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X Syndrome (x + syndrome)
Kinds of X Syndrome Selected AbstractsTrial of fenobam, an mGluR5 antagonist, in adults with Fragile X SyndromeJOURNAL OF INTELLECTUAL DISABILITY RESEARCH, Issue 10 2008R. Hagerman Background: Recent advances in the study of the Fragile X knockout mouse model have demonstrated enhanced activity of the metabolic glutamate receptor 5 (mGluR5) pathway. The use of mGluR5 antagonists has rescued behavioural, cognitive and dendritic structural abnormalities in the knockout mouse. An initial phase II trial in adults with FXS was approved by the FDA. Method: We have completed this initial trial of fenobam (50 mg to 150 mg/dose) in twelve adults with FXS (mean age 23.9 (SD 5.4; range 18.7,30.7 years) seen either at UC Davis MIND Institute or at RUSH, University in Chicago, to assess safety, side-effects, and metabolism after a single dose. Results: Outcome measures included prepulse inhibition (PPI) and a continuous performance task (CPT). All patients tolerated this single dose without significant side-effects. The metabolism of fenobam in patients with FXS is similar to controls and peaks at approximately 180 minutes after oral dose. Fifty percent of the patients had a 20% or more improvement in PPI that is significantly different from test-retest changes in PPI previously reported in individuals with FXS (p = 0.03). This effect was more pronounced in males. The majority of patients scored at ceiling on the CPT so it was not a helpful measure to assess medication benefits. Conclusion: This work documents the safety and aspects of the metabolism of fenobam in patients with FXS and will facilitate further expansion of fenobam trials in patients with FXS. Although fenobam is a targeted treatment for FXS, subgroups of autism may also benefit from fenobam treatment. [source] A review of mathematical learning disabilities in children with fragile X syndromeDEVELOPMENTAL DISABILITIES RESEARCH REVIEW, Issue 1 2009Melissa M. Murphy Abstract The prevalence rate of mathematical learning disabilities (MLD) among children with fragile X syndrome who do not meet criteria for intellectual and developmental disabilities (,50% of female children) exceeds the rate reported in the general population. The purpose of this article is two-fold: (1) to review the findings on MLD in persons with fragile X syndrome; and (2) to discuss fragile X syndrome as a possible model for understanding pathways to MLD. © 2009 Wiley-Liss, Inc. Dev Disabil Res Rev 2009;15:21,27. [source] Language development and fragile X syndrome: Profiles, syndrome-specificity, and within-syndrome differencesDEVELOPMENTAL DISABILITIES RESEARCH REVIEW, Issue 1 2007Leonard Abbeduto Abstract Fragile X syndrome (FXS) is the leading inherited cause of mental retardation. In this article, we review what is known about the language and related problems of individuals with FXS. In doing so, we focus on the syndrome-specific features of the language phenotype and on the organismic (i.e., genetic and individual neurocognitive and behavioral) and environmental factors associated with within-syndrome variation in the phenotype. We also briefly review those aspects of the behavioral phenotype of FXS that are relevant for understanding syndrome-specific features of, and within-syndrome variability in, language. The review includes summaries of research on the prelinguistic foundations for language development and on each of the major components of language (i.e., vocabulary, morphosyntax, and pragmatics). Throughout the review, we point out implications of existing research for intervention as well as directions for future research. © 2007 Wiley-Liss, Inc. MRDD Research Reviews 2007;13:36,46. [source] Language phenotypes and intervention planning: Bridging research and practiceDEVELOPMENTAL DISABILITIES RESEARCH REVIEW, Issue 1 2007Deborah J. Fidler Abstract This paper focuses on the communication and language phenotypes associated with three genetic disorders: Down syndrome, Williams syndrome, and fragile X syndrome. It is argued that there is empirical evidence that these disorders predispose children to specific profiles of strength and weakness in some areas of speech, language, and communication, and that intervention planning for children with each syndrome may take an approach informed by these profiles. Issues related to within-group variability, shared outcomes among syndromes, and the need for empirical validation for syndrome-specific recommendations are discussed. © 2007 Wiley-Liss, Inc. MRDD Research Reviews 2007; 13:47,57. [source] The neuroanatomy and neuroendocrinology of fragile X syndromeDEVELOPMENTAL DISABILITIES RESEARCH REVIEW, Issue 1 2004David Hessl Abstract 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. MRDD Research Reviews 2004;10:17,24. © 2004 Wiley-Liss, Inc. [source] Fragile X-associated Tremor/Ataxia Syndrome (FXTAS)DEVELOPMENTAL DISABILITIES RESEARCH REVIEW, Issue 1 2004Paul J. Hagerman