International League Against Epilepsy Takes Important Step in Uncovering the Genetic Underpinnings of Epilepsy

There has always been a question about why some people develop epilepsy, a brain disease that causes a person to have repeated seizures, and why others do not. In past centuries it was often explained in spiritual terms. It was a common belief that a person afflicted with epilepsy was possessed or bewitched. That explanation no longer has credibility in the current scientific age, but the question about “why this person and not the other” has remained challenging to answer. In a study just published in the prestigious Lancet Neurology, an international group of epilepsy researchers have made an important first step in discovering that whether or not we develop epilepsy may be determined by the combination of genes that we inherit.

Since the first identification of a single gene mutation that caused a particular type of epilepsy that ran in a family (Autosomal Dominant Nocturnal Frontal Lobe Epilepsy), the search for the inherited cause of epilepsy focused on families in which many members had the disease. It became clear that there were a number of such genes causing familial epilepsies but there were family members who carried one of these genes but who did not have the disease. Laboratory studies also revealed that there was more to the development of epilepsy than the single gene mutation. Subsequent studies showed that epilepsies of all kinds were more common in some families than in others. That observation led epilepsy researchers to conclude that the risk for epilepsy was related to multiple genetic factors. Determining those factors among the thousands of genes active in people would greatly improve our understanding of the biology of epilepsy, a disease that has a higher mortality than cancer and affects at least 50 million people worldwide.

The study reported in Lancet Neurology is a key step in the journey to understand epilepsy genetics. Because of the huge variability in each person’s genetic makeup, finding the genes that increase the risk required evaluating thousands of people from different countries and different ethnic backgrounds. The International League Against Epilepsy with its global reach created the ILAE Consortium on Complex Epilepsies, bringing investigators together from Europe, Asia and North America who performed a genome wide association study on over 34,000 people of whom more than 8,000 had epilepsy. The people studied had European, Asian and African ancestry. Two genes stood out as having broad implications for epilepsy. One, a sodium channel subunit that regulates neuronal excitability (SCN1A),had previously been associated with certain familial and severe childhood epilepsies; this finding suggests it has an even broader role. Another gene for the protein protocadherin, which helps bind cells together, was also strongly associated with epilepsy. This discovery was unexpected and suggests that the factors that contribute to common epilepsies are more complex than originally thought, and may involve the basic structure of the brain.

According to Sam Berkovic, an internationally recognized epilepsy genetics researcher who participated in this work, the study emphasizes the complexity of the genetics of epilepsy and the importance of the collaboration of multinational groups to our understanding of the many factors that contribute to epilepsy. “For years we have focused on those genes that regulate the excitability of the brain. Findings such as these really turn our concepts on their head. It was a really exciting finding.” Emilio Perucca, President of the International League Against Epilepsy commented, “We are very pleased that the League has been able to bring together this outstanding group of researchers in our efforts to provide better treatments for the disease. It is a great example of how an international organization can play a key role in bringing people together around a common goal.”

August 18, 2014