Lifespan changes in working memory in fragile X premutation males

Fragile X syndrome is the world’s most common hereditary cause of developmental delay in males and is now well characterized at the biological, brain and cognitive levels. The disorder is caused by the silencing of a single gene on the X chromosome, the FMR1 gene. The premutation (carrier) status, however, is less well documented but has an emerging literature that highlights a more subtle profile of executive cognitive deficiencies that mirror those reported in fully affected males. Rarely, however, has the issue of age-related declines in cognitive performance in premutation males been addressed. In the present study, we focus specifically on the cognitive domain of working memory and its subcomponents (verbal, spatial and central executive memory) and explore performance across a broad sample of premutation males aged 18–69 years matched on age and IQ to unaffected comparison males. We further tease apart the premutation status into those males with symptoms of the newly identified neurodegenerative disorder, the fragile X-associated tremor/ataxia syndrome (FXTAS) and those males currently symptom-free. Our findings indicate a specific vulnerability in premutation males on tasks that require simultaneous manipulation and storage of new information, so-called executive control of memory. Furthermore, this vulnerability appears to exist regardless of the presence of FXTAS symptoms. Males with FXTAS symptoms demonstrated a more general impairment encompassing phonological working memory in addition to central executive working memory. Among asymptomatic premutation males, we observed the novel finding of a relationship between increased CGG repeat size and impairment to central executive working memory.     

The trajectory of mathematics skills and working memory thresholds in girls with fragile X syndrome

Fragile X syndrome is a common genetic disorder associated with executive function deficits and poor mathematics achievement. In the present study, we examined changes in math performance during the elementary and middle school years in girls with fragile X syndrome, changes in the working memory loads under which children could complete a cognitive switching task, and the association between these two areas of function, in girls with fragile X syndrome relative to their peers. Our findings indicate that the trajectory of math and executive function skills of girls with fragile X differs from that of their peers and that these skills contribute to predicting math achievement and growth in math performance over time. Also, changes in math performance were associated with incremental increases in working memory demands, suggesting that girls with fragile X have a lower threshold for being able to perform under increasing task demands. Still, we found improvement in executive function performance between 10 and 12 years in girls with fragile X rather than a performance plateau as has been reported in other studies. The findings implicate the importance of early intervention in mathematics for girls with fragile X that addresses poor calculation skills, the supporting numerical skills, and deficits in executive functions, including working memory.     

Selective spatial processing deficits in an at-risk subgroup of the fragile X premutation

Until a decade ago, it was assumed that males with the fragile X premutation were unaffected by any cognitive phenotype. Here we examined the extent to which CGG repeat toxicity extends to visuospatial functioning in male fragile X premutation carriers who are asymptomatic for a late-onset neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). Thirty-three premutation males aged 20-68 years [divided into two groups: 16 low-repeat carriers (CGG ≥ 55 ≤ 100) and 17 high-repeat carriers (CGG>100)] with a family history of fragile X syndrome and 62 non-affected adult males with normal FMR1 alleles were recruited. Subjects underwent neuropsychological tests of visuospatial and visual working memory functioning and visuoperceptual processing. On measures of visuospatial processing, the high-repeat carriers performed significantly worse than the normal allele group when age and IQ were covaried out. With increasing age and only in carriers of a larger (>100 repeats) premutation allele was there a greater decrement in visuospatial working memory functioning. Performance on spatial and perceptual judgement tasks failed to show similar specificity in males within the upper premutation range. We conclude that identification of selective visuospatial impairments in carriers of a larger premutation allele indicates greater CGG repeat toxicity in specific neural regions. Longitudinal follow-up studies will be needed to determine whether subtle decline in visuospatial functioning is associated with the later onset of motor symptoms of FXTAS.     

