Female infertility associated with the FMR1 gene premutation

Cover Page

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription Access

Abstract

Background: The FMR1 gene premutation (the number of CGG repeats ranging from 55 to 200) is considered to be an important genetic factor associated with the development of premature ovarian failure (POF), decreased ovarian reserve and impaired reproductive function in women. Despite the extremely low levels of anti-Müllerian hormone (AMH) and the presence of severe symptoms of hypoestrogenism, there is a possibility of spontaneous pregnancy in some cases. This requires an individual approach and timely genetic counseling.

Case report: This was an observation of a 27-year-old patient with the FMR1 premutation (34-94 CGG repeats), AMH level of 0.01 ng/ml and severe ovarian hypoplasia revealed by ultrasound scanning of the pelvic organs. After undergoing hormone replacement therapy (HRT) and ovulation stimulation, the patient became pregnant and her pregnancy resulted in timely delivery of a girl.

Conclusion: This clinical observation emphasizes the importance of a personalized approach to the management of patients with FMR1 gene mutation. The aim of this approach is not only to control hypoestrogenism, but also to achieve conception using modern opportunities of assisted reproduction and fertility preservation programs.

About the authors

Natalia A. Savelyeva

Lapino Clinical Hospital, Mother and Child Group of Companies

Author for correspondence.
Email: n.saveleva@mcclinics.ru
ORCID iD: 0000-0001-9719-9447

PhD, gynecologist-reproductologist, E.G. Lebedeva Center for Innovative Reproductive Technologies

