Fragile X Syndrome

Living reference work entry


Fragile X syndrome is the most common form of heritable intellectual disability, affecting approximately 1 in 1,250 males and 1 in 2,000 females (Webb 1989). The prevalence appears to be 1 in 4,000–6,000 males and 1 in 8,000–10,000 females. Martin and Bell first documented X-linked mental retardation in 1943. Subsequent identification of a fragile site on the long arm of the X chromosome (Lubs 1969), discovery of cell culture medium-dependent fragile site, and recognition of a unique constellation of physical features served to distinguish fragile X syndrome from other X-linked mental retardation syndromes.


Depression Serotonin Neuropathy Folate Melatonin 


  1. American Academy of Pediatrics. (1996). Health supervision for children with fragile X syndrome. Pediatrics, 98, 297–300.Google Scholar
  2. Bardoni, B., Mandel, J. L., & Fisch, G. S. (2000). FMR1 gene and fragile X syndrome. American Journal of Medical Genetics (Seminars in Medical Genetics), 97, 153–163.CrossRefGoogle Scholar
  3. Berry-Kravis, E., Sumis, A., Hervey, C., et al. (2012). Clinic-based retrospective analysis of psychopharmacology for behavior in fragile X syndrome. International Journal of Pediatrics, 2012, 1–81.CrossRefGoogle Scholar
  4. Brown, W. T. (1995). Perspectives and molecular diagnosis of the fragile X syndrome. Clinics in Laboratory Medicine, 15, 859–875.PubMedGoogle Scholar
  5. Brown, S. S. G., & Stanfield, A. C. (2015). Fragile X premutation carriers: A systematic review of neuroimaging findings. Journal of the Neurological Sciences, 352, 19–28.CrossRefPubMedGoogle Scholar
  6. Caskey, C. T., Pizzuti, A., Fu, Y.-H., et al. (1992). Triplet repeat mutations in human disease. Science, 256, 784–789.CrossRefPubMedGoogle Scholar
  7. Crawford, D. C., Acuna, J. M., & Sherman, S. L. (2001). FMR1 and the fragile X syndrome: Human genome epidemiology review. Genetics in Medicine, 3, 359–371.CrossRefPubMedPubMedCentralGoogle Scholar
  8. Das, S., Kubota, T., Song, M., et al. (1997). Methylation analysis of the fragile X syndrome by PCR. Genetic Testing, 1, 151–155.CrossRefPubMedGoogle Scholar
  9. Davenport, M. H., Schaefer, T. L., Friedmann, K. J., et al. (2016). Pharmacotherapy for fragile X syndrome: Progress to date. Drugs, 76, 431–445.CrossRefPubMedGoogle Scholar
  10. Davids, J. R., Hagerman, R. J., & Eilert, R. E. (1990). Orthopaedic aspects of fragile-X syndrome. Journal of Bone and Joint Surgery (America), 72, 889–896.Google Scholar
  11. De Boulle, K., Verkerk, A. J. M. H., Reyniers, E., et al. (1993). A point mutation in the FMR-1 gene associated with fragile X mental retardation. Nature Genetics, 3, 31–35.CrossRefPubMedGoogle Scholar
  12. De Vries, B. B., Halley, D. J., Oostra, B. A., et al. (1998). The fragile X syndrome. Journal of Medical Genetics, 35, 579–589.CrossRefPubMedPubMedCentralGoogle Scholar
  13. Dyer-Friedman, J., Glaser, B., & Hessl, D. (2002). Genetic and environmental influences on the cognitive outcomes of children with fragile X syndrome. Journal of the American Academy of Child and Adolescent Psychiatry, 41, 237–244.CrossRefPubMedGoogle Scholar
  14. Dykens, E. M., Hodapp, R. M., & Leckman, J. F. (1994). Behavior and development in fragile X syndrome. Thousand Oaks: Sage.Google Scholar
  15. Fu, Y.-H., Kuhl, D. P. A., Pizzuti, A., et al. (1991). Variation of the CGG repeat at the fragile X site results in genetic instability: Resolution of the Sherman paradox. Cell, 67, 1047–1058.CrossRefPubMedGoogle Scholar
