RNA interference: a new mechanism by which FMRP acts in the normal brain? What can Drosophila teach us?

Fragile X syndrome is the most common heritable form of mental retardation caused by loss-of-function mutations in the FMR1 gene. The FMR1 gene encodes an RNA-binding protein that associates with translating ribosomes and acts as a negative translational regulator. Recent work in Drosophila melanogaster has shown that the fly homolog of FMR1 (dFMR1) plays an important role in regulating neuronal morphology, which may underlie the observed deficits in behaviors of dFMR1 mutant flies. Biochemical analysis has revealed that dFMR1 forms a complex that includes ribosomal proteins and, surprisingly, Argonaute2 (AGO2), an essential component of the RNA-induced silencing complex (RISC) that mediates RNA interference (RNAi) in Drosophila. dFMR1 also associates with Dicer, another essential processing enzyme of the RNAi pathway. Moreover, both a micro-RNA (miRNA) and short interfering RNAs (siRNAs) can coimmunoprecipitate with dFMR1. Together these findings suggest that dFMR1 functions in an RNAi-related apparatus to regulate the expression of its target genes at the level of translation. These findings raise the possibility that Fragile X syndrome may be the result of a protein synthesis abnormality caused by a defect in an RNAi-related apparatus. Because the core mechanisms of complex behaviors such as learning and memory and circadian rhythms appear to be conserved, studies of Fragile X syndrome using Drosophila as a model provide an economy-of-scale for identifying biological processes that likely underlie the abnormal morphology of dendritic spines and behavioral disturbances observed in Fragile X patients.     

Mapping self-reports of working memory deficits to executive dysfunction in Fragile X Mental Retardation 1 (FMR1) gene premutation carriers asymptomatic for FXTAS

Fragile X Syndrome is a neurodevelopmental disorder that is caused by the silencing of a single gene on the X chromosome, the Fragile X Mental Retardation 1 (FMR1) gene. In recent years, the premutation (“carrier”) status has received considerable attention and there is now an emerging consensus that despite intellectual functioning being within the average range premutation males present with subtle executive function impairments that include poor inhibitory control, working memory deficits, and poor planning skills. The ranges of these skills, although not nearly as severe as seen in the full mutation, nonetheless serve to differentiate males with the premutation from males in the unaffected population. In the present study we extend these findings to suggest that behavioral markers, specifically self-report on the Brown Attention-Deficit Disorder Rating Scales, may serve as a clinically useful indicator or “signature” of the Fragile X Premutation status. We discuss the possibility that this measure provides a means to identify those at greatest risk for developing the newly identified neurodegenerative disorder that affects some premutation males – Fragile X Tremor/Ataxia Syndrome (FXTAS).     

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   

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.     

Women’s Attitudes Toward Testing for Fragile X Carrier Status: A Qualitative Analysis

Fragile X syndrome (FXS) is primarily due to a repeat expansion mutation found in the FMR1 X-linked gene. We have conducted a qualitative analysis of responses from women concerning their attitudes toward testing for carrier status of the fragile X mutation among reproductive-age women. We obtained responses from focus groups including women with and without FXS in their families. We found the following themes: (1) mothers of children with FXS have difficulty formulating their opinions on population screening because of their unique experiences surrounding their own carrier diagnosis and their relationship with their children with FXS, (2) the motivation for carrier testing and need for information differ by family history of FXS and parental status, and (3) the timing of carrier testing with respect to a woman’s life stage dictates whether carrier information will be viewed as beneficial or detrimental. There was evidence that non-carrier women from the general population would be wholly unprepared for positive carrier results. These findings have significant implications for genetic counseling as well as for population screening.     

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.     

