Genotype-Phenotype Relationships in Fragile X Families

摘要

ABSTRACT Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder with variable progression caused by the FMR1 premutation. A variety of molecular changes have been documented in those with FXTAS, including mitochondrial dysfunction, sequestration of specific proteins by the CGG-repeat– containing hairpin loops of the FMR1 mRNA, chronic DNA damage repair, and production of the FMRpolyG polypeptide through RAN translation. Although there are many reports of the clinical phenotype of FXTAS, there has never been a longitudinal study of those affected by FXTAS, and consequently, there are no known biomarkers of progression. The proposed project will address this critical need through a prospective longitudinal study of 100 individuals (60 males and 40 females) with FXTAS seen at the MIND Institute at UC Davis. One hundred patients will be followed every 2 years at the MIND Institute, and an additional 20 patients with FXTAS will be seen at La Trobe University in Australia to replicate and validate the findings at the MIND. We will quantify the progression of FXTAS through repetitive assessment of specific clinical measures, including neurological/motor, psychiatric, cognitive, event related potentials (ERP), eye-tracking studies, and MRI/DTI measures. In addition, we will document the molecular/biochemical markers for each stage of FXTAS and correlate these markers with the rate of progression in the clinical domains, including MRI/DTI imaging. We will also identify comorbid conditions or diagnoses that occur with FXTAS, such as autoimmune disease, Parkinsonian features, substance abuse, hypertension, and diabetes; we will evaluate whether these co- morbid conditions affect the progression of FXTAS. We will document the variability of FXTAS progression across domains. We will assess whether females progress more slowly than males with FXTAS, even for those at higher risk for immune-mediated disorders. We plan to develop molecular and biochemical markers of progression and quantitative clinical measures that can be utilized for outcome measures in future clinical trials of treatment of FXTAS. The biochemical/molecular markers will include measures of mitochondrial dysfunction, oxidative stress, reactive oxygen species, ASFMR1 isoforms, activation ratio, CGG repeats, AGG anchors, and long non-coding RNAs. In an exploratory aim, we will try to detect FMRpolyG protein in tissues, including fibroblasts, lymphocytes, and other tissues that are collected during the course of clinical care, as well as in the brains that are available for collection after death. We will also assess lifestyle factors such as obesity, exercise, and alcohol and drug abuse that may affect the progression of FXTAS.