Young adult female fragile X premutation carriers show age- and genetically-modulated cognitive impairments

The high frequency of the fragile X premutation in the general population and its emerging neurocognitive implications highlight the need to investigate the effects of the premutation on lifespan cognitive development. Until recently, cognitive function in fragile X premutation carriers (fXPCs) was presumed to be unaffected by the mutation. Here we show that young adult female fXPCs show subtle, yet significant, age- and FMR1 gene mutation-modulated cognitive impairments as tested by a quantitative magnitude comparison task. Our results begin to define the neurocognitive endophenotype associated with the premutation in adults, who are at risk for developing a neurodegenerative disorder associated with the fragile X premutation. Results from the present study may potentially be applied toward the design of early interventions wherein we might be able to target premutation carriers most at risk for degeneration for preventive treatment.     

The perception of biological and mechanical motion in female fragile X premutation carriers

Previous studies reported impaired visual information processing in patients with fragile X syndrome and in premutation carriers. In this study, we assessed the perception of biological motion (a walking point-light character) and mechanical motion (a rotating shape) in 25 female fragile X premutation carriers and in 20 healthy non-carrier controls. Stimuli were moving stimulus dots embedded among a cloud of noise dots. Sensitivity (d′) for motion detection was determined. Emotional symptoms were assessed by Hamilton’s depression and anxiety rating scales. Results revealed that the premutation carriers displayed lower sensitivities for biological and mechanical motion relative to the non-carriers. This deficit was more pronounced in the case of biological stimuli. The premutation carriers displayed higher depression and anxiety scores relative to the non-carriers. Higher depression, but not anxiety, scores were associated with decreased sensitivity for biological, but not mechanical, motion in the carrier group. These results suggest that motion perception deficits are detectable in fragile X premutation carriers, and that the impairment of biological motion perception is associated with depressive symptoms.     

Advances in research on the fragile X syndrome

Fragile X syndrome is a neurodevelopmental disorder that results from a single gene mutation on the X chromosome. The purpose of this review is to summarize key advances made in understanding the fragile X premutation gene seen in carriers and the full mutation gene seen in persons with the syndrome. DNA testing has replaced cytogenetic testing as the primary method for identification of fragile X, although the efficacy of protein level screening is being explored. The premutation is associated with no effects, although there is evidence of physical effects-primarily premature menopause and mild outward features of the fragile X syndrome-among premutation carriers. There is much controversy regarding premutation effects on psychological development. The few experimental studies carried out to date do not suggest noticeable or significant effects. One challenge in addressing this controversy is the sometimes ambiguous differentiation between premutation and full mutation genes. There is a well-established yet highly variable phenotype of the full mutation. Research from this decade has helped to address specific aspects of this phenotype, including the early course of its development in males, the influence of home and family environments, the nature of social difficulties and autistic features seen in boys and girls with fragile X, and the potential role of hyperarousal or hyper-reactivity. Studies in these areas, and on the role of FMR protein, will contribute towards ongoing advances in our understanding of fragile X syndrome and its mechanisms. The variability in physical, social, and cognitive features, as described in this review, is one that prohibits clear-cut screening guidelines designed to avoid high rates of both false positives and false negatives. Results from recent studies indicate the need to consider behavioral features in selecting candidates for fragile X screening. MRDD Research Reviews 2000;6:96-106.     

Exploring inhibitory deficits in female premutation carriers of fragile X syndrome: Through eye movements

There is evidence which demonstrates that a subset of males with a premutation CGG repeat expansion (between 55 and 200 repeats) of the fragile X mental retardation 1 gene exhibit subtle deficits of executive function that progressively deteriorate with increasing age and CGG repeat length. However, it remains unclear whether similar deficits, which may indicate the onset of more severe degeneration, are evident in female PM-carriers. In the present study we explore whether female PM-carriers exhibit deficits of executive function which parallel those of male PM-carriers. Fourteen female fragile X premutation carriers without fragile X-associated tremor/ataxia syndrome and fourteen age, sex, and IQ matched controls underwent ocular motor and neuropsychological tests of select executive processes, specifically of response inhibition and working memory. Group comparisons revealed poorer inhibitory control for female premutation carriers on ocular motor tasks, in addition to demonstrating some difficulties in behaviour self-regulation, when compared to controls. A negative correlation between CGG repeat length and antisaccade error rates for premutation carriers was also found. Our preliminary findings indicate that impaired inhibitory control may represent a phenotype characteristic which may be a sensitive risk biomarker within this female fragile X premutation population.     

