Radiological Findings in FXTAS

  • Susan M. Rivera
  • Glenn T. Stebbins
  • Jim Grigsby


In this chapter we review the radiological and structural brain findings associated with fragile X-associated tremor/ataxia syndrome (FXTAS). We will review what is currently known about radiological signs of the disorder including both white matter lesions and mild to severe cortical loss. We will also review brain–molecular relationships in FXTAS including associations that have been observed between cortical and white matter changes and molecular variables such as CGG repeat length. Similarly, we will review relationships that have been reported between brain abnormalities and the neuropsychological phenotype in FXTAS (which includes working memory, executive functioning, and information processing deficits). Lastly, we will review recent findings on both the integrity of white matter tracts in the brain (using diffusion tensor imaging) and in vivo brain function (using functional magnetic resonance imaging) in individuals with the FX premutation with and without FXTAS. While much knowledge has been gained about the neuropathology of FXTAS, future work will focus on continuing our understanding of the developmental time course of this pathogenesis as well as searching for brain biomarkers of the disease in asymptomatic premutation carriers.


White Matter Fractional Anisotropy Diffusion Tensor Imaging White Matter Integrity Cerebellar Volume 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was partially supported by NINDS grant NS044299 [JG].


  1. Adams, J. S., Adams, P. E., Nguyen, D. et al. 2007. Volumetric brain changes in females with fragile X-associated tremor/ataxia syndrome (FXTAS). Neurology 69: 851–859.PubMedCrossRefGoogle Scholar
  2. Arocena, D. G., Iwahashi, C. K., Won, N. et al. 2005. Induction of inclusion formation and disruption of lamin A/C structure by premutation CGG-repeat RNA in human cultured neural cells. Hum Mol Genet 14: 3661–3671.PubMedCrossRefGoogle Scholar
  3. Basser PJ, Mattiello J, Le Bihan D. (1994). MR diffusion tensor spectroscopy and imaging. Biophysical Journal, 66, 259–267.Google Scholar
  4. Basser, P. J., Pierpaoli, C. 1996. Microstructural and physiological features of tissues elucidated by quantitative-diffusion-tensor MRI. J Magn Reson B 111: 209–219.PubMedCrossRefGoogle Scholar
  5. Brega, A. G., Goodrich, G., Bennett, R. E. et al. 2008. The primary cognitive deficit among males with fragile X-associated tremor/ataxia syndrome (FXTAS) is a dysexecutive syndrome. J Clin Exp Neuropsychol 15: 1–17.Google Scholar
  6. Brunberg, J., Jaquemont, S., Hagerman, R. J. et al. 2002. Fragile X premutation carriers: characteristic MR imaging findings in adult male patients with progressive cerebellar and cognitive dysfunction. Am J Neuroradiol 23: 1757–1766.PubMedGoogle Scholar
  7. Cabeza, R., Nyberg, L. 2000. Neural bases of learning and memory: functional neuroimaging evidence. Curr Opin Neurol 13: 415–421.PubMedCrossRefGoogle Scholar
  8. Capelli, L. P., Goncalves, M. R., Kok, F. et al. 2007. Fragile X-associated tremor/ataxia syndrome: intrafamilial variability and the size of the FMR1 premutation CGG repeat. Mov Disord 22: 866–870.PubMedCrossRefGoogle Scholar
  9. Cohen, S., Masyn, K., Adams, J. et al. 2006. Molecular and imaging correlates of the fragile X-associated tremor/ataxia syndrome. Neurology 67: 1426–1431.PubMedCrossRefGoogle Scholar
  10. Fuster, J. 2008. The prefrontal cortex, 4th ed. London: Academic Press.Google Scholar
  11. Greco, C. M., Berman, R. F., Martin, R. M. et al. 2006. Neuropathology of fragile X-associated tremor/ataxia syndrome (FXTAS). Brain 129: 243–255.PubMedCrossRefGoogle Scholar
  12. Greco, C. M., Hagerman, R. J., Tassone, F. et al. 2002. Neuronal intranuclear inclusions in a new cerebellar tremor/ataxia syndrome among fragile X carriers. Brain 125: 1760–1771.PubMedCrossRefGoogle Scholar
  13. Grigsby, J., Brega, A. G., Engle, K. et al. 2008. Cognitive profile of fragile X premutation carriers with and without fragile X-associated tremor/ataxia syndrome. Neuropsychology 22: 48–60.PubMedCrossRefGoogle Scholar
  14. Grigsby, J., Brega, A. G., Jacquemont, S. et al. 2006. Impairment in the cognitive functioning of men with fragile X-associated tremor/ataxia syndrome (FXTAS). J Neurol Sci 248: 227–233.PubMedCrossRefGoogle Scholar
