Genotype/Phenotype Relationships in FXTAS

  • Emily Allen
  • Maureen A. Leehey
  • Flora Tassone
  • Stephanie Sherman
Chapter

Abstract

In this chapter we explore the effects of molecular measures of the FMR1 gene on clinical, cognitive, radiological, and pathological phenotypes associated with fragile X-associated tremor/ataxia syndrome (FXTAS). In addition to reviewing the FXTAS phenotype, we will also present methods that have been developed for quantifying severity of FXTAS symptoms, including development and use of the FXTAS rating scale, the neuropathy screening scale, and use of the CATSYS system to assess early, prodromal symptoms. In our review of phenotypic features, we focus primarily on studies in which findings were correlated with FMR1 molecular measures. The phenotypes considered include (1) clinical neurological measures, (2) cognitive measures with a focus on executive function, (3) psychiatric phenotypes, (4) radiological outcomes, and (5) pathological measures. Because women are more mildly affected than men and may, in fact, have a different presentation, we will review FXTAS among men and women separately. Overall, our goal in this chapter is to begin to define alleles that are “at risk” for FXTAS. Based on this review, it is clear that there is a strong correlation of the increasing risk for FXTAS with increasing repeat size. However, much work needs to be done to further define the properties of the CGG repeat sequence that contribute to increased risk and severity of symptoms of FXTAS among men and women.

