Skip to main content

Advertisement

SpringerLink
Log in

FXTAS: A progressive neurologic syndrome associated with fragile X premutation

  • Published:
Current Neurology and Neuroscience Reports Aims and scope Submit manuscript

Abstract

The FMR1 gene is involved in two different syndromes: Fragile X syndrome and Fragile X-associated tremor/ataxia syndrome (FXTAS). Fragile X syndrome is a childhood disease and is associated with mental retardation as the main clinical characteristic, whereas FXTAS develops in men and women over 50 years of age. FXTAS represents a new form of inclusion disorder with a high prevalence in the general population. The neurologic phenotype of FXTAS includes intention tremor and ataxia. Associated features are dementia, parkinsonism, neuropathy, and autonomic dysfunction. Elevated FMR1 transcripts have been proposed as the molecular basis of the pathogenic mechanism leading to FXTAS. This review discusses recent developments in the clinical phenotype, prevalence and screening, animal models, and molecular mechanisms of RNA-based pathogenesis in FXTAS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Fu YH, Kuhl DP, Pizzuti A, et al.: Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. Cell 1991, 67:1047–1058.

    Article  PubMed  CAS  Google Scholar 

  2. Verkerk AJ, Pieretti M, Sutcliffe JS, et al.: Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 1991, 65:905–914.

    Article  PubMed  CAS  Google Scholar 

  3. Oberlé I, Rousseau F, Heitz D, et al.: Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome. Science 1991, 252:1097–1102.

    Article  PubMed  Google Scholar 

  4. Sutcliffe JS, Nelson DL, Zhang F, et al.: DNA methylation represses FMR-1 transcription in fragile X syndrome. Hum Mol Genet 1992, 1:397–400.

    Article  PubMed  CAS  Google Scholar 

  5. Pieretti M, Zhang FP, Fu YH et al.: Absence of expression of the FMR-1 gene in fragile X syndrome. Cell 1991, 66:817–822.

    Article  PubMed  CAS  Google Scholar 

  6. Verheij C, Bakker CE, de Graaff E, et al.: Characterization and localization of the FMR-1 gene product associated with fragile X syndrome. Nature 1993, 363:722–724.

    Article  PubMed  CAS  Google Scholar 

  7. Willemsen R, Oostra BA, Bassell GJ, Dictenberg J: The fragile X syndrome: from molecular genetics to neurobiology. Ment Retard Dev Disabil Res Rev 2004, 10:60–67.

    Article  PubMed  Google Scholar 

  8. Nolin SL, Brown WT, Glicksman A, et al.: Expansion of the fragile X CGG repeat in females with premutation or intermediate alleles. Am J Hum Genet 2003, 72:454–464.

    Article  PubMed  CAS  Google Scholar 

  9. Hagerman RJ: The physical and behavioural phenotype. In Fragile-X Syndrome: Diagnosis, Treatment and Research. Edited by Hagerman RJ, Hagerman P. Baltimore: The Johns Hopkins University Press; 2002:3–109.

    Google Scholar 

  10. Hagerman RJ, Leavitt BR, Farzin F, et al.: Fragile-X-associated tremor/ataxia syndrome (FXTAS) in females with the FMR1 premutation. Am J Hum Genet 2004, 74:1051–1056. First description of five female carriers of the FMR1 PM who presented with FXTAS, including neuropathology of one patient showing the presence of intranuclear inclusions.

    Article  PubMed  CAS  Google Scholar 

  11. Sherman SL: Premature ovarian failure among fragile x premutation carriers: parent-of-origin effect? Am J Hum Genet 2000, 67:11–13.

    Article  PubMed  CAS  Google Scholar 

  12. Tassone F, Hagerman PJ: Expression of the FMR1 gene. Cytogenet Genome Res 2003, 100:124–128. Review paper summarizing the results of different studies about elevated FMR1 mRNA levels in the different groups. Dysregulation of FMR1 gene expression is discussed and the underlying molecular mechanisms are discussed.