  16. Goldson, E., & Hagerman, R. J. (1992). The fragile X syndrome. Developmental Medicine and Child Neurology, 34, 822–832.Google Scholar
  17. Hagerman, R. J. (2001). Fragile X syndrome. In S. B. Cassidy & J. E. Allanson (Eds.), Management of genetic syndromes. New York: Wiley-Liss.Google Scholar
  18. Hagerman, R. J., & Cronister, A. (Eds.). (1996). Fragile X syndrome: Diagnosis, treatment, and research. Baltimore: Johns Hopkins University Press.Google Scholar
  19. Hagerman, R., & Hagerman, P. (2013). Advances in clinical and molecular understanding of the FMR1 premutation and fragile X-associated tremor/ataxia syndrome. Lancet Neurology, 12, 786–798.CrossRefPubMedPubMedCentralGoogle Scholar
  20. Hagerman, R. J., & Silverman, A. C. (1991). Fragile X syndrome. Diagnosis, treatment, and research. Baltimore: Johns Hopkins University Press.Google Scholar
  21. Hagerman, R. J., Jackson, C., Amiri, K., et al. (1992). Girls with fragile X syndrome: Physical and neurocognitive status and outcome. Pediatrics, 89, 395–400.PubMedGoogle Scholar
  22. Hagerman, R. J., Hull, C. E., Safanda, J. F., et al. (1994). High functioning fragile X males: Demonstration of an unmethylated fully expanded FMR-1 mutation associated with protein expression. American Journal of Medical Genetics, 51, 298–308.CrossRefPubMedGoogle Scholar
  23. Hagerman, R. J., Kimbro, L. T., & Taylor, A. K. (1998). Fragile X syndrome: A common cause of mental retardation and premature menopause. Contemporary OB/GYN, 43, 47–70.Google Scholar
  24. Hammond, L. S., Macias, M. M., Tarleton, J. C., et al. (1997). Fragile X syndrome and deletions in FMR1: New case and review of the literature. American Journal of Medical Genetics, 72, 430–434.CrossRefPubMedGoogle Scholar
  25. Holden, J. J. A., Percy, M., Allingham-Hawkins, D., et al. (1999). Eighth international workshop on the fragile X syndrome and X-linked mental retardation. American Journal of Medical Genetics, 83, 221–236. August 16-22, 1997.CrossRefPubMedGoogle Scholar
  26. Kallinen, J., Heinonen, S., Mannermaa, A., et al. (2000). Prenatal diagnosis of fragile X syndrome and the risk of expansion of a permutation. Clinical Genetics, 58, 111–115.CrossRefPubMedGoogle Scholar
  27. Kau, A. S. M., Meyer, W. A., & Kaufmann, W. E. (2002). Early development in males with fragile X syndrome: A review of the literature. Microscopy Research and Technique, 57, 174–178.CrossRefPubMedGoogle Scholar
  28. Kaufmann, W. E., & Reiss, A. L. (1999). Molecular and cellular genetics of fragile X syndrome. American Journal of Medical Genetics, 88, 11–24.CrossRefPubMedGoogle Scholar
  29. Kenneson, A., & Warren, S. T. (2001). The female and the fragile X reviewed. Seminars in Reproductive Medicine, 19, 159–165.CrossRefPubMedGoogle Scholar
  30. Laxova, R. (1994). Fragile X syndrome. Advances in Pediatrics, 41, 305–342.PubMedGoogle Scholar
  31. Lozano, R., Rosero, C. A., & Hagerman, R. J. (2014). Fragile X spectrum disorders. Intractable & Rare Diseases Research, 3, 134–146.CrossRefGoogle Scholar
  32. Lubs, H. A. (1969). A marker X chromosome. American Journal of Human Genetics, 21, 231–244.PubMedPubMedCentralGoogle Scholar
  33. Musci, T. J., & Moyer, K. (2010). Prenatal carrier testing for fragile X: Counseling issues and challenges. Obstetrics and Gynecology Clinics of North America, 37, 61–70.CrossRefPubMedGoogle Scholar