References

  1. Adams, J. S., Adams, P. E. et al. 2007. Volumetric brain changes in females with fragile X-associated tremor/ataxia syndrome (FXTAS). Neurology 69(9): 851–859.PubMedCrossRefGoogle Scholar
  2. Aguilar, D., Sigford, K. E. et al. 2008. A quantitative assessment of tremor and ataxia in FMR1 premutation carriers using CATSYS. Am J Med Genet A 146(5): 629–635.Google Scholar
  3. Allen, E. G., He, W. et al. 2004. A study of the distributional characteristics of FMR1 transcript levels in 238 individuals. Hum Genet 114(5): 439–447.PubMedCrossRefGoogle Scholar
  4. Allen, E. G., Juncos, J. et al. 2008. Detection of early FXTAS motor symptoms using the CATSYS computerised neuromotor test battery. J Med Genet 45(5): 290–297.PubMedCrossRefGoogle Scholar
  5. Allen, E. G., Sullivan, A. K. et al. 2007. Examination of reproductive aging milestones among women who carry the FMR1 premutation. Hum Reprod 22(8): 2142–2152.PubMedCrossRefGoogle Scholar
  6. Arocena, D. G., Iwahashi, C. K. 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(23): 3661–3671.PubMedCrossRefGoogle Scholar
  7. Bacalman, S., Farzin, F. et al. 2006. Psychiatric phenotype of the fragile X-associated tremor/ataxia syndrome (FXTAS) in males: newly described fronto-subcortical dementia. J Clin Psychiatry 67(1): 87–94.PubMedCrossRefGoogle Scholar
  8. Berry-Kravis, E., Goetz, C. G. et al. 2007. Neuropathic features in fragile X premutation carriers. Am J Med Genet A 143(1): 19–26.PubMedGoogle Scholar
  9. Berry-Kravis, E., Lewin, F. et al. 2003. Tremor and ataxia in fragile X premutation carriers: blinded videotape study. Ann Neurol 53(5): 616–623.PubMedCrossRefGoogle Scholar
  10. Biancalana, V., Toft, M. et al. 2005. FMR1 premutations associated with fragile X-associated tremor/ataxia syndrome in multiple system atrophy. Arch Neurol 62(6): 962–966.PubMedCrossRefGoogle Scholar
  11. Bourgeois, J. A., Cogswell, J. B. et al. 2007. Cognitive, anxiety and mood disorders in the fragile X-associated tremor/ataxia syndrome. Gen Hosp Psychiatry 29(4): 349–356.PubMedCrossRefGoogle Scholar
  12. Brega, A. G., Goodrich, G. 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
  13. Brunberg, J. A., Jacquemont, S. et al. 2002. Fragile X premutation carriers: characteristic MR imaging findings of adult male patients with progressive cerebellar and cognitive dysfunction. AJNR Am J Neuroradiol 23(10): 1757–1766.PubMedGoogle Scholar
  14. Coffey, S. M., Cook, K. et al. 2008. Expanded clinical phenotype of women with the FMR1 premutation. Am J Med Genet A 146(8): 1009–1016.Google Scholar
  15. Cohen, S., Masyn, K. et al. 2006. Molecular and imaging correlates of the fragile X-associated tremor/ataxia syndrome. Neurology 67(8): 1426–1431.PubMedCrossRefGoogle Scholar
  16. Cornish, K. M., Li, L. et al. 2008. Age-dependent cognitive changes in carriers of the fragile X syndrome. Cortex 44(6): 628–636.PubMedCrossRefGoogle Scholar
  17. Ennis, S., Ward, D. et al. 2006. Nonlinear association between CGG repeat number and age of menopause in FMR1 premutation carriers. Eur J Hum Genet 14(2): 253–255.PubMedCrossRefGoogle Scholar
  18. Fahn, S., Elton, R. et al. 1987. Unified Parkinson’s disease rating scale. In S. Fahn, C. Marsden, D. Calne and M. Goldstein (Ed.), Recent development in Parkinson’s disease, Vol. 2. Florham Park, NJ: Macmillan Health Care Information, pp. 53–164.Google Scholar
  19. Fahn, S., Tolosa, E. et al. 1987. Clinical rating scale for tremor. In J. Jankovic and E. Tolosa (Ed.), Parkinson’s disease and movement disorders. Baltimore, Munich: Urban & Schwartzenberg, pp. 225–234.Google Scholar
  20. Feng, Y., Lakkis, L. et al. 1995. Quantitative comparison of FMR1 gene expression in normal and premutation alleles. Am J Hum Genet 56(1): 106–113.PubMedCrossRefGoogle Scholar
  21. Garcia-Alegria, E., Ibanez, B. et al. 2007. Analysis of FMR1 gene expression in female premutation carriers using robust segmented linear regression models. RNA (New York) 13(5): 756–762.CrossRefGoogle Scholar
  22. Greco, C. M., Berman, R. F. et al. 2006. Neuropathology of fragile X-associated tremor/ataxia syndrome (FXTAS). Brain 129(Pt 1): 243–255.PubMedGoogle Scholar
  23. Greco, C. M., Hagerman, R. J. et al. 2002. Neuronal intranuclear inclusions in a new cerebellar tremor/ataxia syndrome among fragile X carriers. Brain 125(Pt 8): 1760–1771.PubMedCrossRefGoogle Scholar
  24. Grigsby, J., Brega, A. G. et al. 2008. Cognitive profile of fragile X premutation carriers with and without fragile X-associated tremor/ataxia syndrome. Neuropsychology 22(1): 48–60.PubMedCrossRefGoogle Scholar
  25. Grigsby, J., Brega, A. G. et al. 2006. Impairment in the cognitive functioning of men with fragile X-associated tremor/ataxia syndrome (FXTAS). J Neurol Sci 248(1–2): 227–233.PubMedCrossRefGoogle Scholar
  26. Grigsby, J., Brega, A. G. et al. 2007. Impairment of executive cognitive functioning in males with fragile X-associated tremor/ataxia syndrome. Mov Disord 22(5): 645–650.PubMedCrossRefGoogle Scholar
  27. Grigsby, J., Leehey, M. A. et al. 2006. Cognitive impairment in a 65-year-old male with the fragile X-associated tremor-ataxia syndrome (FXTAS). Cogn Behav Neurol 19(3): 165–171.PubMedCrossRefGoogle Scholar
  28. Hagerman, R. J., Leavitt, B. R. et al. 2004. Fragile-X-associated tremor/ataxia syndrome (FXTAS) in females with the FMR1 premutation. Am J Hum Genet 74(5): 1051–1056.PubMedCrossRefGoogle Scholar