Recommendations from Multi-disciplinary Focus Groups on Cascade Testing and Genetic Counseling for Fragile X-associated Disorders

The purpose of this paper is to report the outcome of a collaborative project between the Fragile X Research and Treatment Center at the Medical Investigation of Neurodevelopmental Disorders (M.I.N.D.) Institute at the University of California at Davis, the National Fragile X Foundation (NFXF), and the Centers for Disease Control and Prevention (CDC). The objective of this collaboration was to develop and disseminate protocols for genetic counseling and cascade testing for the multiple disorders associated with the fragile X mental retardation 1 (FMR1) mutation. Over the last several years, there has been increasing insight into the phenotypic range associated with both the premutation and the full mutation of the FMR1 gene. To help develop recommendations related to screening for fragile X-associated disorders, four, two day advisory focus group meetings were conducted, each with a different theme. The four themes were: (1) fragile X-associated tremor/ataxia syndrome (FXTAS); (2) premature ovarian failure (POF) and reproductive endocrinology; (3) psychiatric, behavioral and psychological issues; and (4) population screening and related ethical issues.     

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

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.     

Vernier acuity and the magnocellular system revisited: Response to Skottun and Skoyles

Skottun and Skoyles (2009) recently presented a comment on Vernier acuity and magnocellular dysfunctions in fragile X premutation carriers (Kéri & Benedek, 2009). The authors concluded that our finding that the magnocellular deficit, as revealed by luminance-contrast sensitivity measurements, is associated with impaired Vernier acuity for achromatic gratings does not mean that this procedure is suitable for the investigation of the magnocellular pathways, given that deficits outside the magnocellular system also lead to impaired Vernier acuity. However, Skottun and Skoyles (2009) did not consider the dissociation between achromatic and isoluminant color Vernier and the convergence of Vernier and luminance-contrast sensitivity measurements.     

Emotional Reaction to Fragile X Premutation Carrier Tests Among Infertile Women

Female fragile X premutation carriers are at ∼10-fold increased risk of premature ovarian failure (follicle stimulating hormone >40 mIU/mL, amenorrhea, age <40). A milder degree of premature ovarian aging (diminished ovarian reserve, where follicle stimulating hormone levels are typically 10–20 mIU/mL) results in infertility. Approximately 10% of fertility clinic patients have this diagnosis. A cohort of 20 women diagnosed with diminished ovarian reserve provided a blood specimen (confidential results), and completed structured questionnaires that assessed emotional reactions to potentially being a premutation carrier (pretest questionnaire, n = 20) and the posttest known carrier status (3 month follow-up questionnaire, n = 18 non-carriers). Responses were measured using 9-point scales, and analyzed with Fisher exact and Wilcoxon exact tests. While most participants did not view fragile X premutations as a serious medical condition, perceptions of seriousness were positively correlated with anger and regret about not knowing sooner of the potential association of these premutations with infertility. Overall, when women (pretest) imagined themselves as carriers, their self-esteem and Health Orientation Scale responses were unchanged with the exception of feeling more afraid (p = 0.004). Despite strongly wishing for negative test results, they were glad to know there might be a medical explanation for their infertility. Financial Support: This work was financially supported by a University of Virginia School of Medicine Research & Development Award.     

