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From the Department of Neurology, University of Colorado at Denver and Health Sciences Center, Denver, CO (M.A.L., D.A.H.); Neurological Sciences, Pediatrics and Biochemistry, RUSH University Medical Center, Chicago, IL (E.B-K., R.L.); Neurological Sciences, RUSH University Medical Center, Chicago, IL (C.G.G.); Department of Neurology, University of California at Davis Medical Center, Sacramento, CA (L.Z.); Department of Statistics, North Carolina State University, Raleigh, NC (L.L.); Department of Pediatrics, University of Colorado at Denver and Health Sciences Center, Denver, CO (C.D.R., A.R.); Department of Pediatrics, University of California at Davis Medical Center and the M.I.N.D. Institute, Sacramento, CA (J.C., L.G., R.J.H.); Service de Génétique, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland (S.J.); Department of Biochemistry and Molecular Medicine, University of California at Davis School of Medicine, Davis, CA (F.T., P.J.H.); Department of Medicine, University of Colorado at Denver and Health Sciences Center, Denver, CO (J.G.).
* To whom correspondence should be addressed. E-mail: maureen.leehey{at}uchsc.edu.
ABSTRACT
Background: Fragile X–associated tremor/ataxia syndrome (FXTAS) is a recently described, underrecognized neurodegenerative disorder of aging fragile X mental retardation 1 (FMR1) premutation carriers, particularly men. Core motor features are action tremor, gait ataxia, and parkinsonism. Carriers have expanded CGG repeats (55 to 200); larger expansions cause fragile X syndrome, the most common heritable cause of mental retardation and autism. This study determines whether CGG repeat length correlates with severity and type of motor dysfunction in premutation carriers.
Methods: Persons aged 
50 years with a family history of fragile X syndrome underwent structured videotaping. Movement disorder neurologists, blinded to carrier status, scored the tapes using modified standardized rating scales. CGG repeat length analyses for women incorporated the activation ratio, which measures the percentage of normal active chromosome X alleles.
Results: Male carriers (n = 54) had significantly worse total motor scores, especially in tremor and ataxia, than age-matched male noncarriers (n = 51). There was a trend toward a difference between women carriers (n = 82) and noncarriers (n = 39). In men, increasing CGG repeat correlated with greater impairment in all motor signs. In women, when activation ratio was considered, increasing CGG correlated with greater ataxia.
Conclusions: CGG repeat size is significantly associated with overall motor impairment in premutation carriers. Whereas this association is most pronounced for men and covers overall motor impairment—tremor, ataxia, and parkinsonism—the association exists for ataxia among women carriers. This is the first report of a significant correlation between the premutation status and a motor feature of fragile X–associated tremor/ataxia syndrome in women.
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  D. B. Bailey Jr, M. Raspa, E. Bishop, and D. Holiday No Change in the Age of Diagnosis for Fragile X Syndrome: Findings From a National Parent Survey Pediatrics, August 1, 2009; 124(2): 527 - 533. [Abstract] [Full Text] [PDF]
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 V. Hashem, J. N. Galloway, M. Mori, R. Willemsen, B. A. Oostra, R. Paylor, and D. L. Nelson Ectopic expression of CGG containing mRNA is neurotoxic in mammals Hum. Mol. Genet., July 1, 2009; 18(13): 2443 - 2451. [Abstract] [Full Text] [PDF]
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