Genetic Mutations and SUDEP

Sunday, November 15, 2015

The Gene DEPDC5

The recent finding by Nascimento and colleagues (Neurology: Genetics 2015) that two of nine members of a family with epilepsy due to a mutation in the gene DEPDC5 died from SUDEP (sudden unexpected death in epilepsy) has lead to speculation that mutations in this gene may cause SUDEP. Mutations in this gene are associated with a range of familial epilepsies, often causing focal seizures arising from the frontal or temporal lobes.

In the large family described in the publication, a gene mutation that affects approximately half of offspring can affect many people with seizures of various types and severity. The two brothers who died from SUDEP both had had nocturnal convulsions (tonic-clonic seizures) and were not adherent with their antiseizure medication, two of the greatest risk factors for SUDEP.

It is likely that DEPDC5 is NOT a “SUDEP” gene, but simply an epilepsy gene. For any individual with epilepsy – whether genetic or acquired from causes like head injury or brain infection – the risk of SUDEP is related to factors such as convulsions, nocturnal seizures, and missing medications.

Genetics and Epilepsy

There are now approximately 90 genes and additional chromosomal disorders that are associated with epilepsy. All likely pose a risk of causing SUDEP. In general, the more severe the epilepsy is the greater the risk of SUDEP. Genes such as SCN1A (Dravet Syndrome) and SCN2A and chromosomal disorders such as DUP15q cause severe epilepsies that often do not respond to medications and have high rates of SUDEP. Similarly, people with presumably non-genetic epilepsy but who have ongoing seizures after epilepsy surgery also have high rates of SUDEP.

So the risk of SUDEP is mainly tied to the epilepsy severity and control of convulsive seizures. We do not know of a mutation in any gene that independently confers a risk of SUDEP beyond these factors, though some genes that may also influence heart function, such as SCN1A, and defects in these genes could possibly be the most dangerous.

We do encourage any family that has lost a loved one to SUDEP to consider genetic as well as other factors (changes in respiration or heart rhythm during seizures). By enrolling your family member in the North American SUDEP Registry (NASR), we will work to obtain all of the clinical, neuro- and cardiac physiology data, MRI, and, when available, genetic data. In many cases, medical examiners retain blood spot cards or small sections of tissue that can be used to do genetic testing – which NASR does whenever possible.

For any questions, feel free to reach out to Dr. Orrin Devinsky or Dr. Daniel Friedman.

 

Authored by: Daniel Friedman MD | SUDEP Editor and Orrin Devinsky MD | Editor Emeritus on 11/2015

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