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

Behavior Genetics (Impact Factor: 3.21). 09/2008; 38(5):493-502. 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.

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    • "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). "
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    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 · Frontiers in Genetics
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    • "However, these studies were small, limited by the screening tools and by poor recall. Later, much larger research studies did demonstrate a relationship between the number of CGG repeats and the presence of depression [76] as well as the severity of depressive symptoms [77]. When comparing 93 women with the premutation screened using the strict criteria of the structured clinical interview for the DSM-IV (SCID) to a large national databank, the lifetime prevalence of major depressive disorder was 43.0% versus 31.9% "
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    ABSTRACT: Changes in the fragile X mental retardation 1 gene (FMR1) have been associated with specific phenotypes, most specifically those of fragile X syndrome (FXS), fragile X tremor/ataxia syndrome (FXTAS), and fragile X primary ovarian insufficiency (FXPOI). Evidence of increased risk for additional medical, psychiatric, and cognitive features and conditions is now known to exist for individuals with a premutation, although some features have been more thoroughly studied than others. This review highlights the literature on medical, reproductive, cognitive, and psychiatric features, primarily in females, that have been suggested to be associated with changes in the FMR1 gene. Based on this review, each feature is evaluated with regard to the strength of evidence of association with the premutation. Areas of need for additional focused research and possible intervention strategies are suggested.
    Full-text · Article · Jul 2014 · Journal of Neurodevelopmental Disorders
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    • "FXPM carriers are at increased risk for developing progressive neurodegenerative syndromes, including fragile X-associated tremor/ataxia syndrome (FXTAS; Hagerman et al., 2001) and fragile X-associated primary ovarian insufficiency (FXPOI) in females (Allingham-Hawkins et al., 1999). Further evidence suggests that FXPM carriers have a higher incidence of neuropsychological symptoms (Cornish et al., 2005, 2009; Hunter et al., 2008; Kogan et al., 2008). These features are thought to be caused by a toxic gain of function of elevated levels of CGG repeat-containing FMR1 mRNA (Jin et al., 2003; Hessl et al., 2005; Brouwer et al., 2008a; Hagerman, 2013). "
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    ABSTRACT: The (CGG)n-repeat in the 5'-untranslated region of the fragile X mental retardation gene (FMR1) gene is polymorphic and may become unstable on transmission to the next generation. In fragile X syndrome, CGG repeat lengths exceed 200, resulting in silencing of FMR1 and absence of its protein product, fragile X mental retardation protein (FMRP). CGG repeat lengths between 55 and 200 occur in fragile X premutation (FXPM) carriers and have a high risk of expansion to a full mutation on maternal transmission. FXPM carriers have an increased risk for developing progressive neurodegenerative syndromes and neuropsychological symptoms. FMR1 mRNA levels are elevated in FXPM, and it is thought that clinical symptoms might be caused by a toxic gain of function due to elevated FMR1 mRNA. Paradoxically, FMRP levels decrease moderately with increasing CGG repeat length in FXPM. Lowered FMRP levels may also contribute to the appearance of clinical problems. We previously reported increases in regional rates of cerebral protein synthesis (rCPS) in the absence of FMRP in an Fmr1 knockout mouse model and in a FXPM knockin (KI) mouse model with 120 to 140 CGG repeats in which FMRP levels are profoundly reduced (80%-90%). To explore whether the concentration of FMRP contributes to the rCPS changes, we measured rCPS in another FXPM KI model with a similar CGG repeat length and a 50% reduction in FMRP. In all 24 brain regions examined, rCPS were unaffected. These results suggest that even with 50% reductions in FMRP, normal protein synthesis rates are maintained.
    Full-text · Article · Jul 2014 · ASN Neuro
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