Approximately half of Dravet syndrome patients experience the morbid outcome of sudden unexpected death in epilepsy (SUDEP). 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) Nav1.1. 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. (more…)
New stem cell research reveals dangerous cardiac effects of a gene mutation in patients with Dravet syndrome
Patients with a rare disease called Dravet syndrome are at heightened risk for sudden unexplained death in epilepsy. Researchers are using stem cells to identify the effects of a gene mutation on the heart, which may lead to fatal arrhythmias.
Imagine putting your child to bed, only to have them pass away inexplicably in their sleep. This is the chilling reality for many victims of sudden unexpected death in epilepsy, or SUDEP — which claims the lives of 1 in every 1,000 people with epilepsy or other seizure disorders.
Patients with a rare disease called Dravet syndrome are at heightened risk for 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.
Eighty percent of patients with Dravet syndrome have variants in a gene, SCN1A, which codes for Nav1.1 sodium channels in the heart and the brain. Sodium channels are 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 arise in the heart as well.
“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 the journal Stem Cell Reports.
Isom and her clinical colleague, Jack M. Parent, M.D., professor of neurology and co-director of the Comprehensive Epilepsy Center at U-M, first looked to mouse models and then at cells collected from children with Dravet syndrome.
Their discovery: 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. Then, they converted those cells into induced pluripotent stem cells, which are cells that have the capacity to become any cell in the body.
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 that child get a full cardiac workup to check for abnormalities, which turned out to be present.
Although heart arrhythmias may help explain the suddenness of SUDEP, uncertainties remain.
“The question is, why do you die after the 1000th 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.”
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 cells from a healthy child without epilepsy. When they 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 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 NIH grants T32HL007853, UL1TR000433, R37-NS076752, and U01-NS090364.
Materials provided by Michigan Medicine – University of Michigan. Note: Content may be edited for style and length.
Chad R. Frasier, Helen Zhang, James Offord, Louis T. Dang, David S. Auerbach, Huilin Shi, Chunling Chen, Alica M. Goldman, L. Lee Eckhardt, Vassilios J. Bezzerides, Jack M. Parent, Lori L. Isom. Channelopathy as a SUDEP Biomarker in Dravet Syndrome Patient-Derived Cardiac Myocytes. Stem Cell Reports, 2018; DOI: 10.1016/j.stemcr.2018.07.012
The US Food and Drug Administration today approved stiripentol (Diacomit) for the treatment of seizures associated with Dravet syndrome epilepsy. This is just the second approved form of treatment specifically for patients with Dravet syndrome.
The drug is approved for use in patients 2 years of age and older who are taking clobazam. Stiripentol is not supported by clinical data for use as a monotherapy option for Dravet syndrome.
Stiripentol is available in capsules to be taken orally, or in powder form for oral suspension. The daily dosage is 50mg/kg/day taken in 2 or 3 divided doses (16.67 mg/kg three times daily or 25 mg/kg twice daily). Capsules should be swallowed whole with water during a meal. The powder form should be mixed in water and taken immediately after a meal.
Data from two 12-week studies of stiripentol are included in the FDA’s prescribing information for Diacomit. The studies included 33 patients receiving Diacomit and 31 receiving placebo for a period of 8 weeks. All patients were 3 to ≥18 years of age and taking both clobazam and valproate.
The primary efficacy endpoint of both studies was the responder rate, with responders defined as patients who experienced a greater than 50% decrease in the frequency (per 30 days) of generalized clonic or tonic-clonic seizures during the double-blind treatment period compared to the 4-week baseline period.
In Study 1, the responder rate for patients taking stiripentol was 71% (15 of 21) compared to 5% taking placebo (1 of 20). For Study 2, the response rates were 67% (8 of 12) and 9.1% (1 of 11), respectively.
The most commonly reported side effects of stiripentol, occurring in ≥10% of patients and more frequently than on placebo, included somnolence (67%), decreased appetite (45%), agitation (27%), ataxia (27%), weight decreased (27%), hypotonia (24%), nausea (15%), tremor (15%), dysarthria (12%), and insomnia (12%).
Earlier this year, the FDA approved the use of cannabidiol (Epidiolex) oral solution for the treatment of seizures associated with Dravet syndrome as well as Lennox-Gastaut syndrome, another rare and severe form of epilepsy.
Source: Article by Cecilia Pessoa Gingerich for MDmag.com
Zogenix has confirmed the efficacy of its experimental epilepsy drug in a second, late-stage clinical trial, paving the way for a marketing submission by the end of the year.
The small biotech company, based in Emeryville, Calif., said its lead drug, ZX008, reduced by more than half the average monthly convulsive seizures compared with a placebo in children and teenagers with Dravet syndrome, a rare and severe type of epilepsy.
Dravet syndrome is a very rare type of epilepsy that causes frequent and severe seizures, often beginning in the first year of life. While there is currently no definitive cure for Dravet syndrome, there are treatments available to reduce the number of seizures that can help make the condition more manageable. (more…)