Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The FMR1 gene contains a trinucleotide repeat tract which can expand from a normal size of around 30 repeats to over 200 repeats, causing mental retardation (Fragile X Syndrome). Evidence suggests that premutation males (55-200 repeats) are susceptible to a late-onset tremor/ataxia syndrome and females to premature ovarian failure, and that intermediate alleles ( approximately 41-55 repeats) and premutations may be in excess in samples with special educational needs. We explored the relationship between FMR1 allele length and cognitive ability in 621 low ability and control children assessed at 4 and 7 years, as well as 122 students with high IQ. The low and high ability and control samples showed no between-group differences in incidence of longer alleles. In males there was a significant negative correlation between allele length and non-verbal ability at 4 years (p = 0.048), academic achievement in maths (p = 0.003) and English (p = 0.011) at 7 years, and IQ in the high ability group (p = 0.018). There was a significant negative correlation between allele length and a standardised score for IQ and general cognitive ability at age 7 in the entire male sample (p = 0.002). This suggests that, within the normal spectrum of allele length, increased repeat numbers may have a limiting influence on cognitive performance.
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PMID:Investigating the relationship between FMR1 allele length and cognitive ability in children: a subtle effect of the normal allele range on the normal ability range? 1690 2

The human FMR1 gene contains a CGG repeat in its 5' untranslated region. The repeat length in the normal population is polymorphic (5-55 CGG repeats). Lengths beyond 200 CGGs (full mutation) result in the absence of the FMR1 gene product, FMRP, through abnormal methylation and gene silencing. This causes Fragile X syndrome, the most common inherited form of mental retardation. Elderly carriers of the premutation, defined as a repeat length between 55 and 200 CGGs, can develop a progressive neurodegenerative syndrome: Fragile X-associated tremor/ataxia syndrome (FXTAS). In FXTAS, FMR1 mRNA levels are elevated and it has been hypothesised that FXTAS is caused by a pathogenic RNA gain-of-function mechanism. We have developed a knock in mouse model carrying an expanded CGG repeat (98 repeats), which shows repeat instability and displays biochemical, phenotypic and neuropathological characteristics of FXTAS. Here, we report further repeat instability, up to 230 CGGs. An expansion bias was observed, with the largest expansion being 43 CGG units and the largest contraction 80 CGG repeats. In humans, this length would be considered a full mutation and would be expected to result in gene silencing. Mice carrying long repeats ( approximately 230 CGGs) display elevated mRNA levels and decreased FMRP levels, but absence of abnormal methylation, suggesting that modelling the Fragile X full mutation in mice requires additional repeats or other genetic manipulation.
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PMID:Elevated Fmr1 mRNA levels and reduced protein expression in a mouse model with an unmethylated Fragile X full mutation. 1715 Feb 13

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive neurological condition occurring in fragile X premutation carriers, predominantly males, and resulting in CNS dysfunction including tremor, ataxia, Parkinsonism, and cognitive decline. Neuropathic signs have also been described. The objective of this study was to compare neuropathic signs in fragile X premutation carriers versus controls and determine the relationship of these signs to CGG repeat length and tremor/ataxia. A neuropathy scale was utilized to compare distal tendon reflexes and vibration sense in subjects from a large cohort of carriers and controls undergoing neurological exam and structured videotaping sessions for movement disorder rating. The male carrier group displayed more impairment on total neuropathy, vibration and reflex scores than the corresponding control group, while female carriers were not significantly different from controls. In males, after correction for age effects, there was a correlation between CGG repeat length and both total neuropathy and reflex impairments. Age-adjusted partial correlation analyses showed an association between neuropathy scores and severity of ataxia but not tremor in carrier males and females. These data suggest that neuropathic signs are associated with the fragile X premutation, presumably occurring through the same mechanism proposed for CNS disease, namely, toxicity from expanded-CGG-repeat FMR1 mRNA.
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PMID:Neuropathic features in fragile X premutation carriers. 1715 65

Recent advances in our understanding of the clinical and molecular features of the fragile-X mental-retardation 1 gene, FMR1, highlight the importance of single-gene disorders. 15 years after its discovery, FMR1 continues to reveal new and unexpected clinical presentations and molecular mechanisms. Loss of function of FMR1 is a model for neurodevelopmental and behavioural disorders, including mental retardation, autism, anxiety, and mood instability. In addition, overexpression and CNS toxicity of FMR1 mRNA causes a late-onset neurodegenerative disorder, the fragile-X-associated tremor/ataxia syndrome (FXTAS). A similar mechanism is probably involved in premature ovarian failure, which affects up to 20% of female carriers of an altered FMR1 gene.
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PMID:Fragile-X syndrome and fragile X-associated tremor/ataxia syndrome: two faces of FMR1. 1716 1

The fragile X-associated tremor/ataxia syndrome (FXTAS) is a newly discovered late-onset neurodegenerative disorder caused by a premutation in the FMR1 X-linked gene. We present examples of a discrepancy between obvious brain changes observed on MRI, and minimal clinical neurological manifestations in three older carriers of this premutation. This discrepancy occurred in three of nine carriers ascertained in an unbiased manner. If the systematic follow-up studies of adult carriers confirm this trend, this will have an impact on early diagnosis of neurological involvement and possible prevention. If MRI changes precede clinical manifestation of FXTAS this may explain the low detection rate of fragile X carriers among patients with neurological syndromes associated with tremor/ataxia.
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PMID:Tremor/ataxia syndrome and fragile X premutation: diagnostic caveats. 1719 94

