FXTAS
Action Tremor and Dementia in Male Carriers of Fragile X
Funded by: National Institute of Neurological Disorders and Stroke
Project Period: 9/03 - 6/08
Abstract
Objective: To define the clinical features of Fragile X-associated
tremor-ataxia syndrome (FXTAS), a progressive neurologic disorder consisting of intention
tremor, ataxia, and dementia, with generalized brain atrophy and inclusion bodies, among
older men. Fragile X syndrome (FXS) is a developmental disorder involving a trinucleotide
repeat expansion (CGG) in the fragile X mental retardation 1 gene (FMR1). The full
mutation is associated with methylation, transcriptional silencing, and mental retardation
among males, and milder cognitive impairment among females. Carriers of the FXS gene are
said to possess the premutation, a smaller trinucleotide expansion (55 to 200 CGG repeats).
Recent data suggest that carriers may have subtle cognitive and affective developmental
anomalies.
Methods: We are comparing a sample of males with FXTAS to an age-
and education-matched sample of FXS carrier males without signs of neurologic disorder,
and a matched group of healthy controls (n = 40 per group). The measures used include a
standardized neurologic evaluation, comprehensive neuropsychological examination, functional
assessment, brain MRI (with volumetric analyses), and genetic studies (CGG repeats, FMR1
mRNA level, and level of the FMR1 protein [FMRP]). Data are collected at baseline, and
at 18- and 36-month follow-ups. Analyses will include between-groups comparisons on the
neurologic, neuropsychological, and volumetric measures, as well as repeated measures
analyses across the three time points, in order to obtain a thorough picture of the clinical
features and intermediate-term trajectory of the disorder.
Potential Impact of the Research: Our research over the past four years
suggests that a subgroup of adult males with the premutation develop a neurologic disorder
resembling some of the spinocerebellar ataxias. It is first clinically apparent when they
are in their 50s or 60s, and is characterized by action tremor and other motor findings,
dementia, and generalized brain atrophy. The prevalence of this disorder has not been
definitively established, but our data suggest it is common enough that it represents an
important public health problem. The results of this study will provide important
information on the clinical features of this previously unknown disorder, including its
rate of progression and relationship to the FXS premutation. Further knowledge of the
nature of the phenotype, and of its association with the FMR1 gene, is of substantial
clinical importance for the differential diagnosis, management, and appropriate treatment
of movement disorders. To date, we have enrolled and examined approximately 30 subjects.
There are insufficient data to conduct a formal analysis, but a review of findings to date
suggests that FXTAS subjects enrolled so far show a phenotype consistent with our prior
research.
Key Staff: Grigsby, Bennett, Bounds, Brega, Hall, Leehey, Rubinstein
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