Collaborative International Study Finds Childhood Epilepsy Genes

An international team of researchers recently identified gene mutations that can cause severe, difficult-to-treat forms of childhood epilepsy. Many of the mutations disrupt functioning in the synapse, the highly dynamic junction at which nerve cells communicate with one another.

“This research represents a paradigm shift in epilepsy research, giving us a new target on which to focus treatment strategies,” said pediatric neurologist Dennis Dlugos, MD, director of the Pediatric Regional Epilepsy Program at The Children’s Hospital of Philadelphia, and one of the study’s co-authors. “There is tremendous potential for new drug development and personalized treatment strategies, which is our task for the years to come.”

Epilepsies are amongst the most common disorders of the central nervous system, affecting up to 3 million patients in the United States. Up to one third of all epilepsies are resistant to treatment with antiepileptic medication and may be associated with other disabilities such as intellectual impairment and autism. In many patients with severe epilepsies, no cause for the seizures can be identified, but there is increasing evidence that genetic factors may play a causal role.

Multiple researchers from the U.S. and Europe performed the research, the largest collaborative study to date focused on the genetic roots of severe epilepsies. The scientists reported their results recently in the American Journal of Human Genetics. Two international research consortia collaborated on the study: the Epi4K/EPGP Consortium, funded by the National Institute of Neurological Disorders and Stroke (NINDS), and the European EuroEPINOMICS consortium.

The study adds to the list of gene mutations previously reported to be associated with these severe epilepsy syndromes, called epileptic encephalopathies. The researchers sequenced the exomes of 356 patients with severe childhood epilepsies, as well as their parents. The scientists looked for “de novo” mutations — those that arose in affected children, but not in their parents. In all, they identified 429 such de novo mutations.

The research teams used a method called family-based exome sequencing, which looks at the part of the human genome that carries the blueprints for proteins. When comparing the sequence information in children with epilepsy with that of their parents, the researchers were able to identify the de novo changes that arose in the genomes of the affected children. While de novo changes are increasingly recognized as the genetic cause for severe seizure disorders, not all de novo changes are necessarily disease-causing.

But the most surprising finding is related to a gene called DNM1, which was found to be mutated in five patients. When the researchers looked on a network level, they found that many of the genes that were found to be mutated in patients had a clear connection with the function of the synapse.

This research finding, says Dr. Dlugos, provides important information about the functional roles of the genes that were identified. “We knew that synaptic genes were important but not to this extent,” he added.

To learn more about The Children’s Hospital of Philadelphia’s epilepsy resources and research, see the Pediatric Regional Epilepsy Program website.