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Journal of Intellectual Disability... Apr 2020Fragile X syndrome (FXS) is a single-gene disorder highly associated with anxiety; however, measuring anxiety symptoms in FXS and other neurogenetic syndromes is...
BACKGROUND
Fragile X syndrome (FXS) is a single-gene disorder highly associated with anxiety; however, measuring anxiety symptoms in FXS and other neurogenetic syndromes is challenged by common limitations in language, self-awareness and cognitive skills required for many traditional assessment tasks. Prior studies have documented group-level differences in threat-related attentional biases, assessed via eye tracking, in FXS and non-FXS groups. The present study built on this work to test whether attentional biases correspond to clinical features of anxiety among adolescents and young adults with FXS.
METHODS
Participants included 21 male adolescents with FXS ages 15-20 years who completed an adapted eye-tracking task that measured attentional bias towards fearful faces of varied emotional intensity.
RESULTS
Among participants without anxiety disorders, attentional bias towards fear increased across age, similar to non-FXS paediatric anxiety samples. In contrast, participants with anxiety disorders exhibited greater stability in fear-related attentional biases across age. Across analyses, subtle fear stimuli were more sensitive to within-group anxiety variability than full-intensity stimuli.
CONCLUSIONS
Our results provide novel evidence that although threat-related attentional biases may correspond with anxiety outcomes in FXS, these associations are complex and vary across developmental and task factors. Future studies are needed to characterise these associations in more robust longitudinal samples, informing whether and how eye-tracking tasks might be optimised to reliably predict and track anxiety in FXS.
Topics: Adolescent; Adult; Anxiety Disorders; Attentional Bias; Comorbidity; Fragile X Syndrome; Humans; Male; Young Adult
PubMed: 32020687
DOI: 10.1111/jir.12715 -
ASN Neuro 2018Fragile X syndrome (FXS) is a neurodevelopmental disorder that causes intellectual disability. It is a leading known genetic cause of autism. In addition to cognitive,... (Review)
Review
Fragile X syndrome (FXS) is a neurodevelopmental disorder that causes intellectual disability. It is a leading known genetic cause of autism. In addition to cognitive, social, and communication deficits, humans with FXS demonstrate abnormal sensory processing including sensory hypersensitivity. Sensory hypersensitivity commonly manifests as auditory, tactile, or visual defensiveness or avoidance. Clinical, behavioral, and electrophysiological studies consistently show auditory hypersensitivity, impaired habituation to repeated sounds, and reduced auditory attention in humans with FXS. Children with FXS also exhibit significant visuospatial impairments. Studies in infants and toddlers with FXS have documented impairments in processing texture-defined motion stimuli, temporal flicker, perceiving ordinal numerical sequence, and the ability to maintain the identity of dynamic object information during occlusion. Consistent with the observations in humans with FXS, fragile X mental retardation 1 ( Fmr1) gene knockout (KO) rodent models of FXS also show seizures, abnormal visual-evoked responses, auditory hypersensitivity, and abnormal processing at multiple levels of the auditory system, including altered acoustic startle responses. Among other sensory symptoms, individuals with FXS exhibit tactile defensiveness. Fmr1 KO mice also show impaired encoding of tactile stimulation frequency and larger size of receptive fields in the somatosensory cortex. Since sensory deficits are relatively more tractable from circuit mechanisms and developmental perspectives than more complex social behaviors, the focus of this review is on clinical, functional, and structural studies that outline the auditory, visual, and somatosensory processing deficits in FXS. The similarities in sensory phenotypes between humans with FXS and animal models suggest a likely conservation of basic sensory processing circuits across species and may provide a translational platform to not just develop biomarkers but also to understand underlying mechanisms. We argue that preclinical studies in animal models of FXS can facilitate the ongoing search for new therapeutic approaches in FXS by understanding mechanisms of basic sensory processing circuits and behaviors that are conserved across species.
