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Volumetric brain changes in females with fragile X-associated tremor/ataxia syndrome (FXTAS)

From the M.I.N.D. Institute (J.S.A., P.E.A., K.K., S.M.R., P.J.H., R.J.H.) and the Department of Pediatrics (J.S.A., R.J.H.), Public Health Sciences, Division of Biostatistics (D.N.), Radiology (J.A.B.), Biochemistry and Molecular Medicine (F.T., W.Z., P.J.H.), Neuroscience (K.K.), Psychology (S.M.R.), and Neurology (C.D., L.Z.), University of California, Davis, CA; and the Department of Medicine, University of Colorado at Denver and Health Sciences Center, Denver, CO (J.G.).

Address correspondence and reprint requests to Dr. Randi Hagerman, M.I.N.D. Institute, University of California–Davis Medical Center, 2825 50th Street, Sacramento, CA 95817 randi.hagerman{at}ucdmcucdavis.edu

Background: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder occurring in male and rare female carriers of a premutation expansion (55 to 200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene.

Methods: Volumetric MRI studies, clinical staging, cognitive testing, and molecular analysis were conducted in 15 female premutation carriers affected by FXTAS (age 59.5 ± 10.3 years), 20 unaffected female carriers (43.3 ± 11.2 years), 11 genetically normal female controls (51.0 ± 10.3 years), 36 affected male carriers (65.0 ± 5.6 years), 25 unaffected male carriers (53.5 ± 12.5 years), and 39 male controls (58.0 ± 15.0 years). Female and male carriers with FXTAS were matched on duration of disease.

Results: We found less pronounced reductions of cerebellar volume and a lower incidence of involvement (symmetric high T2 signal) of the middle cerebellar peduncles (MCP sign) in females affected by FXTAS (13%) compared with affected males (58%). We found reduced brain volumes and increased white matter disease associated with the presence of FXTAS in females compared with female controls. We also observed significant associations between reduced cerebellar volume and both increased severity of FXTAS symptoms and increased length of the CGG repeat expansion in male premutation carriers, but not in females.

Conclusions: Females affected by fragile X-associated tremor/ataxia syndrome (FXTAS) demonstrated milder brain changes than affected males, although they showed a similar pattern of radiologic findings consistent with brain atrophy and white matter disease. FXTAS should be considered (by ordering fragile X DNA testing) in females who present with late-onset ataxia, action tremor, or neuropathy, particularly in those with a family history of mental retardation, autism, or premature ovarian failure.

Supported by National Institute of Child Health and Development grants HD036071 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 Centers for Disease Control and Prevention, the IDeA Laboratory, and the M.I.N.D. Institute.

Disclosure: The authors report no conflicts of interest.

Received December 4, 2006. Accepted in final form March 27, 2007.