    Article  PubMed  CAS  Google Scholar 

  13. Kenneson A, Zhang F, Hagedorn CH, Warren ST: Reduced FMRP and increased FMR1 transcription is proportionally associated with CGG repeat number in intermediate-length and premutation carriers. Hum Mol Genet 2001, 10:1449–1454.

    Article  PubMed  CAS  Google Scholar 

  14. Primerano B, Tassone F, Hagerman RJ, et al.: Reduced FMR1 mRNA translation efficiency in Fragile X patients with premutations. RNA 2002, 8:1–7.

    Article  Google Scholar 

  15. Allen EG, He W, Yadav-Shah M, Sherman SL: A study of the distributional characteristics of FMR1 transcript levels in 238 individuals. Hum Genet 2004, 114:439–447.

    Article  PubMed  CAS  Google Scholar 

  16. Hagerman PJ, Hagerman RJ: The fragile-X premutation: a maturing perspective. Am J Hum Genet 2004, 74:805-816. 17. Hagerman PJ, Hagerman RJ: Fragile X-associated tremor/ ataxia syndrome (FXTAS). Ment Retard Dev Disabil Res Rev 2004, 10:25–30.

    Article  PubMed  Google Scholar 

  17. Jacquemont S, Hagerman RJ, Leehey M, et al.: Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates. Am J Hum Genet 2003, 72:869–878. This paper describes a large series of FXTAS patients (n = 26) who were analyzed in a clinical, radiologic, and molecular manner, and diagnostic criteria were proposed to help clinicians to recognize FXTAS.

    Article  PubMed  CAS  Google Scholar 

  18. Hagerman PJ, Greco CM, Hagerman RJ: A cerebellar tremor/ ataxia syndrome among fragile X premutation carriers. Cytogenet Genome Res 2003, 100:206–212.

    Article  PubMed  CAS  Google Scholar 

  19. Hagerman RJ, Leehey M, Heinrichs W, et al.: Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology 2001, 57:127–130. This is the first reported evidence of FXTAS in PM males. Patients normally present with either intention tremor or ataxia.

    PubMed  CAS  Google Scholar 

  20. Greco CM, Hagerman RJ, Tassone F, et al.: Neuronal intranuclear inclusions in a new cerebellar tremor/ataxia syndrome among fragile X carriers. Brain 2002, 125:1760–1771. First neurohistologic report on the brains of four carriers of the PM. All cases showed intranuclear inclusions in both neurons and astroglia throughout the brain.

    Article  PubMed  CAS  Google Scholar 

  21. Brunberg JA, Jacquemont S, Hagerman RJ, et al.: Fragile X premutation carriers: characteristic mr imaging findings of adult male patients with progressive cerebellar and cognitive dysfunction. Am J Neuroradiol 2002, 23:1757–1766.

    PubMed  Google Scholar 

  22. Storey R, Billimoria P: Increased T2 signal in the middle cerebellar peduncles on MRI is not specific for fragile X premutation syndrome. J Clin Neurosci 2005, 12:42–43.

    Article  PubMed  CAS  Google Scholar 

  23. Tassone F, Hagerman RJ, Garcia-Arocena D, et al.: Intranuclear inclusions in neural cells with premutation alleles in fragile X associated tremor/ataxia syndrome. J Med Genet 2004, 41:E43.

    Article  PubMed  CAS  Google Scholar 

  24. Berry-Kravis E, Potanos K, Weinberg D, et al.: Fragile X-associated tremor/ataxia syndrome in sisters related to X-inactivation. Ann Neurol 2004, 57:144–147. This report presents data about two PM carrier sisters in whom severity of clinical signs correlated with the X-inactivation ratio. It is hypothesized that female PM carriers who predominantly express the X chromosome with the PM may demonstrate significant signs of FXTAS.

