UMLS:C0040822 - FACTA Search

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Query: UMLS:C0040822 (tremor)
18,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by expanded CGG (CGG^exp) trinucleotides in the 5'UTR of the FMR1 gene encoding fragile X mental retardation protein (FMRP). The patients, with the number of the repeats ranging from 55 to 200, show specific manifestation of clinical symptoms that include intention tremor, gait ataxia, cognitive deficits, and brain atrophy. Accumulation of toxic polyglycine (FMRpolyG), a by-product of the CGG^exp repeat-associated non-ATG (RAN) translation, is considered to be one of the main factors triggering neurodegenerative processes in FXTAS patients. Nevertheless, the nature of the FMRpolyG-induced cell damage, especially in the context of its soluble and inclusion-associated forms, is still elusive. Targeting either biosynthesis, cellular stability or aggregation capacity of toxic FMRpolyG could be considered as a potential therapeutic strategy for FXTAS. Therefore, we tested a variety of quantitative methods based on forced expression of genetic constructs carrying CGG^exp repeats in the context of the FMR1 5'UTR fused to GFP, mCherry or Firefly luciferase gene in or out of frame to the polyglycine encoding sequence. We show that FMRpolyG translation either from native or an AUG-induced start codon as well as the translation yield of the FMRP open reading frame equivalent located downstream of the CGG^exp element can be effectively estimated using fluorescence microscopy, flow cytometry or luciferase assay. We also quantitatively estimated soluble fraction and insoluble form of FMRpolyG aggregated in foci using an electrophoretic separation of cell lysates and fluorescence microscopy, respectively. Importantly, we show that dependent on a fusion tag, FMRpolyG has a different potential for aggregate formation. Our established protocols enable sensitive tracking of FMRP and FMRpolyG quantitative and qualitative changes after treatment with potential therapeutic agents for FXTAS. Furthermore, they can be modified for application to other RAN translation- and aggregation-related diseases.
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PMID:Quantitative Evaluation of Toxic Polyglycine Biosynthesis and Aggregation in Cell Models Expressing Expanded CGG Repeats. 2997 Oct 92

Fragile X-associated tremor ataxia syndrome is an inherited neurodegenerative disorder caused by premutation expansions (55-200 CGG repeats) of the FMR1 gene. There is accumulating evidence to suggest that early cognitive and brain imaging signs may be observed in some premutation carriers without motor signs of FXTAS, but few studies have examined the relationships between subcortical brain volumes and cognitive performance in this group. This study examined the relationships between caudate volume and select cognitive measures (executive function and information processing speed) in men at risk of developing FXTAS and controls with normal FMR1 alleles (<45 CGG repeats). The results showed that men with premutation alleles performed worse on measures of executive function and information processing speed, and had significantly reduced caudate volume, compared to controls. Smaller caudate volume in the premutation group was associated with slower processing speed. These findings provide preliminary evidence that early reductions in caudate volume may be associated with cognitive slowing in men with the premutation who do not present with cardinal motor signs of FXTAS. If confirmed in future studies with larger PM cohorts, these findings will have important implications for the identification of sensitive measures with potential utility for tracking cognitive decline.
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PMID:Reduced caudate volume and cognitive slowing in men at risk of fragile X-associated tremor ataxia syndrome. 3004 72

