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Journal of Assisted Reproduction and Genetics

, Volume 34, Issue 3, pp 315–323 | Cite as

Fragile X premutation in women: recognizing the health challenges beyond primary ovarian insufficiency

  • Luis R. Hoyos
  • Mili Thakur
Review

Abstract

Fragile X premutation carriers have 55–200 CGG repeats in the 5’ untranslated region of the FMR1 gene. Women with this premutation face many physical and emotional challenges in their life. Approximately 20% of these women will develop fragile X-associated primary ovarian insufficiency (FXPOI). In addition, they suffer from increased rates of menstrual dysfunction, diminished ovarian reserve, reduction in age of menopause, infertility, dizygotic twinning, and risk of having an offspring with a premutation or full mutation. Consequent chronic hypoestrogenism may result in impaired bone health and increased cardiovascular risk. Neuropsychiatric issues include risk of developing fragile X-associated tremor/ataxia syndrome, neuropathy, musculoskeletal problems, increased prevalence of anxiety, depression, and sleep disturbances independent of the stress of raising an offspring with fragile X syndrome and higher risk of postpartum depression. Some studies have reported a higher prevalence of thyroid abnormalities and hypertension in these women. Reproductive health providers play an important role in the health supervision of women with fragile X premutation. Awareness of these risks and correlation of the various manifestations could help in early diagnosis and coordination of care and services for these women and their families. This paper reviews current evidence regarding the possible conditions that may present in women with premutation-sized repeats beyond FXPOI.

Keywords

Fragile X premutation Primary ovarian insufficiency Premature ovarian insufficiency Fragile X-associated tremor/ataxia syndrome Health concerns in fragile X premutation carriers 

