Fragile X premutation is a significant risk factor for premature ovarian failure: The international collaborative POF in fragile X study?preliminary data

Abstract

The preliminary results of an international collaborative study examining premature menopause in fragile X carriers are presented. A total of 760 women from fragile X families was surveyed about their fragile X carrier status and their menstrual and reproductive histories. Among the subjects, 395 carried a premutation, 128 carried a full mutation, and 237 were noncarriers. Sixty-three (16%) of the premutation carriers had experienced menopause prior to the age of 40 compared with none of the full mutation carriers and one (0.4%) of the controls. Based on these preliminary data, there is a significant association between fragile X premutation carrier status and premature menopause.

Fragile X-associated disorders: a clinical overview

“…Premutation carrier females of FraX have an increased risk of chronic muscle pain and thyroid disease-particularly hypothyroidism, which is associated with increased symptoms of depression and anxiety [73][74][75]. Elevated levels of follicle stimulating hormone are common [76], and ovarian insufficiency occurs in approximately 20% of individuals [77].…”

“…Primary ovarian insufficiency (POI) is defined as the cessation of menses before the age of 40 and occurs in approximately 20% of premutation females with FraX [77,84] compared to 1% of the general population [85]. POI is characterized by loss of oocytes, lack of folliculogenesis, reduced ovarian oestrogen production, elevated serum gonadotropin levels, amenorrhoea, and infertility in women before the age of 40.…”

Immunocytochemical characterization of FMRP, FXR1P and FXR2P during embryonic development in the mouse

“…Interestingly, the tissue-specific Fmr1 gene expression coincides with the organ involvement in the fragile X phenotype. The high expression of Fmrp in female primordial germ cells is of special interest with respect to the significant higher risk for premature ovarian failure (POF) in females with a premutation [25]. A recent study has suggested a role for paternal genomic imprinting as the cause of POF in females carrying a premutation [26].…”

FMR1 repeat sizes in the gray zone and high end of the normal range are associated with premature ovarian failure

“…In the last 10 years, it has become apparent that female carriers of premutation size alleles are at an increased risk of POF. Approximately 20% of premutation carriers experience POF (Schwartz et al 1994;Allingham-Hawkins et al 1999). Premutation size alleles are found in $7% of individuals with sporadic POF and in 21% of familial POF cases but have a prevalence of only 0.4% in control women (for a review, see Sherman 2000).…”