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Newswise Philadelphia, Sept. 25, 2014 An international research team has identified gene mutations causing 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, M.D., director of the Pediatric Regional Epilepsy Program at The Childrens Hospital of Philadelphia, and a study co-author. There is tremendous potential for new drug development and personalized treatment strategies, which is our task for the years to come.

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 online today in the American Journal of Human Genetics (epub ahead of print).

Two international research consortia collaborated on the studythe Epi4K/EPGP Consortium, funded by the National Institute of Neurological Disorders and Stroke (NINDS) and the European EuroEPINOMICS consortium. The genetic analysis was performed at the NINDS-funded Epi4K Sequencing, Biostatistics, and Bioinformatics Core at Duke University, led by Drs. David Goldstein, Erin Heinzen and Andrew Allen.

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

In 12 percent of the children, these mutations were considered to unequivocally cause the childs epilepsy. In addition to several known genes for childhood epilepsies, the study team found strong evidence for additional novel genes, many of which are involved in the function of the synapse.

Epilepsies are amongst the most common disorders of the central nervous system, affecting up to 3 million patients in the U.S. 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. Severe epilepsies are particularly devastating in children. 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.

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.

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Large International Study Pinpoints Synapse Genes with Major Roles in Severe Childhood Epilepsies