New genetic cause of severe childhood epilepsy identified

By Allen Cone
New genetic cause of severe childhood epilepsy identified
Researched have identified a new genetic cause of severe, difficult-to-treat childhood epilepsy. Photo by geralt/pixabay

Oct. 18 (UPI) -- A new genetic cause of severe and difficult-to-treat childhood epilepsy syndrome has been identified, offering clues to the potential medical treatments for the rare condition, according to researchers.

Researchers found spontaneous mutations in one gene, called CACNA1E, disrupt the flow of calcium in brain cells, leading to epileptic overactivity. The findings were published Thursday in the American Journal of Human Genetics.


"Whether or not we can predict disease course and severity from the genetic change is a frequent question from patients, families, and clinicians," first author Dr. Katherine L. Helbig, a research genetic counselor in the Neurogenetics Program at Children's Hospital of Philadelphia, wrote in a blog post. "There is some suggestion that this may at some point be possible for CACNA1E."

Epileptic encephalopathies are a group of severe brain disorders of an early age. The condition includes aggressive seizures as well as cognitive, behavioral and neurological problems that sometimes results in early death, according to the Epilepsy Foundation. Around 58 percent of infants survived less than one year, according to a study published in Brazil.

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Up to 30 percent of individuals with epileptic encephalopathies are linked to genetics.

"Even though variants in this gene were only just discovered to cause disease, we already have a good understanding of how changes in the gene's associated protein affect brain function -- causing neural overactivity in epilepsy," Helbig said. "Furthermore, although much follow-up research remains to be done, we found that there is a possibility that specific anti-seizure medications could reduce this overactivity in some patients."

The CACNA1E gene has been suspected of playing a key role in how neurons regulate their electrical activity although it wasn't known to cause the human disease.

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Researchers focused on the gene, performing next-generation sequencing in 30 infants and young children with severe epilepsy.

They pinpointed disease-causing variants in CACNA1E. The gene variants were mostly de novo-present in the affected children, but not found in their parents.

De novo mutations disrupt a calcium channel in brain cells, causing it to activate too easily or to inactivate too slowly, leading to epilepsy.

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"The fact that we were able to identify 30 patients at this stage of research indicates that we could be looking at a more common cause of genetic epilepsy than we would have initially assumed," Helbig said in a press release. "This research enables us to give some families an answer as to why their child has severe epilepsy. It also offers the potential that we can build on this knowledge to find new strategies for treatment."


Most of the affected children had severe developmental delays, low muscle tone, contractures starting at birth and movement disorder.

"Many of the children were initially thought to have a severe muscular condition because of their contractures," Helbig said. "We were surprised to find that a genetic epilepsy had such severe symptoms." Helbig is a specialist genetic counselor in CHOP Neurology, which has deep experience in investigating and treating genetic epilepsies.

Some patients responded to topiramate and eventually became seizure free. No other anti-epileptic medications.

"Although more research must be done to investigate this observation more systematically, it does suggest that CACNA1E-encephalopathy may be amenable to a targeted therapy," she wrote.

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