Genetic Counseling for FXTAS and FMR1-Associated Disorders

  • Louise W. Gane
  • Katherine Howard
  • Liane Abrams


Since its identification in 2001, awareness of fragile X-associated tremor/ataxia syndrome (FXTAS) has increased. The number of patients and families impacted by the condition continues to grow. Families with and without a history of fragile X syndrome (FXS) are impacted. Patients are usually identified based on their neurological findings such as intentional tremor, balance and gait difficulties, cognitive impairment, and brain MRI abnormalities.


Genetic Counseling Preimplantation Genetic Diagnosis FMR1 Gene Genetic Counseling Session Full Mutation 
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.



We thank Dr. Robert Hendren, Theresa Contenti, and Beverly Wardlaw for their continued support and efforts on behalf of our development work for fragile X-associated disorders. We thank Page Sorensen, junior specialist, for her work on this chapter as without her we would not have been able to complete the many details. We would also like to thank all the patients who have been diagnosed with FXTAS, those diagnosed with fragile X syndrome, and their many family members including those who have made contributions to this chapter. It is because of each of them that we continue to learn, change, and grow in our understanding of fragile X-associated disorders.


  1. Alexopoulos, G. S., Raue, P., Arean, P. 2003. Problem-solving therapy versus supportive therapy in geriatric major depression with executive dysfunction. Am J Geriatr Psychiatry 11(1): 46–52.PubMedGoogle Scholar
  2. Apessos, A., Abou-Sleiman, P. M., Harper, J. C., et al. 2001. Preimplantation genetic diagnosis of the fragile x syndrome by use of linked polymorphic markers. Prenat Diagn 21(6): 504–511.PubMedCrossRefGoogle Scholar
  3. Aziz, M., Stathopulu, E., Callias, M., et al. 2003. Clinical features of boys with fragile x premutations and intermediate alleles. Am J Med Genet 121B(1): 119–127.PubMedCrossRefGoogle Scholar
  4. Bacalman, S., Farzin, F., Bourgeois, J. A., 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
  5. Bombard, Y., Penziner, E., Suchowersky, O., et al. 2008. Engagement with genetic discrimination: concerns and experiences in the context of Huntington disease. Eur J Hum Genet 16(3): 279–289.PubMedCrossRefGoogle Scholar
  6. Bourgeois, J., Coffey, S., Rivera, S., et al. 2009. A review of Fragile x premutation disorders – expanding the psychiatric perspective. J Clin Psychiatry 70(6): 852–862.Google Scholar
  7. Bourgeois, J. A., Farzin, F., Brunberg, J. A., et al. 2006. Dementia with mood symptoms in a fragile x premutation carrier with the fragile x-associated tremor/ataxia syndrome: clinical intervention with donepezil and venlafaxine. J Neuropsychiatry Clin Neurosci 18(2): 171–177.PubMedCrossRefGoogle Scholar
  8. Cameron, J. I., Cheung, A. M., Streiner, D. L., et al. 2006. Stroke survivors’ behavioral and psychologic symptoms are associated with informal caregivers’ experiences of depression. Arch Phys Med Rehabil 87(2): 177–183.PubMedCrossRefGoogle Scholar
  9. Cameron, J. I., Franche, R. L., Cheung, A. M., et al. 2002. Lifestyle interference and emotional distress in family caregivers of advanced cancer patients. Cancer 94(2): 521–527.PubMedCrossRefGoogle Scholar
  10. Castellvi Bel, S., Mila, M., Soler, A., et al. 1995. Prenatal diagnosis of fragile X syndrome: (CGG)n expansion and methylation of chorionic villus samples. Prenat Diagn 15(9): 801–807.PubMedCrossRefGoogle Scholar
  11. Clifford, S., Dissanayake, C., Bui, Q. M., et al. 2007. Autism spectrum phenotype in males and females with fragile x full mutation and premutation. J Autism Dev Disord 37(4): 738–747.PubMedCrossRefGoogle Scholar
  12. Coffey, S. M., Cook, K., Tartaglia, N., et al. 2008. Expanded clinical phenotype of women with the fmr1 premutation. Am J Med Genet A 146(8): 1009–1016.Google Scholar
  13. Cornish, K. M., Sudhalter, V., Turk, J. 2004. Attention and language in fragile x. Ment Retard Dev Disabil Res Rev 10(1): 11–16.PubMedCrossRefGoogle Scholar
