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Gaceta Medica de Mexico 2020Fragile X syndrome is the monogenetic condition that produces more cases of autism and intellectual disability. The repetition of CGG triplets (> 200) and their... (Review)
Review
Fragile X syndrome is the monogenetic condition that produces more cases of autism and intellectual disability. The repetition of CGG triplets (> 200) and their methylation entail the silencing of the FMR1 gene. The FMRP protein (product of the FMR1 gene) interacts with ribosomes by controlling the translation of specific messengers, and its loss causes alterations in synaptic connectivity. Screening for fragile X syndrome is performed by polymerase chain reaction. Current recommendation of the American Academy of Pediatrics is to test individuals with intellectual disability, global developmental retardation or with a family history of presence of the mutation or premutation. Hispanic countries such as Colombia, Chile and Spain report high prevalence of fragile X syndrome and have created fragile X national associations or corporations that seek to bring patients closer to available diagnostic and treatment networks.
Topics: Attention Deficit Disorder with Hyperactivity; Autistic Disorder; Checklist; Child, Preschool; Female; Fragile X Mental Retardation Protein; Fragile X Syndrome; Gene Silencing; Genetic Testing; Humans; Intellectual Disability; Male; Mutation; Pedigree; Phenotype; Ribosomes; Sex Factors; Synaptic Transmission
PubMed: 32026885
DOI: 10.24875/GMM.19005275 -
International Journal of Molecular... Feb 2022Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by the full mutation as well as highly localized methylation of the fragile X mental retardation 1 ()... (Review)
Review
Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by the full mutation as well as highly localized methylation of the fragile X mental retardation 1 () gene on the long arm of the X chromosome. Children with FXS are commonly co-diagnosed with Autism Spectrum Disorder, attention and learning problems, anxiety, aggressive behavior and sleep disorder, and early interventions have improved many behavior symptoms associated with FXS. In this review, we performed a literature search of original and review articles data of clinical trials and book chapters using MEDLINE (1990-2021) and ClinicalTrials.gov. While we have reviewed the biological importance of the fragile X mental retardation protein (FMRP), the FXS phenotype, and current diagnosis techniques, the emphasis of this review is on clinical interventions. Early non-pharmacological interventions in combination with pharmacotherapy and targeted treatments aiming to reverse dysregulated brain pathways are the mainstream of treatment in FXS. Overall, early diagnosis and interventions are fundamental to achieve optimal clinical outcomes in FXS.
Topics: Animals; Brain; Fragile X Mental Retardation Protein; Fragile X Syndrome; Humans; Phenotype
PubMed: 35216055
DOI: 10.3390/ijms23041935 -
International Journal of Molecular... Jun 2020The fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder seen in older premutation (55-200 CGG repeats) carriers of The premutation has... (Review)
Review
The fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder seen in older premutation (55-200 CGG repeats) carriers of The premutation has excessive levels of mRNA that lead to toxicity and mitochondrial dysfunction. The clinical features usually begin in the 60 s with an action or intention tremor followed by cerebellar ataxia, although 20% have only ataxia. MRI features include brain atrophy and white matter disease, especially in the middle cerebellar peduncles, periventricular areas, and splenium of the corpus callosum. Neurocognitive problems include memory and executive function deficits, although 50% of males can develop dementia. Females can be less affected by FXTAS because of a second X chromosome that does not carry the premutation. Approximately 40% of males and 16% of female carriers develop FXTAS. Since the premutation can occur in less than 1 in 200 women and 1 in 400 men, the FXTAS diagnosis should be considered in patients that present with tremor, ataxia, parkinsonian symptoms, neuropathy, and psychiatric problems. If a family history of a fragile X mutation is known, then DNA testing is essential in patients with these symptoms.
Topics: Age of Onset; Ataxia; Atrophy; Early Diagnosis; Female; Fragile X Mental Retardation Protein; Fragile X Syndrome; Humans; Magnetic Resonance Imaging; Male; Mutation; Sex Characteristics; Tremor; Trinucleotide Repeat Expansion
PubMed: 32575683
DOI: 10.3390/ijms21124391 -
Colombia Medica (Cali, Colombia) 2014Fragile X Syndrome (FXS) is a genetic disease due to a CGG trinucleotide expansion, named full mutation (greater than 200 CGG repeats), in the fragile X mental... (Review)
Review
Fragile X Syndrome (FXS) is a genetic disease due to a CGG trinucleotide expansion, named full mutation (greater than 200 CGG repeats), in the fragile X mental retardation 1 gene locus Xq27.3; which leads to an hypermethylated region in the gene promoter therefore silencing it and lowering the expression levels of the fragile X mental retardation 1, a protein involved in synaptic plasticity and maturation. Individuals with FXS present with intellectual disability, autism, hyperactivity, long face, large or prominent ears and macroorchidism at puberty and thereafter. Most of the young children with FXS will present with language delay, sensory hyper arousal and anxiety. Girls are less affected than boys, only 25% have intellectual disability. Given the genomic features of the syndrome, there are patients with a number of triplet repeats between 55 and 200, known as premutation carriers. Most carriers have a normal IQ but some have developmental problems. The diagnosis of FXS has evolved from karyotype with special culture medium, to molecular techniques that are more sensitive and specific including PCR and Southern Blot. During the last decade, the advances in the knowledge of FXS, has led to the development of investigations on pharmaceutical management or targeted treatments for FXS. Minocycline and sertraline have shown efficacy in children.