References

  1. 1.
    Fu YH, Kuhl DP, Pizzuti A, Pieretti M, Sutcliffe JS, Richards S, et al. Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. Cell. 1991;67(6):1047–58.CrossRefPubMedGoogle Scholar
  2. 2.
    Maddalena A, Richards CS, McGinniss MJ, Brothman A, Desnick RJ, Grier RE, et al. Technical standards and guidelines for fragile X: the first of a series of disease-specific supplements to the Standards and Guidelines for Clinical Genetics Laboratories of the American College of Medical Genetics. Quality Assurance Subcommittee of the Laboratory Practice Committee. Genet Med. 2001;3(3):200–5.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Sherman S, Pletcher BA, Driscoll DA. Fragile X syndrome: diagnostic and carrier testing. Genet Med. 2005;7(8):584–7.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Genetics ACoOaGCo. ACOG Committee Opinion No 469: carrier screening for fragile X syndrome. Obstet Gynecol. 2010;116(4):1008–10.CrossRefGoogle Scholar
  5. 5.
    Sutcliffe JS, Nelson DL, Zhang F, Pieretti M, Caskey CT, Saxe D, et al. DNA methylation represses FMR-1 transcription in fragile X syndrome. Hum Mol Genet. 1992;1(6):397–400.CrossRefPubMedGoogle Scholar
  6. 6.
    Pieretti M, Zhang FP, Fu YH, Warren ST, Oostra BA, Caskey CT, et al. Absence of expression of the FMR-1 gene in fragile X syndrome. Cell. 1991;66(4):817–22.CrossRefPubMedGoogle Scholar
  7. 7.
    Jin P, Warren ST. Understanding the molecular basis of fragile X syndrome. Hum Mol Genet. 2000;9(6):901–8.CrossRefPubMedGoogle Scholar
  8. 8.
    Zalfa F, Giorgi M, Primerano B, Moro A, Di Penta A, Reis S, et al. The fragile X syndrome protein FMRP associates with BC1 RNA and regulates the translation of specific mRNAs at synapses. Cell. 2003;112(3):317–27.CrossRefPubMedGoogle Scholar
  9. 9.
    Kim M, Bellini M, Ceman S. Fragile X mental retardation protein FMRP binds mRNAs in the nucleus. Mol Cell Biol. 2009;29(1):214–28.CrossRefPubMedGoogle Scholar
  10. 10.
    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(14):1449–54.CrossRefPubMedGoogle Scholar
  11. 11.
    Greco CM, Berman RF, Martin RM, Tassone F, Schwartz PH, Chang A, et al. Neuropathology of fragile X-associated tremor/ataxia syndrome (FXTAS). Brain. 2006;129(Pt 1):243–55.PubMedGoogle Scholar
  12. 12.
    Gokden M, Al-Hinti JT, Harik SI. Peripheral nervous system pathology in fragile X tremor/ataxia syndrome (FXTAS). Neuropathology. 2009;29(3):280–4.CrossRefPubMedGoogle Scholar
  13. 13.
    Greco CM, Soontrapornchai K, Wirojanan J, Gould JE, Hagerman PJ, Hagerman RJ. Testicular and pituitary inclusion formation in fragile X associated tremor/ataxia syndrome. J Urol. 2007;177(4):1434–7.CrossRefPubMedGoogle Scholar
  14. 14.
    Hantash FM, Goos DM, Crossley B, Anderson B, Zhang K, Sun W, et al. FMR1 premutation carrier frequency in patients undergoing routine population-based carrier screening: insights into the prevalence of fragile X syndrome, fragile X-associated tremor/ataxia syndrome, and fragile X-associated primary ovarian insufficiency in the United States. Genet Med. 2011;13(1):39–45.CrossRefPubMedGoogle Scholar
  15. 15.
    Tassone F, Iong KP, Tong TH, Lo J, Gane LW, Berry-Kravis E, et al. FMR1 CGG allele size and prevalence ascertained through newborn screening in the United States. Genome Med. 2012;4(12):100.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Oostra BA, Willemsen R. FMR1: a gene with three faces. Biochim Biophys Acta. 2009;1790(6):467–77.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Murray A, Ennis S, MacSwiney F, Webb J, Morton NE. Reproductive and menstrual history of females with fragile X expansions. Eur J Hum Genet. 2000;8(4):247–52.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Wittenberger MD, Hagerman RJ, Sherman SL, McConkie-Rosell A, Welt CK, Rebar RW, et al. The FMR1 premutation and reproduction. Fertil Steril. 2007;87(3):456–65.CrossRefPubMedGoogle Scholar
  19. 19.
    De Caro JJ, Dominguez C, Sherman SL. Reproductive health of adolescent girls who carry the FMR1 premutation: expected phenotype based on current knowledge of fragile x-associated primary ovarian insufficiency. Ann N Y Acad Sci. 2008;1135:99–111.CrossRefPubMedGoogle Scholar
  20. 20.