    Article  Google Scholar 

  25. Zuhlke C, Budnik A, Gehlken U, et al.: FMR1 premutation as a rare cause of late onset ataxia. Evidence for FXTAS in female carriers. J Neurol 2004, 251:1418–1419.

    Article  PubMed  Google Scholar 

  26. Dombrowski C, Levesque S, Morel ML, et al.: Premutation and intermediate-size FMR1 alleles in 10 572 males from the general population: loss of an AGG interruption is a late event in the generation of fragile X syndrome alleles. Hum Mol Genet 2002, 11:371–378.

    Article  PubMed  CAS  Google Scholar 

  27. Pesso R, Berkenstadt M, Cuckle H, et al.: Screening for fragile X syndrome in women of reproductive age. Prenat Diagnosis 2000, 20:611–614.

    Article  CAS  Google Scholar 

  28. Toledano-Alhadef H, Basel-Vanagaite L, Magal N, et al.: Fragile-X carrier screening and the prevalence of premutation and fullmutation carriers in Israel. Am J Hum Genet 2001, 69:351–360.

    Article  PubMed  CAS  Google Scholar 

  29. Jacquemont S, Hagerman RJ, Leehey MA, et al.: Penetrance of the fragile x-associated tremor/ataxia syndrome in a premutation carrier population. JAMA 2004, 291:460–469. This family-based study demonstrates that male carriers of the PM are at high risk of developing FXTAS. The penetrance of FXTAS increases with age, and calculations on the prevalence of FXTAS in the general population point to 1:3000 men aged older than 50 years.

    Article  PubMed  CAS  Google Scholar 

  30. Oostra BA, Willemsen R: A fragile balance: FMR1 expression levels. Hum Mol Genet 2003, 12(Suppl 2):R249-R257.

    Article  PubMed  CAS  Google Scholar 

  31. Ranum LP, Day JW: Pathogenic RNA repeats: an expanding role in genetic disease. Trends Genet 2004, 20:506–512.

    Article  PubMed  CAS  Google Scholar 

  32. Macpherson J, Waghorn A, Hammans S, Jacobs P: Observation of an excess of fragile-X premutations in a population of males referred with spinocerebellar ataxia. Hum Genet 2003, 112:619–620.

    PubMed  CAS  Google Scholar 

  33. Di Maria E, Grasso M, Pigullo S, et al.: Further evidence that a tremor:ataxia syndrome may occur in fragile X premutation carriers: findings from two clinical series. Am J Hum Genet 2003, S73:555.

    Google Scholar 

  34. Milunsky JM, Maher TA: Fragile X carrier screening and spinocerebellar ataxia in older males. Am J Med Genet 2004, 125A:320.

    Article  Google Scholar 

  35. Van Esch H, Dom R, Bex D, et al.: Screening for FMR-1 premutations in 122 older Flemish males presenting with ataxia. Eur J Hum Genet 2005, 13:121–123.

    Article  PubMed  Google Scholar 

  36. Brussino A, Gellera C, Saluto A, et al.: FMR1 gene premutation is a frequent genetic cause of late-onset sporadic cerebellar ataxia. Neurology 2005, 64:145–147.

    PubMed  CAS  Google Scholar 

  37. Tan EK, Zhao Y, Puong KY, et al.: Fragile X premutation alleles in SCA, ET, and parkinsonism in an Asian cohort. Neurology 2004, 63:362–363.

    PubMed  CAS  Google Scholar 

  38. Garcia Arocena D, Louis ED, Tassone F, et al.: Screen for expanded FMR1 alleles in patients with essential tremor. Mov Disord 2004, 19:930–933.

    Article  PubMed  Google Scholar 

  39. Deng H, Le W, Jankovic J: Premutation alleles associated with Parkinson disease and essential tremor. JAMA 2004, 292:1685–1686.

    Article  PubMed  CAS  Google Scholar 

  40. Tan EK, Zhao Y, Puong KY, et al.: Expanded FMR1 alleles are rare in idiopathic Parkinson’s disease. Neurogenetics 2005, 6:51–52.

