Brain Advance Access originally published online on December 5, 2005
Brain 2006 129(1):243-255; doi:10.1093/brain/awh683
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Neuropathology of fragile X-associated tremor/ataxia syndrome (FXTAS)
Departments of 1 Pathology, 2 Radiology, 3 Psychiatry and Behavioral Sciences, 4 Pediatrics and 5 MIND Institute, University of California, Davis, Medical Center, Sacramento, CA, 6 Departments of Neurosurgery and 7 Biochemistry and Molecular Medicine, University of California, Davis, School of Medicine, Davis, CA, Departments of 8 Medicine and 9 Neurology, University of Colorado Health Sciences Center, Denver, CO, 10 Children's Hospital of Orange County Research Institute, Orange, CA and 11 Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
Correspondence to: Paul J. Hagerman, MD, PhD, Department of Biochemistry and Molecular Medicine, University of California, Davis, School of Medicine, One Shields Avenue, Davis, CA, USA E-mail: pjhagerman{at}ucdavis.edu
Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder that affects carriers, principally males, of premutation alleles (55–200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. Clinical features of FXTAS include progressive intention tremor and gait ataxia, accompanied by characteristic white matter abnormalities on MRI. The neuropathological hallmark of FXTAS is an intranuclear inclusion, present in both neurons and astrocytes throughout the CNS. Prior to the current work, the nature of the associations between inclusion loads and molecular measures (e.g. CGG repeat) was not defined. Post-mortem brain and spinal cord tissue has been examined for gross and microscopic pathology in a series of 11 FXTAS cases (males, age 67–87 years at the time of death). Quantitative counts of inclusion numbers were performed in various brain regions in both neurons and astrocytes. Inclusion counts were compared with specific molecular (CGG repeat, FMR1 mRNA level) and clinical (age of onset, age of death) parameters. In the current series, the three most prominent neuropathological characteristics are (i) significant cerebral and cerebellar white matter disease, (ii) associated astrocytic pathology with dramatically enlarged inclusion-bearing astrocytes prominent in cerebral white matter and (iii) the presence of intranuclear inclusions in both brain and spinal cord. The pattern of white matter pathology is distinct from that associated with hypertensive vascular disease and other diseases of white matter. Spongiosis was present in the middle cerebellar peduncles in seven of the eight cases in which those tissues were available for study. There is inclusion formation in cranial nerve nucleus XII and in autonomic neurons of the spinal cord. The most striking finding is the highly significant association between the number of CGG repeats and the numbers of intranuclear inclusions in both neurons and astrocytes, indicating that the CGG repeat is a powerful predictor of neurological involvement in males, both clinically (age of death) and neuropathologically (number of inclusions).
Key Words: trinucleotide repeat; dementia; RNA toxicity; Parkinson; FMR1
Abbreviations: FXTAS = fragile X-associated tremor/ataxia syndrome; GFAP = glial fibrillary acidic protein; MCPs = middle cerebellar peduncles; ROIs = regions of interest
Received July 14, 2005. Revised October 5, 2005. Accepted October 6, 2005.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  A. L. Ludwig, C. Raske, F. Tassone, D. Garcia-Arocena, J. W. Hershey, and P. J. Hagerman Translation of the FMR1 mRNA is not influenced by AGG interruptions Nucleic Acids Res., September 14, 2009; (2009) gkp713v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 C. M. Greco, F. Tassone, D. Garcia-Arocena, N. Tartaglia, S. M. Coffey, T. K. Vartanian, J. A. Brunberg, P. J. Hagerman, and R. J. Hagerman Clinical and Neuropathologic Findings in a Woman With the FMR1 Premutation and Multiple Sclerosis Arch Neurol, August 1, 2008; 65(8): 1114 - 1116. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E G Allen, J Juncos, R Letz, M Rusin, D Hamilton, G Novak, L Shubeck, S W Tinker, and S L Sherman Detection of early FXTAS motor symptoms using the CATSYS computerised neuromotor test battery J. Med. Genet., May 1, 2008; 45(5): 290 - 297. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Leehey, E. Berry-Kravis, C. G. Goetz, L. Zhang, D. A. Hall, L. Li, C. D. Rice, R. Lara, J. Cogswell, A. Reynolds, et al. FMR1 CGG repeat length predicts motor dysfunction in premutation carriers Neurology, April 15, 2008; 70(16_Part_2): 1397 - 1402. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Soontarapornchai, R. Maselli, G. Fenton-Farrell, F. Tassone, P. J. Hagerman, D. Hessl, and R. J. Hagerman Abnormal Nerve Conduction Features in Fragile X Premutation Carriers Arch Neurol, April 1, 2008; 65(4): 495 - 498. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Amiri, R. J. Hagerman, and P. J. Hagerman Fragile X Associated Tremor/Ataxia Syndrome: An Aging Face of the Fragile X Gene Arch Neurol, January 1, 2008; 65(1): 19 - 25. [Full Text] [PDF]
|
|
|
|
|
|
P. D. Ladd, L. E. Smith, N. A. Rabaia, J. M. Moore, S. A. Georges, R. S. Hansen, R. J. Hagerman, F. Tassone, S. J. Tapscott, and G. N. Filippova An antisense transcript spanning the CGG repeat region of FMR1 is upregulated in premutation carriers but silenced in full mutation individuals Hum. Mol. Genet., December 15, 2007; 16(24): 3174 - 3187. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Adams, P. E. Adams, D. Nguyen, J. A. Brunberg, F. Tassone, W. Zhang, K. Koldewyn, S. M. Rivera, J. Grigsby, L. Zhang, et al. Volumetric brain changes in females with fragile X-associated tremor/ataxia syndrome (FXTAS) Neurology, August 28, 2007; 69(9): 851 - 859. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Kraff, H.-T. Tang, R. Cilia, M. Canesi, G. Pezzoli, S. Goldwurm, P. J. Hagerman, and F. Tassone Screen for Excess FMR1 Premutation Alleles Among Males With Parkinsonism Arch Neurol, July 1, 2007; 64(7): 1002 - 1006. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Tassone, A. Beilina, C. Carosi, S. Albertosi, C. Bagni, L. Li, K. Glover, D. Bentley, and P. J. Hagerman Elevated FMR1 mRNA in premutation carriers is due to increased transcription RNA, April 1, 2007; 13(4): 555 - 562. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Ginestroni, L. Guerrini, R. D. Nave, C. Tessa, E. Cellini, M.T. Dotti, P. Brunori, N. De Stefano, S. Piacentini, and M. Mascalchi Morphometry and 1H-MR Spectroscopy of the Brain Stem and Cerebellum in Three Patients with Fragile X-Associated Tremor/Ataxia Syndrome AJNR Am. J. Neuroradiol., March 1, 2007; 28(3): 486 - 488. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Hessl, S. Rivera, K. Koldewyn, L. Cordeiro, J. Adams, F. Tassone, P. J. Hagerman, and R. J. Hagerman Amygdala dysfunction in men with the fragile X premutation Brain, February 1, 2007; 130(2): 404 - 416. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Grandfathers of Fragile X Boys Need Evaluation Journal Watch Pediatrics and Adolescent Medicine, November 1, 2006; 2006(1101): 4 - 4. [Full Text]
|
|
|
|
|
|
S. Cohen, K. Masyn, J. Adams, D. Hessl, S. Rivera, F. Tassone, J. Brunberg, C. DeCarli, L. Zhang, J. Cogswell, et al. Molecular and imaging correlates of the fragile X-associated tremor/ataxia syndrome Neurology, October 24, 2006; 67(8): 1426 - 1431. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. Osborne and C. A. Thornton RNA-dominant diseases Hum. Mol. Genet., October 15, 2006; 15(suppl_2): R162 - R169. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Davenport Shaky older men (and now women) Practical Neurology, October 1, 2006; 6(5): 314 - 317. [Full Text] [PDF]
|
|
|
|
|
|
S. Jacquemont, M. A Leehey, R. J Hagerman, L. A Beckett, and P. J Hagerman Size bias of fragile X premutation alleles in late-onset movement disorders J. Med. Genet., October 1, 2006; 43(10): 804 - 809. [Abstract] [Full Text] [PDF]
|
|