Aging Symptom Trajectories in Mother Carriers of the FMR1 Premutation

PROJECT SUMMARY/ABSTRACT About 1 in 151 women in the US are carriers of a genetic abnormality called the FMR1 premutation (FXpm). Mothers who carry the FXpm are at risk for passing the mutated gene to their children, which may result in fragile X syndrome. The FXpm is also associated with substantially increased risk for disease, including neurodegenerative disease, premature menopause, psychiatric involvement, and executive and social deficits. New evidence suggests that FXpm carrier mothers may experience premature age-related decline across multiple symptom domains. The aging expression of FXpm phenotype is particularly concerning when applied within the context of fragile X families because these symptoms impact not only the carrier mother, but also her ability to care and advocate for her children with fragile X syndrome. However, almost all evidence of age- related decline in this group has been gleaned from cross-sectional data that are insufficient for drawing robust longitudinal trajectories. This represents a substantial barrier to effective clinical management, as we lack the data needed to understand the long-term effects of the FXpm genotype and its implications for families. This proposal seeks to determine the stability of key FXpm phenotypes (mental health, executive, social) across midlife and early old age in FXpm carrier mothers compared to healthy controls (Aim 1); investigate autonomic and molecular-genetic factors associated with age-related symptom expression and their interface with parenting stress (Aim 2); and evaluate functional limitations associated with FXpm symptoms across age (Aim 3). We will accomplish these aims by adopting an accelerated longitudinal design to track age-related change occurring across 45-80 years in 75 FXpm carrier mothers compared to 75 control mothers. The over- arching goal is to inform the critical age periods and risk factors in age-related decline, as well as to lay the groundwork for future mechanistic studies. This work is necessary to develop strategies to ameliorate FXpm symptoms, which will improve outcomes for both FXpm carrier mothers and their children with fragile X syndrome.