Topics: Animals; Disease Models, Animal; Fragile X Mental Retardation Protein; Fragile X Syndrome; Humans; Phenotype; Sensation Disorders
PubMed: 30231625
DOI: 10.1177/1759091418801092 -
Revista de Neurologia Mar 2019The fragile X associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disease associated with the repetition of CGG triplets (55-200 CGG repetitions) in the... (Review)
Review
The fragile X associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disease associated with the repetition of CGG triplets (55-200 CGG repetitions) in the FMR1 gene. The premutation of the FMR1 gene, contrasting with the full mutation (more than 200 CGG repetitions), presents an increased production of messenger and a similar or slightly decreased production of FMRP protein. FXTAS affects 40% of men and 16% of women carriers of the premutation. It presents with a wide constellation of neurological signs such as intention tremor, cerebellar ataxia, parkinsonism, executive function deficits, peripheral neuropathy and cognitive decline leading to dementia among others. In this review, we present what is currently known about the molecular mechanism, the radiological findings and the pathology, as well as the complexity of the diagnosis and management of FXTAS.
Topics: Antidepressive Agents; Ataxia; Brain; Deep Brain Stimulation; Female; Fragile X Mental Retardation Protein; Fragile X Syndrome; Humans; Male; Memantine; Neurologic Examination; Pregnanolone; Symptom Assessment; Tremor
PubMed: 30805918
DOI: 10.33588/rn.6805.2018457 -
Journal of Neurodevelopmental Disorders Jul 2021Whilst up to 60% of males with fragile X syndrome (FXS) meet criteria for autism spectrum disorder (ASD), the prevalence and nature of ASD in females with FXS remains... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Whilst up to 60% of males with fragile X syndrome (FXS) meet criteria for autism spectrum disorder (ASD), the prevalence and nature of ASD in females with FXS remains unclear.
METHOD
A systematic literature search identified papers reporting ASD prevalence and/or symptomatology in females with FXS.
RESULTS AND CONCLUSION
Meta-analysis suggested that rates of ASD for females with FXS are reliably higher than for females in the general population (a random effects model estimated weighted average prevalence at 14%, 95% CI 13-18%). Whilst papers highlighted a number of social and repetitive difficulties for females with FXS, characteristic profiles of impairment are not clear. Possible associations between ASD traits and IQ, and between ASD and levels of fragile X mental retardation protein, are suggested, but data are equivocal.
Topics: Autism Spectrum Disorder; Female; Fragile X Syndrome; Humans; Male; Prevalence
PubMed: 34294028
DOI: 10.1186/s11689-021-09362-5 -
The Western Journal of Medicine Feb 1997The fragile X syndrome is the most common inherited cause of mental retardation that is known. The prevalence of mental retardation from this syndrome ranges from 1 in... (Review)
Review
The fragile X syndrome is the most common inherited cause of mental retardation that is known. The prevalence of mental retardation from this syndrome ranges from 1 in 1,250 to 1 in 4,000 in the general population, although the prevalence of female carriers has been reported to be as high as 1 in 259. The discovery of the FMR1 gene mutation in 1991 has simplified diagnosis, enhanced our understanding of the spectrum of involvement in the fragile X syndrome, and stimulated research regarding the normal function of the FMR1 protein in brain development. Advances have also occurred in the treatment of the fragile X syndrome, and psychopharmacologic and educational interventions are reviewed here.
Topics: Adult; Child; Diagnosis, Differential; Female; Follow-Up Studies; Fragile X Syndrome; Humans; Incidence; Male; Mental Disorders; Psychotropic Drugs
PubMed: 9109330
DOI: No ID Found -
Neurobiology of Disease May 2024Fragile X Syndrome (FXS) is a neurodevelopment disorder characterized by cognitive impairment, behavioral challenges, and synaptic abnormalities, with a genetic basis... (Review)
Review
Fragile X Syndrome (FXS) is a neurodevelopment disorder characterized by cognitive impairment, behavioral challenges, and synaptic abnormalities, with a genetic basis linked to a mutation in the FMR1 (Fragile X Messenger Ribonucleoprotein 1) gene that results in a deficiency or absence of its protein product, Fragile X Messenger Ribonucleoprotein (FMRP). In recent years, mass spectrometry (MS) - based proteomics has emerged as a powerful tool to uncover the complex molecular landscape underlying FXS. This review provides a comprehensive overview of the proteomics studies focused on FXS, summarizing key findings with an emphasis on dysregulated proteins associated with FXS. These proteins span a wide range of cellular functions including, but not limited to, synaptic plasticity, RNA translation, and mitochondrial function. The work conducted in these proteomic studies provides a more holistic understanding to the molecular pathways involved in FXS and considerably enhances our knowledge into the synaptic dysfunction seen in FXS.
