Relationships between motor scores and cognitive functioning in FMR1 female premutation X carriers indicate early involvement of cerebello-cerebral pathways.

Abstract

Background Smaller expansions of CGG trinucleotide repeats in the FMR1 X-linked gene termed ‘premutation’ lead to a neurodegenerative disorder: Fragile X Associated Tremor/Ataxia Syndrome (FXTAS) in nearly half of aged carrier males, and 8-16% females. Core features include intention tremor, ataxia, and cognitive decline, and white matter lesions especially in cerebellar and periventricular locations. A ‘toxic’ role of elevated and expanded FMR1 mRNA has been linked to the pathogenesis of this disorder. The emerging issue concerns the trajectory of the neurodegenerative changes: is the pathogenetic effect confined to overt clinical manifestations? Here we explore the relationships between motor and cognitive scale scores in a sample of 57 asymptomatic adult female premutation carriers of broad age range. Methods Three motor scale scores (ICARS-for tremor/ataxia, UPDRS-for parkinsonism, and the Clinical Tremor) were related to 11 cognitive tests and two psychiatric pathology scores - DASS and SCL-90 - using Spearman’s rank correlations. Robust regression, applied in relationships between all phenotypic measures, and genetic molecular and demographic data, identified age and educational levels as common correlates of these measures, which were incorporated as confounders in correlation analysis. Results Cognitive tests demonstrating significant correlations with motor scores were those assessing psychomotor speed/visual attention (SDMT; TMT-A) and those dependent on various aspects of executive functioning for their execution: sequencing and alternation (TMTB-A); working memory (DS backwards); and non-verbal reasoning (MR). The largest number of motor x cognitive correlations involved ICARS and Tremor scales, which reflect the type of motor dysfunctions seen in FXTAS. Conclusions Subtle motor impairments correlating with cognitive deficits may occur in female premutation carriers not meeting diagnostic criteria for FXTAS. This pattern of cognitive deficits is consistent with those seen in other cerebellar disorders. Our results provide evidence that more than one category of clinical manifestation reflecting cerebellar changes – motor and cognitive - may be simultaneously affected by premutation carriage across a broad age range in asymptomatic carriers. Future longitudinal studies should determine whether cognitive dysfunction tracking motor impairments is driven by the premutation status common to all carriers, or only to a subset of carriers who will develop FXTAS in older age.

Upper and Lower Limb Movement Kinematics in Aging FMR1 Gene Premutation Carriers

“…Increased age was associated with decreased stride length and increased cadence CoV in the FMR1 premutation carriers, while age was not associated with any gait measurements in the healthy controls. This finding demonstrates that premutation carriers may show an earlier or more rapid decline in gait control relative to healthy aging [ 3 , 4 , 76 , 77 ], though it should be noted that our control group was younger than our FMR1 premutation carriers ( Table 1 ). We also found that lower IQ was associated with an increased cadence CoV and COM standard deviation in the healthy controls, but not in the FMR1 premutation carriers, suggesting that sensorimotor and broader cognitive issues may be independently affected during aging in premutation carriers.…”