Longitudinal Interviews of Couples Diagnosed with Diminished Ovarian Reserve Undergoing Fragile X Premutation Testing

About 10 % of infertile/subfertile women are diagnosed with diminished ovarian reserve (DOR), of which?<?5 % will become pregnant spontaneously. Fragile X (FMR1) genetic testing may provide a reason for her early ovarian aging and/or have reproductive implications. Seven women with DOR (genetic study subset) and the male partners of six of these women were separately interviewed about the experience of being asked to undergo this unanticipated genetic test. Three interviews were conducted (before, within 1 week after, and 3 months after learning the test results). None of the participants carried the FMR1 premutation (largest FMR1 allele 27–50 CGG repeats). For women, their pregnancy-seeking journey was long and exhausting. Women understood the reproductive implications of carrying the FMR1 premutation, and hoped for a negative result. Being offered a genetic test caused women to pause and re-think their future reproductive plans. Husbands viewed the infertility journey as filled with unknowns, of which the genetic test results would be one more puzzle piece. The expense of fertility testing/treatment was mentioned by both spouses, though more notably by husbands. The introduction of a possible genetic cause of infertility, with additional potential health consequences for future biological children, caused women to re-think their quest for pregnancy. In contrast, the genetic test was viewed as an additional source of information for their husbands as opposed to raising concern regarding potential reproductive ramifications.     

Genetic Counseling for Fragile X Syndrome: Updated Recommendations of the National Society of Genetic Counselors

These recommendations describe the minimum standard criteria for genetic counseling and testing of individuals and families with fragile X syndrome, as well as carriers and potential carriers of a fragile X mutation. The original guidelines (published in 2000) have been revised, replacing a stratified pre- and full mutation model of fragile X syndrome with one based on a continuum of gene effects across the full spectrum of FMR1 CGG trinucleotide repeat expansion. This document reviews the molecular genetics of fragile X syndrome, clinical phenotype (including the spectrum of premature ovarian failure and fragile X-associated tremor-ataxia syndrome), indications for genetic testing and interpretation of results, risks of transmission, family planning options, psychosocial issues, and references for professional and patient resources. These recommendations are the opinions of a multicenter working group of genetic counselors with expertise in fragile X syndrome genetic counseling, and they are based on clinical experience, review of pertinent English language articles, and reports of expert committees. These recommendations should not be construed as dictating an exclusive course of management, nor does use of such recommendations guarantee a particular outcome. The professional judgment of a health care provider, familiar with the facts and circumstances of a specific case, will always supersede these recommendations.     

Attitudes Toward Fragile X Mutation Carrier Testing from Women Identified in a General Population Survey

Fragile X syndrome is primarily due to a CGG repeat expansion found in the FMR1 X-linked gene. In a previous study, we conducted focus groups with women to assess their attitudes towards fragile X carrier screening. In this follow-up study, we conducted in-depth interviews of general population reproductive-age women who were identified as carriers. We explored their attitudes toward testing for carrier status of the fragile X mutation. These women underwent screening primarily to participate in a research project rather than in search of a diagnosis for specific symptoms. As such, these women were wholly unprepared for positive carrier results. Their responses about their results and carrier screening, in many cases, were being worked out over the course of the interview itself. The most salient finding of this work is the apparent lack of relevance of carrier status to these women. Many expressed that although the information could be relevant in the future, it is not relevant at this stage of their lives in terms of family planning (either with respect to having unaffected offspring or to premature ovarian failure) and personal relationships. Although issues of abortion seemed prominent in the focus groups, we found that carrier status did not have an apparent effect on women’s attitudes about termination. We hypothesize this may be related to the fact that women had not processed their new carrier status and had not related it to previously-formed personal opinions. The findings of this work have significant implications for genetic counseling and population screening. Genetic counselors should be mindful that general population women may not recognize the immediate importance of their carrier status even when literature is provided and discussed prior to providing a sample. As part of comprehensive genetic counseling, counselors should identify the reproductive life stage of the woman receiving the new information and help her identify when this information would be more meaningful in her life. Counselors can assist in setting up a personalized road map with specific types of services that will be more applicable to the woman as her carrier status becomes more relevant.     

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.     

