A large team of international researchers has identified a gene that causes developmental and epileptic encephalopathy (DEE), and the findings may lead to medical therapies to treat children with this severe and intractable pediatric epilepsy syndrome.
DEEs are severe neurodevelopmental disorders that often begin in infancy or early childhood. They feature refractory seizures, high levels of epileptiform activity on electroencephalography, severe hypotonia, and profound developmental impairment or even developmental regression. They often are associated with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early mortality.
In their study, published on October 18, 2018, in the American Journal of Human Genetics,1 the investigators identified a number of spontaneous pathogenic mutations in the calcium voltage-gated channel subunit α1 E gene (CACNA1E) in 30 participants with DEE. Participants with CACNA1E variants had disruptions in these brain-cell calcium channel, causing the channel to activate too easily or to inactivate too slowly, and giving rise to epilepsy.2
Administering the antiseizure drug topiramate, which blocks these calcium channels, led to freedom from seizures in 5 of the study participants.
“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 over activity in epilepsy,” said first author Katherine L. Helbig, MS, CGC, a research genetic counselor in the Neurogenetics Program in the Division of Neurology at Children’s Hospital of Philadelphia. “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 over activity in some patients.”2
1. Helbig KL, Lauerer RJ, Bahr JC, et al. De novo pathogenic variants in CACNA1E cause developmental and epileptic encephalopathy with contractures, macrocephaly, and dyskinesias [published online October 18, 2018]. Am J Hum Genet. https://doi.org/10.1016/j.ajhg.2018.09.006.
2. New causative gene found in severe childhood epilepsy [press release]. Philadelphia, PA: Children’s Hospital of Philadelphia; October 18, 2018.https://www.newswise.com/articles/new-causative-gene-found-in-severe-childhood-epilepsy.