Abstract Carriers of fragile X mental retardation 1 (FMR1) premutation alleles (55 to 200 CGG repeats) are generally spared the more serious neurodevelopmental problems associated with the full-mutation carriers (>200 repeats) of fragile X syndrome. However, some adult male premutation carriers (55,200 repeats) develop a neurological syndrome involving intention tremor, ataxia, dementia, parkinsonism, and autonomic dysfunction. In excess of one-third of male premutation carriers over 50 years of age develop the fragile X- associated tremor/ataxia syndrome (FXTAS). FXTAS also represents a new form of inclusion disease, with eosinophilic intranuclear inclusions found throughout the brain in both neurons and astrocytes. Because FXTAS appears to be relatively specific to male premutation carriers, who are known to possess elevated levels of FMR1 mRNA, the neuropathology may arise as a consequence of a toxic gain-of-function of the mRNA itself, although this proposal requires additional direct testing. One of the critical needs at present is a better estimate for the prevalence of this disorder, because FXTAS is likely to be underdiagnosed in the adult movement disorders clinics. MRDD Research Reviews 2004;10:25,30. © 2004 Wiley-Liss, Inc. [source] Anterior to posterior limb of the internal capsule morphology in fragile X syndromeDEVELOPMENTAL MEDICINE & CHILD NEUROLOGY, Issue 10 2009Cherine Fahim PhD No abstract is available for this article. [source] Epilepsy in fragile X syndromeDEVELOPMENTAL MEDICINE & CHILD NEUROLOGY, Issue 11 2002Elizabeth Berry-Kravis MD PhD Epilepsy is reported to occur in 10 to 20% of individuals with fragile X syndrome (FXS). A frequent seizure/EEG pattern in FXS appears to resemble that of benign focal epilepsy of childhood (BFEC, benign rolandic epilepsy). To evaluate seizure frequency and type in a Chicago FXS cohort, data regarding potential seizure history were reviewed for 136 individuals with FXS (age range 2 to 51 years: 113 males and 23 females). Seizures occurred in 15 males (13.3%) and one female (4.3%): of these, 12 had partial seizures. EEG findings were available for 35 individuals (13 of 16 with seizures and 22 of 120 without seizures) and showed an epileptiform abnormality in 10 (77%) individuals with seizures and five (23%) individuals without seizures - the most common epileptiform pattern being centrotemporal spikes. Seizures were easily controlled in 14 of the 16 individuals with seizures. Many individuals, including all with centrotemporal spikes, had remission of seizures in childhood. The most common seizure syndrome resembled BFEC and this pattern had the best prognosis for epilepsy remission. Deficiency of FMRP (fragile X mental retardation protein) appears to lead to increased neuronal excitability and susceptibility to epilepsy, but particularly seems to facilitate mechanisms leading to the BFEC pattern. [source] Visual search in typically developing toddlers and toddlers with Fragile X or Williams syndromeDEVELOPMENTAL SCIENCE, Issue 1 2004Gaia Scerif Visual selective attention is the ability to attend to relevant visual information and ignore irrelevant stimuli. Little is known about its typical and atypical development in early childhood. Experiment 1 investigates typically developing toddlers' visual search for multiple targets on a touch-screen. Time to hit a target, distance between successively touched items, accuracy and error types revealed changes in 2- and 3-year-olds' vulnerability to manipulations of the search display. Experiment 2 examined search performance by toddlers with Fragile X syndrome (FXS) or Williams syndrome (WS). Both of these groups produced equivalent mean time and distance per touch as typically developing toddlers matched by chronological or mental age; but both produced a larger number of errors. Toddlers with WS confused distractors with targets more than the other groups; while toddlers with FXS perseverated on previously found targets. These findings provide information on how visual search typically develops in toddlers, and reveal distinct search deficits for atypically developing toddlers. [source] Male and female Fmr1 knockout mice on C57 albino background exhibit spatial learning and memory impairmentsGENES, BRAIN AND BEHAVIOR, Issue 6 2010K. B. Baker Impaired spatial learning is a prominent deficit in fragile X syndrome (FXS). Previous studies using the Fmr1 knockout (KO) mouse model of FXS have not consistently reported a deficit in spatial learning. Fmr1 KO mice bred onto an albino C57BL/6J- Tyrc-Brd background showed significant deficits in several primary measures of performance during place navigation and probe trials in the Morris water maze. Fmr1 KO mice were also impaired during a serial reversal version of the water maze task. We examined fear conditioning as an additional cognitive screen. Knockout mice exhibited contextual memory deficits when trained with unsignaled shocks; however, deficits were not found in a separate group of KO