Dravet Syndrome Gene Mutation Linked to Sudden Unexpected Death Epilepsy

*Updated on 8/31/2018 at 11:22 AM EST

The risk of sudden unexpected death in epilepsy (SUDEP) in children with Dravet syndrome is estimated to be 15-fold greater than other childhood-onset epilepsies. The causes behind SUDEP remain largely unknown, and there are no biomarkers that can be used to predict patients who are at increased risk.

Now, investigators from Michigan Medicine have found that the high risk for SUDEP in patients with Dravet syndrome may be from a predisposition to cardiac arrhythmias and seizures caused by de novo variants in the SCN1A gene.

Many patients with Dravet syndrome carry de novo variants in SCN1A that result in haploinsufficiency for the voltage-gated sodium channel (VGSC) Na_v1.1. Because SCN1A is expressed in the heart and the brain, the investigators postulated that alterations in “cardiac excitability” could contribute to the mechanism of SUDEP in those with SCN1A­-linked Dravet syndrome.

“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,” said Lori Isom, PhD, chair of the Department of Pharmacology at Michigan Medicine, in a recent statement. “We were able to gather evidence that they do.”

To prove their hypothesis, the investigators first turned to mouse models. They found that mutations associated with Dravet syndrome in mice resulted in deadly irregularities within the sodium channels of the heart, which according to the investigators, could result in ventricular arrhythmias. These findings suggested that cardiac arrhythmias may be a key contributor to the mechanism of SUDEP in this patient population.

To see if the same held true for humans, the investigators collected international skin cells from 4 SCN1A-linked pediatric patients with Dravet syndrome and 2 controls without epilepsy for their study. They converted the cells into induced pluripotent stem cells, which are capable of becoming any cell in the body. For their study, they chose to convert them to cardiac cells (iPSC-CMs). By doing this, they were able to demonstrate an increase in sodium current in the heart cells, despite the loss of the SCN1A gene. In the patient with the largest increase in sodium current, cardiac abnormalities were revealed.

“Your body needs to maintain homeostasis…It doesn’t just stand there and take the insult, it does something in response,” explained Dr. Isom. “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.”

Using CRISPR-Cas9 technology, the team molecularly deleted the SCN1A gene from the cell samples collected from a healthy child without epilepsy and provided additional evidence of the SCN1A mutation’s capacity to cause disruption in the heart. Upon repeating the experiment in these cells, the duo noted the same increase in sodium current.

“Taken together, our Dravet syndrome patient-derived iPSC-CM and limited clinical data suggest that the high risk of SUDEP in patients results from a predisposition to cardiac arrhythmias in addition to neuronal hyperexcitability,” the authors write, “reflecting haploinsufficiency of SCN1A in heart and brain and the resulting compensatory overexpression of other VGSC genes in those tissues.”

For future studies, the investigators plan to assess the potential use of repurposed drugs to treat Dravet syndrome and other forms of epilepsy by looking at other genetic mutations related to SUDEP.

“This is personalized medicine,” added Dr. Isom. “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.”

Editor's Note: The statistic previously used in the first sentence of this article was incorrect; half of patients with Dravet syndrome do not die from SUDEP. SUDEP is estimated to occur in 50% of the 15% to 20% of patients who die from Dravet syndrome. The article has since been updated.