Topics: Animals; Blotting, Southern; Child; DNA Methylation; Female; Fragile X Mental Retardation Protein; Fragile X Syndrome; Humans; Male; Mutation; Polymerase Chain Reaction; Promoter Regions, Genetic; Sex Factors; Trinucleotide Repeat Expansion
PubMed: 25767309
DOI: No ID Found -
Colombia Medica (Cali, Colombia) 2023Fragile X syndrome is caused by the expansion of CGG triplets in the gene, which generates epigenetic changes that silence its expression. The absence of the protein... (Review)
Review
Fragile X syndrome is caused by the expansion of CGG triplets in the gene, which generates epigenetic changes that silence its expression. The absence of the protein coded by this gene, FMRP, causes cellular dysfunction, leading to impaired brain development and functional abnormalities. The physical and neurologic manifestations of the disease appear early in life and may suggest the diagnosis. However, it must be confirmed by molecular tests. It affects multiple areas of daily living and greatly burdens the affected individuals and their families. Fragile X syndrome is the most common monogenic cause of intellectual disability and autism spectrum disorder; the diagnosis should be suspected in every patient with neurodevelopmental delay. Early interventions could improve the functional prognosis of patients with Fragile X syndrome, significantly impacting their quality of life and daily functioning. Therefore, healthcare for children with Fragile X syndrome should include a multidisciplinary approach.
Topics: Humans; Child; Fragile X Syndrome; Autism Spectrum Disorder; Quality of Life; Intellectual Disability; Fragile X Mental Retardation Protein
PubMed: 37664646
DOI: 10.25100/cm.v54i2.5089 -
American Journal of Medical Genetics.... Jan 2018Fragile X syndrome (FXS) is the most common inherited form of intellectual disability, typically due to CGG-repeat expansions in the FMR1 gene leading to lack of... (Review)
Review
Fragile X syndrome (FXS) is the most common inherited form of intellectual disability, typically due to CGG-repeat expansions in the FMR1 gene leading to lack of expression. We identified a rare FMR1 gene mutation (c.413G>A), previously reported in a single patient and reviewed the literature for other rare FMR1 mutations. Our patient at 10 years of age presented with the classical findings of FXS including intellectual disability, autism, craniofacial findings, hyperextensibility, fleshy hands, flat feet, unsteady gait, and seizures but without the typical CGG-repeat expansion. He had more features of FXS than the previously reported patient with the same mutation. Twenty individuals reported previously with rare missense or nonsense mutations or other coding disturbances of the FMR1 gene ranged in age from infancy to 50 years; most were verbal with limited speech, had autism and hyperactivity, and all had intellectual disability. Four of the 20 individuals had a mutation within exon 15, three within exon 5, and two within exon 2. The FMR1 missense mutation (c.413G>A) is the same as in a previously reported male where it was shown that there was preservation of the post-synaptic function of the fragile X mental retardation protein (FMRP), the encoded protein of the FMR1 gene was preserved. Both patients with this missense mutation had physical, cognitive, and behavioral features similarly seen in FXS.
