Fragile X syndrome and epilepsy.
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ABSTRACT:
SUBMITTER: Qiu LF
PROVIDER: S-EPMC5552528 | biostudies-other | 2008 Oct
REPOSITORIES: biostudies-other
Similar Datasets
Project description: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.
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Project description:Transcriptome analysis of RNA samples collected from human control and FXS iPS cell-derived neural progenitors at day 1 and day 7 of differentiation Lack of fragile X mental retardation protein results in fragile X syndrome (FXS), which is the most common inherited intellectual disability syndrome and serves as an excellent model disease to study molecular mechanisms behind neuropsychiatric comorbidities. We compared the transcriptomes of human neural progenitors (NPCs) generated from patient-derived induced pluripotent stem cells (iPSCs) of three FXS and three control male donors. Altered expression of RAD51C, PPIL3, GUCY1A2, MYD88, TRAPPC4, LYNX1, and GTF2A1L in FXS NPCs suggested changes related to triplet repeat instability, RNA splicing, testes development, and pathways previously shown to be affected in FXS. LYNX1 is a cholinergic break of tissue plasminogen activator (tPA)-dependent plasticity, and its reduced expression was consistent with augmented tPA-dependent radial glial process growth in NPCs derived from FXS iPSC lines. An analysis of gene expression in LYNX1-related signaling pathways revealed that NPCs derived from an FXS male with concomitant epilepsy differed from the other FXS NPCs. The differently expressed genes comprised several epilepsy-related genes, including genes shown to cause the auditory epilepsy phenotype in the murine model of FXS. Functional enrichment analysis highlighted regulation of insulin-like growth factor pathway in human NPCs modeling FXS with epilepsy. Our results link early gene expression changes of FXS NPCs with the pathogenesis of FXS and comorbid epilepsy.
2022-12-31 | GSE216875 | GEO
Project description:Fragile X syndrome is caused by the expansion of CGG triplets in the FMR1 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.
| S-EPMC10469670 | biostudies-literature
Project description:Fragile X syndrome (FXS) is the most common form of heritable mental retardation and the leading identified cause of autism. FXS is caused by transcriptional silencing of the FMR1 gene that encodes the fragile X mental retardation protein (FMRP), but the pathogenesis of the disease is unknown. According to one proposal, many psychiatric and neurological symptoms of FXS result from unchecked activation of mGluR5, a metabotropic glutamate receptor. To test this idea we generated Fmr1 mutant mice with a 50% reduction in mGluR5 expression and studied a range of phenotypes with relevance to the human disorder. Our results demonstrate that mGluR5 contributes significantly to the pathogenesis of the disease, a finding that has significant therapeutic implications for fragile X and related developmental disorders.
| S-EPMC2199268 | biostudies-literature
Project description:Almost all patients with Fragile X Syndrome (FXS) exhibit a CGG repeat expansion (full mutation) in the Fragile Mental Retardation 1 gene (FMR1). Here, the authors report five unrelated males with FXS harboring a somatic full mutation/deletion mosaicism.Mutational profiles were only elucidated by using a combination of molecular approaches (CGG-based PCR, Sanger sequencing, MS-MLPA, Southern blot and mPCR).Four patients exhibited small deletions encompassing the CGG repeats tract and flanking regions, whereas the remaining had a larger deletion comprising at least exon 1 and part of intron 1 of FMR1 gene. The presence of a 2-3 base pairs microhomology in proximal and distal non-recurrent breakpoints without scars supports the involvement of microhomology mediated induced repair (MMBIR) mechanism in three small deletions.The authors data highlights the importance of using different research methods to elucidate atypical FXS mutational profiles, which are clinically undistinguishable and may have been underestimated.
