Monday, February 22, 2016

The contribution of genetics to sudden unexpected death in epilepsy (SUDEP) risk is not clear. Some people with epilepsy may harbor genetic variations that predispose them to sudden death. The idea of “SUDEP genes” arises from clinical and experimental observations that some genes encode proteins that are important for regulating both brain and heart, and mutations in such genes can lead to both epilepsy and potentially fatal cardiac rhythms. Other proposed mechanisms for how SUDEP occurs, such as post-seizure respiratory failure or post-seizure blood pressure collapse, may also be modulated by genes.

A Study of Genetic Risk Factors

To examine the possible contribution of genetic factors to SUDEP, Bagnall and colleagues analyzed whole exome sequencing data from 61 SUDEP cases from 3 sources: 2 medical examiner offices and participants in an epilepsy genetics research program who subsequently died. Using bioinformatic tools, they examined the proportion of SUDEP cases who had rare, potentially harmful mutations in genes associated with cardiac rhythm or breathing problems or epilepsy.

The authors found that among the 61 SUDEP cases:

  • 15% had variants in 1 of 32 known cardiac-rhthym-related genes that were either known or suspected to be disease causing. Three cases had mutations in the KCNH2 gene, associated with long-QT syndrome type 2, which has been associated with cardiac arrhythmias, sudden death, and seizures.
  • 25% had potentially harmful variants in 1 of 72 known epilepsy-related genes. The most common gene affected (6 out of 15 cases) was DEPDC5, a gene associated with familial focal epilepsy with variable foci. Other SUDEP cases harbored mutations in genes encoding for sodium channels.
  • No SUDEP cases had potentially harmful variants in 5 genes associated with central breathing abnormalities.

Study Results: Clarity and More Questions

These results suggest that a high proportion of SUDEP cases have rare genetic variants and harmful mutations. Some of these genetic abnormalities, such as those associated with arrhythmias, are in pathways clearly associated with mechanisms of sudden death. The results also support screening patients with electrocardiograms for arrhythmia risk.

For other mutations, the biological connection between the gene and sudden death is less clear. For instance, are genetic mutations associated with epilepsy SUDEP genes? This would only be the case if the gene mutations lead to a risk of sudden death beyond what is expected from the seizures they cause.

Much larger genetic studies of both people living with epilepsy and SUDEP cases are needed to determine the specific contribution of mutations in DEPDC5 and other epilepsy-related genes to excess SUDEP risk.

Please speak to your neurologist to discuss if genetic testing is appropriate for you or your family member. If you are bereaved by SUDEP and would like to participate in research to help better understand the role of genetics in SUDEP, contact the North American SUDEP Registry or the Center for SUDEP Research.

Authored by: Daniel Friedman MD | SUDEP Editor on 2/2016