Children’s Hospital of Philadelphia research finds new mechanisms for Dravet syndrome

Dysfunction in an important cell subtype in the brain’s neuronal network contributes to chronic symptoms in patients with Dravet syndrome, according to an expert at Children’s Hospital of Philadelphia.

According to a press release from the hospital, the researchers found that a pathogenic variant in the SCN1A gene, which makes the protein Nav1.1, was found to be present in more than 90% of children with Dravet syndrome.

“A prediction of our work is that the success of therapies under development may depend on the ability to increase expression of Nav1.1 at the parvalbumin interneuron axon,” Ethan Goldberg, MD, PhD, a pediatric neurologist, director of the Epilepsy Neurogenetics Initiative at Children’s Hospital of Philadelphia and lead author of the study, said in the release.

Nav1.1 is a sodium channel that helps develop seizure-suppressing interneurons and is important for the activity of parvalbumin interneuron, a subtype of interneuron. However, the researchers found that chronic dysfunction was caused by impaired synaptic transmission, with parvalbumin interneurons not fully recovering the ability to generate electrical activity down to the synapse to inhibit other neurons, impairing seizure suppression.

Children diagnosed with Dravet syndrome are at an increased early mortality risk due to this dysfunction in seizure suppression. The researchers noted that increasing SCN1A expression in the axon may repair impaired signaling and synaptic transmission and therefore improve symptoms of Dravet syndrome, according to the release.

“Dravet syndrome affects 1 in 14,000 children in the world and has a profound impact on children and their families,” Goldberg said. “We can model Dravet syndrome in the laboratory to understand precisely how the loss of SCN1A produces the clinical features characteristic of the disease to drive development of novel therapies and, one day, a cure.”