SUDEP and Genetics

Epilepsy News From: Wednesday, May 07, 2014

Much of the research into the genetic risks of sudden unexpected death in epilepsy, known as SUDEP, has focused on single gene mutations that give rise to shared risks for both epilepsy and sudden death, primarily from heart arrhythmias and autonomic dysfunction.

There has been evidence, primarily from work done in mice where key genes have been altered, that deletions of genes that encode ion channels that control the excitability of both neurons and cardiac cells can lead to both a predisposition to seizures and to arrhythmic sudden death.

Linking these presumed shared susceptibility genes to SUDEP in humans has been elusive, but case series suggest that genes associated with cardiac arrhythmias may occur in some individuals with epilepsy and even in human cases of SUDEP.

A recent case report by Klassen and colleagues may move us beyond a search for a single causal gene to the concept that a genetic susceptibility to both epilepsy and sudden death may be more complex, perhaps involving the interaction of multiple genes.

  • In this report, the authors describe the detailed genetic analysis of a 3-year-old girl with severe myoclonic epilepsy of infancy (Dravet syndrome) who died of SUDEP and her living parents.

  • They found that in addition to a mutation in the SCN1A sodium channel gene, a known cause of Dravet syndrome, she also harbored duplications in 9 genes that may also be involved in seizures, heart defects and respiratory abnormalities.

  • Some of these duplications where also found in her unaffected parents, suggesting that these defects alone are not enough to cause obvious disease.

  • One duplication, in the potassium channel gene KCNA1, previously linked to seizures and sudden death in laboratory mice, was found only in the patient, suggesting a relationship to her seizures and SUDEP.

  • This study shows that detailed genetic analysis can uncover potentially complex interactions of genetic pathways that contribute to SUDEP risk.

  • We all carry variations within our genetic material. These variations are typically well-tolerated; our biological networks adapt to the resulting subtle differences in protein function.

  • However, it is possible that a mutation, deletion or duplication of some genes can stress this network beyond the limits of compensation, resulting in a heightened risk of SUDEP.

  • Alternatively, these perturbations may each add some risk of SUDEP, combining in different ways and under the right circumstances, predispose the patient to seizure-related death.

  • More studies using this detailed approach to the analysis of gene networks will hopefully improve our understanding of the pathophysiology of SUDEP.

Authored by

Daniel Friedman MD

Reviewed Date

Wednesday, May 07, 2014

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