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 mutations can cause a variety of disabilities, including cognitive deficits, attention-deficit/hyperactivity disorder, autism, and other socioemotional problems, in individuals with the full mutation form (fragile X syndrome) and distinct difficulties, including primary ovarian insufficiency, neuropathy and the fragile X-associated tremor/ataxia syndrome, in some older premutation carriers. Therefore, multigenerational family involvement is commonly encountered when a proband is identified with a FMR1 mutation. Studies of metabotropic glutamate receptor 5 pathway antagonists in animal models of fragile X syndrome have demonstrated benefits in reducing seizures, improving behavior, and enhancing cognition. Trials of metabotropic glutamate receptor 5 antagonists are beginning with individuals with fragile X syndrome. Targeted treatments, medical and behavioral interventions, genetic counseling, and family supports are reviewed here.
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PMID:Advances in the treatment of fragile X syndrome. 1911 5

The FMR1 gene is involved in three different syndromes, the fragile X syndrome (FXS), premature ovarian insufficiency (POI) and the fragile X-associated tremor/ataxia syndrome (FXTAS) at older age. Fragile X syndrome is caused by an expansion of a CGG repeat above 200 units in the FMR1 gene resulting in the absence of the FMR1 mRNA and protein. The FMR1 protein is proposed to act as a regulator of mRNA transport and of translation of target mRNAs at the synapse. FXS is seen as a loss of function disorder. POI and FXTAS are found in individuals with an expanded repeat between 50 and 200 CGGs and are associated with increased FMR1 mRNA levels. The presence of elevated FMR1 mRNA in FXTAS suggests that FXTAS may represent a toxic RNA gain-of-function effect. The molecular basis of POI is yet unknown. The role of the FMR1 gene in these disorders is discussed.
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PMID:FMR1: a gene with three faces. 1923 46

Within the past few years, there has been a significant change in identifying and characterizing the FMR1 premutation associated phenotypes. The premutation has been associated with elevated FMR1 mRNA levels and slight to moderate reductions in FMRP levels. Furthermore, it has been established that approximately 20% of female premutation carriers present primary ovarian insufficiency (POI) and that fragile X-associated tremor/ataxia syndrome (FXTAS) occurs in one-third of all male premutation carriers older than 50 years. Besides POI and FXTAS, new disorders have recently been described among individuals (especially females) with the FMR1 premutation. Those pathologies include thyroid disease, hypertension, seizures, peripheral neuropathy, and fibromyalgia. However there are few reports related to FXTAS penetrance among female premutation carriers or regarding these disorders recently associated to the FMR1 premutation. Therefore, we have evaluated 398 fragile X syndrome (FXS) families in an attempt to provide an estimation of the premutation associated phenotypes penetrance. Our results show that signs of FXTAS are detected in 16.5% of female premutation carriers and in 45.5% of premutated males older than 50 years. Furthermore, among females with the FMR1 premutation, penetrance of POI, thyroid disease and chronic muscle pain is 18.6, 15.9 and 24.4%, respectively. The knowledge of this data might be useful for accurate genetic counselling as well as for a better characterization of the clinical phenotypes of FMR1 premutation carriers.
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PMID:Penetrance of FMR1 premutation associated pathologies in fragile X syndrome families. 1936 23

Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a progressive neurodegenerative disorder that has been diagnosed in a substantial fraction of older male fragile X premutation carriers. Patients affected by FXTAS have elevated levels of ribo-rCGG repeat containing FMR1 mRNA with normal to slightly reduced levels of FMRP in blood leukocytes. Coupled with the absence of FXTAS in fragile X syndrome patients, this suggests premutation-sized elongated rCGG repeats in the FMR1 transcript rather than alterations in the levels of FMRP are responsible for the FXTAS pathology. Mice expressing rCGG in the context of Fmr1 or the enhanced green fluorescent protein specifically in Purkinje neurons were generated to segregate the effects of rCGG from alterations in Fmr1 and to provide evidence that rCGG is necessary and sufficient to cause pathology similar to human FXTAS. The models exhibit the presence of intranuclear inclusions in Purkinje neurons, Purkinje neuron cell death and behavioral deficits. These results demonstrate that rCGG expressed in Purkinje neurons outside the context of Fmr1 mRNA can result in neuronal pathology in a mammalian system and demonstrate that expanded CGG repeats in RNA are the likely cause of the neurodegeneration in FXTAS.
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PMID:Ectopic expression of CGG containing mRNA is neurotoxic in mammals. 1937 84

The FXTAS syndrome (Fragile X-associated tremor/ataxia syndrome) is a specific neurodegenerative syndrome affecting subjects carrying a premutation of the FMR1 (fragile X mental retardation 1) gene. It affects mainly men with the premutation and aged more than 50 years. This syndrome is separate and distinct from the fragile X syndrome. The FXTAS syndrome remains underestimated today. It should be considered in patients older than 50 years with tremors and cerebellar ataxia, especially when Parkinson disease or cognitive disorders are present or when there is a family history of infertility, early menopause, or mental retardation. In these patients, hyperintense signals of mid-cerebellar peduncle images on T2 and FLAIR MRI justify genetic testing for the FMR1 premutation.
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PMID:[Tremor/ataxia syndrome related to Fragile X premutation]. 1941 33

