Bianca Grenier, a mother of two children suffering from a rare variant of a rare disease, has found her own way to advance research in the oft-neglected field of rare disease research, with novel fundraisers to support work by medical geneticist Dr. Nancy Braverman.

Source: Jean-Benoît Nadeau for FMHS Focus

It took Bianca Grenier and Patrick Dubois four and a half years and dozens of doctors’ appointments and medical tests to get a diagnosis of the disease affecting two of their three children. Jérémy, 14, and Éliane, 8, both suffer from peroxisome biogenesis disorders in the Zellweger syndrome spectrum (PBD-ZSS), an extremely rare hereditary disease. “Just figuring out what was happening to our children was an odyssey,” says 38-year-old Bianca Grenier, a former caretaker who saw her life turned upside down by the disease with a complicated name. “It is a very rare disease with very diverse manifestations,” explains Dr. Nancy Braverman, medical geneticist at the McGill University Health Centre (MUHC), professor in the Department of Pediatrics at McGill University and a senior scientist at the Research Institute of the MUHC (RI-MUHC). “Jérémy had motor problems while Éliane was overwhelmed by fatigue that made her sleep 20 hours a day.” Fortunately, the two children, whom she has been monitoring since 2018, are responding well to a treatment that lets them lead almost normal lives, even though they can never stray far from wheelchairs and walkers. “I’m lucky,” says Grenier. “My children will never get better, but they can still walk.”

Instead of letting herself be defeated by the disease, Grenier decided to fight. A few months after learning of the diagnosis in 2018, she launched her first fundraising campaign, selling Christmas cakes to raise money for research. The campaign, which was carried out with the help of a pastry manufacturer in the Granby region where she lives, raised $7,000 in the first year. Grenier donated the money to Braverman’s laboratory. In 2020, her third year of fundraising, Grenier switched to selling soap and was able to raise $3,000 despite the pandemic. “We actually ran out of soap,” she says proudly, though she regrets not being able to raise more. “Fundraising could take over my life, but I have my children to look after.”

Grenier has no illusions about how important her financial contribution is in the big picture. The advantages are mostly psychological, she says. “As parents, we feel so helpless. Fundraising is the only thing I can do to feel useful.”

Braverman thinks Grenier is being modest. “Every little bit counts. Sure, it’s a drop in the bucket, but it’s more about the principle. The fundraising effort has been a source of motivation for my lab.” Studying a virtually unknown disease, figuring out which diagnostic methods are reliable, documenting which remedies are most effective, creating a therapy, this all requires times and money—just getting to a small Phase 1 clinical trial can cost over $4 million, whether the trial is successful or not. “The funding we received from the Grenier-Dubois family allowed us to start developing high-efficiency small-molecule screening tests to identify the molecules capable of acting on the gene, and to produce an initial summary of clinical, biochemical and molecular knowledge.”

The Dubois-Grenier family’s case is an exceptional one: their children are both affected by the rarest version of a rare disease linked to the malformation of 13 genes known as Pex, which are responsible for producing the membrane called peroxisome, involved in the metabolism of fatty acids and amino acids. The most common form of the disease, linked to the Pex-1 and -6 genes, leads to vision and hearing disorders and cognitive problems. “But Jérémy and Éliane don’t show any signs of this. They are cognitively intact. Their problem is the Pex-16, which provokes the degeneration of the white matter of the brain that leaves them with abnormal muscle tone and atrophy. The fact that they actually respond well to a medication is one of the most intriguing aspects of this disease,” says Braverman.

A laboratory intern, 4th-year McGill medical student Anthony Cheung, was the first to notice this pharmacological peculiarity of the Grenier-Dubois children’s case while he was collecting information on the disease. According to Braverman, his observation piqued her interest and prompted the American College of Medical Genetics to offer her the rare privilege of making a 10-minute presentation to the 5,000 participants at the annual conference the following April. “Whenever you see such an important improvement, it gets things moving and creates momentum. Some people attending the meeting may already be thinking of a therapy,” says Braverman.

Fighting rare diseases requires collaboration and originality, says Braverman. For example, even before the genetic diagnosis of the disease, neurologists at the Faculty of Medicine and Health Sciences at Université de Sherbrooke had thought to treat Jérémy and Éliane with Sinemet, a drug normally used to treat Parkinson’s disease. And recently, a collaboration between a neurologist, a radiologist and a neuroradiologist at the IR-MUHC led to the development of a reliable diagnostic method using MRI, which will make it possible to identify more cases and begin treatments earlier.

“People with rare diseases don’t just suffer from the disease, itself. They also suffer from the shortcomings of the medical system, from incorrect diagnoses and delayed treatments offered at exorbitant prices,” explains Émilie Pichette, a second-year medical student at McGill and president of RareDIG, an interest group working to raise awareness about the field of rare diseases and encouraging students to study them. The World Health Organization defines a disease as “rare,” she explains, if it affects less than one person in 2000. But the stakes are high given that the 7,000 known rare diseases affect 5% of the world’s population. Nearly 80% of these diseases are hereditary. Last year, Émilie Pichette was among a group of 50 McGill students who produced a series of articles on different diseases for the National Organization for Rare Disorders.

Like geneticists all around the world, Braverman is searching for the Holy Grail: gene therapy that will replace or correct the pathological gene.

Her screening tests have already identified a molecule that could have an impact on Pex-1. She hopes to be able to use the test to do the same for Pex-16. However, a first attempt had disappointing results. “That’s research for you. If it worked all the time, it wouldn’t be research. We have other ideas, so we’ll try again. We won’t give up.”

The fact that the Grenier-Dubois family is extremely motivated to participate in all aspects of the research—including examinations, tests, interviews and giving skin samples—makes Dr. Braverman’s job easier. “The progress in gene therapy today makes me very hopeful,” says Bianca Grenier. “A few years ago, my children’s disease would never have been diagnosed. Now we’re starting to find out what’s going on and that’s opening doors for us. We’re on the doorstep.”

To read this article in its original French. 

March 31 2021