Fragile X-Associated Diminished Ovarian Reserve and Primary Ovarian Insufficiency from Molecular Mechanisms to Clinical Manifestations

Abstract

Fragile X syndrome (FXS), is caused by a loss-of-function mutation in the FMR1 gene located on the X-chromosome, which leads to the most common cause of inherited intellectual disability in males and the leading single-gene defect associated with autism. A full mutation (FM) is represented by more than 200 CGG repeats within the FMR1 gene, resulting in FXS. A FM is inherited from women carrying a FM or a premutation (PM; 55-200 CGG repeats) allele. PM is associated with phenotypes distinct from those associated with FM. Some manifestations of the PM are unique; fragile-X-associated tremor/ataxia syndrome (FXTAS), and fragile-X-associated primary ovarian insufficiency (FXPOI), while others tend to be non-specific such as intellectual disability. In addition, women carrying a PM may suffer from subfertility or infertility. There is a need to elucidate whether the impairment of ovarian function found in PM carriers arises during the primordial germ cell (PGC) development stage, or due to a rapidly diminishing oocyte pool throughout life or even both. Due to the possibility of expansion into a FM in the next generation, and other ramifications, carrying a PM can have an enormous impact on one's life; therefore, preconception counseling for couples carrying the PM is of paramount importance. In this review, we will elaborate on the clinical manifestations in female PM carriers and propose the definition of fragile-X-associated diminished ovarian reserve (FXDOR), then we will review recent scientific findings regarding possible mechanisms leading to FXDOR and FXPOI. Lastly, we will discuss counseling, preventative measures and interventions available for women carrying a PM regarding different aspects of their reproductive life, fertility treatment, pregnancy, prenatal testing, contraception and fertility preservation options.

Keywords: FMR1 premutation carriers; diminished ovarian reserve; fragile X syndrome; fragile-X-associated diminished ovarian reserve; fragile-X-associated primary ovarian insufficiency.

Figure 1

Proposed model of major points of gonadal impairment consequent to FMR1 premutation (PM) presence during fetal and adult life. (A) Establishment of the primordial germ cell (PGC) pool in a fetus with a PM. Due to reduced FMRP, the final endowment, as well as maintenance of the PGC, could be affected. The graph outlines the relationship between the number of oogonia and gestational age till birth. Damage to the PGCs and consequent reduction in the PGC pool size will result in reduced number of oogonia, thus shifting the graph downwards, from the non-carrier range (black line) to the PM carrier range (blue line). (B) Cellular dysfunction in the adult ovary of a PM carrier. The ovary suffers damage at the cellular level, which is clinically manifested as a diminished ovarian reserve. As seen on the left, the impairment occurs in the granulosa as well as the stroma cells of the ovary. Reduction in the number of oocytes/follicles could occur as a consequence of the mRNA-induced granulosa cell toxicity and subsequent dysfunction, detrimental effect of the inclusions containing FMRpolyG on the stroma cells, or both. On the right, a schematic representation of the number of oocytes, in non-carriers (black line) or PM patients (blue line). The graph emphasizes that the PM carriers’ ovaries contain fewer oocytes than non-carriers’, at any age.