Family history of FXTAS is associated with age-related cognitive-linguistic decline among mothers with the FMR1 premutation

Abstract

Background Women who carry a premutation allele of the FMR1 gene are at increased vulnerability to an array of age-related symptoms and disorders, including age-related decline in select cognitive skills. However, the risk factors for age-related decline are poorly understood, including the potential role of family history and genetic factors. In other forms of pathological aging, early decline in syntactic complexity is observed and predicts the later onset of neurodegenerative disease. To shed light on the earliest signs of degeneration, the present study characterized longitudinal changes in the syntactic complexity of women with the FMR1 premutation across midlife, and associations with family history of fragile X-associated tremor/ataxia syndrome (FXTAS) and CGG repeat length. Methods Forty-five women with the FMR1 premutation aged 35–64 years at study entry participated in 1–5 longitudinal assessments spaced approximately a year apart (130 observations total). All participants were mothers of children with confirmed fragile X syndrome. Language samples were analyzed for syntactic complexity and participants provided information on family history of FXTAS. CGG repeat length was determined via molecular genetic testing. Results Hierarchical linear models indicated that women who reported a family history of FXTAS exhibited faster age-related decline in syntactic complexity than those without a family history, with that difference emerging as the women reached their mid-50 s. CGG repeat length was not a significant predictor of age-related change. Conclusions Results suggest that women with the FMR1 premutation who have a family history of FXTAS may be at increased risk for neurodegenerative disease, as indicated by age-related loss of syntactic complexity. Thus, family history of FXTAS may represent a personalized risk factor for age-related disease. Follow-up study is needed to determine whether syntactic decline is an early indicator of FXTAS specifically, as opposed to being a more general age-related cognitive decline associated with the FMR1 premutation.

Insight and Recommendations for Fragile X-Premutation-Associated Conditions from the Fifth International Conference on FMR1 Premutation

“…A growing number of cross-sectional reports, which have shown associations between older age and increased dysexecutive symptoms in PM women, have been suggestive of premature age-related decline [222,252,254,257,258]. Rare longitudinal research also demonstrated age-related decline of cognitive-executive skills in a subset of PM women with a family history of FXTAS, and identified a higher CGG repeat number as risk factors for a decline [259][260][261]. Segal et al (2023) found an association between the number of CGG repeats and working memory among PM females [262].…”

Mortality in Women across the FMR1 CGG Repeat Range: The Neuroprotective Effect of Higher Education

“…One exception [108] found evidence suggestive of differential sensitivity to positive emotional support among mid-size premutation carriers as compared to those with higher or lower numbers of repeats within the premutation range. Another indication of differential sensitivity in response to positive aspects of the environment [114] focused on women with premutation CGG repeats; this study reported that women (mean age of 45) who had between 70 and 100 repeats and who had a college degree had better cognitive functioning than those with fewer or a greater number of CGG repeats within the premutation range.…”

Combined extended reality and reinforcement learning to promote healthcare and reduce social anxiety in fragile X syndrome: a new assessment tool and a rehabilitative strategy

“…Thus, emotional dysregulation is downstream of physiological excessive arousal, while sensory sensitivity, cognitive inflexibility, and intolerance to uncertainty are downstream of emotion dysregulation. This situation may be viewed as deleterious for the individuals' quality of life, with an increased burden on parents and caregivers, and their healthcare might be significantly hampered (Gabis et al, 2023;Klusek et al, 2023;Prior et al, 2023;Wall et al, 2023). To tackle this issue, one may envisage technology-aided interventions and/or artificial intelligence-based setups (Stasolla et al, 2017;Movaghar et al, 2022).…”