Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder associated with a premutation cytosine-guanine-guanine (CGG) trinucleotide repeat expansion of the FMR1 gene. FXTAS is estimated to be the most common single-gene form of ataxia in the aging population. Gait ataxia and intention tremor are the primary behavioral symptoms of FXTAS, though clinical evaluation of these symptoms often is subjective, contributing to difficulties in reliably differentiating individuals with FXTAS and asymptomatic premutation carriers. This study aimed to clarify the extent to which quantitative measures of gait and upper limb kinematics may serve as biobehavioral markers of FXTAS degeneration. Nineteen premutation carriers (aged 46-77 years), including 9 with possible, probable, or definite FXTAS and 16 sex- and IQ-matched healthy controls, completed tests of non-constrained walking and reaching while both standing (static reaching) and walking (dynamic reaching) to quantify gait and upper limb control, respectively. For the non-constrained walking task, participants wore reflective markers and walked at their preferred speed on a walkway. During the static reaching task, participants reached and lifted boxes of different sizes while standing. During the dynamic reaching task, participants walked to reach and lift the boxes. Movement kinematics were examined in relation to clinical ratings of neuromotor impairments and CGG repeat length. During non-constrained walking, individuals with FXTAS showed decreased stride lengths and stride velocities, increased percentages of double support time, and increased variabilities of cadence and center of mass relative to both asymptomatic premutation carriers and controls. While individuals with FXTAS did not show any static reaching differences relative to the other two groups, they showed multiple differences during dynamic reaching trials, including reduced maximum reaching velocity, prolonged acceleration time, and jerkier movement of the shoulder, elbow, and hand. Gait differences during non-constrained walking were associated with more severe clinically rated posture and gait symptoms. Reduced maximum reaching velocity and increased jerkiness during dynamic reaching were each related to more severe clinically rated kinetic dysfunction and overall neuromotor symptoms in FMR1 premutation carriers. Our findings suggest kinematic alterations consistent with gait ataxia and upper limb bradykinesia are each selectively present in individuals with FXTAS, but not asymptomatic aging premutation carriers. Consistent with neuropathological and magnetic resonance imaging (MRI) studies of FXTAS, these findings implicate cerebellar and basal ganglia degeneration associated with neuromotor decline. Our results showing associations between quantitative kinematic differences in FXTAS and clinical ratings suggest that objective assessments of gait and reaching behaviors may serve as critical and reliable targets for detecting FXTAS risk and monitoring progression.
Keywords: FMR1 gene; basal ganglia; cerebellum; fragile X−associated tremor/ataxia syndrome; gait; kinematics; reaching.