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 Clinical Tremor) were related to 11 cognitive tests 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 then incorporated as confounders in correlation analysis. Results Cognitive tests demonstrating significant correlations with motor scores were those assessing non-verbal reasoning on Matrix Reasoning (p-values from 0.006 to 0.011), and sequencing and alteration on Trails-B (p-values from 0.008 to 0.001). Those showing significant correlations with two motor scores-ICARS and Clinical Tremor- were psychomotor speed on Symbol Digit Modalities (p-values from 0.014 to 0.02) and working memory on Digit Span Backwards (p-values from 0.024 to 0.011). Conclusions Subtle motor impairments correlating with cognitive, particularly executive, 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.

Delineating the Relationships Between Motor, Cognitive-Executive and Psychiatric Symptoms in Female FMR1 Premutation Carriers

“…CGG repeat length ranged from 56 to 133. We reported in a previous study (23) that the scores on the ICARS and the UPDRS were elevated in a proportion of the female carriers from the same sample as in the current study. However, we categorize this increase as sub-symptomatic for FXTAS since it had not generated any specific medical diagnoses, or realization of abnormality on the part of those individuals presenting with evidently abnormal scores.…”

“…On the basis of FXTAS criteria, none of the female PM carriers met diagnostic criteria for inclusion as FXTAS. Based on formal testing by two neurologists (ES & DZL), elevated scores on standard neurological motor rating scales (see below) were identified in 27 female PM carriers; however, we classified this increase as “sub-symptomatic for FXTAS” based on standard testing using motor and cognitive scale scores as previously described ( 23 ).…”

“…Standard methods were employed to isolate genomic DNA from peripheral blood lymphocytes using polymerase chain reaction and Southern blot analyses as described in our previous publications ( 23 ). Briefly, the Southern blot analysis involved digestion with 10 micrograms (μg) of isolated DNA using EcoRI and NruI.…”

“…In a recent study, we have shown that mild motor deficits (cerebellar ataxia and tremor scores) were correlated with setshifting, working memory and psychomotor speed in female PM carriers without a diagnosis of FXTAS (23). Thus, there is converging evidence for the view that there is a continuum of subclinical changes that accumulate over the lifetime, irrespective of the final clinical endpoint.…”

Molecular Pathogenesis and Peripheral Monitoring of Adult Fragile X-Associated Syndromes

“…Therefore, the motor, cognitive and reproductive impairments generally ascribed to FXTAS and FXPOI diagnoses do not follow a strict boundary between sexes. Meanwhile PM women who are asymptomatic for classical FXTAS may develop subtle motor and cognitive impairments that are suspicious to be cerebellar-dependent [65], PM men can develop intranuclear inclusions in brain as well as in testicular tissues, prominently in the Leydig cells that are responsible for secreting testosterone to maintain spermatogenesis [15,16,66]. A potential association of such inclusions with cases of infertility [66] resembles the situation of granulosa cells and POI in PM women.…”