Global dot integration in typically developing children and in Williams Syndrome

Williams Syndrome (WS) is a neurodevelopmental disorder that results in deficits in visuospatial perception and cognition. The dorsal stream vulnerability hypothesis in WS predicts that visual motion processes are more susceptible to damage than visual form processes. We asked WS participants and typically developing children to detect the global structure Glass patterns, under “static” and “dynamic” conditions in order to evaluate this hypothesis. Sequentially presented Glass patterns are coined as dynamic because they induce illusory motion, which is modeled after the interaction between orientation (form) and direction (motion) mechanisms. If the dorsal stream vulnerability holds in WS participants, then they should process real and illusory motion atypically. However, results are consistent with the idea that form and motion integration mechanisms are functionally delayed or attenuated in WS. Form coherence thresholds for both static and dynamic Glass patterns in WS were similar to those of 4–5 year old children, younger than what is predicted by mental age. Dynamic presentation of Glass patterns improved thresholds to the same degree as typical participants. Motion coherence thresholds in WS were similar to those of mental age matches. These data pose constraints on the dorsal vulnerability hypothesis, and refine our understanding of the relationship between form and motion processing in development.     

Ocular motor indicators of executive dysfunction in fragile X and Turner syndromes

Fragile X and Turner syndromes are two X-chromosome-related disorders associated with executive function and visual spatial deficits. In the present study, we used ocular motor paradigms to examine evidence that disruption to different neurological pathways underlies these deficits. We tested 17 females with fragile X, 19 females with Turner syndrome, and 40 females with neither disorder who comprised the comparison group. Group differences emerged for both the fragile X and Turner syndrome groups, each relative to the comparison group: Females with fragile X had deficits in generating memory-guided saccades, predictive saccades, and saccades made in the overlap condition of a gap/overlap task. Females with Turner syndrome showed deficits in generating memory-guided saccades, but not during either the predictive saccade or gap/overlap task. Females with Turner syndrome, but not females with fragile X, showed deficits in visually guided saccades and anti-saccades. These findings indicate that different brain regions are affected in the two disorders, and suggest that different pathways lead to the similar cognitive phenotypes described for fragile X and Turner syndromes.     

Duty to Re-Contact: A Study of Families at Risk for Fragile X

DNA testing for Fragile X syndrome is now routinely available through a large number of diagnostic laboratories. We have surveyed individuals from British Columbia Fragile X families identified prior to the availability of DNA testing for FMR1 to determine if they are subsequently receiving information about DNA testing. Of the 78 individuals first seen before the cloning of the FMR1 gene, 39 (50%) had not been seen in the clinic to discuss DNA testing. We initiated a contact program with these 39 patients to determine their interest in DNA testing. Contact was made with 28 individuals, 20 of whom stated interest in testing either for themselves or for a relative. Patient opinions about DNA testing were assessed through questionnaires. In those individuals who stated an interest in DNA testing, the most common reason for wishing testing was to provide information to children or grandchildren. The most common disadvantages of testing indicated by this group were that they had finished their families and that they felt the test would not have a direct impact. The most common reasons individuals were not interested in DNA testing were that there were no family members appropriate to test and that the respondent had completed his or her family. DNA testing has been performed for 13 of the 28 (46%) contacted individuals and/or at least one relative. In view of the high level of interest for testing in families who had not been seen since the cloning of the FMR1 gene, we feel that FMR1 screening programs should include actively contacting previously seen individuals.     

On using Vernier acuity to assess magnocellular sensitivity

A recent study [Keri, S., & Benedek, G. (2009). Visual pathway deficit in female fragile × premutation carriers: A potential endophenotype. Brain and Cognition, 69, 291–295] has found Vernier acuity deficiencies together with contrast sensitivity defects consistent with a magnocellular deficit in female fragile × premutation carriers. This may appear to support the notion that Vernier acuity may serve as a test of magnocellular sensitivity. However, Vernier acuity deficiencies have been reported in other conditions (e.g., schizophrenia, amblyopia and cortical visual impairment) where there is little evidence for magnocellular deficits. The observation that Vernier acuity deficiencies can occur without magnocellular deficits indicates that Vernier acuity is not a reliable test of magnocellular sensitivity.     

