected death in epilepsy. Neurol. 2017; 8: 348.
5. Bleakley, L.E. et al. Are variants causing cardiac arrhythmia risk factors in sudden unexpected death in epilepsy? Neurol. 2020; 11: 925.
6. Bagnall, R.D. et al. Exome-based analysis of cardiac arrhythmia, respiratory control, and epilepsy genes in sudden unexpected death in epilepsy. Neurol. 2016; 79(4): 522-534.
7. Soh, M.S. et al. Loss-of-function variants in Kv11.1 cardiac channels as a biomarker for SUDEP. Clin. Transl. Neurol. 2021; Epub ahead of print.