A team at the Centre de recherche Azrieli du CHU Sainte-Justine has reached a major milestone in the understanding of a rare and severe form of genetic encephalopathy associated with the DHDDS gene. By developing the first mouse model that faithfully reproduces one of the human forms of the disease, researcher Alexey Pshezhetsky, a professor in the Department of Pediatrics, and Dr. Elsa Rossignol, a professor in the Department of Neuroscience, both at UdeM, are providing the scientific community with an unprecedented tool to investigate the biological mechanisms underlying this neurodevelopmental disorder and accelerate the development of new therapeutic strategies.
In 5 seconds
The mechanisms underlying a rare and severe form of genetic encephalopathy are becoming clearer thanks to the work of a team at the Azrieli Research Center at Sainte-Justine University Hospital.
From the discovery of the first cases to a deeper understanding of the disease
This encephalopathy manifests in early childhood through intellectual disability, epileptic seizures, involuntary movements, and coordination difficulties that progressively worsen over time.
"We identified the first individuals affected by this disease here at CHU Sainte-Justine about ten years ago, but at that time, very little was known about its underlying mechanisms or its true prevalence," explains Alexey Pshezhetsky. "Today, approximately 200 patients with this disease have been identified worldwide. Despite this progress, the cellular and molecular processes driving the disease remained largely unknown."
Using a one-of-a-kind mouse model developed in collaboration with researchers from Quebec and abroad, the team was able to track with exceptional precision the effects of one of the disease-causing mutations, from its molecular consequences to its neurological manifestations. By combining genetics, biochemistry, proteomics, and lipidomics approaches, the study provides a comprehensive picture of the disruptions affecting the central nervous system. In particular, the researchers uncovered how a defect in the production of molecules essential for protein glycosylation leads to alterations in neuronal circuits within the brain. These changes are causing not only with epileptic seizures, but also with movement disorders and cognitive deficits.
A tool to better understand and better treat the disease
Beyond providing an in-depth characterization of this rare disorder, the study establishes, for the first time, a direct link between a genetic mutation, the molecular abnormalities observed in the brain, and the resulting neurological symptoms.
The model also offers an unprecedented platform for evaluating future targeted therapies, including the repurposing of drugs already approved for other conditions. The team demonstrated that acetazolamide, a medication currently used in some patients with genetic neurological disorders, reduced susceptibility to epileptic seizures in their experimental model. However, studies using patient-derived neurons, as well as clinical trials, will be required to validate the therapeutic potential of this approach.
Ten years after the first cases were identified at Santé Québec – CHU Sainte-Justine, this study marks a significant step toward a better understanding of the disease, more informed patient care, and ultimately, the development of targeted treatments for young patients.
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