Russian Federation, Moscow

Yulia A. Fetisova

Lapino Clinical Hospital, Mother and Child Group of Companies

Email: n.saveleva@mcclinics.ru

Head of the E.G. Lebedeva Center for Innovative Reproductive Technologies

Russian Federation, Moscow

Elena E. Baranova

MGIMO-MED Medical University

Email: n.saveleva@mcclinics.ru

PhD, Associate Professor, Department of Fundamental Disciplines

Russian Federation, Moscow Region

References

  1. National Center for Biotechnology Information. FMR1 fragile X messenger ribonucleoprotein 1 [Homo sapiens (human)]. Gene ID: 2332. Available at: https://www.ncbi.nlm.nih.gov/gene/2332
  2. Hunter J.E., Berry-Kravis E., Hipp H., Todd P.K., Adam M.P., Feldman J. et al. FMR1 Disorders. In: Adam M.P., eds. GeneReviews®. Seattle (WA): University of Washington; 1998. Updated May 16, 2024.
  3. Nelson L.M., Covington S.N., Rebar R.W. An update: spontaneous premature ovarian failure is not an early menopause. Fertil. Steril. 2005; 83(5): 1327-32. https://dx.doi.org/10.1016/j.fertnstert.2004.11.059
  4. Tassone F., Protic D., Allen E.G., Archibald A.D., Baud A., Brown T.W. et al. Insight and recommendations for fragile X-premutation-associated conditions from the Fifth International Conference on FMR1 Premutation. Cells. 2023; 12(18): 2330. https://dx.doi.org/10.3390/cells12182330
  5. Hessl D., Rosselot H., Miller R., Espinal G., Famula J., Sherman S.L. et al. The International fragile X premutation registry: building a resource for research and clinical trial readiness. J. Med. Genet. 2022; 59(12): 1165-70. https:// dx.doi.org/10.1136/jmedgenet-2022-108568
  6. Рштуни С.Д., Зарецкая Н.В., Кузнецова М.В., Марченко Л.А. Особенности наследования тринуклеотидных CGG повторов в гене FMR1 от женщин с преждевременной недостаточностью яичников: серия случаев. Акушерство и гинекология. 2023; 3: 91-8. [Rshtuni S.D., Zaretskaya N.V., Kuznetsova M.V., Marchenko L.A. FMR1 inherited from women with premature ovarian failure: case series. Obstetrics and Gynecology. 2023; (3): 91-8 (in Russian)]. https://dx.doi.org/10.18565/ aig.2022.285
  7. Allen E.G., Sullivan A.K., Marcus M., Small C., Dominguez C., Epstein M.P. et al. Examination of reproductive aging milestones among women who carry the FMR1 premutation. Hum. Reprod. 2007; 22(8): 2142-52. https:// dx.doi.org/10.1093/humrep/dem148
  8. De Caro J.J., Dominguez C., Sherman S.L. Reproductive health of adolescent girls who carry the FMR1 premutation: expected phenotype based on current knowledge of fragile x-associated primary ovarian insufficiency. Ann. NY Acad. Sci. 2008; 1135: 99-111. https://dx.doi.org/10.1196/annals.1429.029
  9. Stone W.L., Basit H., Shah M., Los E. Fragile X Syndrome. 2023 Oct 28. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan–.
  10. Hessl D., Rosselot H., Miller R., Espinal G., Famula J., Sherman S.L. et al. The International fragile X premutation registry: building a resource for research and clinical trial readiness. J. Med. Genet. 2022; 59(12): 1165-70. https:// dx.doi.org/10.1136/jmedgenet-2022-108568
  11. Hipp H.S., Charen K.H., Spencer J.B., Allen E.G., Sherman S.L. Reproductive and gynecologic care of women with fragile X primary ovarian insufficiency (FXPOI). Menopause. 2016; 23(9): 993-9. https://dx.doi.org/10.1097/GME.0000000000000658
  12. Rose B.I., Brown S.E. An explanation of the mechanisms underlying fragile X-associated premature ovarian insufficiency. J. Assist. Reprod. Genet. 2020; 37(6): 1313-22. https://dx.doi.org/10.1007/s10815-020-01774-x
  13. Friedman-Gohas M., Elizur S.E., Dratviman-Storobinsky O., Aizer A., Haas J., Raanani H. et al. FMRpolyG accumulates in FMR1 premutation granulosa cells. J. Ovarian. Res. 2020; 13(1): 22. https://dx.doi.org/10.1186/ s13048-020-00623-w
  14. Meng L., Jan S.Z., Hamer G., van Pelt A.M., van der Stelt I., Keijer J. et al. Preantral follicular atresia occurs mainly through autophagy, while antral follicles degenerate mostly through apoptosis. Biol Reprod. 2018; 99(4): 853-63. https://dx.doi.org/10.1093/biolre/ioy116
  15. Conca Dioguardi C., Uslu B., Haynes M., Kurus M., Gul M., Miao D.Q. et al. Granulosa cell and oocyte mitochondrial abnormalities in a mouse model of fragile X primary ovarian insufficiency. Mol. Hum. Reprod. 2016; 22(6): 384-96. https://dx.doi.org/10.1093/molehr/gaw023
  16. Fink D.A., Nelson L.M., Pyeritz R., Johnson J., Sherman S.L., Cohen Y. et al. Fragile X associated primary ovarian insufficiency (FXPOI): case report and literature review. Front. Genet. 2018; 9: 529. https://dx.doi.org/10.3389/fgene.2018.00529
  17. Popat V.B., Vanderhoof V.H., Calis K.A., Troendle J.F., Nelson L.M. Normalization of serum luteinizing hormone levels in women with 46, XX spontaneous primary ovarian insufficiency. Fertil. Steril. 2008; 89(2): 429-33. https:// dx.doi.org/10.1016/j.fertnstert.2007.02.032
  18. Sonigo C., Mayeur A., Sadoun M., Pinto M., Benguigui J., Frydman N. et al. What is the threshold of mature oocytes to obtain at least one healthy transferable cleavage-stage embryo after preimplantation genetic testing for fragile X syndrome? Hum. Reprod. 2021; 36(11): 3003-13. https://dx.doi.org/10.1093/humrep/deab214
  19. Hutchinson A.P., Pereira N., Lilienthal D.P., Coveney S., Lekovich J.P., Elias R.T. et al. Impact of FMR1 pre-mutation status on blastocyst development in patients undergoing pre-implantation genetic diagnosis. Gynecol. Obstet. Invest. 2018; 83(1): 23-8. https://dx.doi.org/10.1159/000455849
  20. Fernández R.M., Peciña A., Lozano-Arana M.D., Sánchez B., García-Lozano J.C., Borrego S. et al. Clinical and technical overview of preimplantation genetic diagnosis for fragile X syndrome: experience at the University Hospital Virgen del Rocio in Spain. Biomed. Res. Int. 2015; 2015: 965839. https:// dx.doi.org/10.1155/2015/965839
  21. Liu X.S., Wu H., Krzisch M., Wu X., Graef J., Muffat J. et al. Rescue of fragile X syndrome neurons by DNA methylation editing of the FMR1 gene. Cell. 2018; 172(5): 979-92.e6. https://dx.doi.org/10.1016/j.cell.2018.01.012

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Согласие на обработку персональных данных

 

Используя сайт https://journals.rcsi.science, я (далее – «Пользователь» или «Субъект персональных данных») даю согласие на обработку персональных данных на этом сайте (текст Согласия) и на обработку персональных данных с помощью сервиса «Яндекс.Метрика» (текст Согласия).