  14. Cran, D. G., Johnson, L. A. 1996. The predetermination of embryonic sex using flow cytometrically separated x and y spermatozoa. Hum Reprod Update 2(4): 355–363.PubMedCrossRefGoogle Scholar
  15. Curlis, Y., Zhang, C., Holden, J. J., et al. 2005. Haplotype study of intermediate-length alleles at the fragile x (fmr1) gene: Atl1, fmrb, and microsatellite haplotypes differ from those found in common-size fmr1 alleles. Hum Biol 77(1): 137–151.PubMedCrossRefGoogle Scholar
  16. de Jong, A., de Wert, G. 2002. Screening for carriers of the fragile x syndrome; ethical exploration. Ned Tijdschr Geneeskd 146(13): 611–615.PubMedGoogle Scholar
  17. Farzin, F., Perry, H., Hessl, D., et al. 2006. Autism spectrum disorders and attention-deficit/hyperactivity disorder in boys with the fragile x premutation. J Dev Behav Pediatr 27(2 Suppl): S137–S144.PubMedCrossRefGoogle Scholar
  18. Filipovic-Sadic, S., Sah, S., Chen, L., Krosting, J., Sekinger, E., Zhang, W., Hagerman, P. J., Stenzel, T. T., Hadd, A., Latham, G. J., & Tassone, F. 2010 Mar. A novel FMR1 PCR method for the routine detection of low-abundance expanded alleles and full mutations in fragile X syndrome. Clin Chem 56(3): 399–408.Google Scholar
  19. Gane, L. W., Flynn, L., Hagerman, R. J. 2005. Needs and priorities of FXTAS patients and spouses determined using q-sort methodology. Proceedings of the 12th International Workshop on Fragile X and X-Linked Mental Retardation, August 26–29, 2005, Williamsburg, VA.Google Scholar
  20. Geraedts, J. P., Harper, J., Braude, P., et al. 2001. Preimplantation genetic diagnosis (PGD), a collaborative activity of clinical genetic departments and IVF centres. Prenat Diagn 21(12): 1086–1092.PubMedCrossRefGoogle Scholar
  21. Goodlin-Jones, B., Tassone, F., Gane, L. W., et al. 2004. Autistic spectrum disorder and the fragile x premutation. J Dev Behav Pediatr 25(6): 392–398.PubMedCrossRefGoogle Scholar
  22. Grasso, M., Faravelli, F., Nigro, C. L., et al. 1999. Mosaicism for the full mutation and a microdeletion involving the CGG repeat and flanking sequences in the fmr1 gene in eight fragile x patients. Am J Med Genet 85(3): 311–316.PubMedCrossRefGoogle Scholar
  23. 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(1–2): 227–233.PubMedCrossRefGoogle Scholar
  24. Grunfeld, E., Coyle, D., Whelan, T., et al. 2004. Family caregiver burden: results of a longitudinal study of breast cancer patients and their principal caregivers. CMAJ 170(12): 1795–1801.PubMedGoogle Scholar
  25. Hagerman, P. J., Hagerman, R. J. 2004. The fragile-x premutation: a maturing perspective. Am J Hum Genet 74(5): 805–816.PubMedCrossRefGoogle Scholar
  26. Hagerman, R. J. 2006. Lessons from fragile x regarding neurobiology, autism, and neurodegeneration. J Dev Behav Pediatr 27(1): 63–74.PubMedCrossRefGoogle Scholar
  27. Hagerman, R. J., Hall, D. A., Coffey, S., et al. 2008. Treatment of fragile x-associated tremor ataxia syndrome (FXTAS) and related neurological problems. Clin Interv Aging 3(2): 251–262.PubMedGoogle Scholar
  28. Hessl, D., Glaser, B., Dyer-Friedman, J., et al. 2006. Social behavior and cortisol reactivity in children with fragile x syndrome. J Child Psychol Psychiatry 47(6): 602–610.PubMedCrossRefGoogle Scholar
  29. Hessl, D., Tassone, F., Loesch, D. Z., 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
  30. Jacquemont, S., Farzin, F., Hall, D., et al. 2004a. Aging in individuals with the fmr1 mutation. Am J Ment Retard 109(2): 154–164.PubMedCrossRefGoogle Scholar
  31. Jacquemont, S., Hagerman, R. J., Leehey, M. A., et al. 2003. Penetrance of the fragile x-associated tremor/ataxia syndrome (FXTAS) in a premuation carrier population: initial results from a California family-based study. Proceedings of the 53rd Annual Meeting, Los Angeles, CA. Am J Hum Genet 73(Suppl 5)A10: 163.Google Scholar
  32. Jacquemont, S., Hagerman, R. J., Leehey, M. A., et al. 2004b. Penetrance of the fragile x-associated tremor/ataxia syndrome in a premutation carrier population. JAMA 291(4): 460–469.PubMedCrossRefGoogle Scholar
