The emerging fragile X premutation phenotype: Evidence from the domain of social cognition

Department of Psychology, McGill University, Montréal, Quebec, Canada
Brain and Cognition (Impact Factor: 2.48). 03/2005; 57(1):53-60. DOI: 10.1016/j.bandc.2004.08.020
Source: PubMed


Fragile X syndrome is a neurodevelopmental disorder that is caused by large methylated expansions of a CGG repeat (>200) region upstream of the FMR1 gene that results in the lack of expression of the fragile X mental retardation protein (FMRP). Affected individuals display a neurobehavioral phenotype that includes a significant impairment in social cognition alongside deficits in attentional control, inhibition and working memory. In contrast, relatively little is known about the trajectory and specificity of any cognitive impairment associated with the fragile X premutation ("carrier-status") (approximately 55-200 repeats). Here, we focus on one aspect of cognition that has been well documented in the fragile X full mutation, namely social cognition. The results suggest that premutation males display a pattern of deficit similar in profile, albeit milder in presentation, to that of the full mutation. However, little evidence emerged for a correlation between CGG repeat length and severity of phenotypic outcomes. The findings are discussed in the context of functional neuroimaging and brain-behaviour-molecular correlates. We speculate that the deficiencies in social cognition are attributable to impairment of neural pathways modulated by the cerebellum.


Available from: Ann Dalton, May 04, 2014
    • "Social relationships can be compromised by difficulties in areas such as communication, perspective-taking, social information processing, attention, and self-regulation. Some genetic syndromes are characterized by atypical social phenotypes, such as hypersociability in Williams syndrome (Jarvinen, Korenberg, & Bellugi, 2013) and social withdrawal in Fragile X (Cornish et al., 2005). Difficulties with social relationships may stem from brain-based differences but the social environment, if one of rejection, potentially acts to canalize or exacerbate them. "
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    • "In line with previous reports by Cornish and Grigsby [4,5,51], analyses across shared measures of inhibition and working memory detected very subtle differences (which were of minimal clinical significance) on a measure of response inhibition (Stroop task), but on no other cognitive measures. Taken together, current findings provide evidence of a subtle, suboptimal level of cognitive performance among a subset of unaffected carriers, involving mild deficits in inhibition and working memory among a subset of male carriers, results which are relatively consistent with earlier research [59-61]. "
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    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.
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    • "We were interested in knowing whether changes in rCPS occur in FXPM because of reports that patients with FXPM have symptoms suggesting a milder form of FXS (Cornish et al., 2005; Hunter et al., 2008; Kogan et al., 2008; Cornish et al., 2009) and because FMRP concentrations in lymphocytes may be decreased in these patients (Tassone et al., 2000). We hypothesized that with reduced concentrations of FMRP, rCPS might be increased but to a lesser extent than seen in Fmr1 KO mice. "
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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.
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