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Keywords:

  • neurodegeneration;
  • dementia;
  • parkinson;
  • ataxia;
  • RNA toxicity

Abstract

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurological disorder among carriers of premutation CGG-repeat expansions within the FMR1 gene. Principal features of FXTAS include progressive action tremor and gait ataxia, with associated features of parkinsonism, peripheral neuropathy, dysautonomia, and cognitive decline. Although both clinical and neuropathologic features of FXTAS are known to be highly associated with CGG repeat length, the relationship between repeat length and age-of-onset is not known. To address this issue, the ages of onset of action tremor and gait ataxia were documented by history for 93 male carriers. For this cohort, the mean ages of onset were 62.6 ± 8.1 years (range, 39–78 years) for tremor, and 63.6 ± 7.3 years (range, 47–78 years) for ataxia; the mean CGG repeat number was 88.5 ± 14 (range, 60–133). Analysis of the relationship between clinical onset and molecular measures revealed significant correlations between CGG repeat number and onset of both tremor (P = 0.001) and ataxia (P = 0.002), as well as overall onset (P < 0.0001). Our findings indicate that the CGG repeat number is a potential predictor of the age of onset of core motor features of FXTAS. © 2007 Wiley-Liss, Inc.