  29. Hagerman, R. J., Leehey, M. et al. 2001. Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology 57(1): 127–130.PubMedCrossRefGoogle Scholar
  30. Hessl, D., Tassone, F. et al. 2005. Abnormal elevation of FMR1 mRNA is associated with psychological symptoms in individuals with the fragile X premutation. Am J Med Genet B Neuropsychiatr Genet 139(1): 115–121.Google Scholar
  31. Huntington Study Group. 1996. Unified Huntington’s disease rating scale: reliability and consistency. Mov Disord 11: 136–142.CrossRefGoogle Scholar
  32. Jacquemont, S., Hagerman, R. J. et al. 2003. Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates. Am J Hum Genet 72(4): 869–878.PubMedCrossRefGoogle Scholar
  33. Jacquemont, S., Hagerman, R. J. et al. 2004. Penetrance of the fragile X-associated tremor/ataxia syndrome in a premutation carrier population. JAMA 291(4): 460–469.PubMedCrossRefGoogle Scholar
  34. Jacquemont, S., Leehey, M. A. et al. 2006. Size bias of fragile X premutation alleles in late-onset movement disorders. J Med Genet 43(10): 804–809.PubMedCrossRefGoogle Scholar
  35. Jakala, P., Hanninen, T. et al. 1997. Fragile-X: neuropsychological test performance, CGG triplet repeat lengths, and hippocampal volumes. J Clin Invest 100(2): 331–338.PubMedCrossRefGoogle Scholar
  36. Kenneson, A., Zhang, F. et al. 2001. Reduced FMRP and increased FMR1 transcription is proportionally associated with CGG repeat number in intermediate-length and premutation carriers. Hum Mol Genet 10(14): 1449–1454.PubMedCrossRefGoogle Scholar
  37. Leehey, M. A., Berry-Kravis, E. et al. 2008. FMR1 CGG repeat length predicts motor dysfunction in premutation carriers. Neurology 70(16 Pt 2): 1397–1402, PHST- 2007/12/05 [ahead of print].PubMedCrossRefGoogle Scholar
  38. Leehey, M. A., Berry-Kravis, E. et al. 2008. FMR1 CGG repeat length predicts motor dysfunction in premutation carriers. Neurology 70(16 Pt 2): 1397–1402, PHST- 2007/12/05 [ahead of print].PubMedCrossRefGoogle Scholar
  39. Loesch, D. Z., Churchyard, A. et al. 2005. Evidence for, and a spectrum of, neurological involvement in carriers of the fragile X pre-mutation: FXTAS and beyond. Clin Genet 67(5): 412–417.PubMedCrossRefGoogle Scholar
  40. Loesch, D. Z., Cook, M. et al. 2008. A low symptomatic form of neurodegeneration in younger carriers of the FMR1 premutation, manifesting typical radiological changes. J Med Genet 45(3): 179–181, PHST-2007/12/05 [ahead of print].PubMedCrossRefGoogle Scholar
  41. Loesch, D. Z., Litewka, L. et al. 2005. Magnetic resonance imaging study in older fragile X premutation male carriers. Ann Neurol 58(2): 326–330.PubMedCrossRefGoogle Scholar
  42. Moore, C. J., Daly, E. M. et al. 2004a. A neuropsychological investigation of male premutation carriers of fragile X syndrome. Neuropsychologia 42(14): 1934–1947.PubMedCrossRefGoogle Scholar
  43. Moore, C. J., Daly, E. M. et al. 2004b. The effect of pre-mutation of X chromosome CGG trinucleotide repeats on brain anatomy. Brain 127(Pt 12): 2672–2681.PubMedCrossRefGoogle Scholar
  44. Primerano, B., Tassone, F. et al. 2002. Reduced FMR1 mRNA translation efficiency in fragile X patients with premutations. RNA 8(12): 1482–1488.PubMedGoogle Scholar
  45. Rodriguez-Revenga, L., Madrigal, I., Pagonabarraga, J. et al. 2009. Penetrance of FMR1 premutation associated pathologies in fragile X syndrome families. Eur J Hum Genet 17: 1359–1362.Google Scholar
  46. Sevin, M., Kutalik, Z. et al. 2009. The penetrance of marked cognitive impairment in older male carriers of the FMR1 gene premutation. J Med Genet 46: 818–824.PubMedCrossRefGoogle Scholar
  47. Soontarapornchai, K., Maselli, R. et al. 2008. Abnormal nerve conduction features in fragile X premutation carriers. Arch Neurol 65(4): 495–498.PubMedCrossRefGoogle Scholar
  48. Tassone, F., Adams, J. et al. 2007. CGG repeat length correlates with age of onset of motor signs of the fragile X-associated tremor/ataxia syndrome (FXTAS). Am J Med Genet B Neuropsychiatr Genet 144(4): 566–569.Google Scholar
  49. Tassone, F., Hagerman, R. J. et al. 2000. Transcription of the FMR1 gene in individuals with fragile X syndrome. Am J Med Genet 97(3): 195–203.PubMedCrossRefGoogle Scholar
  50. Tassone, F., Hagerman, R. J. et al. 2004. Intranuclear inclusions in neural cells with premutation alleles in fragile X associated tremor/ataxia syndrome. J Med Genet 41(4): e43.PubMedCrossRefGoogle Scholar
  51. Trouillas, P., Takayanagi, T. et al. 1997. International cooperative ataxia rating scale for pharmacological assessment of the cerebellar syndrome. The ataxia neuropharmacology committee of the world federation of neurology. J Neurol Sci 145(2): 205–211.PubMedCrossRefGoogle Scholar
  52. Zuhlke, C., Budnik, A. et al. 2004. FMR1 premutation as a rare cause of late onset ataxia–evidence for FXTAS in female carriers. J Neurol 251(11): 1418–1419.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Emily Allen
    • 1
  • Maureen A. Leehey
    • 2
  • Flora Tassone
    • 3
  • Stephanie Sherman
    • 1
  1. 1.Department of Human GeneticsEmory University School of MedicineAtlantaUSA
  2. 2.Department of NeurologyUniversity of Colorado at Denver and Health Sciences CenterAuroraUSA
  3. 3.Department of Biochemistry and Molecular Medicine, School of MedicineUniversity of CaliforniaDavisUSA

Personalised recommendations