Watching your child undergo bouts of epileptic seizures can be painful and frightening. While a majority of kids outgrow epileptic seizures by the time they hit their teens, there are some who suffer from severe forms that can be life-threatening. Now new research has opened doors for a more targeted approach for treating epilepsy by identifying gene mutations that disrupt functioning of the synapses in the brain, causing severe, difficult-to-treat forms of childhood epilepsy.

What is epilepsy?

The brain is a complex circuit with millions of interconnected neurons. These neurons communicate with each other by sending tiny electrical impulses. When a large number of neurons send out electrical impulses at the same time, the overload of electricity overwhelms the brain, and this results in an epileptic seizure.

Epilepsy affects around three million patients in the U.S. Many forms of epilepsy are associated with severe neurological damage that leads to intellectual disabilities and autism. Many patients with severe epilepsies do not respond to antiepileptic medication.

Scientists have previously implicated a large number of genes known to cause epilepsy. This current research, a collaborative effort between scientists from Epi4K/EPGP Consortium and European EuroEPINOMICS consortium, has added to the list of gene mutations that causes severe forms of childhood epilepsy, called epileptic encephalopathies.

"This research represents a paradigm shift in epilepsy research, giving us a new target on which to focus treatment strategies," said pediatric neurologist and study coauthor Dr. Dennis Dlugos in a statement. "There is tremendous potential for new drug development and personalized treatment strategies, which is our task for the years to come." The findings were published online in the American Journal of Human Genetics.

For the study, researchers sequenced the exomes, 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" mutations, or mutations that arise only in children and are not passed on from parents. The scientists 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 of affected children with their parents, the scientists were able to identify the de novo changes that caused epilepsy. In all, they identified 429 such de novo mutations.

While not all mutations were disease-causing, in around 12 percent of the children, these mutations were tied to epilepsies.

The scientists were surprised to find a gene called DNM1, which had mutated in five patients. The gene carries the code for dynamin-1, a structural protein that plays a role in shuttling small vesicles between the body of the neuron and the synapse. These vesicles are structures that contain neurotransmitters, which enable transmission between neurons.

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 provides important clues for developing drug targets for the genes involved in epilepsy, say the researchers.

Source: Helbig I, Dlugos D, et al. De Novo Mutations in Synaptic Transmission Genes Including DNM1 Cause Epileptic Encephalopathies, American Journal of Human Genetics. 2014.