| S-EPMC4956488 | biostudies-literature
Project description:Fragile X syndrome is rare but a prominent cause of intellectual disability. It is usually caused by a de novo mutation that occurs on multiple haplotypes and thus would not be expected to be detectible using genome-wide association (GWA). We conducted GWA in 89 male FXS cases and 266 male controls, and detected multiple genome-wide significant signals near FMR1 (odds ratio?=?8.10, P?=?2.5?×?10-10). These findings withstood robust attempts at falsification. Fine-mapping yielded a minimum P?=?1.13?×?10-14, but did not narrow the interval. Comprehensive functional genomic integration did not provide a mechanistic hypothesis. Controls carrying a risk haplotype had significantly longer FMR1 CGG repeats than controls with the protective haplotype (P?=?4.75?×?10-5), which may predispose toward increases in CGG number to the premutation range over many generations. This is a salutary reminder of the complexity of even "simple" monogenetic disorders.
| S-EPMC6457435 | biostudies-literature
Project description:Fragile X Syndrome (FXS) is the most common cause of inherited intellectual disability with prevalence rates estimated to be 1:5,000 in males and 1:8,000 in females. The increase of >200 Cytosine Guanine Guanine (CGG) repeats in the 5' untranslated region of the Fragile X Mental Retardation 1 (FMR1) gene results in transcriptional silencing on the FMR1 gene with a subsequent reduction or absence of fragile X mental retardation protein (FMRP), an RNA binding protein involved in the maturation and elimination of synapses. In addition to intellectual disability, common features of FXS are behavioral problems, autism, language deficits and atypical physical features. There are still no currently approved curative therapies for FXS, and clinical management continues to focus on symptomatic treatment of comorbid behaviors and psychiatric problems. Here we discuss several treatments that target the neurobiological pathway abnormal in FXS. These medications are clinically available at present and the data suggest that these medications can be helpful for those with FXS.
| S-EPMC6930353 | biostudies-literature
Project description:Fragile X syndrome (FXS) is the most frequent form of inherited intellectual disability and is also linked to other neurologic and psychiatric disorders. FXS is caused by a triplet expansion that inhibits expression of the FMR1 gene; the gene product, FMRP, regulates mRNA metabolism in the brain and thus controls the expression of key molecules involved in receptor signaling and spine morphology. While there is no definitive cure for FXS, the understanding of FMRP function has paved the way for rational treatment designs that could potentially reverse many of the neurobiological changes observed in FXS. Additionally, behavioral, pharmacological, and cognitive interventions can raise the quality of life for both patients and their families.
| S-EPMC3533539 | biostudies-other
Project description:Fragile X syndrome (FXS) is an inherited disorder that results in intellectual disability and a characteristic behavioral profile that includes autism spectrum disorder, attention deficit hyperactivity disorder, sensory hypersensitivity, hyperarousal, and anxiety. The epigenetic silencing of FMR1 and the consequent absence of its protein product, FMRP, is the most common cause of fragile X. The development of animal models of fragile X syndrome 20 years ago has produced a considerable increase in our understanding of the consequences of the absence of FMRP on the structure and function of the nervous system. Some of the insights gained have led to proposals of treatment strategies that are based on cellular and molecular changes observed in animals lacking FMRP. One such proposal is treatment with lithium, a drug with a long history of clinical efficacy in psychiatry and a drug with newly described uses in degenerative disorders of the nervous system. Lithium treatment has been studied extensively in both mouse and fruit fly models of FXS, and it has been shown to reverse numerous behavioral, physiological, cellular, and molecular phenotypes. A report of a pilot clinical trial on a limited number of adult FXS patients indicated that measurable improvements in behavior and function were seen after 2 months of lithium treatment. A double-blind clinical trial of lithium treatment in FXS patients is now needed.
| S-EPMC4063496 | biostudies-other
Project description:Down syndrome is the most common identifiable genetic cause of intellectual disability, with a unique physical gestalt that makes diagnosis possible during the newborn period. However, the physical characteristics of Fragile X syndrome are fairly subtle, resulting in the first clinical suspicion often arising from delayed developmental milestones. In addition, maladaptive behavior and autistic-like tendencies, such as hand flapping, poor eye contact, and hand biting, may be noted in Fragile X syndrome but are not as commonly observed in Down syndrome. Recognition of a potential secondary diagnosis, such as Fragile X syndrome, in individuals with Down syndrome is critical because there have been advances in targeted pharmacologic treatments for both conditions. Thus, an accurate diagnosis has implications in improving the individual's quality of life.
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