Approximately 30-40% of male and 8-16% of female carriers of the Fragile X premutation will develop a neurodegenerative movement disorder characterized by intentional tremor, gait ataxia, autonomic dysfunction, cognitive decline, and Parkinsonism during their lifetime. At the molecular level, premutation carriers have increased expression levels of the FMR1 and the antisense FMR1 (ASFMR1) mRNAs. Both genes undergo alternative splicing giving rise to a number of different transcripts. Alteration in the alternative splicing process might be associated with FXTAS. In this study, we have investigated the correlation between objective measures of movement (balance and tremor using the CATSYS battery) and the expression of both the FMR1 and the ASFMR1 genes. In addition, we investigated whether their expression level and that of the ASFMR1 131 bp splice isoform could distinguish between premutation carriers with FXTAS and non-FXTAS premutation carriers. Confirming previous findings, the expression levels of transcripts at the FMR1 locus positively correlated with the CGG repeat number and significantly differentiated the premutation carriers from the control groups. Furthermore, premutation carriers with and without FXTAS, showed a significant difference in the expression level of the ASFMR1 131 bp splice isoform when compared to age and gender matched controls. However, there was no significant difference in the ASFMR1 131 bp splice isoform expression level when comparing premutation carriers with and without FXTAS. Finally, our results indicate significant group differences in CATSYS dominant hand reaction time and postural sway with eyes closed in premutation carriers without FXTAS compared to controls. In addition, a significant inverse association between the tremor intensity and the expression level of ASFMR1 131 bp splice isoform in premutation carriers compared to controls, was observed, suggesting a potential role in the pathogenesis of FXTAS.
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PMID:Assessment of Molecular Measures in Non-FXTAS Male Premutation Carriers. 3018 7

Fragile X syndrome (FXS) is the most common congenital hereditary disease of low intelligence after Down syndrome. Its main pathogenic gene is fragile X mental retardation 1 (FMR1) gene associated with intellectual disability, autism, and fragile X-related primary ovarian insufficiency (FXPOI) and fragile X-associated tremor/ataxia syndrome (FXTAS). FMR1 gene transcription leads to the absence of fragile X mental retardation protein (FMRP). How to relieve or cure disorders associated with FXS has also become a clinically disturbing problem. Previous studies have recently shown that long noncoding RNAs (lncRNAs) contribute to the pathogenesis. And it has been identified that several lncRNAs including FMR4, FMR5, and FMR6 contribute to developing FXPOI/FXTAS, originating from the FMR1 gene locus. FMR4 is a product of RNA polymerase II and can regulate the expression of relevant genes during differentiation of human neural precursor cells. FMR5 is a sense-oriented transcript while FMR6 is an antisense lncRNA produced by the 3' UTR of FMR1. FMR6 is likely to contribute to developing FXPOI, and it overlaps exons 15-17 of FMR1 as well as two microRNA binding sites. Additionally, BC1 can bind FMRP to form an inhibitory complex and lncRNA TUG1 also can control axonal development by directly interacting with FMRP through modulating SnoN-Ccd1 pathway. Therefore, these lncRNAs provide pharmaceutical targets and novel biomarkers. This review will: (1) describe the clinical manifestations and traditional pathogenesis of FXS and FXTAS/FXPOI; (2) summarize what is known about the role of lncRNAs in the pathogenesis of FXS and FXTAS/FXPOI; and (3) provide an outlook of potential effects and future directions of lncRNAs in FXS and FXTAS/FXPOI researches.
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PMID:Long Noncoding RNA Can Be a Probable Mechanism and a Novel Target for Diagnosis and Therapy in Fragile X Syndrome. 3119 98

Fragile X-associated tremor ataxia syndrome is an untreatable neurological and neuromuscular disorder caused by unstable expansion of 55-200 CGG nucleotide repeats in 5' UTR of Fragile X intellectual disability 1 (FMR1) gene. The expansion of CGG repeats in the FMR1 mRNA elicits neuronal cell toxicity through two main pathogenic mechanisms. First, mRNA with CGG expanded repeats sequester specific RNA regulatory proteins resulting in splicing alterations and formation of ribonuclear inclusions. Second, repeat-associated non-canonical translation (RANT) of the CGG expansion produces a toxic homopolymeric protein, FMRpolyG. Very few small molecules are known to modulate these pathogenic events, limiting the therapeutic possibilities for FXTAS. Here, we found that a naturally available biologically active small molecule, Curcumin, selectively binds to CGG RNA repeats. Interestingly, Curcumin improves FXTAS associated alternative splicing defects and decreases the production and accumulation of FMRpolyG protein inclusion. Furthermore, Curcumin decreases cell cytotoxicity promptly by expression of CGG RNA in FXTAS cell models. In conclusion, our data suggest that small molecules like Curcumin and its derivatives may be explored as a potential therapeutic strategy against the debilitating repeats associated neurodegenerative disorders.
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PMID:Curcumin Regulates the r(CGG)^exp RNA Hairpin Structure and Ameliorate Defects in Fragile X-Associated Tremor Ataxia Syndrome. 3231 19

