FXTAS in Women with the FMR1 Premutation: Establishing the Profile, Predictors, and Progression of Symptoms across Adulthood

University Of South Carolina At Columbia, Columbia SC

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT: PROJECT 2 About 1 in 151 females and 1:458 males in the US are carriers of a genetic abnormality called the FMR1 premutation (FXpm). Carriers of the FXpm are at major risk for age-related disease, including Fragile X Tremor/Ataxia Syndrome (FXTAS), a late-onset neurodegenerative disorder characterized by motor and cognitive decline that is a cause of disability and early death. Women have been critically underrepresented— and often excluded—from research on FXTAS, which has left FXpm women, their providers, and the scientific community without even a basic understanding of the profile, predictors, and progression of FXTAS symptoms in women, hindering scientific progress and thwarting clinical efforts to counsel, prevent, diagnose, and treat. Project 2 of this Center application seeks to determine the timing, severity, and progression of FXTAS-related symptom expression in FXpm women across adulthood (Aim 1), using an accelerated longitudinal design to capture trajectories across 35-80 years in a large, demographically representative sample of FXpm women contrasted to matched controls. We also seek to identify predictive language and vocal prodromal markers and clinical risk factors (Aim 2), and predictive FMR1 molecular genetic and environmental factors (Aim 3) that account for heterogeneity in the severity and progression of FXTAS-related symptoms in FXpm women across adulthood. This work is essential to understand critical age periods, identify personalized risk factors, improve diagnosis, and inform the eventual development of treatment targets to reduce risk for FXTAS-related decline in FXpm women, which will improve outcomes for both women who carry the FXpm genotype, their caretakers, and their children living with fragile X syndrome. The knowledge gained will also stimulate further research into sex effects and mechanistic differences.