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

Behavior Genetics (Impact Factor: 2.84). 09/2008; 38(5):493-502. DOI: 10.1007/s10519-008-9214-3

ABSTRACT 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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    • "In fXPCs, there is higher prevalence of ADHD diagnoses in women (Hunter, Rohr, & Sherman, 2010) and boys (Farzin et al., 2006), and increased ADHD symptoms in men (Dorn, Mazzocco, & Hagerman, 1994) and boys (Aziz et al., 2003). Furthermore, self-reported inattention and impulsivity in female fXPCs is positively associated with CGG repeat length (Hunter et al., 2008a). Indicative of impaired cognitive inhibition, fXPCs report higher levels of obsessive– compulsive symptoms, which are positively associated with mRNA levels (Hessl et al., 2005). "
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    ABSTRACT: Objective: Fragile X premutation carriers (fXPCs) have an expansion of 55 -200 CGG repeats in the FMR1 gene. Male fXPCs are at risk for developing a neurodegenerative motor disorder (FXTAS) often accompanied by inhibitory control impairments, even in fXPCs without motor symptoms. Inhibitory control impairments might precede, and thus indicate elevated risk for motor impairment associated with FXTAS. We tested whether inhibitory impairments are observable in fXPCs by assessing oculomotor performance. Method: Participants were males aged 18-48 years asymptomatic for FXTAS. FXPCs (n = 21) and healthy age-matched controls (n = 22) performed four oculomotor tasks. In a Fixation task, participants fixated on a central cross and maintained gaze position when a peripheral stimulus appeared. In a Pursuit task, participants maintained gaze on a square moving at constant velocity. In a Prosaccade task, participants fixated on a central cross, then looked at a peripheral stimulus. An Antisaccade task was identical to the Prosaccade task, except participants looked in the direction opposite the stimulus. Inhibitory cost was the difference in saccade latency between the Antisaccade and Prosaccade tasks. Results: Relative to controls, fXPCs had longer saccade latency in the Antisaccade task. In fXPCs, inhibitory cost was positively associated with vermis area in lobules VI-VII. Conclusion: Antisaccades require inhibitory control to inhibit reflexive eye movements. We found that eye movements are sensitive to impaired inhibitory control in fXPCs asymptomatic for FXTAS. Thus, eye movements may be useful in assessing FXTAS risk or disease progression. (PsycINFO Database Record (c) 2014 APA, all rights reserved).
    Neuropsychology 04/2014; 28(4). DOI:10.1037/neu0000066 · 3.43 Impact Factor
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    • "Cognitively, female carriers without FXTAS have demonstrated visuospatial deficits (e.g. Goodrich-Hunsaker et al. 2011), attention problems (Hunter et al. 2008) and language dysfluencies progressing with age (Sterling et al. 2013). In a study examining older female carriers with and without FXTAS, Yang et al. (2013a) reported neuropsychological and electrophysiological phenotypes of hypofrontality in both carrier groups, with overall frontal/executive dysfunction more prominent in the FXTAS group, but more significant working memory decrement among female carriers without FXTAS. "
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    ABSTRACT: FXTAS, a neurodegenerative disorder, affects Fragile X (FMR1) gene premutation carriers in late-life. Studies have shown cognitive impairments in FXTAS including executive dysfunction, working memory, and visuospatial deficits. However, less is known about cognition in females with FXTAS. Thus, we examined semantic processing and verbal memory in female FXTAS patients with event-related potentials (ERPs) and neuropsychological testing. 61 females (34 FXTAS Mage = 62.7, 27 controls Mage = 60.4) were studied with 32-channel ERPs during a category judgment task in which semantically congruous (50%) and incongruous items were repeated ~10-140s later. N400 and P600 amplitude data were submitted to ANCOVA. Neuropsychological testing demonstrated lower performance in verbal learning and executive function in females with FXTAS. ERP analyses revealed a significant reduction of the N400 congruity effect (incongruous - congruous) in the FXTAS group. The N400 congruity effect reduction in females with FXTAS was mainly due to increased N400 amplitude to congruous new words. No significant abnormalities of the N400 repetition effect or the P600 repetition effect were found, indicating preserved implicit memory and verbal memory, respectively, in females with FXTAS. The decreased N400 congruity effect suggests abnormal semantic expectancy and/or semantic network disorganization in female FXTAS patients. The enhanced N400 amplitude to congruous new words may reflect decreased cognitive flexibility among FXTAS women, making access to less typical category exemplar words more difficult.
    Genes Brain and Behavior 12/2013; DOI:10.1111/gbb.12114 · 3.51 Impact Factor
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    • "Regarding the association between repeat number and cognitive impairments, although Hunter et al. [2008b] did not find elevated rates in premutation carriers, Grigsby et al. [2006] reported a positive association between number of repeats in premutation carrier males with FXTAS and cognitive and functional impairment. Sherman and colleagues noted some evidence supporting the association of repeat number with depression and negative affect in male premutation carriers age 18–50, and with negative affect in females, but no association with anxiety disorders [Hunter et al., 2008a]. Bourgeois et al. [2011] reported significant elevations in rates of mood and anxiety disorders in carriers with FXTAS and to a lesser extent in carriers without FXTAS. "
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    ABSTRACT: The primary goal of this study was to calculate the prevalence of the premutation of the FMR1 gene and of the "gray zone" using a population-based sample of older adults in Wisconsin (n = 6,747 samples screened). Compared with past research, prevalence was relatively high (1 in 151 females and 1 in 468 males for the premutation and 1 in 35 females and 1 in 42 males for the gray zone as defined by 45-54 CGG repeats). A secondary study goal was to describe characteristics of individuals found to have the premutation (n = 30, 7 males and 23 females). We found that premutation carriers had a significantly higher rate of divorce than controls, as well as higher rates of symptoms that might be indicative of fragile X-associated tremor ataxia syndrome (FXTAS; numbness, dizziness/faintness) and fragile X primary ovarian insufficiency (FXPOI; age at last menstrual period). Although not statistically significant, premutation carriers were twice as likely to have a child with disability.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 07/2012; 159B(5):589-97. DOI:10.1002/ajmg.b.32065 · 3.27 Impact Factor
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