Disorders associated with fragile X syndrome involve a trinucleotide (CGG) repeat expansion in the FMR1 gene. Recently, a progressive movement disorder (fragile X-associated tremor/ataxia syndrome [FXTAS]) has been identified in premutation carriers, persons with 55 to 200 CGG repeats. In addition to ataxia, action tremor, and Parkinsonism, early case reports suggested that FXTAS involves impaired cognition, but the precise nature of the impairment has not been elucidated. In this first, preliminary study of the subject, circumscribed aspects of cognitive functioning were examined in 25 men with FXTAS. Subjects' performance on the cognitive tests was compared with normative data. Scores on two measures of executive cognitive functioning showed a high prevalence of substantial impairment. Capacity for inhibition was severely affected in one-quarter of this highly educated sample; information processing speed was profoundly impaired in most subjects. Although mean verbal and performance IQ scores were not significantly different from the general population, they were quite low given the sample's educational level. Cognitive and functional impairment was greater for men with more CGG repeats, although number of repeats was not associated with age of onset of either tremor or ataxia. The results provide evidence that FXTAS involves marked impairment of executive cognitive abilities.
"Men with FXTAS have impairments in various aspects of inhibitory control, including interference control, cognitive control, and behavioral inhibition, as assessed by the Stroop Color-Word test, Behavioral Dyscontrol Scale, and Controlled Oral Word Association Test (Grigsby et al., 2006, 2007, 2008; Brega et al., 2008). Secondly, men with longer CGG repeat length are impaired in some of these tasks (Grigsby et al., 2006, 2007), and in male fXPCs asymptomatic for FXTAS, CGG repeat length modulates the effect of age on a behavioral inhibition task (Cornish et al., 2011; Hunter et al., 2012). "
[Show abstract][Hide abstract] ABSTRACT: Carriers of the fragile X premutation allele (fXPCs) have an expanded CGG trinucleotide repeat size within the FMR1 gene and are at increased risk of developing fragile x-associated tremor/ataxia syndrome (FXTAS). Previous research has shown that male fXPCs with FXTAS exhibit cognitive decline, predominantly in executive functions such as inhibitory control and working memory. Recent evidence suggests fXPCs may also exhibit impairments in processing temporal information. The attentional blink (AB) task is often used to examine the dynamics of attentional selection, but disagreements exist as to whether the AB is due to excessive or insufficient attentional control. In this study, we used a variant of the AB task and neuropsychological testing to explore the dynamics of attentional selection, relate AB performance to attentional control, and determine whether fXPCs exhibited temporal and/or attentional control impairments. Participants were adult male fXPCs, aged 18–48 years and asymptomatic for FXTAS (n = 19) and age-matched male controls (n = 20). We found that fXPCs did not differ from controls in the AB task, indicating that the temporal dynamics of attentional selection were intact. However, they were impaired in the letter-number sequencing task, a test of executive working memory. In the combined fXPC and control group, letter-number sequencing performance correlated positively with AB magnitude. This finding supports models that posit the AB is due to excess attentional control. In our two-pronged analysis approach, in control participants we replicated a previously observed effect and demonstrated that it persists under more stringent theoretical constraints, and we enhance our understanding of fXPCs by demonstrating that at least some aspects of temporal processing may be spared.
Frontiers in Human Neuroscience 03/2015; 9. DOI:10.3389/fnhum.2015.00037 · 3.63 Impact Factor
"Since the first case reports , it has been apparent that FXTAS is associated with a progressive decline in cognitive functioning. Although deficits in several aspects of cognition have been reported [2-4], the evidence appears to support the idea that the primary disorder is a disturbance of executive functioning (EF) . The executive functions represent an important subset of cognitive abilities. "
[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.
"These deficits can appear even in young individuals and often show a more progressive course in premutation carriers than in the general population. This may be an early sign of the often significant cognitive impairment, primarily in the realm of executive dysfunction that can accompany FXTAS . However, it must be noted that some studies have not found these areas of weakness. "
[Show abstract][Hide abstract] 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.
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