  33. Keysor, C. S., Mazzocco, M. M. 2002. A developmental approach to understanding fragile x syndrome in females. Microsc Res Tech 57(3): 179–186.PubMedCrossRefGoogle Scholar
  34. Leehey, M. A., Berry-Kravis, E., Min, S. J., et al. 2007. Progression of tremor and ataxia in male carriers of the fmr1 premutation. Mov Disord 22(2): 203–206.PubMedCrossRefGoogle Scholar
  35. McConkie-Rosell, A., Abrams, L., Finucane, B., et al. 2007. Recommendations from multi-disciplinary focus groups on cascade testing and genetic counseling for fragile x-associated disorders. J Genet Couns 16(5): 593–606.PubMedCrossRefGoogle Scholar
  36. Mila, M., Mallolas, J. 2001. Fragile x syndrome: premature ovarian failure. Preimplantation and preconception genetic diagnosis. Rev Neurol 33(Suppl 1): S20–S23.PubMedGoogle Scholar
  37. Nolin, S. L., Brown, W. T., Glicksman, A., et al. 2003a. Expansion of the fragile x CGG repeat in females with premutation or intermediate alleles. Am J Hum Genet 72(2): 454–464.PubMedCrossRefGoogle Scholar
  38. Nolin, S. L., Dobkin, C., Brown, W. T. 2003b. Molecular analysis of fragile x syndrome. Curr Protoc Hum Genet  Chapter 9: Unit9.5.
  39. Nolin, S. L., Lewis, F. A., 3rd, Ye, L. L., et al. 1996. Familial transmission of the fmr1 CGG repeat. Am J Hum Genet 59(6): 1252–1261.PubMedGoogle Scholar
  40. NSGC. 2005. Retrieved 12/1/2008, from
  41. Penagarikano, O., Mulle, J. G., Warren, S. T. 2007. The pathophysiology of fragile x syndrome. Annu Rev Genomics Hum Genet 8: 109–129.PubMedCrossRefGoogle Scholar
  42. Platteau, P., Sermon, K., Seneca, S., et al. 2002. Preimplantation genetic diagnosis for fragile xa syndrome: difficult but not impossible. Hum Reprod 17(11): 2807–2812.PubMedCrossRefGoogle Scholar
  43. Pozdnyakova, I., Regan, L. 2005. New insights into fragile x syndrome. Relating genotype to phenotype at the molecular level. FEBS J 272(3): 872–878.PubMedCrossRefGoogle Scholar
  44. Roberts, J. E., Bailey, D. B., Jr., Mankowski, J., et al. 2008. Mood and anxiety disorders in females with the fmr1 premutation. Am J Med Genet B Neuropsychiatr Genet 147B: 1138–1144.CrossRefGoogle Scholar
  45. Seritan, A. L., Nguyen, D. V., Farias, S. T., et al. 2008. Dementia in fragile x-associated tremor/ataxia syndrome (FXTAS): comparison with Alzheimer’s disease. Am J Med Genet B Neuropsychiatr Genet 147B(7): 1138–1144.PubMedCrossRefGoogle Scholar
  46. Sherman, S. L., Taylor, K., Allen, E. G. 2007. Fmr1 premutation: a leading cause of inherited ovarian dysfunction.In Fragile sites: new discoveries and changing perspectives. I. Arrieta. Hauppauge, NY: Nova Science Publishers, pp. 299–320.Google Scholar
  47. Tassone, F., Adams, J., Berry-Kravis, E. M., 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
  48. Tassone, F., Hagerman, R. J., Taylor, A. K., et al. 2000. Elevated levels of fmr1 mRNA in carrier males: a new mechanism of involvement in the fragile-x syndrome. Am J Hum Genet 66(1): 6–15.PubMedCrossRefGoogle Scholar
  49. Tassone, F., Pan, R., Amiri, K., et al. 2008. A rapid polymerase chain reaction-based screening method for identification of all expanded alleles of the fragile x (fmr1) gene in newborn and high-risk populations. J Mol Diagn 10(1): 43–49.PubMedCrossRefGoogle Scholar
  50. Wingrove, K. J., Norris, J., Barton, P. L., et al. 1996. Experiences and attitudes concerning genetic testing and insurance in a Colorado population: a survey of families diagnosed with fragile x syndrome. Am J Med Genet 64(2): 378–381.PubMedCrossRefGoogle Scholar
  51. Wirojanan, J., Angkustsiri, K., Tassone, F., et al. 2008. A girl with fragile x premutation from sperm donation. Am J Med Genet A 146(7): 888–892.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Louise W. Gane
    • 1
  • Katherine Howard
    • 2
  • Liane Abrams
    • 3
  1. 1.UC Davis M.I.N.D. InstituteUniversity of CaliforniaSacramentoUSA
  2. 2.University of Colorado Health Sciences CenterAuroraUSA
  3. 3.National Fragile X FoundationWalnut CreekUSA

Personalised recommendations