mice trained with signaled shocks. No potentially confounding genotypic differences in locomotor activity were observed. A decreased anxiety-like profile was apparent in the open field, as others have noted, and also in the platform test. Also as previously reported, startle reactivity to loud auditory stimuli was decreased, prepulse inhibition and social interaction increased in KO mice. Female Fmr1 KO mice were tested along with male KO mice in all assays, except for social interaction. The female and male KO exhibited very similar impairments indicating that sex does not generally drive the behavioral symptoms of the disorder. Our results suggest that procedural factors, such as the use of albino mice, may help to reliably detect spatial learning and memory impairments in both sexes of Fmr1 KO mice, making it more useful for understanding FXS and a platform for evaluating potential therapeutics. [source] Understanding Fragile X syndrome: molecular, cellular and genomic neuroscience at the crossroads,GENES, BRAIN AND BEHAVIOR, Issue 6 2005Steven O Moldin PhD No abstract is available for this article. [source] What, if anything, is specific about having a rare disorder?HEALTH EXPECTATIONS, Issue 4 2009Patients' judgements on being ill, being rare Abstract Background, Growing efforts are made to improve the situation of persons with rare diseases, but the specific nature of these disorders remains unclear. Objectives, To establish (1) to what extent people with rare disorders think that their disease's rarity causes particular difficulties, (2) to what extent these difficulties relate to other causes than rarity (i.e. other characteristics of the disease or other components of the illness experience), (3) to what extent the rarity of the disease may relate to components of patients' experience other than those that are traditionally addressed (i.e. personal or daily life aspects). Methods, Semi-structured interviews with 29 patients and 15 parents of children with one of six rare diseases (cystic fibrosis, fragile X syndrome, Wilson's disease, mastocytosis, locked-in syndrome and a sixth syndrome). The interviews were conducted in France. The analysis draws on French pragmatic sociology and focuses on the participants' judgements of their experience. Findings, The participants considered as normal and acceptable a range of situations that are often viewed as specific to rare disorders and unfair. This rather positive evaluation was conditional on some specific moral criteria being met. The participants attributed the cause of their difficulties to the failure of health professionals to meet these criteria. In the participants' experience, disease-related associations play a key role and rarity seems to contribute to making them especially important. Conclusions, Patients' experience would be considerably improved if health professionals more often fulfilled their moral expectations, especially regarding diagnosis disclosure and information. (250 words) [source] Fronto-striatal dysfunction and potential compensatory mechanisms in male adolescents with fragile X syndromeHUMAN BRAIN MAPPING, Issue 6 2007Fumiko Hoeft Abstract Response inhibition is an important facet of executive function. Fragile X syndrome (FraX), with a known genetic etiology (fragile X mental retardation-1 (FMR1) mutation) and deficits in response inhibition, may be an ideal condition for elucidating interactions among gene-brain-behavior relationships. Functional magnetic resonance imaging (fMRI) studies have shown evidence of aberrant neural activity when individuals with FraX perform executive function tasks, though the specific nature of this altered activity or possible compensatory processes has yet to be elucidated. To address this question, we examined brain activation patterns using fMRI during a go/nogo task in adolescent males with FraX and in controls. The critical comparison was made between FraX individuals and age, gender, and intelligent quotient (IQ)-matched developmentally delayed controls; in addition to a control group of age and gender-matched typically developing individuals. The FraX group showed reduced activation in the right ventrolateral prefrontal cortex (VLPFC) and right caudate head, and increased contralateral (left) VLPFC activation compared with both control groups. Individuals with FraX, but not controls, showed a significant positive correlation between task performance and activation in the left VLPFC. This potential compensatory activation was predicted by the interaction between FMR1 protein (FMRP) levels and right striatal dysfunction. These results suggest that right fronto-striatal dysfunction is likely an identifiable neuro-phenotypic feature of FraX and that activation of the left VLPFC during successful response inhibition may reflect compensatory processes. We further show that these putative compensatory processes can be predicted by a complex interaction between genetic risk and neural function. Hum Brain Mapp, 2007. © 