Orphan diseases in Canada

Kathy O’Connor could tell something was seriously wrong with her two sons. Instead of growing stronger, they were regressing.

At 11 years old, the once robust T.J., who played hockey and soccer, was having difficulty walking in a straight line and started bumping into walls. His speech slowed and his fine motor skills deteriorated. Casey, about two-and-a-half years younger, experienced similar difficulties – although not as pronounced.

“I guess ‘a nightmare’ is the best description, ” says Ms. O’Connor, a nurse practitioner who lives in Pembroke, Ontario.

What followed was four years of tests and doctors’ visits as the family attempted to find the cause behind T.J.’s and Casey’s declining health and wellbeing. The boys underwent multiple biopsies and MRIs, CT scans and blood tests. Neurologists and cardiologists, urologists and endocrinologists studied the boys but no one could find an answer.

“The not knowing – you can only imagine, ” says Dr. Kym Boycott, a clinician-researcher at the Children’s Hospital of Eastern Ontario in Ottawa, who assessed the O’Connor boys. “It is one of the most difficult things in my job: to watch a beautiful child go backwards, to regress, and not know why.”

Until recently, there was not much Dr. Boycott could do. Her specialty is neurogenetics, which involves studying the genetic factors that contribute to the development of neurological disorders. “When a child who had some undiagnosed degenerative condition came to my clinic and they had all kinds of tests and we still didn’t know what was going on, we’d be stuck. We would have to tell the parents, ‘We don’t have an explanation and we don’t know what’s going to happen.’”

However, the use of next-generation gene sequencing in tracing the genetic origins of rare diseases has “revolutionized the way we look after these kids, ” says Dr. Boycott.

She leads FORGE Canada, a consortium comprised of 150 clinicians and scientists – most of them clinical geneticists – studying the gene mutations behind 200 rare diseases. The FORGE team chose the list of diseases following a national request for proposals to suggest targets for study. Up and running since 2011, FORGE has used next-generation sequencing to crack the mysteries behind more than 100 rare conditions and its investigators are confident they will unravel many more.

Gene sequencing used to be a slow, laborious and costly enterprise. The most popular method, Sanger Sequencing, has been in use since 1977 and, in essence, involves studying the DNA sequence of one section of a single gene at a time. If you were looking for a needle in the haystack, this would be like searching the pile one strand of hay at a time. With next-generation sequencing, all 22, 000 genes in the human genome can be sequenced in parallel. The process takes two to three weeks and costs about the same as sequencing a single gene the old way – about $1, 100. While the use of next-generation sequencing to track the genetic roots of rare diseases is becoming more common, Dr. Boycott was a very early adopter of the technology – thanks to funding from the Canadian Institutes of Health Research (CIHR): “The first description of this being applied to rare diseases was in 2009. CIHR jumped on this early on – because we started with this in 2010 when we had our first workshop. That’s how early we got in the game.”

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