Global team identifies new genes behind severe childhood epilepsy

A large-scale international study on the genes involved in epilepsy has uncovered 25 new mutations on nine key genes behind a devastating form of the disorder during childhood. Among those were two genes never before associated with this form of epilepsy, one of which previously had been linked to autism and a rare neurological disorder, for which an effective therapy already has been developed.

The findings suggest a new direction for developing genome-wide diagnostic screens for newborns to identify who is at risk for epilepsy and, potentially, to develop precise therapies for the condition. The findings appear in the August 11, 2013 online issue of the journal Nature.

The results are the first to emerge from a set of epilepsy-genetics projects known as EPGP and Epi4K, which were launched by the National Institutes of Health in 2007 and 2012, respectively, and involve more than 40 institutions on three continents. While UC San Francisco and Duke University serve as the administrative hubs, the projects involve a team of nearly 150 scientists across 25 specialties, in the hopes of generating this type of advance on the intractable disease.

“The limitations of what we currently can do for epilepsy patients are completely overwhelming,” said Daniel Lowenstein, MD, a UCSF neuroscientist and renowned epilepsy expert who, along with Ruben Kuzniecky, MD, from New York University, is overseeing the Epilepsy Phenome/Genome Project (EPGP). “More than a third of our patients are not treatable with any medication, so the idea of finding specific drug targets, instead of a drug that just bathes the brain and may cause problems with normal brain function, is very appealing.”

The global team started with the most severe forms of the disorder, known as epileptic encephalopathies (EE), which affect roughly one in 2,000 children, often before their first birthdays. Many of these children also experience other severe disabilities, including autism or cognitive dysfunction. Whether the epilepsy contributes to those, or vice versa, is being addressed in a parallel study.

“We knew there was something happening that was unique to these kids, but we had no idea what that was,” said Elliott Sherr, MD, PhD, a UCSF physician-scientist who is the principal investigator of the Epi4K Epileptic Encephalopathy project and who developed this group of patients within EPGP. “In a common disease like cystic fibrosis, you’re likely to see more than one child in a family affected. In this case, it is very rare to have more than one person in the entire family with this condition.”

That lack of clear, inherited links to the disease led them to propose that the condition was being caused by de novo, or brand new, mutations on certain genes. They set out to test that hypothesis.

Searching for Mutations

The team identified children with two classic forms of EE – infantile spasms and Lennox-Gastaut Syndrome -- in which no other family member was affected. They excluded children who had identifiable causes of epilepsy, such as strokes at birth, which are a known risk for this group of disorders. Of the 4,000 patients whose genomes are being analyzed in the Epi4K, 264 children fit that description.