2007 Wiley-Liss, Inc. [source] Closely linked cis -acting modifier of expansion of the CGG repeat in high risk FMR1 haplotypes,HUMAN MUTATION, Issue 12 2007S. Ennis Abstract In its expanded form, the fragile X triplet repeat at Xq27.3 gives rise to the most common form of inherited mental retardation, fragile X syndrome. This high population frequency persists despite strong selective pressure against mutation-bearing chromosomes. Males carrying the full mutation rarely reproduce and females heterozygous for the premutation allele are at risk of premature ovarian failure. Our diagnostic facility and previous research have provided a large databank of X chromosomes that have been tested for the FRAXA allele. Using this resource, we have conducted a detailed genetic association study of the FRAXA region to determine any cis -acting factors that predispose to expansion of the CGG triplet repeat. We have genotyped SNP variants across a 650-kb tract centered on FRAXA in a sample of 877 expanded and normal X chromosomes. These chromosomes were selected to be representative of the haplotypic diversity encountered in our population. We found expansion status to be strongly associated with a ,50-kb region proximal to the fragile site. Subsequent detailed analyses of this region revealed no specific genetic determinants for the whole population. However, stratification of chromosomes by risk subgroups enabled us to identify a common SNP variant which cosegregates with the subset of D group haplotypes at highest risk of expansion (,=17.84, p=0.00002). We have verified that this SNP acts as a marker of repeat expansion in three independent samples. Hum Mutat 28(12), 1216,1224, 2007. © 2007 Wiley-Liss, Inc. [source] Cancer incidence among persons with fragile X syndrome in Finland: a population-based studyJOURNAL OF INTELLECTUAL DISABILITY RESEARCH, Issue 1 2009R. Sund Abstract Background Fragile X syndrome is a common inheritable cause of intellectual disability (ID) and is characterised by a large number of CGG repeats at the gene FMR1 located on the X-chromosome. It has been reported that this genetic mechanism may protect against malignant transformations. Methods We extracted from the Finnish registry on persons with ID a cohort of 302 persons with a fragile X diagnosis during 1982,1986. Follow-up for cancer incidence was performed in the Finnish Cancer Registry until the end of the year 2005. Results There were 11 reported cancers during the mean follow-up of 21.4 years per person. The expected number of cancers based on the average Finnish population was 13.8 and no statistically significant protective effect was detected [standardised incidence ratios (SIR) 0.80, confidence interval (CI) 95% 0.40,1.4]. An increased risk for lip cancer was found (SIR 23, CI 95% 2.8,85). Conclusions Confirmation of hypotheses about the mechanisms linking FXS and cancer needs further research. [source] Newborn screening in Fragile X syndromeJOURNAL OF INTELLECTUAL DISABILITY RESEARCH, Issue 10 2008F. Tassone Background: Screening for the FMR1 mutations has been a topic of considerable discussion since the FMR1 gene was identified. However, Fragile X has not been recommended for newborn screening mainly because of the lack of an accurate screening test and of data on potential benefits. We have recently developed an improved Polymerase Chain Reaction (PCR) method for the identification of premutation and full mutation alleles for the FMR1 gene. Method: The method is inexpensive, accurate and quick and can be performed on a number of sample templates including, importantly, blood spots. We have applied this method for international screening. Specifically, we have screened 5267 anonymous blood spot samples from newborn males from the centre-northwest region of Spain. We have also used this technology to a pilot ,high risk' screening program of individuals with autism and/or intellectual disabilities and family members of a proband with fragile X initiated in Guatemala. This project is a prototype for future screening endeavours. Results: One important outcome from this study is that the frequency of premutation alleles (1 per 250) appears to be higher than previously reported. This is of importance, especially in view of the different phenotypic involvement observed in carriers of premutation alleles, including neurological problems such as FXTAS. Here, we present data on the frequency of premutation/full alleles found in this population and their size distribution. Conclusion: This project is a prototype for future screening endeavours. Results from our pilot program in both Spain and Guatemala will lend strong support for implementing this technology for rapid screening to a much larger scale population screening. [source] Commonalities in the neurobiology between autism and fragile XJOURNAL OF INTELLECTUAL DISABILITY RESEARCH, Issue 10 2008R. Hagerman There is a close association between autism and fragile X syndrome (FXS) with 30% of males with FXS having