Investment offers hope for kids with epilepsy linked to gene mutations

Pictured are Dr. Matthew Farrer and Hamid Eshghi, President of the Djavad Mowafaghian Foundation.

With a generous gift from the Djavad Mowafaghian Foundation, the UBC Faculty of Medicine has uncovered more gene mutations responsible for epilepsy in children who don’t respond to traditional therapies.

The study, led by Dr. Matt Farrer who is an affiliate professor with the Djavad Mowafaghian Centre for Brain Health, will help neurologists provide earlier, more precise diagnoses and personalized treatment options for BC kids with epilepsy.

Epilepsy is a group of neurological disorders characterized by abnormal brain activity and seizures. More than half of new epilepsy diagnoses in Canada each year are in children younger than 10 years of age. In most cases, the cause is unknown and finding a target for treatment can be difficult. For kids who live with a type of epilepsy that can’t be managed with medication, uncontrolled seizures can interfere with normal brain growth and cause problems ranging from intellectual impairment to psychiatric disorders.

“I see the heartache and frustration of these families, and I know it doesn’t have to be this way,” says Dr. Farrer. “Together, we can ensure more children have the opportunity to live seizure free, giving their brains a chance to develop in a normal, healthy way. At the Djavad Mowafaghian Centre for Brain Health, this is one the greatest gifts we can offer to children.”

Dr. Farrer’s team found that more than 30 per cent of BC children with treatment-resistant epilepsy had a genetic cause. By rapidly identifying in these children the gene mutations known to cause epilepsy, the team reduced the time to diagnosis and improved health outcomes. The study involved 180 children; 80 received a diagnosis, with 59 of these pinpointing the precise molecular cause. The researchers found multiple mutations in three novel genes leading to seizure disorder, allowing them to help more families like Isobel’s.

Isobel, now four, experienced her first seizure at just three days old, but was soon having up to nineteen seizures a day.

“All her examinations were coming back completely normal,” says her mother, Kimberly. “She was followed by so many doctors because they had no idea what it was. It was really scary.”

Isobel’s doctors at BC Children’s Hospital were able to adjust her medication until the seizures stopped when she was five months old. Her parents were offered genetic testing to hopefully identify the cause.

“It wasn’t a difficult decision. We knew in our hearts we wanted to know because down the line it might help Isobel,” says Kimberly. “But again, the results came back completely normal.”

Nearly a year later, another research team reported that they had identified two siblings with a variant in a new epilepsy gene. Dr. Farrer’s team re-evaluated Isobel’s results and found the mutation there, too—which led Isobel to get the targeted treatment she needed.

“When you’re a mom, you always find ways to blame yourself. I connected Isobel’s problems with so many things that happened during a very difficult pregnancy and birth,” says Kimberly. “It’s a big deal to know that the cause wasn’t anything I had done. And now we just do what we do because she’s doing great.” In fact, Isobel has not had a seizure in over a year; she’s healthy, happy, with a talent for gymnastics, and will shortly start school.

Dr. Farrer’s team discovered many gene mutations for neurologic disorders using whole exome sequencing, a comprehensive method of DNA analysis that processes all 22,000 of an individual’s genes at once. This approach is also effective in providing an early, precise diagnosis for kids with unknown-cause epilepsy, so doctors can deliver effective treatment to prevent developmental delay and long-term disability.

Dr. Farrer recently accepted a new appointment as the Director of Clinical Genomics for the University of Florida, and it is his goal to build a partnership between the two institutions. Underpinning this will be NeuroSeq, a secure, interactive web tool developed by Dr. Farrer’s lab that makes genomic data available to accredited scientists around the world. The level of global collaboration the platform enables, allied with capabilities within the Djavad Mowafaghian Centre for Brain Health, means that causes of pediatric epilepsy that were considered rare can be identified.

Based on the team’s research and advocacy, the BC Ministry of Health approved sequencing for seizure disorders as a comprehensive diagnostic test based on whole exome sequencing in April 2017. This policy made BC the first province in Canada to provide routine, comprehensive genetic sequencing of children with epilepsy.

But a new standard of care for pediatric epilepsy is only the beginning.

Clinical Professor Mary Connolly and Clinical Assistant Professor Michelle Demos in the UBC Department of Pediatrics, who worked with Dr. Farrer on the original study, will continue the research and correlate the clinical and genomic data of approximately 50 more children with unknown-cause epilepsy.  They hope this will uncover more molecular causes for seizure disorders that enable early diagnosis and precise treatment in the clinic and development of new drugs in the laboratory.

“Our team has made major advances in our abilities to diagnose patients with genetic forms of epilepsy,” says Dr. Demos. “The Djavad Mowafaghian Foundation’s gift has laid the foundation for us to diagnose more patients, and it will be an important step in achieving our vision of precision medicine in epilepsy. Personalizing treatments for individual patients will lead to a better quality of life for kids with epilepsy and their families.”

The Djavad Mowafaghian Foundation’s recent gift builds on their incredible support of UBC in the past decade. Notably, the foundation donated $15 million to help build the Djavad Mowafaghian Centre for Brain Health. Opened in 2014, the centre unites research and clinical care in neuroscience, psychiatry and neurology.