New Fragile X-Associated Syndrome Findings May Point to Treatments

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Novel findings on how fragile X-associated tremor/ataxia syndrome (FXTAS) first develops may point to new ways to study the disease and possibly potential therapies for it. FXTAS, caused by “premutation” expansions of the FMR1 gene, to date has no approved treatments.

The study was published in the Journal of Neurodevelopmental Disorders. The work was led by researchers David Hessl, a professor in the Department of Psychiatry and Behavioral Sciences, and Susan Rivera, professor and chair in the Department of Psychology, both of the UC Davis Mind Institute.

Hessl and Rivera have been following 64 men who carry the FMR1 premutation for as long as 15 years or more. The research team is also following a group of men without the premutation as study controls. This is the first time FMR1 carriers have been tracked in a long-term (longitudinal) study.

Both FXTAS and fragile X syndrome are caused by mutations in the FMR1 gene, But the symptoms and age of onset are vastly different. Fragile X syndrome arises during early development, causing intellectual disability, other learning problems, and autism-related characteristics, while FXTAS usually begins in late adulthood and is primarily a neurodegenerative movement disorder.

Not everyone with the FMR1 premutation develops FXTAS, which causes cognitive decline, tremor and balance issues similar to Parkinson’s disease.

“People, particularly men, who have this premutation variant of the FMR1 gene are at high risk of developing FXTAS later in life,” said Hessl. “But we haven’t known how to predict who will develop the disease or how quickly it will progress. Also, if we’re conducting a treatment study, we don’t yet know the best ways to track response to the intervention. We needed to establish key metrics for clinical severity.”

The researchers wanted to investigate which participants began showing the earliest measurable signs of FXTAS, and when. Symptoms include trembling of the limbs with movement (intention tremor), uncoordinated walking (gait ataxia), and cognitive decline.

Simultaneously, the team has been looking for biological and brain imaging markers that would help clinicians identify patients during the earliest stages of the syndrome – even before they showed obvious symptoms – to intervene more effectively.

Of the 64 participants, 18 have developed FXTAS so far. During these patients’ progression, the researchers identified a number of early indicators, such as loss of visual working memory, manual dexterity, and movement speed, indicating the patients were developing FXTAS.

“Those tasks tap into brain circuits that are already starting to deteriorate before they develop motor signs that a neurologist might see in an exam,” Hessl said.

Clarifying the syndrome’s pathological evolution will help clinical researchers by providing a template to measure patient responses to therapy. In addition, as new treatments emerge, these metrics could help guide care.

“There are treatments being developed for FXTAS that could be tried earlier in individuals who are most at risk,” said Hessl. “Getting a patient started on a prophylactic regimen before they show obvious signs of disease might be more effective than waiting until it is further along.”

Hessl also directs the International Fragile X Premutation Registry with the National Fragile X Foundation.

“We want to collaborate as a field and develop some well-standardized and reliable methods that can be used in future clinical trials, ideally even in clinics in different countries,” said Hessl. “It’s exciting to start making progress in this direction.”

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