The Epidemiology of FXTAS



The prevalence of the FMR1 premutation ranges from 1/116 to 1/259 in women and from 1/251 to 1/1,250 in men. Population studies investigating the prevalence of FXTAS in the general population have not been conducted due to the rarity of the disorder. The prevalence of FXTAS is estimated to be 1/4,000 in men over the age of 55, due to age-dependent penetrance. The prevalence in women is thought to be much lower, at approximately 1/7,800, because of the protection of the second X chromosome. Many screening studies have been conducted in movement disorder populations, attempting to ascertain undiagnosed FXTAS cases and premutation expansions. These studies have yielded low rates, with a rate of 1.3% in cerebellar ataxia patients, <1% in parkinsonian disorders, such as Parkinson disease and multiple system atrophy, and 0% in essential tremor. Screening studies vary widely in the type of patients included, both in ethnicity and in gender. Wider inclusion criteria for screening should increase the rates of ascertainment of both FXTAS and premutation expansions in future studies.


Parkinson Disease Multiple System Atrophy Essential Tremor Cerebellar Ataxia Spinocerebellar Ataxia 
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  1. Annesi, G. N., Tarantino, P., Cutuli, N., Annesi, F., Marco, E. V., Zappia, M., Morgante, L., Arabia, G., Pugliese, P., Condino, F., Carrideo, S., Civitelli, D., Caracciolo, M., Romeo, N., Spadafora, P., Candiano, I. C., Quattrone, A. 2004. FRAXE intermediate alleles are associated with Parkinson’s disease. Neurosci Lett 368: 21–24.PubMedCrossRefGoogle Scholar
  2. Arocena, D. G., Louis, E. D., Tassone, F., Gilliam, T. C., Ottman, R., Jacquemont, S., Hagerman, P. J. 2004. Screen for expanded FMR1 alleles in patients with essential tremor. Mov Disord 19: 930–947.CrossRefGoogle Scholar
  3. Berkenstadt, M., Ries-Levavi, L., Cuckle, H., Peleg, L., Barkai, G. 2007. Preconceptional and prenatal screening for fragile X syndrome: experience with 40,000 tests. Prenat Diagn 27: 991–994.PubMedCrossRefGoogle Scholar
  4. Berry-Kravis, E., Potanos, K., Weinberg, D., Zhou, L., Goetz, C. G. 2005. Fragile x-associated tremor/ataxia syndrome in sisters related to X-inactivation. Ann Neurol 57: 144–147.PubMedCrossRefGoogle Scholar
  5. Biancalana, V., Toft, M., Le Ber, I., Tison, F., Scherrer, E., Thibodeau, S., Mandel, J. L., Brice, A., Farrer, M. J., Dürr, A. 2005. FMR1 premutations associated with fragile X-associated tremor/ataxia syndrome in multiple system atrophy. Arch Neurol 62: 962–966.PubMedCrossRefGoogle Scholar
  6. Brusse, E., Maat-Kievit, J. A., van Swieten, J. C. 2007. Diagnosis and management of early- and late-onset cerebellar ataxia. Clin Genet 71: 12–24.PubMedCrossRefGoogle Scholar
  7. Brussino, A., Gellera, C., Saluto, A., Mariotti, C., Arduino, C., Castelloti, B., Camerlingo, M., de Angelis, V., Orsi, L., Tosca, P., Migone, N., Taroni, F., Brusco, A. 2005. FMR1 gene premutation is a frequent cause of late-onset sporadic cerebellar ataxia. Neurology 64: 145–147.PubMedCrossRefGoogle Scholar
  8. Cilia, R., Kraff, J., Canesi, M., Pezzoli, G., Goldwurm, S., Amiri, K., Tang, H. T., Pan, R., Hagerman, P. J., Tassone, F. 2009. Screening for the presence of FMR1 premutation alleles in women with parkinsonism. Arch Neurol 66(2): 244–249.Google Scholar
