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.

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Available from: Ann Dalton, May 04, 2014
    • "A premutation syndrome (55– 200 repeats) has also been reported with elevated FMR1 mRNA and reduced FMRP levels, where RNA toxicity is a possible underlying molecular mechanism (Garcia-Arocena & Hagerman, 2010; Bagni et al, 2012). Premutation carriers display only subtle symptoms which are, however, still reminiscent of FXS, including deficits in social cognition, executive functioning, working memory, or selective attention (Moore et al, 2004; Cornish et al, 2005, 2008; Jacquemont et al, 2007; Kogan et al, 2008). Many of the FMRP mRNA targets, for example CAMK2A, PSD-95, GABRB1, NLGN2, have been linked to schizophrenia or ASD (Pasciuto & Bagni, 2014b). "
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    ABSTRACT: Fragile X syndrome (FXS) is mostly caused by a CGG triplet expansion in the fragile X mental retardation 1 gene (FMR1). Up to 60% of affected males fulfill criteria for autism spectrum disorder (ASD), making FXS the most frequent monogenetic cause of syndromic ASD. It is unknown, however, whether normal variants (independent of mutations) in the fragile X gene family (FMR1, FXR1, FXR2) and in FMR2 modulate autistic features. Here, we report an accumulation model of 8 SNPs in these genes, associated with autistic traits in a discovery sample of male patients with schizophrenia (N = 692) and three independent replicate samples: patients with schizophrenia (N = 626), patients with other psychiatric diagnoses (N = 111) and a general population sample (N = 2005). For first mechanistic insight, we contrasted microRNA expression in peripheral blood mononuclear cells of selected extreme group subjects with high- versus low-risk constellation regarding the accumulation model. Thereby, the brain-expressed miR-181 species emerged as potential "umbrella regulator", with several seed matches across the fragile X gene family and FMR2. To conclude, normal variation in these genes contributes to the continuum of autistic phenotypes.
    No preview · Article · Nov 2015 · EMBO Molecular Medicine
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    • "Similar observation was noted by Yim et al.[63]. It has been documented that children with the premutation alleles have cognitive deficits, behavioral problems and/or autism spectrum disorder646566. Learning problems, developmental delay and/or autistic features have been identified in boys with premutation ; these symptoms were observed in our group of boys with premutations. Attention problems in most premutation individuals seem to be milder than those seen in full mutation carriers. "
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    ABSTRACT: Background: Fragile X syndrome (FXS) is the most common form of inherited mental retardation. Frequency of fragile X syndrome among male siblings and relatives of mentally retarded patients is relatively high. Cytogenetic diagnosis of FXS is unreliable since it is ineffective for the diagnosis of premutated males or females. Proper molecular diagnosis is a pre-requisite for providing proper counseling advice. Subjects and methods: Sixty-four males with idiopathic mental retardation, ranging in age from 4.2 to 19. years (10.92. ±. 4.00) were clinically pre-selected, based on scoring protocol comprising eight features of the syndrome, before molecular testing. A rapid polymerase chain reaction-based screening was applied for detection of expanded FMR1 alleles. Samples that did not yield the normal band lengths were subjected to a second PCR screen. The secondary screen utilizes a chimeric primer demonstrating the presence or absence of an expanded allele. Results: Amplification of FMRI gene by PCR of tested patients revealed that 8 cases (12.5%) have full mutation and 6 cases (9.4%) have premutation. A wide range of Fra X-scoring ranging from 1 to 7 features was detected in examined cases. Significant clinical features included large prominent ears, hyperextensibility of joints and macroorchidism in post pubertal males. Conclusions: A simplified checklist of fragile X should be used for patients with idiopathic MR and those patients above score 3 should be tested for FXS. The diagnostic assay may be used as a screening method for fragile X syndrome being rapid and cost effective compared to other techniques. In addition, screening of all relatives of proven patients should be performed to detect clinically unidentified cases for provision of proper counseling and optimal management of detected cases.
    Full-text · Article · Nov 2015 · Egyptian Journal of Medical Human Genetics
    • "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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    No preview · Article · Sep 2014 · Journal of Policy and Practice in Intellectual Disabilities
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