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From the Departments of Human Development (S.C, K.M.), Pediatrics (S.C., J.A., R.H.), Psychiatry (D.H.), Psychology (S.R.), Biochemistry and Molecular Medicine (F.T., P.J.H.), Radiology (J.B.), and Neurology (C.D.C., L.Z.) and MIND Institute (S.C., J.A., D.H., S.R., J.C., R.H.), University of California at Davis Medical Center, Sacramento, and Departments of Neurology (M.L.) and Medicine (J.G.), University of Colorado Health Sciences Center, Denver; and School of Psychological Sciences (D.L.), La Trobe University, Melbourne, Australia.
Address correspondence and reprint requests to Dr. R. Hagerman, MIND Institute, University of California–Davis Medical Center, 2825 50 St., Sacramento, CA 95817; e-mail: randi.hagerman{at}ucdmc.ucdavis.edu
Objectives: To assess changes in regional brain volumes associated with the fragile X–associated tremor/ataxia syndrome (FXTAS) and the molecular correlates of these changes.
Methods: We administered molecular, MRI, and neurocognitive tests to 36 male premutation carriers (ages 51 to 79), 25 affected and 11 unaffected with FXTAS, and to 21 control subjects of similar age and education.
Results: We found differences among the three groups in whole brain, cerebrum, cerebellum, ventricular volume, and whole-brain white matter hyperintensity, with the affected group showing significantly more pathology than the control and unaffected groups. Brainstem volume was significantly smaller in the unaffected group vs controls but did not differ from the affected group. Within the premutation sample, CGG repeat length correlated with reductions in IQ and cerebellar volume and increased ventricular volume and whole-brain white matter hyperintensity.
Conclusions: The current findings, coupled with recent evidence linking the degree of neuropathology (numbers of intranuclear inclusions) to the size of the premutation allele, provide evidence that the neurodegenerative phenotype in the fragile X–associated tremor/ataxia syndrome is a consequence of the CGG repeat expansion.
Supported by National Institute of Child Health and Development grants HD36071 and HD02274, National Institute of Neurological Disorders and Stroke grants NS044299 and NS43532, National Institute of Aging grant P30 AG10129, the Alzheimer Disease Center, the IDeA Laboratory, and the MIND Institute.
Disclosure: The authors report no conflicts of interest.
Received November 28, 2005. Accepted in final form June 14, 2006.
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