Researchers have identified a previously unknown genetic cause of late-onset cerebellar ataxia. The finding will help with diagnosis and open up new treatment options for this progressive disease.
One to three people in every 100,000 will develop some form of late-onset ataxia. Until recently, the majority of patients with late-onset ataxia lacked a genetic diagnosis.
Together with neurologists from the Universities of Montreal and Sherbrooke, Bernard Brais, a neurologist and researcher at the Montreal Neurological Institute-Hospital of McGill University, and Stephan Züchner of the University of Miami’s Miller School of Medicine studied 66 Quebec patients with late-onset ataxia for which a genetic cause had not yet been found.
FGF14 Gene Variant
The researchers discovered that 61% of the patients carried the same novel disease-causing variant in the gene FGF14, making it the most prevalent genetic cause of late-onset ataxia in Quebec. They discovered that in patients, a brief region of repetitive DNA underwent a significant size expansion process known as repeat expansion.
The team contacted international collaborators in Tübingen, Germany, Perth, Australia, London, United Kingdom, and Bengaluru, India to confirm their initial findings. They discovered that the same FGF14 error was also present in 10–18% of late-onset cerebellar ataxia patients in these separate cohorts.
These results backed up the idea that a repeat expansion in FGF14 is one of the most common genetic causes of late-onset ataxia so far.
Coordination And Walking Problems
In addition to pinpointing the gene, the team examined the brains of deceased patients and neurons derived from patients and discovered that the error reduces the expression of the gene and its protein.
Patients with FGF14-related late-onset ataxia typically develop unsteadiness (ataxia) in their fifties. The disease may begin with brief episodes of ataxia that are triggered by physical activity and alcohol consumption.
Around 59 years of age on average, coordination problems become permanent. Typically, the disease progresses gradually and impairs walking, speech, and hand coordination.
Frequently, over time, walking aids are necessary. Although ataxia is typically inherited from a parent with the condition, it can also occur in families without a history of the disorder.
The FGF14 GAA repeated sequence of the mutation is of great interest because it is identical to the sequence that causes Friedreich’s ataxia in the FXN gene, the most prevalent cause of autosomal recessive ataxia in the world. Due to this similarity, it is possible that some of the new therapies being developed for Friedreich ataxia could be used to treat people with an FGF14 expansion.
This study suggests that a medication called aminopyridine, which is already available for the treatment of other neurological conditions, may be helpful for patients. Since some patients with an expansion in FGF14 have responded favourably to this therapy, this is particularly encouraging.
“This opens the door to a clinical trial of this drug in these patients. It’s great news for patients in Canada and worldwide. It also makes genetic testing possible so people and families can arrive at the end of their long diagnostic journey,”
The NIH, the Fondation Groupe Monaco, and the Montreal General Hospital Foundation were just a few of the national organizations that provided funding for the study.
- David Pellerin, M.D., Matt C. Danzi, Ph.D., Carlo Wilke, M.D., Mathilde Renaud, M.D., Ph.D., Sarah Fazal, Ph.D., Marie-Josée Dicaire, B.Sc., Carolin K. Scriba, B.Sc., Catherine Ashton, M.B., B.S., Christopher Yanick, B.S., Danique Beijer, Ph.D., Adriana Rebelo, Ph.D., Clarissa Rocca, M.Sc., et al. Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia. New England Journal of Medicine. December 14, 2022 DOI: 10.1056/NEJMoa2207406