Conference Coverage

Genomic Research Could Yield Preventive Therapies for SUDEP


 

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NEW ORLEANS—Genomics research has begun to elucidate the mechanism of sudden unexpected death in epilepsy (SUDEP) and ultimately could lead to preventive therapies, according to a review presented at the 2013 Annual Meeting of the American Neurological Association. Translational research in humans and animals has established the roles of neuro­cardiac channel genes and serotonergic pathways in SUDEP, and both mechanisms are potential targets for therapeutic interventions.

“The molecular networks predisposing [patients] to SUDEP are complex, and novel technologies such as next-generation sequencing will be critical in future discoveries of genes and pathways that are important in the pathophysiology of epilepsy and its comorbidities,” said Alicia Goldman, MD, PhD, Assistant Professor of Neurology and Neurophysiology at Baylor College of Medicine in Houston. “Additionally, we need sophisticated model systems to tease out the risk magnitude of individual genes in their contribution to SUDEP.”

Serotonergic Pathways May Be a Promising Therapeutic Target
Although the cause of SUDEP is uncertain, one major hypothesis is that it results from central respiratory failure. Research conducted in the early 1990s by investigators in the United Kingdom showed that apnea commonly accompanied epileptic seizures. A follow-up study in 2008 by investigators at the University of California, Davis, showed that as many as 33% of seizures are associated with oxygen desaturations that can be prolonged and severe.

The serotonergic pathways are currently considered the principal candidate mechanism underlying respiratory compromise. A series of experimental studies conducted at the Yale School of Medicine showed that a mouse model deficient in serotonergic neurons had impaired arousal in response to hypercapnia, compared with wild-type mice, which woke up promptly under this condition. The mouse model also had an impaired ventilatory response.

Serotonin modulation became an attractive target for SUDEP prevention when investigators at Southern Illinois University discovered that a genetic susceptibility to respiratory arrest and death in a mouse model was ameliorated by pretreatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine. Researchers at the University of California, Davis, demonstrated that patients with epilepsy who were chronically exposed to SSRIs for comorbid depression were less likely to experience ictally induced significant oxygen desaturation.

Cardiac Dysrhythmia Is an Important Risk Factor for SUDEP
Research has indicated that ictal hypoxemia often coexists with cardiac dysrhythmias. This finding was confirmed by a multicenter European study, MORTEMUS, published in Lancet in September 2013. The retrospective review of more than 133,000 video EEG records found a 2.6-times greater incidence of cardiorespiratory arrest and a more than sixfold greater incidence of SUDEP among patients presenting for presurgical evaluation, compared with cases evaluated in the epilepsy monitoring units for other diagnostic reasons. All cases of SUDEP in this study displayed a consistent pattern of seizure-induced cardiorespiratory dysfunction, culminating in terminal apnea and asystole.

Several other clinical studies have documented an increased frequency of cardiac arrhythmias in patients with epilepsy. Dr. Goldman and her collaborators at Baylor College of Medicine found that the KCNQ1 gene, which is linked to long QT syndrome, is expressed in the heart and the brain. A mouse model carrying a human long QT syndrome mutation in the KCNQ1 gene had cardiac arrhythmias and epileptic seizures and was susceptible to SUDEP.

More than 30 genes are now known to be associated with cardiac arrhythmia, and all are expressed in the heart and the brain. They are prime candidate molecular risk factors in SUDEP, and detection of cardiac arrhythmias in patients with epilepsy is an important step toward SUDEP prevention, said Dr. Goldman.

Other Candidate Genetic Risk Factors and Modulators of SUDEP
A growing body of scientific evidence implicates primary epilepsy genes in SUDEP. Whole exome sequencing in a case of SUDEP uncovered a mutation in a sodium channel gene, SCN8A, which was the primary suspected cause of death. Mouse models of severe epilepsy deficient in potassium channel subunit Kv1.1 or sodium channel subunit SCN1A have severe epilepsy, various cardiac dysrhythmias, and high incidence of SUDEP, said Dr. Goldman. Experimental modulation of the parasympathetic system through pretreatment with atropine or scopolamine reduced the incidence of sudden death in these mice.

Novel technologies will speed the discovery of genes and molecular pathways implicated in SUDEP, said Dr. Goldman. But pharmacologic intervention is not the only tool to prevent SUDEP, she added. The overall genetic context of the individual patient can be a potent modulator of disease risk, as evidenced by a mouse model recently described by researchers at Baylor College of Medicine. Reduction of tau protein level in the Kv1.1 mouse model of severe epilepsy not only reduced seizure frequency and severity, but also improved survival.

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