Topics: Alleles; Child; DNA Mutational Analysis; Exons; Facies; Fragile X Mental Retardation Protein; Fragile X Syndrome; Genetic Association Studies; Genotype; High-Throughput Nucleotide Sequencing; Humans; Male; Mutation; Mutation, Missense; Phenotype
PubMed: 29178241
DOI: 10.1002/ajmg.a.38504 -
International Journal of Molecular... May 2023The diagnosis and management of fragile X syndrome (FXS) have significantly improved in the last three decades, although the current diagnostic techniques are not yet... (Review)
Review
The diagnosis and management of fragile X syndrome (FXS) have significantly improved in the last three decades, although the current diagnostic techniques are not yet able to precisely identify the number of repeats, methylation status, level of mosaicism, and/or the presence of AGG interruptions. A high number of repeats (>200) in the fragile X messenger ribonucleoprotein 1 gene () results in hypermethylation of promoter and gene silencing. The actual molecular diagnosis is performed using a Southern blot, TP-PCR (Triplet-Repeat PCR), MS-PCR (Methylation-Specific PCR), and MS-MLPA (Methylation-Specific MLPA) with some limitations, with multiple assays being necessary to completely characterise a patient with FXS. The actual gold standard diagnosis uses Southern blot; however, it cannot accurately characterise all cases. Optical genome mapping is a new technology that has also been developed to approach the diagnosis of fragile X syndrome. Long-range sequencing represented by PacBio and Oxford Nanopore has the potential to replace the actual diagnosis and offers a complete characterization of molecular profiles in a single test. The new technologies have improved the diagnosis of fragile X syndrome and revealed unknown aberrations, but they are a long way from being used routinely in clinical practice.
Topics: Humans; Fragile X Syndrome; DNA Methylation; Gene Silencing; Trinucleotide Repeats; Alleles; Fragile X Mental Retardation Protein; Mutation
PubMed: 37298158
DOI: 10.3390/ijms24119206 -
Cell Dec 2023Short tandem repeat (STR) instability causes transcriptional silencing in several repeat expansion disorders. In fragile X syndrome (FXS), mutation-length expansion of a...
Short tandem repeat (STR) instability causes transcriptional silencing in several repeat expansion disorders. In fragile X syndrome (FXS), mutation-length expansion of a CGG STR represses FMR1 via local DNA methylation. Here, we find megabase-scale H3K9me3 domains on autosomes and encompassing FMR1 on the X chromosome in FXS patient-derived iPSCs, iPSC-derived neural progenitors, EBV-transformed lymphoblasts, and brain tissue with mutation-length CGG expansion. H3K9me3 domains connect via inter-chromosomal interactions and demarcate severe misfolding of TADs and loops. They harbor long synaptic genes replicating at the end of S phase, replication-stress-induced double-strand breaks, and STRs prone to stepwise somatic instability. CRISPR engineering of the mutation-length CGG to premutation length reverses H3K9me3 on the X chromosome and multiple autosomes, refolds TADs, and restores gene expression. H3K9me3 domains can also arise in normal-length iPSCs created with perturbations linked to genome instability, suggesting their relevance beyond FXS. Our results reveal Mb-scale heterochromatinization and trans interactions among loci susceptible to instability.
Topics: Humans; Fragile X Syndrome; Trinucleotide Repeat Expansion; DNA Methylation; Mutation; Fragile X Mental Retardation Protein
PubMed: 38134876
DOI: 10.1016/j.cell.2023.11.019 -
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 -
Genetics in Medicine : Official Journal... May 2021Molecular genetic testing of the FMR1 gene is commonly performed in clinical laboratories. Pathogenic variants in the FMR1 gene are associated with fragile X syndrome,...
Molecular genetic testing of the FMR1 gene is commonly performed in clinical laboratories. Pathogenic variants in the FMR1 gene are associated with fragile X syndrome, fragile X-associated tremor ataxia syndrome (FXTAS), and fragile X-associated primary ovarian insufficiency (FXPOI). This document provides updated information regarding FMR1 pathogenic variants, including prevalence, genotype-phenotype correlations, and variant nomenclature. Methodological considerations are provided for Southern blot analysis and polymerase chain reaction (PCR) amplification of FMR1, including triplet repeat-primed and methylation-specific PCR.The American College of Medical Genetics and Genomics (ACMG) Laboratory Quality Assurance Committee has the mission of maintaining high technical standards for the performance and interpretation of genetic tests. In part, this is accomplished by the publication of the document ACMG Technical Standards for Clinical Genetics Laboratories, which is now maintained online ( http://www.acmg.net ). This subcommittee also reviews the outcome of national proficiency testing in the genetics area and may choose to focus on specific diseases or methodologies in response to those results. Accordingly, the subcommittee selected fragile X syndrome to be the first topic in a series of supplemental sections, recognizing that it is one of the most frequently ordered genetic tests and that it has many alternative methods with different strengths and weaknesses. This document is the fourth update to the original standards and guidelines for fragile X testing that were published in 2001, with revisions in 2005 and 2013, respectively.This versionClarifies the clinical features associated with different FMRI variants (Section 2.3)Discusses important reporting considerations (Section 3.3.1.3)Provides updates on technology (Section 4.1).
Topics: Female; Fragile X Mental Retardation Protein; Fragile X Syndrome; Genetic Testing; Genetics, Medical; Genomics; Humans; Mutation; United States
PubMed: 33795824
DOI: 10.1038/s41436-021-01115-y