Static and dynamic postural control deficits in aging fragile X mental retardation 1 (FMR1) gene premutation carriers

Abstract

Background: Individuals with premutation alleles of the fragile X mental retardation 1 (FMR1) gene are at risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS) during aging. Characterization of motor issues associated with aging in FMR1 premutation carriers is needed to determine neurodegenerative processes and establish new biobehavioral indicators to help identify individuals at greatest risk of developing FXTAS.

Methods: We examined postural stability in 18 premutation carriers ages 46-77 years and 14 age-matched healthy controls. Participants completed a test of static stance and two tests of dynamic postural sway on a force platform to quantify postural variability and complexity. CGG repeat length was measured for each premutation carrier, and MRI and neurological evaluations were conducted to identify carriers who currently met criteria for FXTAS. Of the 18 premutation carriers, seven met criteria for definite/probable FXTAS (FXTAS+), seven showed no MRI or neurological signs of FXTAS (FXTAS-), and four were inconclusive due to insufficient data.

Results: Compared to controls, premutation carriers showed increased center of pressure (COP) variability in the mediolateral (COP_ML) direction during static stance and reduced COP variability in the anterior-posterior (COP_AP) direction during dynamic AP sway. They also showed reductions in COP_ML complexity during each postural condition. FXTAS+ individuals showed reduced COP_AP variability compared to FXTAS- carriers and healthy controls during dynamic AP sway. Across all carriers, increased sway variability during static stance and decreased sway variability in target directions during dynamic sways were associated with greater CGG repeat length and more severe neurologically rated posture and gait abnormalities.

Conclusion: Our findings indicate that aging FMR1 premutation carriers show static and dynamic postural control deficits relative to healthy controls implicating degenerative processes of spinocerebellar and cerebellar-brainstem circuits that may be independent of or precede the onset of FXTAS. Our finding that FXTAS+ and FXTAS- premutation carriers differed on their level of intentional AP sway suggests that neural mechanisms of dynamic postural control may be differentially impacted in patients with FXTAS, and its measurement may be useful for rapidly and precisely identifying disease presence and onset.

Keywords: Cerebellum; FMR1gene premutation allele; Fragile X mental retardation 1 (FMR1) gene; Fragile X-associated tremor/ataxia syndrome (FXTAS); Postural control.

Fig.1

a Center of pressure (COP) standard deviation in the anterior-posterior (AP) and mediolateral (ML) directions. b The α exponent of detrended fluctuation analysis (DFA) of COP time series in both directions are shown as a function of standing condition. FMR1 stands for FMR1 premutation carriers. Between-group differences are marked as * at 0.05 level and ** at 0.01 level. Error bars represent standard error

Fig. 2

Scatter plots of significant statistical correlations presented in Table 3. Data were color-coded based on the diagnostic classification of each individual FMR1 premutation carrier. ICARS scores were missing for two inconclusive individuals due to scheduling issues

Fig. 3

Scatter plot of COP standard deviation in AP directions during dynamic AP sway. Data are color-coded based on the diagnostic classification of FMR1 premutation carriers and healthy controls. Box plots show (left to right) the minimum (cap), first quartile, median, third quartile, and maximum (cap) values of each group. Two data points in the control group were located outside of the 1.5× inter-quartile range