    Allingham-Hawkins DJ, Babul-Hirji R, Chitayat D, Holden JJ, Yang KT, Lee C, et al. Fragile X premutation is a significant risk factor for premature ovarian failure: the International Collaborative POF in fragile X study—preliminary data. Am J Med Genet. 1999;83(4):322–5.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Ennis S, Ward D, Murray A. Nonlinear association between CGG repeat number and age of menopause in FMR1 premutation carriers. Eur J Hum Genet. 2006;14(2):253–5.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Sullivan AK, Marcus M, Epstein MP, Allen EG, Anido AE, Paquin JJ, et al. Association of FMR1 repeat size with ovarian dysfunction. Hum Reprod. 2005;20(2):402–12.CrossRefPubMedGoogle Scholar
  23. 23.
    Tejada MI, García-Alegría E, Bilbao A, Martínez-Bouzas C, Beristain E, Poch M, et al. Analysis of the molecular parameters that could predict the risk of manifesting premature ovarian failure in female premutation carriers of fragile X syndrome. Menopause. 2008;15(5):945–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Allen EG, Sullivan AK, Marcus M, Small C, Dominguez C, Epstein MP, et al. Examination of reproductive aging milestones among women who carry the FMR1 premutation. Hum Reprod. 2007;22(8):2142–52.CrossRefPubMedGoogle Scholar
  25. 25.
    Welt CK, Smith PC, Taylor AE. Evidence of early ovarian aging in fragile X premutation carriers. J Clin Endocrinol Metab. 2004;89(9):4569–74.CrossRefPubMedGoogle Scholar
  26. 26.
    Rohr J, Allen EG, Charen K, Giles J, He W, Dominguez C, et al. Anti-Mullerian hormone indicates early ovarian decline in fragile X mental retardation (FMR1) premutation carriers: a preliminary study. Hum Reprod. 2008;23(5):1220–5.CrossRefPubMedGoogle Scholar
  27. 27.
    Chonchaiya W, Nguyen DV, Au J, Campos L, Berry-Kravis EM, Lohse K, et al. Clinical involvement in daughters of men with fragile X-associated tremor ataxia syndrome. Clin Genet. 2010;78(1):38–46.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Bibi G, Malcov M, Yuval Y, Reches A, Ben-Yosef D, Almog B, et al. The effect of CGG repeat number on ovarian response among fragile X premutation carriers undergoing preimplantation genetic diagnosis. Fertil Steril. 2010;94(3):869–74.CrossRefPubMedGoogle Scholar
  29. 29.
    Gleicher N, Weghofer A, Lee IH, Barad DH. Association of FMR1 genotypes with in vitro fertilization (IVF) outcomes based on ethnicity/race. PLoS One. 2011;6(4):e18781.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Kushnir VA, Yu Y, Barad DH, Weghofer A, Himaya E, Lee HJ, et al. Utilizing FMR1 gene mutations as predictors of treatment success in human in vitro fertilization. PLoS One. 2014;9(7):e102274.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Hinds HL, Ashley CT, Sutcliffe JS, Nelson DL, Warren ST, Housman DE, et al. Tissue specific expression of FMR-1 provides evidence for a functional role in fragile X syndrome. Nat Genet. 1993;3(1):36–43.CrossRefPubMedGoogle Scholar
  32. 32.
    Hagerman RJ, Leehey M, Heinrichs W, Tassone F, Wilson R, Hills J, et al. Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology. 2001;57(1):127–30.CrossRefPubMedGoogle Scholar
  33. 33.
    Jacquemont S, Hagerman RJ, Leehey MA, Hall DA, Levine RA, Brunberg JA, et al. Penetrance of the fragile X-associated tremor/ataxia syndrome in a premutation carrier population. JAMA. 2004;291(4):460–9.CrossRefPubMedGoogle Scholar
  34. 34.
    Jacquemont S, Hagerman RJ, Leehey M, Grigsby J, Zhang L, Brunberg JA, et al. Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates. Am J Hum Genet. 2003;72(4):869–78.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Hagerman PJ, Hagerman RJ. The fragile-X premutation: a maturing perspective. Am J Hum Genet. 2004;74(5):805–16.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Coffey SM, Cook K, Tartaglia N, Tassone F, Nguyen DV, Pan R, et al. Expanded clinical phenotype of women with the FMR1 premutation. Am J Med Genet A. 2008;146A(8):1009–16.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Rodriguez-Revenga L, Madrigal I, Pagonabarraga J, Xunclà M, Badenas C, Kulisevsky J, et al. Penetrance of FMR1 premutation associated pathologies in fragile X syndrome families. Eur J Hum Genet. 2009;17(10):1359–62.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Berry-Kravis E, Abrams L, Coffey SM, Hall DA, Greco C, Gane LW, et al. Fragile X-associated tremor/ataxia syndrome: clinical features, genetics, and testing guidelines. Mov Disord. 2007;22(14):2018–30. quiz 140.CrossRefPubMedGoogle Scholar