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurological progressive disorder associated with the FMR1 gene premutation. We report on variable presentation of findings associated with FXTAS in 3 brothers aged 68, 74, and 73 years, carrying premutation alleles of (CGG)(123,) (CGG)(109), and (CGG)(91) triplets, respectively. Based on previously proposed diagnostic criteria for the syndrome, clinical and radiological data allowed establishing a "definite" diagnosis of FXTAS in the two carriers of the longest (CGG)(n). The carrier of the (CGG)(91) allele, although presenting a major radiological sign of the syndrome (symmetrical white-matter lesions in the middle cerebellar peduncles), did not have any significant neurological manifestation at 73 years of age.
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PMID:Fragile X-associated tremor/ataxia syndrome: intrafamilial variability and the size of the FMR1 premutation CGG repeat. 1729 Apr 48

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurological disorder among carriers of premutation CGG-repeat expansions within the FMR1 gene. Principal features of FXTAS include progressive action tremor and gait ataxia, with associated features of parkinsonism, peripheral neuropathy, dysautonomia, and cognitive decline. Although both clinical and neuropathologic features of FXTAS are known to be highly associated with CGG repeat length, the relationship between repeat length and age-of-onset is not known. To address this issue, the ages of onset of action tremor and gait ataxia were documented by history for 93 male carriers. For this cohort, the mean ages of onset were 62.6 +/- 8.1 years (range, 39-78 years) for tremor, and 63.6 +/- 7.3 years (range, 47-78 years) for ataxia; the mean CGG repeat number was 88.5 +/- 14 (range, 60-133). Analysis of the relationship between clinical onset and molecular measures revealed significant correlations between CGG repeat number and onset of both tremor (P = 0.001) and ataxia (P = 0.002), as well as overall onset (P < 0.0001). Our findings indicate that the CGG repeat number is a potential predictor of the age of onset of core motor features of FXTAS.
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PMID:CGG repeat length correlates with age of onset of motor signs of the fragile X-associated tremor/ataxia syndrome (FXTAS). 1742 88

Carriers of FMR1 alleles with 55-200 repeats in the 5' UTR are at risk for Fragile X associated tremor and ataxia syndrome. The cause of the neuropathology is unknown but is thought to be RNA-mediated. Maternally transmitted premutation alleles are also at risk of expansion of the repeat tract into the "full mutation" range (>200 repeats). The mechanism responsible for expansion is unknown. Full mutation alleles produce reduced amounts of the FMR1 gene product, FMRP, which leads to Fragile X mental retardation syndrome. We have developed a murine model for Fragile X premutation carriers that recapitulates key features seen in humans including a direct relationship between repeat number and Fmr1 mRNA levels, an inverse relationship with FMRP levels and Purkinje cell dropout that have not been seen in a previously described knock-in mouse model. In addition, these mice also show a differential deficit of FMRP in different parts of the brain that might account for symptoms of the full mutation that are seen in premutation carriers. As in humans, repeat instability is high with expansions predominating and, for the first time in a mouse model, large expansions into the full mutation range are seen that occur within a single generation. Thus, contrary to what was previously thought, mice may be good models not only for the symptoms seen in human carriers of FMR1 premutation alleles but also for understanding the mechanism responsible for repeat expansion, a phenomenon that is responsible for a number of neurological and neurodevelopmental disorders.
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PMID:Regional FMRP deficits and large repeat expansions into the full mutation range in a new Fragile X premutation mouse model. 1744 5

Fragile X Syndrome is the most common form of hereditary mental retardation. It is caused by a large expansion of the CGG trinucleotide repeat (>200 repeats) in the 5'-untranslated region (UTR) of the FMR1 gene that leads to silencing of its transcript. Individuals with CGG repeat expansions approximately between 60 and 200 are referred to as premutation carriers. Fragile X-associated tremor and ataxia syndrome (FXTAS), an RNA-mediated neurodegenerative disease has been described in up to 50% of males carrying premutation alleles. FRAXE, the most common form of non-syndromic X-linked mental retardation, is caused by expansion of a CCG trinucleotide repeat (>200) in the 5'-UTR of the FMR2 gene. While the FRAXE premutation length repeat is observed in the general population, there has not yet been a report of a neurodegenerative phenotype associated with these alleles. In this study, we show that the CCG premutation length repeat leads to an RNA-mediated neurodegenerative phenotype in a Drosophila model. Furthermore, we show that co-expression of both the CCG and CGG-containing RNAs suppresses their independent toxicity and is dependent on the RNAi pathway. These data support the concept that RNA toxicity is the mechanism of neuronal toxicity and suggests potential reversal of RNA-mediated phenotypes with complementary RNA molecules.
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PMID:Argonaute-2-dependent rescue of a Drosophila model of FXTAS by FRAXE premutation repeat. 1763 40

rCGG repeats in premutant alleles of the fragile X gene (FMR1) cause neurodegeneration in Drosophila and are thought to cause fragile X-associated tremor/ataxia syndrome in humans. Two reports in this issue of Neuron (Jin et al. and Sofola et al.) present data indicating a disease mechanism involving disruption of RNA-binding protein function.
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PMID:Fragile X tremor/ataxia syndrome: blame the messenger! 1769 10


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