A Pilot Study of Fragile X Syndrome Screening in Pregnant Women and Women Planning Pregnancy: Implementation,Acceptance, Awareness,and Geographic Factors

We report herein results of a study performed in the Balearic Islands which had the following goals: 1) Determine the proportion of pregnant or non-pregnant women planning pregnancy, who would choose to undergo a screening test for Fragile X Syndrome (FXS), if it is accompanied by the appropriate information; 2) Assess satisfaction and any increase in stress among women who participate in screening; 3) Collect epidemiological information about the incidence of the disease in our population; and 4) Collect demographic and health history data and assess participants’ awareness of the disease. Screening was performed on 3,731 pregnant and non-pregnant women of childbearing age and the results indicate: a very high voluntary rate of participation; a high level of self-reported satisfaction and low levels of stress because of the test; a very high incidence of premutation (1/106) in our population; and a low level of awareness about the existence of FXS (25 %). Additional findings indicate no significant correlation between self-reported health history and premutation detection, and the high premutation incidence does not seem to be specific to the indigenous Balearic population. Based on these results, we discuss the pros and cons of an implementation of preconception and pregnant women screening for FXS within a public health screening program.     

Attitudes Towards Potentially Carrying the FMR1 Premutation: Before vs After Testing of Non-Carrier Females with Diminished Ovarian Reserve

Diminished ovarian reserve (DOR) and premature ovarian failure are associated with elevated FMR1 CGG repeat alleles. We assessed pretest attitudes about potentially carrying the FMR1 premutation (FXP) (>55 CGG repeats) among reproductive age women compared with attitudes after learning their non-carrier status. Ninety-two women with DOR, regular menses and no family history of Fragile X Syndrome underwent FMR1 testing and completed attitudinal questionnaires before (T1) and 3 months after learning the test results (T2). The analysis utilized signed rank tests and α?=?0.05. Very few women thought they were likely to have a FXP (6.6 %). More participants thought FMR1 premutations were “serious” at T2 (62.9 %) than at T1 (46.1 %, p?p?相似文献   

Eating disorder NOS (EDNOS): an example of the troublesome "not otherwise specified" (NOS) category in DSM-IV

The “Not Otherwise Specified” (NOS) category within DSM-IV is designed for disorders of clinical severity that are not specified within broad diagnostic classes. “NOS” diagnoses are intended to be residual categories and they tend to be neglected by researchers. This can be inappropriate. The problems associated with certain NOS diagnoses are well illustrated by “Eating Disorder NOS” (sometimes termed EDNOS), which is the most common category of eating disorder encountered in routine clinical practice yet it has barely been studied. Indeed, there has been no research on its treatment. Interim and longer-term conceptual and practical solutions to the anomalous status of eating disorder NOS are proposed including the creation of a new diagnosis termed “mixed eating disorder”. Several of these solutions are of relevance to NOS categories in general. All the solutions should fulfil criteria for clinical utility.     

Extreme Nonresponse to Acute Phase Cognitive Therapy for Depression: An Attempt to Replicate and Extend

As with other interventions for major depressive disorder (MDD), cognitive therapy (CT) results in treatment failure for about half of all participants. In 2007, Coffman and colleagues in Seattle studied this topic by identifying a group of patients who demonstrated an extremely poor response to CT (i.e., posttreatment BDI score ≥ 31). They called these patients “extreme nonresponders” (ENR) and described the pretreatment characteristics that predicted response status.     

USING PERCENTILE SCHEDULES TO INCREASE EYE CONTACT IN CHILDREN WITH FRAGILE X SYNDROME

Aversion to eye contact is a common behavior of individuals diagnosed with Fragile X syndrome (FXS); however, no studies to date have attempted to increase eye‐contact duration in these individuals. In this study, we employed a percentile reinforcement schedule with and without overcorrection to shape eye‐contact duration of 6 boys with FXS. Results showed that although aversion to eye contact is often thought to be unamenable to change in FXS, it can be shaped in some individuals using percentile schedules either alone or in combination with overcorrection.