autism and 2 to 7% of children with autism having the fragile X mutation. The protein that is missing or deficient in FXS, FMRP, is an RNA binding and transport protein which regulates the translation of many messages important for synaptic plasticity. Typically FMRP inhibits the translation of these messages, such that protein production increases when FMRP is absent. Some of these proteins are known to also cause autism when they are mutated including neuroligin 3 and 4 and the SHANK protein. Therefore, when FMRP is missing there is dysregulation of other proteins that are known to cause autism. FMRP is an important inhibitor of protein production in the metabotropic glutamate receptor 5 pathway (mGluR5) which leads to long term depression (LTD) or the weakening of synaptic connections. Therefore, when FMRP is missing there is enhanced mGluR5 activity leading to enhanced LTD and weak or immature synaptic connections. The use of mGluR5 antagonists to reverse the LTD in the animal models of FXS has led to reversal of the learning, behaviour and dendritic spine abnormalities in these animals. There are now initial studies taking place in humans regarding the use of mGluR5 antagonists to improve behaviour and cognition in FXS. It is likely that these mGluR5 antagonists will also be helpful in a subgroup of patients with non fragile X autism who have similar problems with hyperactivity, hyperarousal and anxiety to those seen in FXS. A second cause of autism is the fragile X premutation but this mechanism of involvement is related to RNA toxicity which perhaps stimulates neuroimmune problems and may mimic other causes of autism. Neurons with the premutation are more vulnerable to environmental toxicity and oxidative stress leading to early cell death. [source] A preliminary study of screening for risk of autism in children with fragile X syndrome: testing two risk cut-offs for the Checklist for Autism in ToddlersJOURNAL OF INTELLECTUAL DISABILITY RESEARCH, Issue 4 2007D. J. Scambler Abstract Objective Risk criteria for the Checklist for Autism in Toddlers (CHAT) and modified risk criteria (i.e. the Denver Criteria) were compared in a group of children with fragile X syndrome (FXS) and autism. Method Participants were 17 children aged 2,4 years with DNA confirmation of FXS. Four children had autism and 13 children did not. Results Preliminary findings regarding the sensitivity and specificity of the CHAT for detecting risk for autism in children with FXS are as follows: using the original CHAT risk criteria, sensitivity and specificity were 50% and 100%, respectively; and using the Denver Criteria, sensitivity and specificity were 75% and 92%, respectively. Conclusions The CHAT and the Denver Criteria resulted in preliminary findings suggesting high levels of sensitivity to autism in children with FXS. [source] The acquisition of stimulus equivalence in individuals with fragile X syndromeJOURNAL OF INTELLECTUAL DISABILITY RESEARCH, Issue 9 2006S. S. Hall Abstract Background Few studies have employed stimulus equivalence procedures to teach individuals with intellectual disabilities (IDs) new skills. To date, no studies of stimulus equivalence have been conducted in individuals with fragile X syndrome (FXS), the most common known cause of inherited ID. Method Five adolescents with FXS were taught basic math and geography skills by using a computerized stimulus equivalence training programme administered over 2 days in 2-h sessions. Results Four of the five participants learned the math relations, with one participant demonstrating stimulus equivalence at post-test. Three of the five participants learned the geography relations, with all three of these participants demonstrating stimulus equivalence at post-test. Conclusions These data indicate that computerized stimulus equivalence procedures, conducted in time-limited sessions, may help individuals with FXS learn new skills. Hypotheses concerning the failure of some participants to learn the training relations and to demonstrate stimulus equivalence at post-test are discussed. [source] Blink rate in boys with fragile X syndrome: preliminary evidence for altered dopamine functionJOURNAL OF INTELLECTUAL DISABILITY RESEARCH, Issue 9 2005J. E. Roberts Abstract Background Dopamine, a neurotransmitter involved in motor and cognitive functioning, can be non-invasively measured via observation of spontaneous blink rates. Blink rates have been studied in a number of clinical conditions including schizophrenia, autism, Parkinsons, and attention deficit/hyperactivity disorder with results implicating either hyper or hypo dopaminergic states. Methods This study examined spontaneous blink rate in boys with fragile X syndrome (FXS). Blink rates of boys (4,8 years old) with FXS (n = 6) were compared with those of age-matched typically developing boys (n = 6) during active and passive tasks. Blink rates (blinks per minute) for each task were compared between the two groups. Then, the relation between