Fragile X-associated tremor/ataxia syndrome is a recently discovered disorder affecting more of one third of older adult male carriers of premutation alleles of fragile X mental retardation 1 (FMR1 gene). There is no established treatment.The 66-year-old right-handed grandfather of a boy with fragile X syndrome, a carrier of premutation alleles of FMR1 gene, developed an action tremor in his right hand when writing. His writing became large and completely illegible. Administration of levetiracetam was associated with subjective and objective improvement, and handwriting became possible again. Levetiracetam was well tolerated, and no adverse effects were reported.
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PMID:Levetiracetam improves intention tremor in fragile x-associated tremor/ataxia syndrome. 1947 Nov 85

Noncoding RNAs play important and diverse regulatory roles throughout the genome and make major contributions to disease pathogenesis. The FMR1 gene is involved in three different syndromes: fragile X syndrome (FXS), primary ovarian insufficiency (POI), and fragile X-associated tremor/ataxia syndrome (FXTAS) in older patients. Noncoding RNAs have been implicated in the molecular pathogenesis of both FXS and FXTAS. Here we will review our current knowledge on the role(s) of noncoding RNAs in FXS and FXTAS, particularly the role of the microRNA pathway in FXS and the role of noncoding riboCGG (rCGG) repeat in FXTAS.
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PMID:RNA-mediated pathogenesis in fragile X-associated disorders. 1963 21

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a recently characterized adult onset neurodegenerative disorder affecting both male and female (male>female) carriers of premutation CGG repeat expansions of the FMR1 gene. Onset typically occurs after the age of 50 years with a lifetime risk of FXTAS in males of about 1 in 3,000-6,000. Core features include progressive gait ataxia and cerebellar tremor with associated features of cognitive deficits, peripheral neuropathy and dysautonomia. The diagnosis of FXTAS is established based on clinical presentation, cerebral imaging and genetic testing. Due to the still low level of awareness of FXTAS and its variable clinical picture FXTAS is substantially underdiagnosed. However, confirming the diagnosis is essential for genetic counseling of the patients as the offspring are at risk for fragile X syndrome, premature ovarian insufficiency (POI) or FXTAS. Furthermore, many features of FXTAS can be treated symptomatically.
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PMID:[Fragile X-associated tremor/ataxia syndrome]. 1976 29

Fragile X-associated tremor/ataxia syndrome (FXTAS) affects older males carrying premutation, that is, expansions of the CGG repeat (in the 55-200 range), in the FMR1 gene. The neurological changes are linked to the excessive FMR1 messenger RNA (mRNA), becoming toxic through a 'gain-of-function'. Because elevated levels of this mRNA are also found in carriers of the smaller expansion (grey zone) alleles, ranging from 40 to 54 CGGs, we tested for a possible role of these alleles in the origin of movement disorders associated with tremor. We screened 228 Australian males affected with idiopathic Parkinson's disease and other causes of parkinsonism recruited from Victoria and Tasmania for premutation and grey zone alleles. The frequencies of either of these alleles were compared with the frequencies in a population-based sample of 578 Guthrie spots from consecutive Tasmanian male newborns (controls). There was a significant excess of premutation carriers (Fisher's exact test p = 0.006). There was also a more than twofold increase in grey zone carriers in the combined sample of the Victorian and Tasmanian cases, with odds ratio (OR ) = 2.36, and 95% confidence intervals (CI): 1.20-4.63, as well as in Tasmanian cases only (OR = 2.33, 95% CI: 1.06-5.13), compared with controls. The results suggest that the FMR1 grey zone alleles, as well as premutation alleles, might contribute to the aetiology of disorders associated with parkinsonism.
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PMID:Small CGG repeat expansion alleles of FMR1 gene are associated with parkinsonism. 1979 83

Women with fragile X mental retardation (FMR1) gene premutations (55-200 CGG repeats) were until recently believed to be unaffected. It is now known that up to 8% of older female FMR1 premutation carriers develop fragile X-associated tremor/ataxia syndrome (FXTAS). Female carriers may also develop primary ovarian insufficiency, thyroid disease, hypertension, seizures, peripheral neuropathy, and fibromyalgia. We present a 60-year-old woman with FMR1 premutation who had depression, anxiety, and conversion disorder with seizures. The FMR1 premutation with its associated mRNA toxicity is postulated as an underlying neurobiological mechanism of conversion symptoms, through functional and structural neural dysconnectivity.
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PMID:Conversion disorder in women with the FMR1 premutation. 1984 97


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