The Fragile Mental Retardation 1 gene (FMR1), at Xq27.3, encodes the fragile mental retardation protein (FMRP), and displays in its 5'-untranslated region a series of polymorphic CGG triplet repeats that may undergo dynamic mutation. Fragile X syndrome (FXS) is the leading cause of inherited intellectual disability among men, and is most frequently due to FMR1 full mutation and consequent transcription repression. FMR1 premutations may associate with at least two other clinical conditions, named fragile X-associated primary ovarian insufficiency (FXPOI) and tremor and ataxia syndrome (FXTAS). While FXPOI and FXTAS appear to be mediated by FMR1 mRNA accumulation, relative reduction of FMRP, and triplet repeat translation, FXS is due to the lack of the RNA-binding protein FMRP. Besides its function as mRNA translation repressor in neuronal and stem/progenitor cells, RNA editing roles have been assigned to FMRP. In this review, we provide a brief description of FMR1 transcribed microsatellite and associated clinical disorders, and discuss FMRP molecular roles in ribonucleoprotein complex assembly and trafficking, as well as aspects of RNA homeostasis affected in FXS cells.
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PMID:FMRP ribonucleoprotein complexes and RNA homeostasis. 3256 Jul 91

There is a dearth of information about cardiovascular problems in fragile X premutation carriers who have 55-200 CGG repeats in fragile X mental retardation 1 (FMR1) gene. The FMR1 expansion in the premutation range leads to toxic RNA gain-of-function resulting in cellular dysregulation. The mechanism of RNA toxicity underlies all of the premutation disorders including fragile X-associated tremor/ataxia syndrome, fragile X-associated primary ovarian insufficiency, and fragile X-associated neuropsychiatric disorder. Cardiovascular problems particularly autonomic dysfunction, hypertension, and cardiac arrhythmias are not uncommon in premutation carriers. Some arterial problems and valvular heart diseases have also been reported. This article reviews cardiovascular problems in premutation carriers and discusses possible contributing mechanisms including RNA toxicity and mild fragile X mental retardation protein deficiency. Further research studies are needed in order to prove a direct association of the cardiovascular problems in fragile X premutation carriers because such knowledge will lead to better preventative treatment.
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PMID:Cardiovascular Problems in the Fragile X Premutation. 3313 71

Dozens of incurable neurological disorders result from expansion of short repeat sequences in both coding and non-coding regions of the transcriptome. Short repeat expansions underlie microsatellite repeat expansion (MRE) disorders including myotonic dystrophy (DM1, CUG_50-3,500 in DMPK; DM2, CCTG_75-11,000 in ZNF9), fragile X tremor ataxia syndrome (FXTAS, CGG_50-200 in FMR1), spinal bulbar muscular atrophy (SBMA, CAG_40-55 in AR), Huntington's disease (HD, CAG_36-121 in HTT), C9ORF72- amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD and C9-ALS/FTD, GGGGCC in C9ORF72), and many others, like ataxias. Recent research has highlighted several mechanisms that may contribute to pathology in this heterogeneous class of neurological MRE disorders - bidirectional transcription, intranuclear RNA foci, and repeat associated non-AUG (RAN) translation - which are the subject of this review. Additionally, many MRE disorders share similar underlying molecular pathologies that have been recently targeted in experimental and preclinical contexts. We discuss the therapeutic potential of versatile therapeutic strategies that may selectively target disrupted RNA-based processes and may be readily adaptable for the treatment of multiple MRE disorders. Collectively, the strategies under consideration for treatment of multiple MRE disorders include reducing levels of toxic RNA, preventing RNA foci formation, and eliminating the downstream cellular toxicity associated with peptide repeats produced by RAN translation. While treatments are still lacking for the majority of MRE disorders, several promising therapeutic strategies have emerged and will be evaluated within this review.
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PMID:Repeat RNA expansion disorders of the nervous system: post-transcriptional mechanisms and therapeutic strategies. 3317 4

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