Study: Heart Abnormalities May Trigger Sudden Unexplained Death in Epilepsy

New stem cell research reveals dangerous cardiac effects of a gene mutation in patients with Dravet syndrome.

1:00 PM

Author | Kelly Malcom

Imagine putting your child to bed, only to have him die inexplicably in his sleep.

This is the chilling reality for many victims of sudden unexpected death in epilepsy, or SUDEP which claims the lives of roughly 1 in every 1,000 people with epilepsy or other seizure disorders.

LISTEN UP: Add the new Michigan Medicine News Break to your Alexa-enabled device, or subscribe to our daily audio updates on iTunes, Google Play and Stitcher.

Patients with a rare disease called Dravet syndrome are at heightened risk of SUDEP. In the disease, seemingly healthy infants develop frequent and prolonged seizures, catastrophically affecting their development and quality of life.

Michigan Medicine scientists have been on a quest to better understand the connection and potential ways to prevent SUDEP in this population.

What they know: Eighty percent of patients with Dravet syndrome have variants in the SCN1A gene, which codes for Nav1.1 sodium channels in the heart and brain. A sodium channel is like a gate that allows sodium ions across a cell membrane, producing an electrical charge.

SCN1A mutations in people with Dravet syndrome result in electrical disturbances inside cells. Although seizures are the result of abnormal electrical signals in the brain, researchers suspected that problems may also arise in the heart.

"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," says Lori Isom, Ph.D., chair of the Department of Pharmacology at Michigan Medicine. "We were able to gather evidence that they do."

The work is published in Stem Cell Reports.

Isom and clinical colleague Jack M. Parent, M.D., professor of neurology and co-director of the Comprehensive Epilepsy Program at the University of Michigan, first looked to mouse models and then at cells collected from children with Dravet syndrome.

They discovered that mutations associated with Dravet syndrome in mice led to irregularities in the heart muscle's sodium channels.

And those irregularities could be fatal. Variants in sodium channels in the heart can cause ventricular arrhythmias, which occur when the lower chambers of the heart begin to beat abnormally.

What stem cells can tell

To see if that finding appeared in people, Isom and Parent collected skin cells from pediatric patients with Dravet syndrome all over the world. They converted those cells into induced pluripotent stem cells, which have the capacity to become any cell in the body.

MORE FROM THE LAB: Subscribe to our weekly newsletter

By turning them into cardiac cells, the researchers were able to show that despite the loss of the SCN1A gene, there was an increase in sodium current in the heart cells.

"Your body needs to maintain homeostasis. … It doesn't just stand there and take the insult, it does something in response," Isom explains. "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."

In fact, Isom recalls that she and Parent sounded an alarm when looking at the cells of one patient: "When we saw a huge increase in sodium current, we looked at each other and said: 'If this was our child, we'd want to know about it.'"

They recommended that the child get a full cardiac workup to check for abnormalities, which turned out to be present.

[W]e looked at each other and said: 'If this was our child, we'd want to know about it.'
Lori Isom, Ph.D.

'Personalized' approach serves many

Although heart arrhythmias may help explain the suddenness of SUDEP, uncertainties remain.

"The question is, why do you die after the 1,000th seizure when you didn't die in the 999th?" Isom says. "Sodium channel-linked cardiac arrhythmias almost always happen in sleep. That was a big red flag to me years ago when we started working on this project."

SEE ALSO: Study: Most Newborns with Epilepsy Benefit from Genetic Testing

To provide further evidence that SCN1A mutation was wreaking havoc in the heart, Parent and Isom's team used CRISPR-Cas9 technology to molecularly delete the gene from the cells of a healthy child without epilepsy. When the researchers repeated their experiment with those cells, they saw the same increase in sodium current.

Next, Isom and Parent plan to look at different genetic mutations related to SUDEP and at the potential use of repurposed drugs to treat Dravet syndrome and other forms of epilepsy.

"This is personalized medicine," Isom says. "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."

The study was co-authored by Chad Frasier, Ph.D., of the Department of Pharmacology, and Helen Zhang of the Department of Neurology. The work is supported by National Institutes of Health grants T32HL007853, UL1TR000433, R37-NS076752 and U01-NS090364.


More Articles About: Lab Report Basic Science and Laboratory Research epilepsy Arrhythmia or Abnormal Heart Rhythms All Research Topics
Health Lab word mark overlaying blue cells
Health Lab

Explore a variety of health care news & stories by visiting the Health Lab home page for more articles.

Media Contact Public Relations

Department of Communication at Michigan Medicine

[email protected]

734-764-2220

Stay Informed

Want top health & research news weekly? Sign up for Health Lab’s newsletters today!

Subscribe
Featured News & Stories doctor close up listening to baby's heart while baby touches stethoscope while doctor smiles in doctor exam room on exam room table with medical equipment in background
Health Lab
Commentary: Employers are failing to insure the working class – Medicaid cuts will leave them even more vulnerable
A physician talks about what Medicaid cuts will impact Americans across the country.
breathing tube in patient close up in hospital bed
Health Lab
Removal of ventilator breathing tube is delayed for some patients, posing health risks
A study by Michigan Medicine determined how many patients who pass spontaneous breathing trials were extubated within six hours and what factors were associated with staying connected to a ventilator.
yellow pills spilling out of bottle
Health Lab
Study sheds light on why some prostate tumors are resistant to treatment
A new study from University of Michigan Rogel Cancer Center researchers identifies a cellular signature that explains why about one-third of prostate cancers respond especially poorly to treatment. 
two foxes on grass
Health Lab
Study reveals mechanisms behind common mutation and prostate cancer
A study from the University of Michigan Rogel Health Cancer Center, published in Science, sheds light on how two distinct classes of mutations in the FOXA1 gene—commonly altered in prostate cancer—drive tumor initiation formation and therapeutic resistance.
History map
News Release
From the Diag to the world: 175 years of U-M medical history
An interactive map and article that trace the history of Michigan Medicine
pink cells up close
Health Lab
Research links iron-mediated cell death and inflammatory bowel disease
New basic science insights into programmed cell death could offer relief for inflammatory bowel disease. The University of Michigan study reveals a connection between lipid reactive oxygen species, iron-mediated cell death and IBD.