    Article  PubMed  CAS  Google Scholar 

  41. Toft M, Aasly J, Bisceglio G, et al.: Parkinsonism, FXTAS, and FMR1 premutations. Mov Disord 2004, 20:230–233.

    Article  Google Scholar 

  42. Garland EM, Vnencak-Jones CL, Biaggioni I, et al.: Fragile X gene premutation in multiple system atrophy. J Neurol Sci 2000, 227:115–118.

    Article  Google Scholar 

  43. Arrasate M, Mitra S, Schweitzer ES, et al.: Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 2004, 431:805–810.

    Article  PubMed  CAS  Google Scholar 

  44. Tassone F, Iwahashi C, Hagerman PJ: FMR1 RNA within the intranuclear inclusions of fragile X-associated Tremor/Ataxia syndrome (FXTAS). RNA Biology 2004, 1:103–105.

    PubMed  CAS  Google Scholar 

  45. Davies SW, Turmaine M, Cozens BA, et al.: Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 1997, 90:537–548.

    Article  PubMed  CAS  Google Scholar 

  46. Petersen A, Larsen KE, Behr GG, et al.: Expanded CAG repeats in exon 1 of the Huntington’s disease gene stimulate dopamine-mediated striatal neuron autophagy and degeneration. Hum Mol Genet 2001, 10:1243–1254.

    Article  PubMed  CAS  Google Scholar 

  47. Taylor JP, Hardy J, Fischbeck KH: Toxic proteins in neurodegenerative disease. Science 2002, 296:1991–1995.

    Article  PubMed  CAS  Google Scholar 

  48. Bontekoe CJ, Bakker CE, Nieuwenhuizen IM, et al.: Instability of a (CGG)(98) repeat in the Fmr1 promoter. Hum Mol Genet 2001, 10:1693–1699.

    Article  PubMed  CAS  Google Scholar 

  49. Willemsen R, Hoogeveen-Westerveld M, Reis S, et al.: The FMR1 CGG repeat mouse displays ubiquitin-positive intranuclear neuronal inclusions; implications for the cerebellar tremor/ ataxia syndrome. Hum Mol Genet 2003, 12:949–959. Generation of a knock-in, expanded repeat mouse model to study the pathogenesis of FXTAS. Elevated levels of FMR1 mRNAs and ubiquitin-positive inclusions were reported, which supports a direct role of the Fmr1 gene, by either GCC expansion per se or by elevated transcript levels in the pathogenesis of FXTAS.

    Article  PubMed  CAS  Google Scholar 

  50. Van Dam D, Errijgers V, Kooy RF, et al.: Cognitive decline, neuromotor and behavioural disturbances in a mouse model for Fragile-X-associated tremor/ataxia syndrome (FXTAS). Behav Brain Res 2005, In press.

  51. Jin P, Zarnescu DC, Zhang F, et al.: RNA-mediated neurodegeneration caused by the fragile x premutation rcgg repeats in Drosophila. Neuron 2003, 39:739–747. Drosophila melanogaster was used as a model to study the pathogenesis of FXTAS using a portion of the human FMR1 5′ UTR containing the PM rCGG repeat. Both inclusions and neurodegeneration were observed, supporting evidence of RNA-mediated neurodegeneration.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical Genetics, Erasmus MC, 3000 DR, PO Box 1738, Rotterdam, The Netherlands

    Rob Willemsen PhD

Authors
  1. Rob Willemsen PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Edwin Mientjes PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ben A. Oostra PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Willemsen, R., Mientjes, E. & Oostra, B.A. FXTAS: A progressive neurologic syndrome associated with fragile X premutation. Curr Neurol Neurosci Rep 5, 405–410 (2005). https://doi.org/10.1007/s11910-005-0065-5

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11910-005-0065-5

Keywords

Search

Navigation