CHOP scientists help lead research pointing to new targets for more effective childhood epilepsy treatments.
An international team of researchers has identified multiple gene mutations that underlie severe, treatment-resistant forms of childhood epilepsy. Many of these mutations interfere with synaptic function—the specialized junctions where neurons communicate—highlighting the synapse as a key area for future therapies.
“This work represents a paradigm shift in epilepsy research, giving us a more precise target for developing treatments,” said pediatric neurologist Dennis Dlugos, M.D., director of the Pediatric Regional Epilepsy Program at The Children’s Hospital of Philadelphia and a study co-author. “These findings open the door to new drug development and more personalized treatment approaches, which will be our focus in coming years.”
The study is the largest collaborative effort to date that examines the genetic causes of severe epilepsies in children. Results from the collaboration were published in the American Journal of Human Genetics.
Two major consortia worked together on this project: the Epi4K/EPGP Consortium, funded by the National Institute of Neurological Disorders and Stroke (NINDS), and the European EuroEPINOMICS consortium. The exome sequencing and associated biostatistics and bioinformatics were conducted at the Epi4K Sequencing, Biostatistics, and Bioinformatics Core at Duke University under the leadership of Drs. David Goldstein, Erin Heinzen and Andrew Allen.
The researchers sequenced the exomes—the protein-coding portions of the genome—of 356 children with severe epilepsies and their parents, searching specifically for de novo mutations: genetic changes present in the affected child but absent in both parents. Across the cohort, they identified 429 de novo mutations. In roughly 12 percent of cases, the team judged these mutations to be the definitive cause of the child’s epilepsy.
Beyond confirming several genes already known to cause childhood epilepsy, the team uncovered strong evidence implicating several novel genes. Many of these newly implicated genes are involved in synaptic transmission and vesicle trafficking—processes essential for neurotransmitter release and neuronal communication.
Epilepsy is one of the most common disorders of the central nervous system, affecting millions of people. Up to one third of epilepsy cases do not respond adequately to available antiepileptic drugs, and severe epilepsies in children are frequently accompanied by intellectual disability and autism spectrum features. While many cases lack a clear cause, growing evidence supports a significant role for genetic factors, particularly de novo mutations, in driving severe pediatric epilepsies.
The team used family-based exome sequencing to compare the protein-coding genomic sequences of affected children and their parents, allowing them to pinpoint de novo changes arising in the children. Not every de novo change causes disease, so the researchers applied statistical and functional filters to identify genes with more mutations in patients than would be expected by chance—the most likely contributors to disease.
“Everyone carries one or two de novo mutations, but our challenge is to determine which of those are pathogenic,” said co-author Ingo Helbig, M.D., now at The Children’s Hospital of Philadelphia. “We highlighted genes that were mutated more often in children with severe epilepsy than would occur randomly. Those genes give us insight into disease mechanisms and potential therapeutic targets.” Helbig helped launch the transatlantic collaboration through the EuroEPINOMICS consortium and serves on the Genetics Commission of the International League Against Epilepsy (ILAE).
One of the most notable discoveries was mutation of the DNM1 gene in five unrelated patients. DNM1 encodes dynamin-1, a protein essential for recycling synaptic vesicles—the tiny sacs that store and release neurotransmitters at neuronal synapses. Network-level analyses showed that many mutated genes converge on pathways regulating synaptic transmission and vesicle trafficking, reinforcing the central role of synaptic dysfunction in these epileptic encephalopathies.
“The prominence of synaptic genes in our findings was striking,” Dlugos added. “We knew synaptic function mattered, but these results show how central it is to many severe, early-onset epilepsies.”
Advocates and research organizations welcomed the results. Dr. Tracy Dixon-Salazar, Associate Research Director at Citizens United for Research in Epilepsy (CURE) and a parent of a child with severe genetic epilepsy, praised the large-scale collaboration: “Pooling genomic data from nearly 400 patients demonstrates the power of teamwork. Large consortia allow us to find new genes faster and better explain the causes of devastating childhood epilepsies.”
Funding for the study came from the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health (grants NS053998, NS077364, NS077274, NS077303, and NS077276), The Andrew’s Foundation, Finding a Cure for Epilepsy and Seizures, the Richard Thalheimer Philanthropic Fund, and the European Science Foundation. In addition to his role at CHOP, Dr. Dlugos is on the faculty of the Perelman School of Medicine at the University of Pennsylvania.
Contact: John Ascenzi – Children’s Hospital of Philadelphia
Source: Children’s Hospital of Philadelphia press release
Image Source: Image credited to PublicDomainPictures and in the public domain
Original Research: Abstract for “De Novo Mutations in Synaptic Transmission Genes Including DNM1 Cause Epileptic Encephalopathies” by EuroEPINOMICS-RES Consortium, Epilepsy Phenome/Genome Project, and Epi4K Consortium in American Journal of Human Genetics. Published online September 25, 2014 (doi:10.1016/j.ajhg.2014.08.013).