blink measures and core FXS-related features [problem behaviours, arousal, fmr 1 protein (FMRP)] were examined within the group of boys with FXS. Results Blink rate in boys with FXS was significantly higher than typically developing boys during passive tasks. Within the FXS group, there were significant correlations between blink rate and problem behaviours and physiological arousal (i.e. heart activity) but not with FMRP. Conclusions Observed differences in spontaneous blink rate between boys with and without FXS and the relation between blink rate and physiological and behavioural measures in boys with FXS suggests that further work examining dopamine dysfunction as, a factor in the pathophysiology of FXS may be warranted. [source] The Human Genome Project , threat or promise?JOURNAL OF INTELLECTUAL DISABILITY RESEARCH, Issue 7 2003B. Carmichael Abstract This paper reflects on some of the arguments against screening from the perspective of a relative of individuals with Fragile X syndrome. It proposes to think about intellectual disability (ID) as including a wide range of limitations beyond that of only the mental handicap. It argues that these limitations impose conditions upon both people with disabilities and their parents, as well as upon their siblings, that in various ways amount to suffering. The claim that people with disabilities are enriching the lives of their relatives is rejected. Furthermore, it is argued that those who ascribe a high moral status to people with disabilities tend to neglect that society does not make much of an effort to offer the necessary support to materialize this status. The claim that screening negatively affects the moral status of persons with ID is rebutted on grounds of the freedom of choice. [source] Fragile X mental retardation protein is required for chemically-induced long-term potentiation of the hippocampus in adult miceJOURNAL OF NEUROCHEMISTRY, Issue 3 2009Yuze Shang Abstract Fragile X syndrome (FXS), a common form of inherited mental retardation, is caused by the lack of fragile X mental retardation protein (FMRP). The animal model of FXS, Fmr1 knockout mice, have deficits in the Morris water maze and trace fear memory tests, showing impairment in hippocampus-dependent learning and memory. However, results for synaptic long-term potentiation (LTP), a key cellular model for learning and memory, remain inconclusive in the hippocampus of Fmr1 knockout mice. Here, we demonstrate that FMRP is required for glycine induced LTP (Gly-LTP) in the CA1 of hippocampus. This form of LTP requires activation of post-synaptic NMDA receptors and metabotropic glutamateric receptors, as well as the subsequent activation of extracellular signal-regulated kinase (ERK) 1/2. However, paired-pulse facilitation was not affected by glycine treatment. Genetic deletion of FMRP interrupted the phosphorylation of ERK1/2, suggesting the possible role of FMRP in the regulation of the activity of ERK1/2. Our study provide strong evidences that FMRP participates in Gly-LTP in the hippocampus by regulating the phosphorylation of ERK1/2, and that improper regulation of these signaling pathways may contribute to the learning and memory deficits observed in FXS. [source] Protective effects of melatonin against oxidative stress in Fmr1 knockout mice: a therapeutic research model for the fragile X syndromeJOURNAL OF PINEAL RESEARCH, Issue 2 2009Yanina Romero-Zerbo Abstract:, Fragile X syndrome is the most common form of inherited mental retardation. It is typically caused by a mutation of the Fragile X mental-retardation 1 (Fmr1) gene. To better understand the role of the Fmr1 gene and its gene product, the fragile X mental-retardation protein in central nervous system functions, an fmr1 knockout mouse that is deficient in the fragile X mental-retardation protein was bred. In the present study, fragile X mental retardation 1-knockout and wild-type mice are used to determine behaviour and oxidative stress alterations, including reduced glutathione, oxidized glutathione and thiobarbituric acid-reactive substances, before and after chronic treatment with melatonin or tianeptine. Reduced glutathione levels were reduced in the brain of fmr1-knockout mice and chronic melatonin treatment normalized the glutathione levels compared with the control group. Lipid peroxidation was elevated in brain and testes of fmr1-knockout mice and chronic melatonin treatment prevents lipid peroxidation in both tissues. Interestingly, chronic treatment with melatonin alleviated the altered parameters in the fmr1-knockout mice, including abnormal context-dependent exploratory and anxiety behaviours and learning abnormalities. Chronic treatment with tianeptine (a serotonin reuptake enhancer) did not normalize the behaviour in fmr1-knockout mice. The prevention of oxidative stress in the fragile X mouse model, by an antioxidant compound such as melatonin, emerges as a new and promising approach for further investigation on treatment trials for the