# Genotype-Phenotype Relationships in Fragile X Families

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2023 · $649,652

## Abstract

PROJECT SUMMARY
The neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS), initially described by
us in 2001, is still considered a male-dominant disorder, with the second, normal X chromosome in females
diminishing neuronal toxicity of the premutation (55 to 200 CGG repeats). Women with FXTAS do have lower
penetrance and less severe tremor and ataxia compared to men; however, against expectations for an X-
linked disorder, females with FXTAS have the preponderance of neuropsychiatric problems, which include pain
symptoms and anxiety, and immune/inflammatory involvement. Our principal objective for the next project
period is to characterize the preFXTAS and FXTAS phenotypes in women compared to men and to assess the
role of neuropsychiatric and autoimmune problems and their molecular underpinnings in the initiation and
progression of FXTAS. Our central hypothesis is that the RNA-toxicity mechanism that underlies the male-
predominant motor dysfunction in FXTAS also drives the well-known susceptibility of females to develop both
psychiatric and immune-related problems. We hypothesize that RNA toxicity and consequent enhanced
reactive oxygen species (ROS) generation are likely to amplify the intrinsic pro-inflammatory state in females,
particularly in those females with pain, where IL6 and TNFα are generally enhanced. During the proposed
project period, we will assess the role of autoimmune, neuropsychiatric, and pain disorders in women with
preFXTAS and FXTAS and determine how this relates to the development and progression of FXTAS. The
clinical phenotype including MRI studies will be assessed under Aim 1. The molecular aspects of these
mechanisms will be addressed under Aim 2. Under Aim 3, we will carry out a detailed correlation analysis of
the interrelationship between the clinical features, their possible molecular underpinnings, and their roles on
rates of progression and severity of FXTAS in males and females. In addition, under Aim 3, we will provide an
initial assessment of the relationship between the clinical features of FXTAS and comorbid conditions, such as
parkinsonism, that are common in carriers. Thus, our ongoing Genotype-Phenotype project will continue to
follow the largest known clinical cohort of premutation carriers with FXTAS, focusing particularly on females for
whom knowledge of phenotypes is more limited. Progression will be assessed every two years through
evaluation of various clinical domains, including medical and neurological testing, quantitative motor testing of
tremor and ataxia, neuropsychological testing of executive function and memory, psychiatric evaluation, and
MRI studies. For each of these clinical domains, progression of symptoms and pathology are quantified; our
preliminary data show that while males progress twice as fast as females in motor dysfunction, females have
twice the penetrance of psychopathology and progress faster in anxiety and depression. Such data will lead to
a b...

## Key facts

- **NIH application ID:** 10585568
- **Project number:** 2R01HD036071-24A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** PAUL J HAGERMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $649,652
- **Award type:** 2
- **Project period:** 1998-06-15 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10585568

## Citation

> US National Institutes of Health, RePORTER application 10585568, Genotype-Phenotype Relationships in Fragile X Families (2R01HD036071-24A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10585568. Licensed CC0.

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