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.

Public Health Relevance

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by the FMR1 gene premutation. The disease course is variable, and there are no targeted treatments for FXTAS. We will follow over 100 patients with FXTAS ages 55 to 75 in a prospective study to develop innovative clinical measures and biological markers for each stage of the disease so that these biomarkers can be utilized as outcome measures for future clinical trials of FXTAS.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD036071-22
Application #
9925821
Study Section
Child Psychopathology and Developmental Disabilities Study Section (CPDD)
Program Officer
King, Tracy
Project Start
1998-06-15
Project End
2022-02-28
Budget Start
2020-03-01
Budget End
2021-02-28
Support Year
22
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California Davis
Department
Pediatrics
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Wang, Xiao-Hong; Yang, Jin-Chen; Soohoo, Robert et al. (2018) Cognitive Deficits and Associated ERP N400 Abnormalities in FXTAS With Parkinsonism. Front Genet 9:327
Ligsay, Andrew; El-Deeb, Marwa; Salcedo-Arellano, Maria J et al. (2018) General Anesthetic Use in Fragile X Spectrum Disorders. J Neurosurg Anesthesiol :
Martínez Cerdeño, Verónica; Hong, Tiffany; Amina, Sarwat et al. (2018) Microglial cell activation and senescence are characteristic of the pathology FXTAS. Mov Disord :
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Shickman, Ryan; Famula, Jessica; Tassone, Flora et al. (2018) Age- and CGG repeat-related slowing of manual movement in fragile X carriers: A prodrome of fragile X-associated tremor ataxia syndrome? Mov Disord 33:628-636
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Jiraanont, Poonnada; Sweha, Stefan R; AlOlaby, Reem R et al. (2017) Clinical and molecular correlates in fragile X premutation females. eNeurologicalSci 7:49-56

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