The University of British Columbia’s Matthew Farrer has added a new area of research to his chair: examining the genetic mutations responsible for epilepsy

When he joined The University of British Columbia (UBC) in 2010 as Canada Excellence Research Chair (CERC) in Neurogenetics and Translational Neuroscience, Matthew Farrer arrived with the reputation of having made some of the most significant contributions to Parkinson’s disease research over the previous decade.

Since taking up his position at UBC, Farrer and his team have continued to make remarkable progress in the fight against the disease. Among his discoveries have been several genes for late-onset (or “typical”) Parkinson’s disease, the most important of which are called VPS35 p.D620N and RME-8 p.N855S. Farrer has also successfully developed “knock-in” mouse models for both genes. This means he can recreate the disease in a mouse by inserting these genes into a specific, targeted place in its genome.

Further research into these models, as well as previous genetic models of a gene called LRRK2 (which Farrer discovered in 2005), has indicated that a central molecular pathway in the brain is perturbed in those with the disease. This has been recognized worldwide as being one of the most important risk factors for Parkinson’s disease.

Farrer’s work suggests that, in many genetic forms of Parkinson’s, the “candle is burning twice as bright but half as long. The human brain compensates really well,” he says, “but, with age, that compensation fails, and symptoms of the disease start to become more apparent.”

Until recently, pharmaceutics focused on alleviating symptoms in affected persons, and on postmortem pathology. “These are clearly important,” says Farrer. “However, our research is showing why those symptoms and pathology occur in the first place—and this is giving better, earlier and more rational targets for drug development.”

With such levels of ongoing success, it may seem surprising that Farrer has seemingly switched track to take on a new challenge: seizure genes, specifically the genetic mutations that cause epilepsy.

“It’s not a change of track, as I remain committed to Parkinson’s research. However, my CERC was from the outset to set up a Centre for Applied Neurogenetics [CAN] and Translational Neuroscience,” he says. “Research into Parkinson’s disease is just one area of this. Our interdisciplinary methods and expertise are just as relevant to all brain disorders, but, in some, the potential to influence care is more immediate.” The team is also working on dementia, multiple sclerosis and seizure disorders, he adds.

Based in the Djavad Mowafaghian Centre for Brain Health—a partnership of Vancouver Coastal Health and UBC’s Faculty of Medicine—Farrer’s CAN has run a research program into treatment-resistant (or “refractory”) epilepsy since 2012.

I thought, “Maybe I can help.”

“It was Mary Connolly who raised the red flag for me about childhood epilepsy,” says Farrer.

Connolly, who is division head in UBC’s Department of Pediatrics and director of the Epilepsy Surgery Program at British Columbia Children’s Hospital, told Farrer of the unmet need to help the families of children with seizure disorders.

“Some of the cases she told me about were heartbreaking,” says Farrer. “And I thought, ‘Maybe I can help.’”

Epilepsy is one of the most debilitating childhood disorders, and is the most common reason children receive treatment from pediatric neurologists. Every year, more than 23,000 Canadians are diagnosed with new-onset epilepsy; 75 to 85 per cent of these cases begin in childhood.

Recurrent seizures are the hallmark of epilepsy. The standard medical response is to provide antiseizure medication.

“Unfortunately,” says Farrer, “this medication simply doesn’t work in some 35 per cent of children with epilepsy.”

“What’s worse,” he adds, “is that research shows patients who don’t respond to two or more antiseizure medications have basically no chance of becoming seizure-free with any other medication. And, in some cases, seizures get worse when treated with some commonly used anti-epileptic medications.”

The impact of pharmaco-resistance is most profound in infants up to three years old. Even more seriously, mortality rates among children with treatment-resistant epilepsy is five times higher than in healthy children. And children and youth with epilepsy often have significantly higher rates of emotional, behavioural, social and academic difficulties than those with other chronic health conditions.

“Research has shown [Tellez-Zenteno in 2007; Berg in 2012] they are at risk of developing intellectual impairment, autism spectrum disorder, attention deficit hyperactivity disorder, as well as major behaviour problems and psychiatric illness,” says Farrer.

“You simply can’t understate the enormous burden epilepsy places on the patient, the patient’s family, society and, of course, the health-care system,” he says.

“Current methods of genetic testing in Canada limit a doctor’s ability to identify these genetic disorders in a timely fashion. And, of course, some will, therefore, go undiagnosed,” he says.

“We need early molecular diagnosis to achieve seizure control in infants and young children with treatment-resistant epilepsy.”

An immediate and sometimes life-saving change in care

In more than 50 per cent of children, the cause of epilepsy remains unknown. The ongoing, uncontrolled seizures have a major impact on their brain development and learning.

“In BC, currently—and, I suspect, in many other provinces—the tests offered for seizure disorders are inadequate. There are only two gene tests available, and one of these requires justification from a spinal tap before it can be ordered,” says Farrer.

“Over the past four years, we’ve shown what can be done using high-throughput sequencing to identify causes for epilepsy. We’ve shown how this information can change care for patients.”

Farrer and his team sequence all 20,000 genes in a single assay, and report on a subset of variability in some 1,000 genes.

“We have done a study of 160 infants and their families, and have found a precise molecular diagnosis in over 30 per cent of the infants,” he says. “This has led to an immediate and sometimes life-saving change in care in 16 per cent. These results are tremendously gratifying for me, and, of course, for the families involved. Our clinical service has been making such a huge difference.”

Farrer’s work is so cutting edge, his group was one of only four highlighted at the American Epilepsy Society meeting in Philadelphia in December 2015.

“The research will have huge benefits to families whose children suffer from seizures,” says Farrer. “Ideally, I would like to see this sort of testing done as routine practice. It is a revolutionary approach: personal, precision and prognostic medicine rather than generalized care. It is an approach that would expedite the diagnosis of many complex disorders, but it all costs money. At least in the short to medium term. In the long term, I believe it would save the provincial health ministries a great deal of money.”

Farrer continues to search the genome of those infants in whom the causes of seizures have not yet been discovered. He is looking for the contributions of novel genes, various groupings of genes, and genomic structural rearrangements. He is also working with UBC’s Faculty of Pharmaceutical Sciences to see whether treatments for the molecular diagnoses they have established can be informed or improved.

He is, he admits, both “wildly optimistic and wildly pessimistic” about the future of his research, and his ability to continue providing this service to families of infants with seizure disorders.

“I’ve been very lucky to get funding through CERC, the BC Leadership Fund and the Alva Foundation,” he says. “These funds will end—and they shouldn’t be used to maintain clinical provision, in any case, despite the need of pediatric neurologists and desperate families.”

With that in mind, he is working with a clinically accredited team to help build a production facility for similar testing. UBC’s School of Pharmaceutical Sciences has “been visionary in supporting this endeavour,” says Farrer.

“I’d like to see all newborns have a genome sequence that will always inform their clinical record and future treatment,” says Farrer. “Of course, this would mean all MDs getting retrained. But, medicine is changing so rapidly.”

“In the 18th century, you might have been offered a leech for a nervous complaint; in the 19th century, it might have been a lobotomy. But that’s because there was nothing better. Today, however, we have transformative technologies in health sequencing and informatics that make economic sense. We just need to find the courage to shake things up a little, so they are available to all.”