Genetic Mutations in SCN1A Put Dravet Patients at Risk of SUDEP, Study Shows

Genetic Mutations in SCN1A Put Dravet Patients at Risk of SUDEP, Study Shows

Researchers found that patients with Dravet syndrome are at higher risk of suffering sudden unexpected death in epilepsy (SUDEP) due to genetic mutations in the SCN1A gene that predispose them to heart arrhythmias.

University of Michigan Medical School investigators now plan to look at the potential use of already approved drugs to treat Dravet syndrome and other types of epilepsy.

Their study, “Channelopathy as a SUDEP Biomarker in Dravet Syndrome Patient-Derived Cardiac Myocytes,” was published in Stem Cell Reports.

Dravet syndrome is a severe type of epilepsy that usually manifests during the first year of life and is characterized by seizures, cognitive deficits, and increased mortality.

Approximately 80 percent of all Dravet patients carry genetic mutations in the SCN1A gene, that encodes for a subunit of a sodium channel called NaV1.1.

Sodium channels are found mostly in the brain and their main function is to control the transport of sodium ions into cells, participating in the generation and transmission of electric signals between nerve cells.

Up to 20 percent of all Dravet patients die from SUDEP. Although the precise cause of SUDEP is still unknown, studies have reported SUDEP is associated with several medical conditions, including central or obstructive apnea (breathing sleep disorders), pulmonary edema (excess fluid in the lungs), dysregulation of cerebral circulation, autonomic dysfunction (nerve damage), and cardiac arrhythmias (disruption of heart rhythm).

Because SCN1A is also expressed in the heart, researchers believe that the high incidence of SUDEP in Dravet patients could at least be partially explained by their genetic predisposition to develop cardiac arrhythmia, a medical condition previously linked with SUDEP.

“We had a hypothesis that since these kids have the same mutation in their sodium channels in the heart and brain, they might have cardiac arrhythmias,” Lori Isom, PhD, chair of the Department of Pharmacology at Michigan Medicine, said in a university news story by Kelly Malcom. “We were able to gather evidence that they do.”

To test this hypothesis, investigators generated induced pluripotent stem cell-derived cardiac myocytes (iPSC-CMs) — heart muscle cells derived from reprogrammed patient stem cells — from four Dravet patients and two healthy individuals who served as controls to analyze cardiac excitability — that is, the ability of these cells to produce and coordinate electric signals among themselves to generate a steady heart rhythm.

iPSC-CMs derived from Dravet patients showed an abnormal increase in sodium current together with higher spontaneous contraction rates compared with cells obtained from control subjects.

“Your body needs to maintain homeostasis. … It doesn’t just stand there and take the insult, it does something in response,” Isom said. “So what the cell does to try and right the ship, so to speak, is to increase the expression of another sodium channel that’s not mutated. But that appears to result in an uncontrolled overexpression, which produces too much sodium current.”

Of note, the patient whose iPSC-CMs had the largest increase in sodium current developed cardiac abnormalities that were revealed after a clinical evaluation.

When researchers genetically engineered iPSC-CMs derived from control subjects to delete the SCN1A gene and mimic Dravet syndrome, they found these cells shared the same abnormal increase in sodium current previously seen in patient-derived iPSC-CMs.

These findings indicate that patients with Dravet syndrome are at high risk of suffering from SUDEP not only because they are more susceptible to experience seizures, but also due to their genetic predisposition for cardiac arrhythmias.

In the future, the team plans to analyze different genetic mutations related to SUDEP and look for repurposed drugs (treatments approved for other indications) to treat Dravet syndrome and other forms of epilepsy. 

“This is personalized medicine,” Isom said. “This is what we’re all after in the grand scheme of things. It takes a long time and a lot of money, but it works. If we can help one child, then it’s worth it.”

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