Study Supports Development of Preventive Treatments for FXTAS

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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In people with fragile X-associated tremor/ataxia syndrome (FXTAS), a condition related to fragile X syndrome that develops late in life, measures of dexterity and memory tend to worsen markedly over time, a new study shows.

The results support the development of preventive treatments for FXTAS, according to its researchers.

The study, “Neuropsychological changes in FMR1 premutation carriers and onset of fragile X-associated tremor/ataxia syndrome,” was published in the Journal of Neurodevelopmental Disorders.

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FXTAS and fragile X are both caused by a similar type of genetic mutation — an abnormal expansion in the FMR1 gene. In people without the mutation, this gene contains a section where three “letters” (CCG) of the genetic code are repeated five to 40 times. In fragile X, there are often more than 200 such repeats. Between these two extremes — from about 55 to 200 repeats — is classified as a “premutation.”

“People, particularly men, who have this premutation variant of the FMR1 gene are at high risk of developing FXTAS later in life,” David Hessl, PhD, a professor at the University of California Davis and co-author of the study, said in a press release.

Whereas fragile X is characterized by developmental and behavioral abnormalities that are present early in life, FXTAS does not become apparent until adulthood and is eponymously characterized by movement problems, namely tremor and ataxia (a lack of control or coordination during voluntary movements). Relatively little is known about this condition, which was first formally described by UC Davis scientists in the early 2000s.

“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,” Hessl said. “We needed to establish key metrics for clinical severity.”

To learn more, the scientists enrolled 64 participants with the FMR1 premutation, who did not have FXTAS, in a study. A group of 30 participants without the premutation (controls) also were included. All participants were males, ages 40–80, at the trial’s start, and over 80% were white.

The participants are being followed regularly — some have been followed for more than 15 years — completing a number of neurological and psychological evaluations as well as tests for the presence of FXTAS.

“The primary importance of this study’s cohort and design is its emphasis on enrollment prior to the onset of FXTAS and the subsequent tracking of changes in functioning during the emergence of disease,” the researchers wrote.

Results showed no notable differences between the controls and premutation carriers at age 40, but at older ages, premutation carriers tended to have a more pronounced decline in visual working memory, motor dexterity, inhibitory control (the ability to resist an impulse), and manual movement speed. After statistical corrections for confounding variables, premutation carriers still showed a faster decline in motor dexterity measures.

To date, 28.1% of the premutation carriers have been formally diagnosed with FXTAS after a neurological examination. Data showed that, compared to those without FXTAS, people with the condition had markedly slower manual movement speed. They also tended to show a faster decline in scores related to memory and planning skills.

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“We show that compared to controls, men with the FMR1 premutation have accelerated decline in manual dexterity and certain domains of executive functioning, including visual working memory, inhibitory control, and that conversion to FXTAS is associated with deterioration in inhibitory control, planning and problem solving, and slowing of manual movement,” the scientists concluded.

A noteworthy finding from the data overall, according to the researchers, is that FXTAS seems consistently associated with worsening over time once it develops later in life. This suggests that prophylactic (preventive) treatments “could be initiated in patients thus identified at high risk, before the onset of FXTAS, to try to stall disease progression,” they wrote.

Hessl said: “There are treatments being developed for FXTAS that could be tried earlier in individuals who are most at risk. 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.”