  9. Coffey, S. M., Cook, K., Tartaglia, N., Tassone, F., Nguyen, D. V., Pan, R., Bronsky, H. E., Yuhas, J., Borodyanskaya, M., Grigsby, J., Doerflinger, M., Hagerman, P. J., Hagerman, R. J. 2008. Expanded clinical phenotype of women with the FMRl premutation. Am J Med Genet A, 146(8): 1009–1016.Google Scholar
  10. Crawford, D. C., Meadows, K. L., Newman, J. L., Taft, L. F., Scott, E., Leslie, M., Shubek, L., Holmgreen, P., Yeargin-Allsopp, M., Boyle, C., Sherman, S. L. 2002. Prevalence of the fragile X syndrome in African Americans. Am J Med Genet 110: 226–233.PubMedCrossRefGoogle Scholar
  11. Deng, H., Jankiovic, J. 2004. Premutation alleles associated with Parkinson disease and essential tremor. JAMA 292: 1685–1688.PubMedCrossRefGoogle Scholar
  12. Dombrowski, C., Levesque, S., Morel, M. L., Rouillard, P., Morgan, K., Rousseau, F. 2002. 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 11: 371–378.PubMedCrossRefGoogle Scholar
  13. Fernandez-Carvajal, I., Walichiewicz, P., Xiaosen, X., Pan, R., Hagerman, P. J., Tassone, F. 2009. Screening for expanded alleles for the FMR1 gene in blood spots from newborn males in a Spanish population. J Mol Diagn 11(4): 324–329.PubMedCrossRefGoogle Scholar
  14. Garland, E. M., Vmencak-Jones, C., Biaggioni, I., Davis, T. L., Montine, T. J., Robertson, D. 2004. Fragile X gene premutation in multiple system atrophy. J Neurol Sci 227: 115–118.PubMedCrossRefGoogle Scholar
  15. Geva, E., Yaron, Y., Shomrat, Y., Ben-Yehuda, A., Zabari, S., Peretz, H., Naiman, T., Yeger, H., Orr-Urtreger, A. September 1, 2000. The risk of fragile X premutation expansion is lower in carriers detected by general prenatal screening than in carriers from known fragile X families. Genet Test 4(3): 289–292.PubMedCrossRefGoogle Scholar
  16. Hagerman, H. 2008. The fragile X prevalence paradox. J Med Genet 45(8): 498–499. 10.1136/jmg.2008.059055.PubMedCrossRefGoogle Scholar
  17. Hagerman, R. J., Leavitt, B. R., Farzin, F., Jacquemont, S., Greco, C. M., Brunberg, J. A., Tassone, F., Hessl, D., Harris, S. W., Zhang, L., Jardini, T., Gane, L. W., Ferranti, J., Ruiz, L., Leehey, M. A., Grigsby, J., Hagerman, P. J. 2004. Fragile-X-associated tremor/ataxia syndrome (FXTAS) in females with the FMR1 premutation. Am J Hum Genet 74: 1051–1056.PubMedCrossRefGoogle Scholar
  18. Hall, D. A., Berry-Kravis, E., Jacquemont, S., Rice, C. D., Cogswell, J., Zhang, L., Hagerman, R., Hagerman, P. J., Leehey, M. A. 2005. Prior diagnosis given to persons with the fragile X-associated tremor/ataxia syndrome. Neurology 65: 299–301.PubMedCrossRefGoogle Scholar
  19. Hall, D. A., Hagerman, R. J., Hagerman, P. J., Jacquemont, S., Leehey, M. A. 2006. Prevalence of FMR1 repeat expansions in movement disorders: a systematic review. Neuroepidemiology 26: 151–155.PubMedCrossRefGoogle Scholar
  20. Hall, D. A., Howard, K., Hagerman, R. J., Leehey, M. A. 2009. Parkinsonism in FMR1 premutation carriers May be indistinguishable from Parkinson disease. Park Rel Dis 15: 156–159.CrossRefGoogle Scholar
  21. Hedrich, K., Pramstaller, P. P., Stübke, K., Hiller, A., Kabakci, K., Purmann, S., Kasten, M., Scaglione, C., Schwinger, E., Volkmann, J., Kostic, V., Vieregge, P., Martinelli, P., Abbruzzese, G., Klein, C., Zühlke, C. 2005. Premutations in the FMR1 gene as a modifying factor in parkin-associated Parkinson’s disease? Mov Disord 20(8): 1060–1062.PubMedCrossRefGoogle Scholar