  15. Grigsby, J., Brega, A. G., Leehey, M. A. et al. 2007. Impairment of executive cognitive functioning in males with fragile X-associated tremor/ataxia syndrome. Mov Disord 22: 645–650.PubMedCrossRefGoogle Scholar
  16. Grigsby, J., Leehey, M. A., Jacquemont, S. et al. 2006. Cognitive impairment in a 65-year-old male with the fragile X-associated tremor-ataxia syndrome (FXTAS). Cogn Behav Neurol 19: 165–171.PubMedCrossRefGoogle Scholar
  17. Hallett, M., Grafman, J. 1997. Executive functioning and motor skill learning, in the cerebellum and cognition, Vol. 41. San Diego, CA: Academic Press, pp. 297–323.Google Scholar
  18. Hashimoto, R., Backer, K., Koldewyn, K. et al. An fMRI Study of the Prefrontal Activity during the Performance of a Working Memory Task in Premutation Carriers of the Fragile X Mental Retardation-1 Gene With and Without Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS).Google Scholar
  19. Iwahashi, C. K., Yasui, D. H., An, H. J. et al. 2006. Protein composition of the intranuclear inclusions of FXTAS. Brain 129: 256–271.PubMedCrossRefGoogle Scholar
  20. Jacquemont, S. 2005. Screening for FXTAS. Eur J Hum Genet 13: 2–3.PubMedCrossRefGoogle Scholar
  21. Jacquemont, S., Farzin, F., Hall, D. et al. 2004. Aging in individuals with the FMR1 mutation. Am J Ment Retard 109: 154–164.PubMedCrossRefGoogle Scholar
  22. Jacquemont, S., Hagerman, R. J., Leehey, M. et al. 2003. Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates. Am J Hum Genet 72: 869–878.PubMedCrossRefGoogle Scholar
  23. Leehey, L. M., Munhoz, R. P., Lang, A. E. et al. 2003. The fragile X premutation presenting as essential tremor. Arch Neurol 60: 117–121.PubMedCrossRefGoogle Scholar
  24. Leiner, H. C., Leiner, A. L., Dow, R. S. 1993. Cognitive and language functions of the human cerebellum. Trends Neurosci 16: 444–447.PubMedCrossRefGoogle Scholar
  25. Loesch, D. Z., Cook, M., Litewka, L. et al. 2008. A low symptomatic form of neurodegeneration in younger carriers of the FMR1 premutation, manifesting typical radiological changes. J Med Genet 45: 179–181.PubMedCrossRefGoogle Scholar
  26. Loesch, D. Z., Litewka, L., Brotchie, P. et al. 2005. Magnetic resonance imaging study in older fragile X premutation male carriers. Ann Neurol 58: 326–330.PubMedCrossRefGoogle Scholar
  27. Louis, E., Moskowitz, C., Friez, M. et al. 2006. Parkinsonism, dysautonomia, and intranuclear inclusions in a fragile X carrier: a clinical-pathological study. Mov Disord 21: 420–425.PubMedCrossRefGoogle Scholar
  28. Middleton, F. A., Strick, P. L. 1997. New concepts about the organization of basal ganglia output, in the basal ganglia and new surgical approaches for Parkinson’s disease, advances in neurology. Philadelphia, PA: Lippincott-Raven, pp. 57–68.Google Scholar
  29. Moore, C. J., Daly, E. M., Tassone, F. et al. 2004. The effect of pre-mutation of X chromosome CGG trinucleotide repeats on brain anatomy. Brain 127: 2672–2681.PubMedCrossRefGoogle Scholar
  30. Ngai, S., Tang, Y. M., Du, L. et al. 2006. Hyperintensity of the middle cerebellar peduncles on fluid-attenuated inversion recovery imaging: variation with age and implications for the diagnosis of multiple system atrophy. AJNR Am J Neuroradiol 27: 2146–2148.PubMedGoogle Scholar
  31. Schmahmann, J. D. 2000. Cerebellum and brainstem, in brain mapping: the systems. San Diego, CA: Academic Press, pp. 207–259.CrossRefGoogle Scholar
  32. Storey, E., Billimoria, P. 2005. Increased T2 signal in the middle cerebellar peduncles on MRI is not specific for fragile X premutation syndrome. J Clin Neurosci 12: 42–43.PubMedCrossRefGoogle Scholar
  33. Tullberg, M., Fletcher, E., DeCarli, C. et al. 2004. White matter lesions impair frontal lobe function regardless of their location. Neurology 63: 246–253.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Susan M. Rivera
    • 1
  • Glenn T. Stebbins
    • 2
  • Jim Grigsby
    • 3
  1. 1.Department of PsychologyUC Davis Center for Mind and BrainDavisUSA
  2. 2.Department of Neurological SciencesRush University Medical CenterChicagoUSA
  3. 3.Departments of Psychology and MedicineUniversity of Colorado DenverDenverUSA

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