Premature ovarian failure in the fragile X syndrome

The full mutation leading to the fragile X syndrome is a dynamic trinucleot ide repeat located in the 5' untranslated region of the FMR1 gene. The prem utation allele contains approximately 60 to 199 repeats, is unstable, and o riginally not considered detrimental; that is, there did not appear to be a phenotype consequence of the long repeat tract. However, in the late 1980s and early 1990s, preliminary findings suggested that nonimpaired heterozyg otes were at risk of early menopause and increased rates of twinning, both indications of ovarian failure. Once premutation carriers could be distingu ished from full mutation carriers, this phenotype was found to be restricte d to premutation carriers only. Based on the recent studies reviewed here, approximately 21% of premutation carriers have premature ovarian failure (P OF) compared to only 1% in the general population, or a relative risk of 21 . Moreover, among women with idiopathic sporadic or the more rare farm of f amiliar POF, approximately 2% and 14%, respectively, carry the premutation. To date, data supporting increased twinning rates are conflicting and need to be resolved. Neither the underlying cellular pathophysiology of POF cau sed by the premutation allele nor molecular mechanism underlying the presen ce of the long repeat tract of the premutation allele is understood. Irresp ective, women who carry the premutation allele should have not only genetic counseling but also fertility counseling to ensure that they reach their g oals for reproduction. Am. J. Med. Genet. (Semin. Med. Genet.) 97:189-194, 2000. (C) 2000 Wiley-Liss. Inc.