  22. Jacquemont, S., Hagerman, R., Leehey, M. A., Hall, D. A., Levine, R. A., Brunberg, J. A., Zhang, L., Jardini, T., Gane, L. W., Harris, S. W., Herman, K., Grigsby, J., Greco, C. M., Berry-Kravis, E., Tassone, F., Hagerman, P. J. 2004. Penetrance of the fragile X-associated tremor/ataxia syndrome in a premutation carrier population. JAMA 291(4): 460–469.PubMedCrossRefGoogle Scholar
  23. Jacquemont, S., Leehey, M. A., Hagerman, R. J., Beckett, L. A., Hagerman, P. J. 2006. Size bias of fragile X premutation alleles in late-onset movement disorders. J Med Genet 43(10): 804–809.PubMedCrossRefGoogle Scholar
  24. Kamm, C., Healy, D., Quinn, N. P., Wullner, U., Moller, J. C., Schols, L., Geser, F., Burk, K., Borglum, A. D., Pellecchia, M. T., Tolosa, E., del Sorbo, F., Nilsson, C., Bandmann, O., Sharma, M., Mayer, P., Gasteiger, M., Haworth, A., Ozawa, T., Lees, A. J., Short, J., Guinti, P., Holinski-Feder, E., Illig, T., Wichmann, H. E., Wenning, G. K., Wood, N. W., Gasser, T. 2005. The fragile X tremor ataxia syndrome in the differential diagnosis of multiple system atrophy: data from the EMSA study group. Brain 128: 1855–1860.PubMedCrossRefGoogle Scholar
  25. Kerber, K. A., Jen, J., Perlman, S., Baloh, R. 2005. Late-onset pure cerebellar ataxia: differentiating those with and without identifiable mutations. J Neurol Sci 238: 41–45.PubMedCrossRefGoogle Scholar
  26. Kraff, J., Tang, H., Cilia, R., Canesi, M., Pezzoli, G., Goldwurm, S., Hagerman, P. J., Tassone, F. 2007. Screen for excess FMR1 premutation alleles among males with parkinsonism. Arch Neurol 64(7): 1002–1006.PubMedCrossRefGoogle Scholar
  27. Kraft, S., Furtado, S., Ranawaya, R., Parboosingh, J., Bleoo, S., McElligott, K., Bridge, P., Spacey, S., Das, S., Suchowersky, O. 2005. Adult onset spinocerebellar ataxia in a Canadian movement disorders clinic. Can J Neurol Sci 32(4): 450–458.PubMedGoogle Scholar
  28. Leehey, M. A., Berry-Kravis, E., Goetz, C., Zhang, L., Hall, D. A., Li, L., Rice, C. D., Lara, R., Cogswell, J. B., Reynolds, A., Gane, L., Jacquemont, S., Tassone, F., Grigsby, J., Hagerman, R. J., Hagerman, R. J. 2008. FMR1 CGG repeat length predicts motor dysfunction in FXTAS. Neurology 70: 1397–1402.PubMedCrossRefGoogle Scholar
  29. MacPherson, J., Waghorn, A., Hammans, S., Jacobs, P. 2003. Observation of an excess of fragile-X premutations in a population of males referred with spinocerebellar ataxia. Hum Genet 112: 619–620.PubMedGoogle Scholar
  30. Milunsky, J. M., Maher, T. A. 2004. Fragile X carrier screening and spinocerebellar ataxia in older males. Am J Med Genet A 125A(3): 320.Google Scholar
  31. Pesso, R., Berkenstadt, M., Cuckle, H., Gak, E., Peleg, L., Frydman, M., Barkai, G. 2000. Screening for fragile X syndrome in women of reproductive age. Prenat Diagn 20: 611–614.PubMedCrossRefGoogle Scholar
  32. Reis, A. H., Ferreira, A., Gomes, K. B., Aguiar, M. J., Fonseca, C. G., Cardoso, F. E., Pardini, V. C., Carvalho, M. R. 2008. Frequency of FMR1 premutation in individuals with ataxia and/or tremor and/or parkinsonism. Genet Mol Res 7(1): 74–84.PubMedCrossRefGoogle Scholar
  33. Rife, M., Badenas, C., Mallolas, J., Jimenez, L., Cervera, R., Maya, A., Glover, G., Rivera, F., Mila, M. 2003. Incidence of fragile X in 5,000 consecutive newborn males. Genet Test 7: 339–343.PubMedCrossRefGoogle Scholar
  34. Rodriguez-Revenga, L., Gomez-Anson, B., Muñoz, E., Jiménez, D., Santos, M., Tintoré, M., Martín, G., Brieva, L., Milà, M. 2007. FXTAS in Spanish patients with ataxia: support for female FMR1 premutation screening. Mol Neurobiol 35(3): 324–328.PubMedCrossRefGoogle Scholar
