Premature ovarian failure (POF) and fragile X premutation females: From POF to fragile X carrier identification, from fragile X carrier diagnosis to POF association data

Abstract

Early menopause in the fragile X carriers has been well documented in several reports. All surveys demonstrated that 13-25% of fragile X carriers experienced premature ovarian failure (POF), defined as menopause before the age of 40 years. In 1995 we started screening two groups of subjects as a part of a Fragile X Research Program: 1) women previously diagnosed as fragile X carriers from the register of our center and 2) women with POF and without a family history of fragile X or other forms of mental retardation. In this study we report the preliminary data collected from 75 fragile X families; in 30 of them, POF was present in one or several subjects, all of whom had a fragile X premutation. None of the women with a full mutation experienced POF in our series of patients. We also identified 89 families without a family history of fragile X or mental retardation, and there were 108 subjects who experienced POF, of which 6.5% had a fragile X premutation. This is 70-fold higher than the background prevalence of fragile X premutation in the Italian population and suggests an association with POF. These data confirm the results of other surveys.

Immune Dysregulation as a Cause of Autoinflammation in Fragile X Premutation Carriers: Link between FMRI CGG Repeat Number and Decreased Cytokine Responses

“…One of the earliest associated disorders observed in premutation carriers was primary ovarian insufficiency (FXPOI), noted in approximately 16–20% of female carriers [6]–[9]. Fragile X-associated tremor/ataxia syndrome (FXTAS) was described later in premutation carriers who developed intention tremor and gait ataxia [10], [11].…”

Immune‐mediated disorders among women carriers of fragile X premutation alleles

“…The prevalence of the premutation allele is 1 in 130–259 women and 1 in 250–813 men in the general population [Fernandez-Carvajal et al, 2009; Hagerman, 2008; Rousseau et al, 1995]. Several disorders are associated with the premutation allele; including fragile X-associated primary ovarian insufficiency (FXPOI; cessation of menses before age 40) [Murray A, 1995; Sullivan et al, 2005; Uzielli et al, 1999]; fragile X-associated tremor/ataxia syndrome (FXTAS) [Hagerman et al, 2001; Leehey et al, 2007]; psychiatric dysfunction, including depression and anxiety [Bourgeois et al, 2010; Roberts et al, 2009]; and hypertension [Coffey et al, 2008; Hamlin et al, 2012]. Recently, immune-mediated disorders (IMDs), specifically autoimmune thyroid disorder (AITD) and fibromyalgia, were found to be associated with the premutation in women with FXTAS compared to age-matched controls [Coffey et al, 2008].…”

Initiation of Translation of the FMR1 mRNA Occurs Predominantly through 5′-End-Dependent Ribosomal Scanning

“…(Reviews: 8; 10) Smaller “premutation” expansions (55 to 200 CGG repeats) are also associated with increased risk of developmental delay and autism 1112 Premutation expansions are additionally linked to two premutation-specific disorders, primary ovarian insufficiency (POI), with loss of ovarian function before the age of 4013; 14; 15; 16; and the neurodegenerative disorder fragile X-associated tremor/ataxia syndrome (FXTAS),17; 18; 19 which involves the core features of intention tremor and gait ataxia and, more variably, cognitive decline, parkinsonism, and peripheral neuropathy. (Reviewed in 20; 21) In contrast to full-mutation alleles, which are generally transcriptionally silent, premutation alleles express up to 8 times more FMR1 mRNA than normal alleles 22…”