The Fragile X-Associated Tremor Ataxia Syndrome (FXTAS)

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Genotype/Phenotype Relationships in FXTAS

  • Emily AllenAffiliated withDepartment of Human Genetics, Emory University School of Medicine Email author 
  • , Maureen A. LeeheyAffiliated withDepartment of Neurology, University of Colorado at Denver and Health Sciences Center
  • , Flora TassoneAffiliated withDepartment of Biochemistry and Molecular Medicine, School of Medicine, University of California
  • , Stephanie ShermanAffiliated withDepartment of Human Genetics, Emory University School of Medicine

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In this chapter we explore the effects of molecular measures of the FMR1 gene on clinical, cognitive, radiological, and pathological phenotypes associated with fragile X-associated tremor/ataxia syndrome (FXTAS). In addition to reviewing the FXTAS phenotype, we will also present methods that have been developed for quantifying severity of FXTAS symptoms, including development and use of the FXTAS rating scale, the neuropathy screening scale, and use of the CATSYS system to assess early, prodromal symptoms. In our review of phenotypic features, we focus primarily on studies in which findings were correlated with FMR1 molecular measures. The phenotypes considered include (1) clinical neurological measures, (2) cognitive measures with a focus on executive function, (3) psychiatric phenotypes, (4) radiological outcomes, and (5) pathological measures. Because women are more mildly affected than men and may, in fact, have a different presentation, we will review FXTAS among men and women separately. Overall, our goal in this chapter is to begin to define alleles that are “at risk” for FXTAS. Based on this review, it is clear that there is a strong correlation of the increasing risk for FXTAS with increasing repeat size. However, much work needs to be done to further define the properties of the CGG repeat sequence that contribute to increased risk and severity of symptoms of FXTAS among men and women.