  35. Rousseau, F., Rouillard, P., Morel, M., Khandjian, E. W., Morgan, K. 1995. Prevalence of carriers of premutation-size alleles of the FMR1 gene – and implications for the population genetics of the fragile X syndrome. Am J Hum Genet 57: 1006–1018.PubMedGoogle Scholar
  36. Ryynanen, M., Heinonen, S., Makkonen, M., Kajanoja, E., Mannermaa, A., Pertti, K. 1999. Feasibility and acceptance of screening for fragile X mutations in low-risk pregnancies. Eur J Hum Genet 7: 212–216.PubMedCrossRefGoogle Scholar
  37. Saul, R. A., Friez, M., Eaves, K., Stapleton, G. A., Collins, J. S., Schwartz, C. E., Stevenson, R. E. 2008. Fragile X syndrome detection in newborns – pilot study. Genet Med 10(10): 714–719.PubMedGoogle Scholar
  38. Seixas, A. I., Maurer, M., Lin, M., Callahan, C., Ahuja, A., Matsura, T., Ross, C. A., Hisama, F. M., Silveria, E., Margolis, R. L. 2005. FXTAS, SCA10, and SCA17 in American patients with movement disorders. Am J Med Genet A 136(1): 87–89.PubMedGoogle Scholar
  39. Tan, E. K., Zhao, Y., Puong, K. Y., Law, H. Y., Chan, L. L., Yew, K., Shen, H., Chandran, V. R., Yuen, Y., Pavanni, R., Wong, M. C., Ng., I. S. 2005. Expanded FMR1 alleles are rare in idiopathic Parkinson’s disease. Neurogenetics 6(1): 51–52.PubMedCrossRefGoogle Scholar
  40. Tan, E. K., Zhao, Y., Puong, K. Y., Law, H. Y., Chan, L. L., Yew, K., Tan, C., Shen, H., Chandran, V. R., Teoh, M. L., Yih, Y., Pavanni, R., Wong, M. C., Ng, I. S. 2004. Fragile X premutation alleles in SCA, ET, and parkinsonism in an Asian cohort. Neurology 63: 362–363.PubMedCrossRefGoogle Scholar
  41. Tassone, F., Adams, J., Berry-Kravis, E., Cohen, S., Brusco, A., Leehey, M. A., Li, L., Hagerman, R. J., Hagerman, P. J. 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
  42. Toft, M., Aasley, J., Bisceglio, G., Adler, C. H., Uitti, R. J., Krygowska-Wajs, A., Lynch, T., Wszolek, Z. K., Farrer, M. J. 2005. Parkinsonism, FXTAS, and FMR1 premutations. Mov Disord 20: 230–233.PubMedCrossRefGoogle Scholar
  43. Toledano-Alhadef, H., Basel-Vanagaite, L., Magal, N., Davidov, B., Ehrlich, S., Drasinover, V., Taub, E., Halpern, G. J., Ginott, N., Shohat, M. 2001. Fragile-X carrier screening and the prevalence of premutation and full-mutation carriers in Israel. Am J Hum Genet 69(2): 351–360.PubMedCrossRefGoogle Scholar
  44. Tzeng, C., Tsai, L., Hwu, W., Lin, S., Chao, M., Jong, Y., Chu, S. Y., Chao, W. C., Lu, C. L. 2005. Prevalence of the FMR1 mutation in Taiwan assessed by large-scale screening of newborn boys and analysis of DXS548-FRAXAC1 haplotype. Am J Med Genet A 133: 37–43.Google Scholar
  45. Van Esch, H., Dom, R., Bex, D., Salden, I., Caeckebeke, J., Wibail, A., Borghgraef, M., Leguis, E., Fryns, J., Matthijs, G. 2005. Screening for FMR1 premutations in 122 older Flemish males presenting with ataxia. Euro J Hum Genet 13: 121–123.CrossRefGoogle Scholar
  46. Yabe, I., Soma, H., Takei, A., Fujik, N., Sasaki, H. 2004. No association between FMR1 premutations and multiple system atrophy. J Neurol 251(11): 1411–1412.PubMedCrossRefGoogle Scholar
  47. Zühlke, C., Budnik, A., Gehlken, U., Dalski, A., Purmann, S., Naumann, M., Schmidt, M., Bürk, K., Schwinger, E. 2004. J Neurol 251(11): 1418–1419.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of Neurological SciencesRush University Medical CenterChicagoUSA
  2. 2.Service de génétiqueCentre Hospitalier Universitaire de LausanneLausanneSwitzerland

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