Within the past few years, there has been a significant change in identifying and characterizing the FMR1 premutation associated phenotypes. The premutation has been associated with elevated FMR1 mRNA levels and slight to moderate reductions in FMRP levels. Furthermore, it has been established that B20% of female premutation carriers present primary ovarian insufficiency (POI) and that fragile X-associated tremor/ataxia syndrome (FXTAS) occurs in one-third of all male premutation carriers older than 50 years. Besides POI and FXTAS, new disorders have recently been described among individuals (especially females) with the FMR1 premutation. Those pathologies include thyroid disease, hypertension, seizures, peripheral neuropathy, and fibromyalgia. However there are few reports related to FXTAS penetrance among female premutation carriers or regarding these disorders recently associated to the FMR1 premutation. Therefore, we have evaluated 398 fragile X syndrome (FXS) families in an attempt to provide an estimation of the premutation associated phenotypes penetrance. Our results show that signs of FXTAS are detected in 16.5% of female premutation carriers and in 45.5% of premutated males older than 50 years. Furthermore, among females with the FMR1 premutation, penetrance of POI, thyroid disease and chronic muscle pain is 18.6, 15.9 and 24.4%, respectively. The knowledge of this data might be useful for accurate genetic counselling as well as for a better characterization of the clinical phenotypes of FMR1 premutation carriers.

Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability and the leading form of the monogenic cause of autism. Fragile X mental retardation type 1 (FMR1) gene premutation is the first single-gene cause of primary ovarian failure (Fragile X-associated primary ovarian insufficiency [FXPOI]) and one of the most common causes of ataxia (fragile X-associated tremor/ataxia syndrome [FXTAS]), multiple additional phenotypes such as fibromyalgia, hypothyroidism, migraine headaches, sleep disturbances, sleep apnea, restless legs syndrome, central pain syndrome, neuropathy and neuropsychiatric alterations has been described. Clinical involvement in men and women carrying the FMR1 premutation currently constitutes a real health problem in the society that should be taken into account. It is important to highlight that while in FXS there is a loss-of-function of the FMR1 gene, in premutation associated disorders there is a gain of FMR1 mRNA function. To date, the tremendous progress achieved in the understanding of the pathophysiology of FXS, has led to the development of several targeted therapies aimed at preventing or improving the neurological manifestations of the disease. This review is an update of the diseases associated with the FMR1 gene. tions. In 1999, the study of fragile X pedigrees revealed a higher incidence of primary ovarian insufficiency related to the FMR1 gene, and this condition was named premature ovarian failure (POF) and then later fragile X premature ovarian insufficiency (FXPOI). 6 This term encompasses a continuum of severity in ovarian dysfunction ranging from normal menses and normal hormonal levels, although reduced fertility, to the most severe form of this condition in which folliclestimulating hormone is elevated, menses are abnormal or absent, and fertility is drastically reduced. 7 After further studies, Hagerman et al described a neurological disease related to the FMR1 premutation that was named fragile X-associated tremor/ataxia syndrome (FXTAS). 8 Finally, since 2007 the spectrum of the clinical phenotype associated with the FMR1 premutation has continuously widened. This review is an update of the diseases associated with the FMR1 gene.2 | FRAGILE X SYNDROME FXS (#MIM300624; ORPHA 908) is the most common cause of inherited ID (1%-2% of all ID) and the leading form of the monogenic cause of autism and autism spectrum disorders (ASD) (Figure 1). The