PROJECT SUMMARY/ABSTRACT
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a severe, progressive disorder of aging caused by
“premutation” expansions (55-200 CGG repeats) of the FMR1 gene on the X chromosome. Premutation
carriers with FXTAS show motor and cognitive declines resulting in loss of independence, reduced quality of
life, and premature death. FXTAS is more penetrant among male (>50% by age 60) than female premutation
carriers (16-20%), which likely is the major reason studies have focused primarily, if not exclusively, on males.
As a result, knowledge of key phenotypes and brain mechanisms associated with FXTAS in females is
severely limited. These knowledge gaps need to be addressed because A) FXTAS is highly impairing in
women and often clinically different than for men, and B) structural brain and genetic associations with clinical
outcomes vary across sexes in FXTAS, suggesting that sex-specific biomarkers are needed to understand
disease pathways and to support the development of targeted therapies. In the proposed R21, quantitative
motor, executive, and memory phenotypes implicated in our preliminary work on females with FXTAS will be
studied in females with FXTAS (FXTAS+), age-matched asymptomatic female premutation carriers (FXTAS-),
and age-matched healthy female controls. Task-based functional magnetic resonance imaging (fMRI) studies
of motor, executive, and memory processes also are proposed; these represent the first known fMRI studies
focused solely on FXTAS in women. We also will test brain-behavior relationships with key genetic and
molecular targets, including CGG repeat length, allele repeat instability (AGG interruptions), and activation
ratio (ratio of cells with the normal FMR1 allele on the active X chromosome), which appears to critically
modulate the impact of the premutation allele on brain aging in females. Based on recent studies showing
overlapping molecular and cellular pathologies in FXTAS and Alzheimer's Disease, we also will conduct
exploratory analyses of the modifying effects of the ApoE and KLOTHO genes on risk for downstream motor
and cognitive impairments in female premutation carriers. These studies are the first step in advancing our
long-term goal of clarifying neurodegenerative mechanisms of FXTAS in women so that more sensitive, sex-
specific methods can be established to track disease progression and advance targeted therapeutics.
