Posture Impairment May be Early Sign of FXTAS in Premutation Carriers

Posture impairment in young people carrying mutations associated with fragile X-associated tremor/ataxia syndrome may already be present before the onset of the first symptoms of the disorder, a study has found.

The study, “Complexity based measures of postural stability provide novel evidence of functional decline in fragile X premutation carriers,” was published in the Journal of NeuroEngineering and Rehabilitation. 

Like fragile X syndrome (FXS), FXTAS is a genetic disorder caused by the expansion of CGG repeats in the fragile X mental retardation 1 (FMR1) gene, which provides instructions for making a protein called FMRP.

However, while fragile X patients normally have more than 200 CGG repeats within the FMR1 gene sequence (full mutation), those with FXTAS normally have between 55 and 200 CGG repeats (premutation). FXTAS affects mostly older male patients and is often associated with motor and cognitive impairments.

“Emerging evidence has shown that both male and female carriers with FXTAS and those younger than the typical age of onset [tend to] exhibit subtle changes in postural stability,” the investigators stated.

“[In addition, some studies have shown] that impairments in postural control were exacerbated when conducting a [simultaneous] cognitive task, suggesting that postural control may be contingent on the attentional load of the cognitive task combined with individual differences in executive control,” they said.

Executive control refers to the ability to carry out goal-directed behaviors using complex mental processes and cognitive abilities.

In this study, a group of researchers from the Trinity College of the University of Dublin in Ireland set out to investigate whether defects in postural control could also be found before the onset of the first symptoms of disease in young female premutation carriers.

The study involved 12 female premutation carriers ages 37–45, and 15 healthy women ages 28–47  (controls).

Postural control was examined using a force platform, on which participants were asked to stand upright with their feet planted in a marked area with arms by their sides. The platform was used to measure body sway movements that occurred while participants had their eyes open or closed. During the assays, all participants were asked to remain as still as possible for 90 seconds.

In addition, all participants were asked to perform two different cognitive tasks while maintaining their balance on the force platform to simulate a dual-task situation (having to perform two tasks at the same time):

• The working memory N-back task, in which they had to respond when a number shown on a screen was the same number shown previously;
• The sustained attention response task (SART), in which they had to respond to all numbers (0 to 9) shown on a screen, except for number 3.

This approach is called multi-scale entropy-based analysis, which quantifies the degree of irregularity or complexity in a time series across multiple scales.

A complexity index (Ci), which reflects the individuals’ ability to maintain balance in response to perturbations, was used to measure body sway movements.

Results showed the performance of both groups during the assays in which participants were asked to stand as still as possible for 90 seconds with their eyes open or closed were very similar.

“There were no differences between groups in path length, sway area, or velocity in either … direction, during the [eyes open] and [eyes closed] conditions. Both groups were also comparable in terms of classical sway parameter during both the SART and N-back tasks,” the researchers stated.

However, while the Ci among premutation carriers was consistent across all tests, in healthy subjects it increased significantly during the dual-task tests.

Further analyses also demonstrated there was a strong inverse correlation between the length of CGG repeats within the FMR1 gene sequence and the Ci among premutation carriers, meaning the individuals’ ability to maintain balance decreased as the number of CGG repeats increased.

“[The] preliminary findings of this study demonstrate the feasibility and subtlety of multi-scale entropy analysis in identifying distinguishing features of functional decline in younger premutation carriers, which may not be distinguishable by classical sway parameters,” the investigators said.

“Given the primary motor features of FXTAS including balance and gait issues, early detection of these motor changes will be vital for detecting carriers who may be at risk of FXTAS, and monitoring progression before the onset of the disorder,” they added.