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Size bias of fragile X premutation alleles in late-onset movement disorders
  1. Sebastien Jacquemont1,
  2. Maureen A Leehey2,
  3. Randi J Hagerman3,
  4. Laurel A Beckett4,
  5. Paul J Hagerman5
  1. 1Service de Génétique, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
  2. 2Department of Neurology, University of Colorado at Denver Health Sciences Center, Denver, Colorado, USA
  3. 3MIND Institute and Department of Pediatrics, University of California Davis Medical Center, Sacramento, California, USA
  4. 4Department of Public Health Sciences, University of California, Davis, California
  5. 5Department of Biochemistry and Molecular Medicine, School of Medicine, University of California
  1. Correspondence to:
 P J Hagerman
 Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, 4303 Tupper Hall, One Shields Avenue, Davis, CA 95616, USA;pjhagerman{at}


Background: Fragile X-associated tremor/ataxia syndrome (FXTAS), caused by premutation expansions (55–200 CGG repeats) of the FMR1 gene, shares clinical features with other movement disorders, particularly in the domains of gait ataxia, intention tremor and parkinsonism. However, the prevalence of FXTAS within other diagnostic categories is not well defined.

Methods: A meta-analysis was conducted of all published (n = 14) genetic screens for expanded FMR1 alleles to assess the prevalence and CGG-repeat size bias of FMR1 premutation alleles in those populations.

Results: In men with late-onset cerebellar ataxia, the prevalence of premutation alleles (1.5%; 16/1049) was 13 times greater than expected based on its prevalence in the general population (2%; 16/818 for age of onset >50 years; odds ratio 12.4; 95% confidence interval 1.6 to 93.5). Meta-analysis of CGG-repeat data for screened patients with premutation alleles shows a shift to larger repeat size than in the general population (p<0.001). 86% (19/22) of premutation alleles were larger than 70 repeats in the patients screened, whereas only approximately 22% of premutation alleles are larger than 70 repeats in the general population.

Conclusions: Expanded FMR1 alleles contribute to cases of late-onset sporadic cerebellar ataxia, suggesting that FMR1 genetic testing should be carried out in such cases. The biased distribution of FMR1 allele sizes has substantial implications for genetic counselling of carriers with smaller alleles who are at a low risk of developing FXTAS, and suggests that the estimated prevalence of FXTAS among men >50 years of age in the general population may be two to threefold lower than the initial figure of 1 in 3000.

  • FXTAS, fragile X-associated tremor/ataxia syndrome
  • MCP, middle cerebellar peduncle
  • MRI, magnetic resonance imaging
  • MSA, multiple system atrophy
  • tremor
  • ataxia
  • parkinsonism
  • RNA toxicity
  • dementia

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  • Published Online First 24 May 2006

  • This work was funded by grants from the National Institute of Neurological Disorders and Stroke (NS43532; PJH) and the National Institute of Child Health and Development (HD36071; RJH). This work was also supported by the Boory Family Fund and by general support from the UC Davis MIND Institute.

  • Competing interests: None.