disease. [source] Molecular phenotype of Fragile X syndrome: FMRP, FXRPs, and protein targetsMICROSCOPY RESEARCH AND TECHNIQUE, Issue 3 2002Walter E. Kaufmann Abstract Fragile X syndrome (FraX) is one of the most prevalent genetic causes of mental retardation. FraX is associated with an unstable expansion of a polymorphism within the 5, untranslated region of the FMR1 gene. The main consequence of this mutation is a reduction in the levels of the gene product (FMRP). FMRP is an RNA-binding protein with multiple spliced variants (isoforms) and high levels of expression in a variety of tissues, including neurons. In the latter cells, it is localized not only to the perikaryon but also to dendrites and dendritic spines. FMRP belongs to a family of proteins that includes the Fragile X Related Proteins or FXRPs. FXRPs share high homology in their functional domains with FMRP, and also associate with mRNA and components of the protein synthesis apparatus. However, FXRPs do not have the same temporo-spatial pattern of distribution (and other properties) of FMRP. Immunochemical assays have confirmed that a functionally uncompensated FMRP deficit is the essence of the FraX molecular phenotype. Here, we report our preliminary study on FXRPs levels in leukocytes from FraX males. By immunoblotting, we found that a marked reduction in FMRP levels is associated with a modest increase in FXR1P and no changes in FXR2P levels. The consequences of this reduced FMRP expression on protein synthesis, in other words, the identification of FMRP targets, can be studied by different molecular approaches including protein interaction and proteomics methods. By two-dimensional gel electrophoresis, we showed that in FraX leukocytes there is a defect in acetylation that involves prominently the regulatory protein annexin-1. Extension of current studies of the molecular phenotype to more brain-relevant tissue samples, a wider range of proteomics-based methods, and correlative analyses of FMRP homologues and FMRP targets with multiple behavioral measures, will greatly expand our understanding of FraX pathogenesis and it will help to develop and monitor new therapeutic strategies. Microsc. Res. Tech. 57:135,144, 2002. © 2002 Wiley-Liss, Inc. [source] Fragile X mental retardation: Misregulation of protein synthesis in the developing brain?MICROSCOPY RESEARCH AND TECHNIQUE, Issue 3 2002Yue FengArticle first published online: 18 APR 200 Abstract Fragile X mental retardation results from the absence of a selective RNA-binding protein, FMRP. Previous studies demonstrated that FMRP forms messenger ribonucleoprotein (mRNP) complexes to associate with translating polyribosomes, suggesting that FMRP is involved in regulating protein synthesis. We are now facing the changing questions: How does FMRP influence protein synthesis in the brain? What is the target for FMRP in learning and memory? How does the absence of FMRP cause misregulation of protein synthesis, which in turn leads to mental impairment in fragile X syndrome? Models for abnormal neuronal function as a result of misregulated translation due to the absence of FMRP are discussed. Microsc. Res. Tech. 57:145,147, 2002. © 2002 Wiley-Liss, Inc. [source] Fragile X syndrome, the Fragile X related proteins, and animal modelsMICROSCOPY RESEARCH AND TECHNIQUE, Issue 3 2002André T. Hoogeveen Abstract The Fragile X syndrome (FraX), which is characterized among other physical and neurologic impairments by mental retardation, is caused by the absence of the product of the FMR1 gene. The Fragile X Mental Retardation Protein (FMRP) is a member of a novel family of RNA-binding proteins. The latter includes two other proteins highly homologous with FMRP: the fragile X related proteins 1 and 2 (FXRP1 and FXRP2). Characterization of FXRPs, including their interaction with FMRP, will provide critical information about the mechanisms of action of FMRP and the role of this group of proteins in FMRP-deficient conditions such as FraX. Genetic manipulations of FMRP and the FXRPs should also provide valuable tools for investigating pathophysiology and gene therapies in FraX. The present review summarizes the strategies used for identifying the FXRPs, their chromosomal localization, molecular structure, and tissue distribution. It also reviews interactions between different members of this family of RNA-binding proteins. Animal models, both knockout and transgenic, of FMRP and the FXRPs are discussed. Phenotypic features of the FMR1 knockout mouse, the FMR1 transgenic rescue mouse, and other novel strategies for manipulating and delivering FMRP and FXRPs to the brain and other tissues are described. Microsc. Res. Tech. 57:148,155, 2002. © 2002 Wiley-Liss, Inc. [source] Genetic variation of the FMR1 gene among four Mexican populations: Mestizo, Huichol, Purepecha, and TarahumaraAMERICAN JOURNAL OF HUMAN BIOLOGY, Issue 3 2008Patricio Barros-Núñez Fragile X syndrome is the most common cause of inherited mental retardation; it is caused by