Researchers to study FXTAS risk in people with FMR1 premutation
Goal to understand who will develop FXTAS later in life and why
Researchers in Kansas and California will investigate people with the FMR1 premutation who are at risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS), a condition related to fragile X syndrome that develops late in life.
The five-year project, supported by a $3.1-million grant from the National Institutes of Health, will study key motor, cognitive, and brain changes among premutation carriers to understand which of them will develop FXTAS and why.
The ultimate goal is to use the findings to help understand the disease’s underlying molecular mechanisms and to identify early signs of the disease and potential treatments to manage symptoms and slow or even prevent its development.
“There are people out there who have FMR1 premutations and live with the fear that they may develop FXTAS one day,” Matt Mosconi, PhD, the project’s leader and director of the University of Kansas Brain Lab and the Kansas Center for Autism Research and Training, said in a university news story. “There also are people with FXTAS who are desperate for a cure. We first need to figure out why these individuals develop FXTAS, whereas other premutation carriers do not, so we can determine the precise causes and then target them with new therapies.”
Similar to fragile X syndrome, FXTAS is caused by excessive repeats of three DNA building blocks — CGG — in the FMR1 gene. People with more than 200 CGG repeats, called full mutation carriers, usually develop fragile X, with symptoms typically becoming apparent in childhood.
FMR1 premutation carriers at risk of FXTAS later in life
FMR1 premutation carriers have between 55 and 200 CGG repeats in the FMR1 gene. While they do not develop fragile X syndrome, they are at risk of FXTAS, which emerges later in life in otherwise healthy individuals.
About 40%-75% of men and 8%-16% of women who carry the premutation go on to develop the disorder. In male premutation carriers, the risk is known to increase with age.
“We now know that FMR1 premutations are not benign,” Mosconi said. “They’re associated with a number of challenges throughout the lifespan. The most severe of these become noticeable when individuals with the premutation or premutation carriers reach middle to later adulthood.”
Symptoms of FXTAS commonly include tremors, lack of control or coordination during voluntary movements (ataxia), balance issues, and cognitive problems. These changes can negatively impact an individual’s quality of life, independence, and longevity.
Randi Hagerman, MD, a co-investigator of the new project at the University of California-Davis MIND Institute, was the first to formally describe the condition, which is often mistaken for other neurological disorders like Alzheimer’s or Parkinson’s disease.
We first need to figure out why these individuals develop FXTAS, whereas other premutation carriers do not, so we can determine the precise causes and then target them with new therapies.
Until now, research into FXTAS has relied on patient reports to identify symptoms. The new project will use precise, objective measures to analyze motor behaviors and brain changes, as well as its potential association with molecular data.
Although men have been studied more often in FXTAS, the study will also include women, who typically have less severe symptoms of the disease.
FXTAS may be more common than it seems, Mosconi said, as physicians may be unaware of the disorder, which can be misdiagnosed as Parkinson’s or Alzheimer’s.
“Unless individuals have a child or a grandchild with fragile X, they often don’t know that they carry this premutation,” Mosconi said. “So, there are people out there that have this permutation, but they don’t know about it.”
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