Genetic and forensic implications in epilepsy and cardiac arrhythmias: a case series

Abstract

Epilepsy affects approximately 3% of the world's population, and sudden death is a significant cause of death in this population. Sudden unexpected death in epilepsy (SUDEP) accounts for up to 17% of all these cases, which increases the rate of sudden death by 24-fold as compared to the general population. The underlying mechanisms are still not elucidated, but recent studies suggest the possibility that a common genetic channelopathy might contribute to both epilepsy and cardiac disease to increase the incidence of death via a lethal cardiac arrhythmia. We performed genetic testing in a large cohort of individuals with epilepsy and cardiac conduction disorders in order to identify genetic mutations that could play a role in the mechanism of sudden death. Putative pathogenic disease-causing mutations in genes encoding cardiac ion channel were detected in 24% of unrelated individuals with epilepsy. Segregation analysis through genetic screening of the available family members and functional studies are crucial tasks to understand and to prove the possible pathogenicity of the variant, but in our cohort, only two families were available. Despite further research should be performed to clarify the mechanism of coexistence of both clinical conditions, genetic analysis, applied also in post-mortem setting, could be very useful to identify genetic factors that predispose epileptic patients to sudden death, helping to prevent sudden death in patients with epilepsy.

Cardiac and Autonomic Mechanisms Contributing to SUDEP

“…Electrocardiogram abnormalities may fluctuate within a given individual and can be unmasked by sodium channel blockers, fever, alcohol, and cocaine intake. Brugada syndrome has been described in coexistance with cryptogenic frontal lobe epilepsy (Partemi et al, 2014;Sandorfi et al, 2013), highlighting another possibility that ion channelopathies common to the heart and the brain could be related to SUDEP in a subset of susceptible patients. Familial and individual association between generalized epilepsy and Brugada syndrome related to SCN5A has also been described (Aurlien et al, 2009;Parisi et al, 2013).…”

“…Family screenings of patients with SUDEP have identified a group of genes potentially related to epilepsy and premature death (Klassen et al, 2014). Mutations in these genes are found in up to 24% of patients with epilepsy with personal or family history of cardiac arrhythmias (Partemi et al, 2014). These mutations may predispose patients to inherent excitability or be important for maintaining cardiorespiratory homeostasis in the context of seizures or hypoxia.…”

Genetic investigation of sudden unexpected death in epilepsy cohort by panel target resequencing

“…We previously performed a genetic study in a large cohort of individuals with epilepsy and cardiac conduction disorders and showed putative pathogenic disease-causing mutations in genes encoding cardiac ion channel in about 25 % of unrelated individuals with epilepsy [7].…”

National Association of Medical Examiners position paper: Recommendations for the investigation and certification of deaths in people with epilepsy

“…Genetic channelopathies, most often sodium and potassium channel gene mutations, may contribute to SUDEP, since these genes are expressed in the brain and heart, and may lower seizure threshold and cause cardiac arrhythmias. 17,18 Given the possible implications for surviving relatives, collection of proper samples is essential. An ethylenediaminetetraacetic acid (EDTA—purple top) tube of blood is the preferred specimen for genetic testing, but a blood spot card or frozen tissue (1 cubic centimeter of liver, spleen, or heart at −80°C) can also be used.…”