Researchers identify clear genetic risk factors in patients with severe epilepsy

Neurologists and epilepsy researchers from NYU Langone Medical Center were among scientists who have 329 random genetic mutations associated with two of the most severe forms of epilepsy, according to a paper published today in Nature. Though well-known that many forms of epilepsy are strongly influenced by genetics, there has been relatively little progress in identifying the genetic differences that contribute to most forms of epilepsy. This study sheds light on why some with an elevated risk for epilepsy never get the disease and why certain medications work better for some patients than others.

"For generations we have been treating most forms of generalized epilepsies with no idea what causes the disease. Now, for the first time, we have identified clear genetic risk factors in patients with severe epilepsy," says study co-author Ruben Kuzniecky, MD, professor of neurology at NYU Langone Medical Center, where he serves as co-director of the NYU Comprehensive Epilepsy Center and director of epilepsy research.

The findings are the first to emerge from the largest investigation into the genetics of epilepsy ever conducted. The study, known as the "Epilepsy Phenome/Genome Project" (EPGP) and representing a consortium of 27 medical centers from around the world, is led by Dr. Kuzniecky and Daniel Lowenstein, MD, professor and vice chair of the Department of Neurology at the University of California, San Francisco (UCSF), and director of the UCSF Epilepsy Center. Since 2007, when the project began, its team of several hundred physicians and staff has collected blood samples and clinical information from more than 4,000 patients with epilepsy and their family members. NYU Langone contributed data for 430 patients, representing the largest enroller in the study. The researchers expect the project's unprecedented dataset to yield results for several years to come.

"This project is one of the most ambitious undertakings in our field," Dr. Kuzniecky says. "It won't be long before it leads to genetic tools that will help us diagnose patients more accurately and tailor treatments specific to their form of epilepsy."

The goal of the project is to find molecular targets that will transform the way epilepsy, a neurological condition characterized by abnormal electrical activity in the brain that causes chronic seizures, is diagnosed and treated. One of the most common neurological disorders, epilepsy affects 1-2 in 100 people worldwide. For most forms of epilepsy, the cause is unknown, but scientists believe genetics play an important role. The risk of epilepsy among people who have parents or siblings with the disorder is about 4 to 8 percent, whereas the risk in the general population is 1 to 2 percent. Yet scientists have discovered only a handful of genes linked to rare forms of epilepsy in only a small number of people.

For more common types of epilepsy, including the two investigated in this study—infantile spasms and Lennox-Gastaut syndrome—the condition is thought to arise from a combination of inherited mutations and random mutations that occur after birth, called de novo mutations. Identifying these de novo mutations is critical to understanding why some people with a family risk of the disease never develop it, while others do, and why certain medications are more effective in some patients than others.

In the study, partly funded through a $15 million grant from the National Institute of Neurological Disorders and Stroke, researchers sequenced DNA extracted from the blood samples of 149 children with infantile spasms, or West Syndrome, a type of seizure associated with severe developmental problems that often affects infants between 4 to 8 months old, and 115 patients with Lennox-Gastaut Syndrome, characterized by seizures in childhood that do not respond to therapy and also cause severe developmental problems. The researchers also analyzed the DNA of parents who do not have the disease, allowing them to isolate genetic mutations in children with epilepsy that arise at or during birth.

The study analysis revealed de novo (random) mutations on nine specific genes with four mutations being completely new ones never before associated with epilepsy. "We found that each mutation carries substantial risk for these forms of epilepsy," says Dr. Kuzniecky. "It's clear that rare individual mutations in different genes converge on specific biological pathways, suggesting a clear direction for personalized therapy and drug development."

Why certain genes are more vulnerable to mutations than others, and why people develop different forms of epilepsy, remains unknown. "Two people could have the same mutation, but express it differently clinically," explains Dr. Kuzniecky. "But we know that the disease follows certain patterns." The mutations were also found to overlap with autism spectrum disorder and severe developmental disorders, suggesting that the disorders may share common molecular miscues.