expansion of CGG repeats in the first exon of the FMR1 gene. The number of CGG repeats varies between 6 and 50 triplets in normal individuals; the most common alleles have 29 or 30 repeats. Allelic patterns in the global populations are similar; however; some reports show statistical differences among several populations. In Mexico, except by a single report on a western Mestizo population, the allelic frequencies of the FMR1 gene are unknown. In this study, we analyze 207, 140, 138, and 40 chromosomes from Mestizos, Tarahumaras, Huichols, and Purepechas respectively. After PCR amplification on DNA modified by sodium bisulfite treatment, molecular analysis of the FMR1 gene showed 30 different alleles among the 525 chromosomes evaluated. Trinucleotide repeat number in the different Mexican populations varied from 15 to 87, with modal numbers of 32 and 30 in Mestizos and Tarahumaras, 29 and 32 in Purepechas and 30 among Huichols. Together, these allelic patterns differ significantly from those reported for Caucasian, Chinese, African, Indonesian, Brazilian, and Chilean populations. The increased number of the unusual allele of 32 repeats observed in the Mexican mestizo population can be explained from its frequency in at least two Mexican native populations. Am. J. Hum. Biol., 2008. © 2008 Wiley-Liss, Inc. [source] Preconceptional and prenatal screening for fragile X syndrome: Experience with 40 000 testsPRENATAL DIAGNOSIS, Issue 11 2007Michal Berkenstadt Abstract Objectives To determine the carrier frequency of fragile X syndrome, and the rate of expansion from premutation (PM) carrier to full mutation (FM) fetus. Methods Results were analyzed on women with no family history of fragile X syndrome, or who were PM/FM carriers, who were tested between January 1994 and June 2004. PM was defined 55,199 repeats, FM above 200. Results Out of 40 079 women screened, 5 FM and 255 PM carriers were detected. There was no significant difference in carrier frequency between those with versus those without family history of mental retardation or developmental abnormalities: 1 in 128 (28/3596) versus 1 in 157 (232/36 483). However, the median of repeats differed significantly: 58 and 66 repeats, respectively, (P < 0.0001). Invasive prenatal diagnosis was carried out in 370 pregnancies (7 FM and 363 PM). Thirty FM fetuses were detected. There was a lower expansion rate in cases without a family history: 10% (17/169 PMs) compared to 50% (11/22 PMs) in those with a history, but this could be accounted for by the difference in allele size. Conclusion There is now sufficient information on screening parameters and prenatal diagnosis of fragile X syndrome to offer testing to women of reproductive age. Copyright © 2007 John Wiley & Sons, Ltd. [source] Pilot study for the neonatal screening of fragile X syndromePRENATAL DIAGNOSIS, Issue 9 2003Article first published online: 2 SEP 200 This original article to which this Erratum refers was published in Prenatal Diagnosis (2002; 22: 459,462). Copyright © 2003 John Wiley & Sons, Ltd. [source] Annotation: What do we know about sensory dysfunction in autism?THE JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY AND ALLIED DISCIPLINES, Issue 12 2005A critical review of the empirical evidence Background:, Unusual responses to sensory stimuli are seen in many children with autism. Their presence was highlighted both in early accounts of autism and in more recent first-person descriptions. There is a widespread belief that sensory symptoms characterize autism and differentiate it from other disorders. This paper examines the empirical evidence for this assumption. Method:, All controlled experimental laboratory investigations published since 1960 were identified through systematic searches using Medline/PubMed and PsycInfo search engines. A total of 48 empirical papers and 27 theoretical or conceptual papers were reviewed. Results:, Sensory symptoms are more frequent and prominent in children with autism than in typically developing children, but there is not good evidence that these symptoms differentiate autism from other developmental disorders. Certain groups, including children with fragile X syndrome and those who are deaf-blind, appear to demonstrate higher rates of sensory symptoms than children with autism. In reviewing the evidence relevant to two theories of sensory dysfunction in autism, over- and under-arousal theory, we find that there is very little support for hyper-arousal and failure of habituation in autism. There is more evidence that children with autism, as a group, are hypo-responsive to sensory stimuli, but there are also multiple failures to replicate findings and studies that demonstrate lack of group differences. Conclusions:, The use of different methods, the study of different sensory modalities, and the changing scientific standards across decades complicate interpretation of this body of work. We close with suggestions for future research in this area. [source] | ||||||||||||||||