Peeling back the layers of Fragile X Syndrome
Fragile X syndrome (FXS), a genetic condition that causes a range of developmental problems, is the most common cause of inherited intellectual disability and autism spectrum disorder. Though symptoms of FXS can range from anxiety to disrupted sleep patterns and sensory disorders, more than 80 per cent of individuals have moderate intellectual disability, joint laxity—a cause of chronic body pain—and speech disorder.
With no “one size fits all” treatment, managing FXS symptoms largely involves non-pharmacological and therapeutic interventions, such as speech or occupational therapy. The lack of pharmacological interventions available for treating key symptoms of FXS could be a thing of the past if Francois Bolduc—who’s spent the last two decades researching FXS—has anything to do with it.
“Working with the brain is very challenging,” says Bolduc, who was the first to show the acute role of the Fragile X gene in learning and memory, “but we’ve found a drug that could have a huge impact on treating individuals with FXS.”
Metformin, a type 2 diabetes medication that is used to control high blood sugar, affects many of the brain’s molecular pathways that are impacted in FXS. Previous studies in other models have shown that metformin can also correct many signs of FXS by normalizing several aspects of neuron-to-neuron communication, which are impaired in FXS. In addition, open label use in individuals with FXS showed improved speech and behavior. What’s needed now is a controlled trial to better understand the efficacy of metformin on behaviour and cognition.
“We aren't developing a cure,” says Bolduc. “Our goal is to develop a treatment that helps improve quality of life—like daily functioning, learning and anxiety—because symptoms like these impact not only the individual, but the family as a whole.”
Bolduc believes that it’s important to focus on the bigger picture. To measure what impact the medication has on the individual and the family, Bolduc integrated a quality of life and health economics component into the trial.
“If a child’s symptoms are better managed, they have the potential to have more independence long-term,” he says. “But we also want to know if their parents are able to be more independent.” He notes that 60 per cent of parents will have to modify or leave their job to care for their child with FXS. “The economic impact for families with a child with FXS is huge—about $30,000 to $40,000 a year.”
The trial, being conducted at the University of Alberta, Montreal’s Sainte-Justine University Hospital Center and the University of California Davis MIND Institute, is also trying to better understand why individuals respond differently to treatments. In order to get a full picture of the diversity between one individual to another, Bolduc will collect blood, urine and stool samples.
“What we’re doing is completely novel,” says Bolduc. “We’re looking to suss out any markers in the body that can predict whether or not an individual with FXS will benefit from metformin treatment."
Using stem-cell technology and non-invasive samples, Bolduc will take blood and urine cells and transform them into brain cells, developing a cell line for each individual, so he can see how their cells react to metformin.
Bolduc likens his research—which began with fruit flies and has evolved into cutting edge genetics and machine learning—to peeling an onion. “It keeps you on your toes,” he says with a laugh. “At every turn you peel back the layers and layers of details, complexity, and possibilities.”
Bolduc is still seeking participants for his project, A Double-Blind, Placebo-Controlled Trial of Meformin in Individuals with Fragile X Syndrome (FXS). If you have patients who are willing to commit to a four-month study, aged six to 25 and have been diagnosed with FXS, please contact the study coordinator at (780) 492-9461.
This project was funded in part through the Stollery Children’s Hospital Foundation through the Women and Children’s Health Research Institute.