Attitude of Medical School Students in China Towards Genetic Testing and Counseling Issues in FXS

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. However, genetic testing protocols and genetic counseling guidelines for FXS are not yet established in mainland China. In the present study, we conducted a comprehensive analysis using a self-administered questionnaire among students at the Xiangya medical school to investigate their attitude towards genetic testing and counseling issues of FXS. We have gained a general understanding of the attitudes of medical students towards these FXS issues in China. This information is of immense importance to develop appropriate genetic tests and to train counselors for FXS. As the medical school students surveyed are prospective physicians who will be a part of the Chinese health system, our survey was focused on the basic knowledge of FXS, population-based FXS screening, confidentiality and reproductive options for mutation carriers. The study demonstrated that only less than one third of the participants had heard about FXS. 94.6 % of participants were in favor of FXS screening for women in their reproductive age who had a genetic history of FXS. Furthermore, only half of the participants would inform their families about their genetic status in case of positive test results, and more than half of the participants supported natural conception and prenatal diagnosis for FXS mutation carriers. Additional findings and research implications are also discussed. This survey targeting potential doctors provides important information for the development of FXS genetic test and counselor training for the Chinese health system.     

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.     

Perspectives on Engagement Barriers and Alternative Delivery Formats from Non-completers of a Community-Run Parenting Program

The purpose of our study was to learn about barriers to participation faced by families who had signed up for but not completed a community-based parenting program that was not part of a research project. We also sought to gauge interest in alternative, web-based methods of delivering a parent training intervention. Semi-structured phone interviews were conducted with 27 parents who had signed up for but not completed a community-based parenting program. Results indicated that practical reasons such as scheduling were the most common barrier faced by parents. Results also suggested substantial interest in alternative web-based and hybrid models of program delivery. Hybrid models would allow participants to move between face-to-face small group classes and web-based classes; allowing for easy make-up of missed small-group sessions. Interventions designed by community organizations and researchers should consider using alternative methods, including hybrid models, of program delivery in order to reach a larger number of individuals.     

Extended Family Impact of Genetic Testing: The Experiences of X-linked Carrier Grandmothers

In many cases, X-linked conditions are transmitted through families “silently” until the first affected individual is diagnosed. Grandmothers are often then tested to help determine the risk to other family members. To date, psychosocial research on carriers of X-linked conditions has focused primarily on mothers and sisters of affected males. In the wider social science literature, studies on grandparents of children with disabilities have centered on their role within the family and relationship with the grandchild. We therefore know little about the impact of carrier testing for a genetic condition on grandparents. This qualitative study aims to contribute towards filling that gap. This study included thirteen grandmothers in families with Fragile X or Duchenne muscular dystrophy; ten had living affected grandsons and three had daughters who chose not to continue with affected male pregnancies after prenatal diagnosis. All thirteen took part in semi-structured interviews and provided a rich and varied data source for conducting thematic analysis. Most of the grandmothers expressed recurring feelings of guilt and a strong sense of responsibility for what had occurred in the family. Other themes included feelings of shock after receiving their test result, changes in family relationships and searching to make sense of the inheritance within the context of the family’s experience. This study provides evidence that X-linked carrier testing can have a profound and lasting impact on grandmothers. Although genetic counseling for X-linked conditions is often focused on the potential reproductive implications for carriers, these findings suggest that grandmothers should also be offered genetic counseling when tests are carried out, because of the likely psychosocial impact of a positive test result.     

Genetic Counseling Considerations in the Evaluation of Families for Lynch Syndrome��A Review

Lynch syndrome is the most common hereditary colorectal cancer syndrome and the most common cause of hereditary endometrial cancer. Identifying and evaluating families for Lynch syndrome is increasing in complexity due to the recognition that: family history-based clinical criteria lack sensitivity and specificity; genetic testing for Lynch syndrome continues to evolve as understanding of the molecular mechanisms underlying it evolves; and the Lynch syndrome phenotype encompasses multiple organ systems and demonstrates overlap with other hereditary cancer syndromes. This document is a summary of considerations when evaluating individuals and families for Lynch syndrome, including information on cancer risks, diagnostic criteria, tumor and genetic testing strategies, and the management of individuals with this condition.     