Topics: Humans; Fragile X Syndrome; Fragile X Mental Retardation Protein; Proteomics; Gene Expression Regulation
PubMed: 38548140
DOI: 10.1016/j.nbd.2024.106486 -
American Journal of Medical Genetics.... Feb 2023Fragile X syndrome (FXS) is caused by hypermethylation of the FMR1 promoter due to the full mutation expansion (full mutation [FM]: CGG ≥ 200 repeats) and silencing...
Fragile X syndrome (FXS) is caused by hypermethylation of the FMR1 promoter due to the full mutation expansion (full mutation [FM]: CGG ≥ 200 repeats) and silencing of FMR1. Assessment of mosaicism for active-unmethylated alleles has prognostic utility. This study examined relationships between FMR1 methylation in different tissues with FMR1 messenger ribonucleic acid (mRNA) and intellectual functioning in 87 males with FXS (1.89-43.17 years of age). Methylation sensitive Southern blot (mSB) and Methylation Specific-Quantitative Melt Aanalysis (MS-QMA) were used to examine FMR1 methylation. FMR1 mRNA levels in blood showed strong relationships with FMR1 methylation assessed using MS-QMA in blood (n = 68; R = 0.597; p = 1.4 × 10 ) and buccal epithelial cells (BEC) (n = 62; R = 0.24; p = 0.003), with these measures also showing relationships with intellectual functioning scores (p < 0.01). However, these relationships were not as strong for mSB, with ~40% of males with only FM alleles that were 100% methylated and non-mosaic by mSB, showing methylation mosaicism by MS-QMA. This was confirmed through presence of detectable levels of FMR1 mRNA in blood. In summary, FMR1 methylation levels in blood and BEC examined by MS-QMA were significantly associated with FMR1 mRNA levels and intellectual functioning in males with FXS. These relationships were not as strong for mSB, which underestimated prevalence of mosaicism.
Topics: Male; Humans; Fragile X Syndrome; Mosaicism; Fragile X Mental Retardation Protein; DNA Methylation; Mutation; RNA, Messenger
PubMed: 36349505
DOI: 10.1002/ajmg.a.63027 -
The Yale Journal of Biology and Medicine Dec 2021Fragile X syndrome is the most common monogenetic cause of inherited intellectual disability and syndromic autism spectrum disorder. Fragile X syndrome is caused by an...
Fragile X syndrome is the most common monogenetic cause of inherited intellectual disability and syndromic autism spectrum disorder. Fragile X syndrome is caused by an expansion (full mutation ≥200 CGGs repeats, normal 10-45 CGGs) of the fragile X mental retardation 1 () gene, epigenetic silencing of the gene, which leads to reduction or lack of the gene's product: the fragile X mental retardation protein. In this cross-sectional study, we assessed general and pharmacotherapy knowledge (GK and PTK) of fragile X syndrome and satisfaction with education in neurodevelopmental disorders (NDDs) among senior medical students in Serbia (N=348), Georgia (N=112), and Colombia (N=58). A self-administered 18-item questionnaire included GK (8/18) and PTK (7/18) components and self-assessment of the participants education in NDDs (3/18). Roughly 1 in 5 respondents had correct answers on half or more facts about fragile X syndrome (GK>PTK), which ranged similarly 5-7 in Serbia, 6-8 in Georgia, and 5-8 in Colombia, respectively. No cohort had an average value greater than 9 (60%) that would represent passing score "cut-off." None of the participants answered all the questions correctly. More than two-thirds of the participants concluded that they gained inadequate knowledge of NDDs during their studies, and that their education in this field should be more intense. In conclusion, there is a major gap in knowledge regarding fragile X syndrome among senior medical students in these three developing countries. The finding could at least in part be generalized to other developing countries aimed toward increasing knowledge and awareness of NDDs and fostering an institutional collaboration between developed and developing countries.
