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

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.

Preimplantation genetic diagnosis versus prenatal diagnosis—decision-making among pregnant FMR1 premutation carriers

“…FMR1 premutation carriers present a spectrum of health disorders, the most prevalent being Fragile X-associated tremor-ataxia syndrome (FXTAS), affecting both males and females in the fifth or sixth decade of life, and Fragile X-associated primary ovarian insufficiency (FXPOI). In addition, FMR1 premutation carriers are reported to have an increased rate of various psychological, endocrine, autoimmune, and metabolic disorders [5]. Since the premutation CGG segment is unstable and may expand, women carrying a premutation allele are at risk of transmitting a full mutation to their offspring, resulting in a FXS-affected child with some phenotypic variation by gender of the offspring [6].…”

The significance of FMR1 CGG repeats in Chinese women with premature ovarian insufficiency and diminished ovarian reserve

“…The main cause of POI is unknown, but genetic factors, autoimmune ovarian damage, iatrogenic and environmental factors are the known causes. Among all the genetic factors implicated for POI, the FMR1 premutation is regarded as the leading single-gene cause of POI [ 34 ]. If FMR1 screening for the target population could select women with high risk of POI, it has long-term benefits to family and enables them in planning the families with an opportunity to adopt alternate methods.…”

A Single Common Assay for Robust and Rapid Fragile X Mental Retardation Syndrome Screening From Dried Blood Spots

“…Moreover, a significant fraction of PM carriers (40% males and 8–16% females) are affected by late-onset fragile X-associated tremor / ataxia syndrome (FXTAS; OMIM 300623) ( Jacquemont et al, 2004 ; Rodriguez-Revenga et al, 2009 ). Another late-onset condition, fragile X-associated premature ovarian insufficiency (FXPOI; OMIM 311360) afflicts 20% of female PM carriers ( Rodriguez-Revenga et al, 2009 ; Hoyos and Thakur, 2017 ).…”