Understudied but ‘significant public health issue’ FXTAS is focus of first-of-its-kind research at KU

LAWRENCE — The most common inherited cause of intellectual disability, fragile X syndrome, is caused by mutations in a single gene, the FMR1 gene. FMR1 mutations occur when parents possess a smaller mutation, or “premutation,” that then mutates further in the child. 

These premutations previously were thought to be benign outside of their potential to cause fragile X syndrome in offspring, but in the past 20 years, scientists have learned that in fact they are linked with multiple severe conditions, including the neurodegenerative condition fragile X-associated tremor/ataxia syndrome, or FXTAS, which affects individuals’ movement and cognitive abilities during aging.

A new research project at the University of Kansas Life Span Institute will focus on increasing understanding of which premutation carriers will develop FXTAS during middle or later adulthood, and why. The hope is that this information will help prevent the disease or advance treatments when it is in its earliest stages. 

“We now know that FMR1 premutations are not benign,” said Matt Mosconi, director of the KU BRAIN Lab and the Kansas Center for Autism Research and Treatment. “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.” 

The five-year, $3.1 million grant from the National Institutes of Health will fund the study of key motor behaviors, cognitive functions and brain changes among individuals with FXTAS. It will be led by Mosconi, and the project also includes co-investigator Randi Hagerman of the University of California-Davis MIND Institute, who first identified FXTAS in several individuals two decades ago. 

“There are people out there who have FMR1 premutations and live with the fear that they may develop FXTAS one day,” Mosconi said. 

“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.”   

Symptoms of FXTAS include tremors and balance problems due to changes in the brain, including changes in the cerebellum. People also may show changes in memory or executive function. These changes can greatly diminish an individual’s quality of life, independence and longevity. 

Previous studies of FXTAS have relied on subjective reports to identify symptoms. The KU project will be the first FXTAS study to use precise, objective measures to analyze motor behaviors and brain changes in relation to molecular assays. The study will also look at women, who tend to have less severe symptoms, in addition to men, who have been more commonly studied in the past.  

Mosconi said that FXTAS may be more common than people realize. Physicians may be unaware of the condition, which can be misdiagnosed because it looks so much like Parkinson’s or Alzheimer’s diseases.  

“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.”  

Researchers want to understand what exactly is changing in the brain, who is affected and how it can be identified earlier. That in turn could lead to better understanding for monitoring its onset and progression, as well as possible means to manage symptoms.