Topics: Autism Spectrum Disorder; Colombia; Cross-Sectional Studies; Developing Countries; Fragile X Mental Retardation Protein; Fragile X Syndrome; Georgia (Republic); Humans; Mutation; Serbia
PubMed: 34970093
DOI: No ID Found -
Molecular Neurobiology Nov 2023Fragile X syndrome (FXS) is an inherited human mental retardation that arises from expansion of a CGG repeat in the Fmr1 gene, causing loss of the fragile X mental...
Fragile X syndrome (FXS) is an inherited human mental retardation that arises from expansion of a CGG repeat in the Fmr1 gene, causing loss of the fragile X mental retardation protein (FMRP). It is reported that N-methyl-D-aspartate receptor (NMDAR)-mediated facilitation of long-term potentiation (LTP) and fear memory are impaired in Fmr1 knockout (KO) mice. In this study, biological, pharmacological, and electrophysiological techniques were performed to determine the roles of D-aspartate (D-Asp), a modulator of NMDAR, and its metabolizing enzyme D-aspartate oxidase (DDO) in Fmr1 KO mice. Levels of D-Asp were decreased in the medial prefrontal cortex (mPFC ); however, the levels of its metabolizing enzyme DDO were increased. Electrophysiological recordings indicated that oral drinking of D-Asp recovered LTP induction in mPFC from Fmr1 KO mice. Moreover, chronic oral administration of D-Asp reversed behavioral deficits of cognition and locomotor coordination in Fmr1 KO mice. The therapeutic action of D-Asp was partially through regulating functions of NMDARs and mGluR5/mTOR/4E-BP signaling pathways. In conclusion, supplement of D-Asp may benefit for synaptic plasticity and behaviors in Fmr1 KO mice and offer a potential therapeutic strategy for FXS.
Topics: Mice; Animals; Humans; D-Aspartic Acid; Fragile X Syndrome; Learning; Long-Term Potentiation; Fragile X Mental Retardation Protein; Mice, Knockout; Brain; Disease Models, Animal; Mice, Inbred C57BL
PubMed: 37453994
DOI: 10.1007/s12035-023-03438-0 -
Pediatrics Jun 2017Fragile X syndrome (FXS) is the most common known inherited form of intellectual disability. Early identification is an important step in linking FXS individuals with... (Review)
Review
BACKGROUND
Fragile X syndrome (FXS) is the most common known inherited form of intellectual disability. Early identification is an important step in linking FXS individuals with appropriate and timely medical and social services. Newborn screening (NBS) is 1 approach that has been used for other conditions to facilitate early identification.
METHODS
A literature review was conducted to identify issues, barriers, challenges, and approaches to addressing challenges related to NBS for FXS. Search terms included: fragile X syndrome, FMR1, newborn screening, screening, and genetic testing. To supplement the literature review, 9 key informant interviews were conducted. Information gathered through these interviews supplemented what was identified in the literature. Information from both the literature review and supplemental interviews was reviewed by 3 researchers who discussed and came to consensus on thematic areas and categorization of issues.
RESULTS
The barriers and challenges related to NBS for FXS identified in the literature and by experts and stakeholders are categorized into 5 thematic areas: public health burden, treatment, timing, screening/testing methodologies, and translating results. Summaries of these issues and barriers are provided, along with potential approaches to addressing them.
CONCLUSIONS
The issues and barriers described in this article highlight limited areas of knowledge that need be addressed to improve our understanding of FXS and the potential benefit of NBS. The landscape of NBS for FXS could be influenced by a series of research findings over time or a larger breakthrough that demonstrates an effective targeted treatment that has to be implemented early in life.
Topics: Cost of Illness; Early Diagnosis; Early Medical Intervention; Fragile X Mental Retardation Protein; Fragile X Syndrome; Health Services Accessibility; Humans; Infant, Newborn; Neonatal Screening; United States
PubMed: 28814541
DOI: 10.1542/peds.2016-1159G