If We Build It … Will They Come? – Establishing a Cancer Genetics Services Clinic for an Underserved Predominantly Latina Cohort

Background: Cancer genetic counseling and testing is a standard of care option for appropriate families and can identify individuals at increased risk prior to diagnosis, when prevention or detection strategies are most effective. Despite documented efficacy of cancer risk reduction in high-risk individuals, underserved and minority individuals have a disproportionate cancer burden and limited access to genetic counseling. Methods: A needs assessment survey documented gaps in knowledge and interest in prevention. Satellite clinics were established at two indigent healthcare systems. Cancer genetics CME lectures were conducted and referral guidelines disseminated to clinicians who referred patients for counseling. Results: An increase in clinician knowledge was demonstrated post-CME and reflected by quality referrals. Eighty-eight percent of patients kept their appointments. In the predominantly Latina⁶ (n=77) clinic population, 71.4% were affected with cancer, and 17 mutation positive families were identified. Preliminary data shows a positive impact on patients' motivation and behavior. The majority has expressed satisfaction and reduction in anxiety. Conclusions: This study demonstrates feasibility and acceptability of cancer genetics services in this population, suggesting the potential to reduce cancer morbidity in underserved, high-risk families.“Latino” is the most common census term for individuals of Spanish, Mexican, Central and South American, Cuban, or Puerto Rican descent, referring to ethnicity, and is generally considered a more ethnically/culturally based term for individuals of the aforementioned groups. As this cohort is female the feminine noun “Latina” is used     

The fragile X syndrome: from molecular genetics to neurobiology

Since the identification of the FMR1 gene basic research has been focused on the molecular characterization of the FMR1 gene product, the fragile X mental retardation protein (FMRP). Recent developments in fragile X research have provided new insights and knowledge about the physiological function of FMRP in the cell and the nerve cell in particular. Currently, compelling evidence suggests a role for FMRP in the transport/translation of dendritically localized mRNAs. In addition, the identification of some of the target mRNAs of FMRP have led to an increased interest in the neurobiology of the syndrome. This review highlights the role of FMRP in dendritic mRNA transport/translation in relation to synaptic plasticity, a molecular mechanism implicated in learning and memory.     

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 neuroanatomy and neuroendocrinology of fragile X syndrome

Fragile X syndrome (FXS), caused by a single gene mutation on the X chromosome, offers a unique opportunity for investigation of gene-brain-behavior relationships. Recent advances in molecular genetics, human brain imaging, and behavioral studies have started to unravel the complex pathways leading to the cognitive, psychiatric, and physical features that are unique to this syndrome. In this article, we summarize studies focused on the neuroanatomy and neuroendocrinology of FXS. A review of structural imaging studies of individuals with the full mutation shows that several brain regions are enlarged, including the hippocampus, amygdala, caudate nucleus, and thalamus, even after controlling for overall brain volume. These regions mediate several cognitive and behavioral functions known to be aberrant in FXS such as memory and learning, information and sensory processing, and social and emotional behavior. Two regions, the cerebellar vermis, important for a variety of cognitive tasks and regulation of motor behavior, and the superior temporal gyrus, involved in processing complex auditory stimuli, are reported to be reduced in size relative to controls. Functional imaging, typically limited to females, has emphasized that individuals with FXS do not adequately recruit brain regions that are normally utilized by unaffected individuals to carry out various cognitive tasks, such as arithmetic processing or visual memory tasks. Finally, we review a number of neuroendocrine studies implicating hypothalamic dysfunction in FXS, including abnormal activation of the hypothalamic-pituitary-adrenal (HPA) axis. These studies may help to explain the abnormal stress responses, sleep abnormalities, and physical growth patterns commonly seen in affected individuals. In the future, innovative longitudinal studies to investigate development of neurobiologic and behavioral features over time, and ultimately empirical testing of pharmacological, behavioral, and even molecular genetic interventions using MRI are likely to yield significant positive changes in the lives of persons with FXS, as well as increase our understanding of the development of psychiatric and learning problems in the general population.