Heterozygous fragile X female: Historical, physical, cognitive, and cytogenetic features

Abstract

Historical, physical, cognitive, and cytogenetic data were documented in 105 heterozygous fragile X [fra(X)] females and 90 controls in a prospective fashion. For comparisons, we divided heterozygotes and controls into those with cognitive impairment (IQ less than 85) and normal IQ (IQ greater than or equal to 85). The only finding that was significantly more frequent in impaired heterozygotes compared with impaired controls chi 2 analysis was shyness. Features that were more frequent in normal IQ heterozygotes compared with normal controls were voluntary thumb dislocation and hyperextensible metacarpal-phalangeal (MP) joints. Comparisons among heterozygotes demonstrated more math problems, hand biting, strabismus, high-arched palate, hyperextensible finger joints, and flat feet in impaired heterozygotes than in normal heterozygotes. Premature menopause was present in 8 of 61 normal heterozygotes and in none of the impaired heterozygotes. A multiple regression analysis demonstrated a significant inverse correlation between the percent fragility and IQ for the heterozygotes as a group. However, no correlation existed between IQ and fragility when the percent fragility was 2% or greater. However, a higher percentage of fragility was positively correlated with the total number of physical findings present.

Expanded clinical phenotype of women with the FMR1 premutation

“…Cronister et al (1991) reported a higher rate of premature ovarian failure (POF) in carrier females than in those with either full mutation expansions (>200 CGG repeats) or normal alleles; an association that has been confirmed by multiple subsequent studies [Allingham-Hawkins et al, 1999;Murray et al, 2000;Sullivan et al, 2005]. More recently, fragile X-associated tremor/ ataxia syndrome (FXTAS), a neurodegenerative movement disorder, has been reported in females with the premutation Zuhlke et al, 2004;Berry-Kravis et al, 2005;Jacquemont et al, 2005;O'Dwyer et al, 2005], although its penetrance and expression appear to be much lower than in male carriers [Jacquemont et al, 2004b].…”

Why do fragile X carrier frequencies differ between Asian and non-Asian populations?

“…Premutation alleles can lead to two known syndromes: fragile X-associated primary ovarian insufficiency (FXPOI [MIM 311360]) (Cronister et al, 1991), and fragile X-associated tremor ataxia syndrome (FXTAS [MIM 300623]) (Hagerman et al, 2001;Jacquemont et al, 2004). FXTAS, characterized by tremor and ataxia, can occur in male and female premutation carriers, and in individuals with transcriptionally active, full-mutation alleles (Loesch et al, 2012).…”

Premature ovarian failure (POF) in Brazilian fragile X carriers

“…Familial cases show a clear pattern of dominant inheritance, with expression restricted to females (Mattison et al, 1984). A possible association of the fragile X premutation with premature ovarian failure was first reported by Cronister et al (1991), who found eight women with POF among 61 normal fra(X) heterozygotes. In a multicenter study of obstetrical and gynecological complications in fra(X) carriers, Schwartz et al (1994) observed that premutated carriers had POF (25%) more frequently than noncarriers (6%).…”