Translation of the FMR1 Premutation Phenotypes Across the Lifespan

University Of South Carolina At Columbia, Columbia SC

Investigators

Abstract

Carriers of the FMR1 premutation allele (FXpm) are at risk to develop Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) and Fragile X-associated Neuropsychiatric Disorders (FXAND). Despite significant impacts including functional limitations, reduced quality of life, poor health, and even reduced life expectancy associated with these conditions,1–3 tremendous knowledge gaps exist that constrain accurate risk prediction and treatment. Variation across age, developmental stages, and sex has not been sufficiently quantified for FXTAS and FXAND. This lack of knowledge translates to poor understanding on whether, when, and how these FMR1-associated conditions emerge and affect individuals and families. The overall objective of this P50 Center, “Translation of the FMR1 Premutation Phenotypes Across the Lifespan,” is to advance understanding of the clinical phenotypes and underlying mechanisms associated with FXTAS and FXAND through the application of a developmental approach that examines these conditions across the lifespan. This P50 FX Center proposal addresses this critical need to characterize the FXpm phenotype across the lifespan in a non-biased sample that will identify novel mechanisms and targets for intervention. To accomplish this objective, the FX center will capitalize on strong collaborations among investigators across two projects. Project 1 - Aim: Identify the developmental trajectory of social communication deficits and their relationship to FXAND in 3 to 5-year-olds with FXpm. Determine the extent to which auditory processing and molecular-genetic variation (i.e., CGG repeat length, mRNA, FMRP, activation ratio in females) predict social communication across age (Roberts/Hogan). Project 2 - Aim: Establish the timing, developmental trajectory and prodromal language/vocal phenotypes predictive of FXTAS-related motor, cognitive, and psychiatric symptoms in FXpm women across 35 to 80 years of age. Identify how age, clinical risk factors, and molecular-genetic variation (i.e., CGG repeat length, mRNA, FMRP, activation ratio) and environmental adversity interact and influence FXTAS risk in women (Klusek).