Investigation of Phenotypes Associated with Mood and Anxiety Among Male and Female Fragile X Premutation Carriers

ArticleinBehavior Genetics 38(5):493-502 · September 2008with7 Reads
DOI: 10.1007/s10519-008-9214-3
The fragile X disorder spectrum, due to a CGG expansion in FMR1, includes fragile X syndrome (>200 repeats) and the premutation-associated disorders of ovarian insufficiency and tremor/ataxia syndrome (~55–199 repeats). Altered neurobehavioral profiles including variation of phenotypes associated with mood and anxiety may be expected among younger premutation carriers given this spectrum of disorders. However, previous studies have produced conflicting findings, providing the motivation to examine these phenotypes further. We investigated measures of mood and anxiety in 119 males and 446 females age 18–50 ascertained from families with a history of fragile X syndrome and from the general population. Scores were analyzed using a linear model with repeat length as the main predictor, adjusting for potential confounders. Repeat length was not associated with anxiety, but was marginally associated with depression and negative affect in males and negative affect only in females. These results suggest that premutation carriers may be at risk for emotional morbidity; however, phenotypic differences were subtle and of small effect size.
    • "While males with FXS usually have moderate to severe intellectual disability (ID), females with a full mutation, display phenotypic involvement ranging from normal cognitive function to ID, depending on X inactivation and resulting levels of FMRP [1, 2]. Affected females with FXS have social anxiety, learning and behavioral disorders, and extreme shyness345. Individuals with 55 -200 CGG repeat alleles have the FMR1 premutation and produce high FMR1 mRNA levels, leading to RNA toxicity, and FMRP expression levels vary from normal to moderately lower FMRP levels678. "
    Article · Jan 2015
    • "As previously reported, high rates of depression and anxiety were endorsed in this sample, with consistent frequencies reported across the adult age groups. Increased risks for depression and anxiety have been described as being related to genetic risk associated with an FMR1 expansion (Johnston et al., 2001; Hunter et al., 2008; Roberts et al., 2009), with some reports noting increased risks for carrier women prior to having a child with FXS (Roberts et al., 2009 ). However , other studies have noted that rates of depression and anxiety among carrier women do not differ significantly from mothers of children with autism (Smith et al., 2012 ). "
    [Show abstract] [Hide abstract] ABSTRACT: Recently, research has indicated an increased risk for greater medical and emotional comorbidity and physical health symptoms among women with an FMR1 expansion. However, these studies have generally been limited in their ability to model multiple risk factors associated with these symptoms by small numbers (n = 112-146) of participants. This study used survey methodology to examine the health experiences of 458 adult women with the premutation with and without a history of a fragile X primary ovarian insufficiency (FXPOI) diagnosis. Results suggest similar findings to those reported in the literature with regard to the frequency of medical, emotional, and reproductive experiences of women with the premutation. In addition to expected reproductive differences, women with a diagnosis of FXPOI were also more likely to experience dizziness, nausea, and muscle weakness than women without a diagnosis of FXPOI. Women with and without FXPOI were more likely to have used reproductive assistance and were more likely to have experienced preeclampsia during at least one pregnancy than is reported in the general population. Having comorbid depression and anxiety was predictive of increased medical conditions and increased daily physical health symptoms.
    Full-text · Article · Sep 2014
    • "Although these results suggest that females show mild early-onset neuropsychological phenotypes irrespective of FXTAS, further research is needed to understand the synergistic effects of age, psychological vulnerability, and risk factors for FXTAS. Indeed, given that prevalence rates for probable attention deficit hyperactivity disorder (4.5 to 25%), anxiety (20.9 to 30%) and depression (14.03 to 47.3%) far exceed the risk of FXTAS (8 to 16%) in women [23,24,3637383940, the molecular and environmental factors contributing to gender-divergent trajectories are yet to be fully characterized. "
    [Show abstract] [Hide abstract] ABSTRACT: The fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder affecting a subset of carriers of the FMR1 (fragile X mental retardation 1) premutation. Penetrance and expression appear to be significantly higher in males than females. Although the most obvious aspect of the phenotype is the movement disorder that gives FXTAS its name, the disorder is also accompanied by progressive cognitive impairment. In this review, we address the cognitive neuropsychological and neurophysiological phenotype for males and females with FXTAS, and for male and female unaffected carriers. Despite differences in penetrance and expression, the cognitive features of the disorder appear similar for both genders, with impairment of executive functioning, working memory, and information processing the most prominent. Deficits in these functional systems may be largely responsible for impairment on other measures, including tests of general intelligence and declarative learning. FXTAS is to a large extent a white matter disease, and the cognitive phenotypes observed are consistent with what some have described as white matter dementia, in contrast to the impaired cortical functioning more characteristic of Alzheimer's disease and related disorders. Although some degree of impaired executive functioning appears to be ubiquitous among persons with FXTAS, the data suggest that only a subset of unaffected carriers of the premutation - both female and male - demonstrate such deficits, which typically are mild. The best-studied phenotype is that of males with FXTAS. The manifestations of cognitive impairment among asymptomatic male carriers, and among women with and without FXTAS, are less well understood, but have come under increased scrutiny.
    Full-text · Article · Jul 2014
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