  34. Naber, S. P. (1995). Molecular diagnosis of fragile X syndrome. Diagnostic Molecular Pathology, 4, 158–161.CrossRefPubMedGoogle Scholar
  35. Nolin, S. L., Brown, W. T., Glicksman, A., et al. (2003). Expansion of the fragile X CGG repeat in females with premutation or intermediate alleles. American Journal of Human Genetics, 72, 454–464.CrossRefPubMedPubMedCentralGoogle Scholar
  36. Oostra, B. A., & Willemsen, R. (2001). Diagnostic tests for fragile X syndrome. Expert Review of Molecular Diagnostics, 1, 226–232.CrossRefPubMedGoogle Scholar
  37. Oostra, B. A., Jacky, P. B., Brown, W. T., et al. (1993). Guidelines for the diagnosis of fragile X syndrome. Journal of Medical Genetics, 30, 410–413.CrossRefPubMedPubMedCentralGoogle Scholar
  38. Opitz, J. M. (1986). On the gates of hell and a most unusual gene (editorial). American Journal of Medical Genetics, 23, 1–10.CrossRefPubMedGoogle Scholar
  39. Park, V., Howard-Peebles, P., Sherman, S., et al. (1994). Fragile X syndrome: Diagnostic and carrier testing. American Journal of Medical Genetics, 53, 380–381.CrossRefGoogle Scholar
  40. Rousseau, F., Heitz, D., Biancalana, V., et al. (1991). Direct diagnosis by DNA analysis of the fragile X syndrome of mental retardation. The New England Journal of Medicine, 325, 1673–1681.CrossRefPubMedGoogle Scholar
  41. Saul, R. A., & Tarleton, J. C. (2012). FMR1-related disorders. GeneReviews. Updated 26 Apr 2012. Available at
  42. Schaefer, T. L., Davenport, M. H., & Erickson, C. A. (2015). Emerging pharmacologic treatment options for fragile X syndrome. The Application of Clinical Genetics, 8, 75–93.PubMedPubMedCentralGoogle Scholar
  43. Sherman, S. L., Morton, N. E., Jacobs, P. A., et al. (1984). The marker (X) syndrome: A cytogenetic and genetic analysis. Annals of Human Genetics, 48, 21–37.CrossRefPubMedGoogle Scholar
  44. Sherman, S. L., Jacobs, P. A., Morton, N. E., et al. (1985). Further segregation analysis of the fragile X syndrome with special reference to transmitting males. Human Genetics, 69, 289–299.CrossRefPubMedGoogle Scholar
  45. Sherman, S., Pletcher, B. A., & Driscoll, D. A. (2005). Fragile X syndrome: Diagnostic and carrier testing. Genetics in Medicine, 7, 584–587.CrossRefPubMedPubMedCentralGoogle Scholar
  46. Tarleton, J. C., & Saul, R. A. (1993). Molecular genetic advances in fragile X syndrome. Journal of Pediatrics, 122, 169–185.CrossRefPubMedGoogle Scholar
  47. Verkerk, A. J. M. H., Pieretti, M., Sutcliffe, J. S., et al. (1991). Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell, 65, 905–914.CrossRefPubMedGoogle Scholar
  48. Warren, S. T., & Nelson, D. L. (1994). Advances in molecular analysis of fragile X syndrome. Journal of the American Medical Association, 271, 536–542.CrossRefPubMedGoogle Scholar
  49. Webb, T. (1989). The epidemiology of the fragile X syndrome. In K. E. Davis (Ed.), The fragile X syndrome (pp. 40–55). Oxford: Oxford University Press.Google Scholar
  50. Willemsen, R., & Oostra, B. A. (2000). FMRP detection assay for the diagnosis of the fragile X syndrome. American Journal of Medical Genetics (Seminars in Medical Genetics), 97, 183–188.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Medical GeneticsShriners Hospitals for ChildrenShreveportUSA
  2. 2.Perinatal and Clinical Genetics, Department of PediatricsLSU Health Sciences CenterShreveportUSA

Personalised recommendations