  39. 39.
    Adams JS, Adams PE, Nguyen D, Brunberg JA, Tassone F, Zhang W, et al. Volumetric brain changes in females with fragile X-associated tremor/ataxia syndrome (FXTAS). Neurology. 2007;69(9):851–9.CrossRefPubMedGoogle Scholar
  40. 40.
    Hunter JE, Rohr JK, Sherman SL. Co-occurring diagnoses among FMR1 premutation allele carriers. Clin Genet. 2010;77(4):374–81.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Au J, Akins R, Berkowitz-Sutherland L, Tang HT, Chen Y, Boyd A, et al. Prevalence and risk of migraine headaches in adult fragile X premutation carriers. Clin Genet. 2013;84:546–51.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Bourgeois JA, Coffey SM, Rivera SM, Hessl D, Gane LW, Tassone F, et al. A review of fragile X premutation disorders: expanding the psychiatric perspective. J Clin Psychiatry. 2009;70(6):852–62.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Karmon Y, Gadoth N. Fragile X associated tremor/ataxia syndrome (FXTAS) with dementia in a female harbouring FMR1 premutation. J Neurol Neurosurg Psychiatry. 2008;79(6):738–9.CrossRefPubMedGoogle Scholar
  44. 44.
    Al-Hinti JT, Nagan N, Harik SI. Fragile X premutation in a woman with cognitive impairment, tremor, and history of premature ovarian failure. Alzheimer Dis Assoc Disord. 2007;21(3):262–4.CrossRefPubMedGoogle Scholar
  45. 45.
    Rodriguez-Revenga L, Pagonabarraga J, Gómez-Anson B, López-Mourelo O, Madrigal I, Xunclà M, et al. Motor and mental dysfunction in mother-daughter transmitted FXTAS. Neurology. 2010;75(15):1370–6.CrossRefPubMedGoogle Scholar
  46. 46.
    Tassone F, Greco CM, Hunsaker MR, Seritan AL, Berman RF, Gane LW, et al. Neuropathological, clinical and molecular pathology in female fragile X premutation carriers with and without FXTAS. Genes Brain Behav. 2012;11(5):577–85.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Franke P, Leboyer M, Gänsicke M, Weiffenbach O, Biancalana V, Cornillet-Lefebre P, et al. Genotype-phenotype relationship in female carriers of the premutation and full mutation of FMR-1. Psychiatry Res. 1998;80(2):113–27.CrossRefPubMedGoogle Scholar
  48. 48.
    Johnston C, Eliez S, Dyer-Friedman J, Hessl D, Glaser B, Blasey C, et al. Neurobehavioral phenotype in carriers of the fragile X premutation. Am J Med Genet. 2001;103(4):314–9.CrossRefPubMedGoogle Scholar
  49. 49.
    Roberts JE, Bailey DB, Mankowski J, Ford A, Sideris J, Weisenfeld LA, et al. Mood and anxiety disorders in females with the FMR1 premutation. Am J Med Genet B Neuropsychiatr Genet. 2009;150B(1):130–9.CrossRefPubMedGoogle Scholar
  50. 50.
    Obadia RW, Iosif A-M, Seritan AL. Postpartum depression in women with the FMR1 premutation. Curr Psychiatr Rev. 2013;9(1):72–6.Google Scholar
  51. 51.
    Bourgeois JA, Seritan AL, Casillas EM, Hessl D, Schneider A, Yang Y, et al. Lifetime prevalence of mood and anxiety disorders in fragile X premutation carriers. J Clin Psychiatry. 2011;72(2):175–82.CrossRefPubMedGoogle Scholar
  52. 52.
    Clifford S, Dissanayake C, Bui QM, Huggins R, Taylor AK, Loesch DZ. Autism spectrum phenotype in males and females with fragile X full mutation and premutation. J Autism Dev Disord. 2007;37(4):738–47.CrossRefPubMedGoogle Scholar
  53. 53.
    Seritan AL, Ortigas M, Seritan S, Bourgeois JA, Hagerman RJ. Psychiatric disorders associated with FXTAS. Curr Psychiatr Rev. 2013;9(1):59–64(6).Google Scholar
  54. 54.
    Winarni TI, Chonchaiya W, Sumekar TA, Ashwood P, Morales GM, Tassone F, et al. Immune-mediated disorders among women carriers of fragile X premutation alleles. Am J Med Genet A. 2012;158A(10):2473–81.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Department of Obstetrics and GynecologyWayne State University School of MedicineDetroitUSA
  2. 2.Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and GynecologyWayne State University School of MedicineDetroitUSA
  3. 3.Division of Genetic and Metabolic Disorders, Department of Pediatrics and Center for Molecular Medicine and GeneticsWayne State University School of MedicineDetroitUSA

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