Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0040822 (tremor)
 18,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Expansion of a CGG.CCG-repeat tract in the 5'-untranslated region of the FMR1 (Fragile X mental retardation 1) gene causes its aberrant transcription. This produces symptoms ranging from premature ovarian failure and Fragile X associated tremor and ataxia syndrome to FMR syndrome, depending on the size of the expansion. The promoter from normal alleles shows four protein-binding regions in vivo. We had previously shown that in mouse brain extracts two of these sites are bound by USF1/USF2 (upstream stimulatory factors 1 and 2) heterodimers and NRF-1 (nuclear respiratory factor-1). We also showed that these sites are involved in the positive regulation of FMR1 transcription in neuronally derived cells. In the present study, we show that Sp1 (specificity protein 1) and Sp3 are also strong positive regulators of FMR1 promoter activity. We also show that, like Sp1 and E-box-binding proteins such as USF1 and USF2, NRF-1 causes DNA bending, in this case producing a bend of 57 degrees towards the major groove. The combined effect of the four protein-induced bends on promoter geometry is the formation of a highly compact arch-like structure in which the 5' end of the promoter is brought in close proximity to the 3' end. We had previously shown that while point mutations in the GC-boxes decrease promoter activity, deletion of either one of them leads to an increase in promoter activity. We can reconcile these observations with the positive effect of Sp1 and Sp3 if protein-induced bending acts, at least in part, to bring together distally spaced factors important for transcription initiation.
 ...
PMID:The roles of Sp1, Sp3, USF1/USF2 and NRF-1 in the regulation and three-dimensional structure of the Fragile X mental retardation gene promoter. 1547 57

In an Italian population of 275 unrelated men affected by adult-onset sporadic progressive cerebellar ataxia, the authors found six patients carrying an FMR1 gene premutation. Age at onset (range, 53 to 69 years) and clinical-neuropathologic findings were consistent with the fragile-X tremor ataxia syndrome (FXTAS), although tremor was not as common as previously described. FXTAS accounted for 4.2% of the cases diagnosed at >50 years, suggesting that it is a frequent genetic cause of late-onset sporadic ataxia.
 ...
PMID:FMR1 gene premutation is a frequent genetic cause of late-onset sporadic cerebellar ataxia. 1564 22

DNA testing broadens diagnostic tools available for hereditary ataxias. However, together with current knowledge of genes and their mutations crop up new phenotype figures of diseases already well known. Diagnostic problems in practice can consist in part due to the very similar symptoms of hereditary ataxias and acquaintance in or availability of new techniques such as DNA testing and result in misdiagnosis. We present a case study of a 57 year-old woman with both expansion of the triplet repetitive sequence of FRDA gene and a premutation in FMR1 gene. At present we diagnose her with Very Late Onset Friedreich s ataxia, but we advise of possible combinations or aggravations of her symptoms due to manifestation of Fragile X premutation tremor/ataxia syndrome. In nontypical phenotypes of DNA verifying hereditary ataxias we recommend searching of comorbidity, specifically from a range of hereditary ataxias with very similar spectra of symptoms.
 ...
PMID:Concomitancy of mutation in FRDA gene and FMR1 premutation in 58 year-old woman. 1572 25

A neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS), occurs in some older men carrying a small CGG repeat expansion (pre-mutation) in the FMR1 gene. We surveyed a sample of older pre-mutation males to estimate the prevalence and spectrum of neurological involvement. Twelve pre-mutation males aged 50-82 years and 11 age-matched normal controls ascertained in an unbiased manner were included in a neurological assessment that also used standard scales for tremor (Clinical Rating Scale for Tremor), ataxia (International Cooperative Ataxia Rating Scale, ICARS) and parkinsonian signs (Unified Parkinson's Disease Rating Scale). Axial FLAIR images of the brain, and neuropsychological and molecular tests were also conducted in pre-mutation carriers. The neurological disorder meeting all the criteria for diagnosis of 'definite' to 'possible' FXTAS occurred in five of 12 pre-mutation carriers (41.7%), and this prevalence was significantly higher compared with normal controls (0%). The ataxia (ICARS) score and the sum of all three tremor/ataxia scores were significantly higher in pre-mutation carriers than in controls, and mRNA was elevated in all but one carrier, but did not correlate with the degree of neurological involvement. In conclusion, the findings provide further evidence that the pre-mutation allele of FMR1 is a significant cause of late-onset neurodegeneration, presenting with a broad spectrum of clinical manifestations.
 ...
PMID:Evidence for, and a spectrum of, neurological involvement in carriers of the fragile X pre-mutation: FXTAS and beyond. 1581 Oct 8

People with 59-200 CGG.CCG-repeats in the 5' UTR of one of their FMR1 genes are at risk for Fragile X tremor and ataxia syndrome. Females are also at risk for premature ovarian failure. These symptoms are thought to be due to the presence of the repeats at the DNA and/or RNA level. We show here that long transcribed but untranslated CGG-repeat tracts are toxic to human cells and alter the expression of a wide variety of different genes including caspase-8, CYFIP, Neurotensin and UBE3A.
 ...
PMID:Long CGG-repeat tracts are toxic to human cells: implications for carriers of Fragile X premutation alleles. 1586 12

The recent identification of fragile X-associated tremor ataxia syndrome (FXTAS) associated with premutations in the FMR1 gene and the possibility of clinical overlap with multiple system atrophy (MSA) has raised important questions, such as whether genetic testing for FXTAS should be performed routinely in MSA and whether positive cases might affect the specificity of current MSA diagnostic criteria. We genotyped 507 patients with clinically diagnosed or pathologically proven MSA for FMR1 repeat length. Among the 426 clinically diagnosed cases, we identified four patients carrying FMR1 premutations (0.94%). Within the subgroup of patients with probable MSA-C, three of 76 patients (3.95%) carried premutations. We identified no premutation carriers among 81 patients with pathologically proven MSA and only one carrier among 622 controls (0.16%). Our results suggest that, with proper application of current diagnostic criteria, FXTAS is very unlikely to be confused with MSA. However, slowly progressive disease or predominant tremor are useful red flags and should prompt the consideration of FXTAS. On the basis of our data, the EMSA Study Group does not recommend routine FMR1 genotyping in typical MSA patients.
 ...
PMID:The fragile X tremor ataxia syndrome in the differential diagnosis of multiple system atrophy: data from the EMSA Study Group. 1594 63

A CGG repeat sequence located in the 5' untranslated region of the FMR1 gene is polymorphic with respect to size and stability of the repeat during parent-offspring transmission. When expanded to over 200 repeats, the gene is hypermethylated and silenced, leading to fragile X syndrome (FXS). Recently, alleles with large unmethylated repeat tracts (premutations) have been associated with ovarian failure and a late-onset tremor/ataxia syndrome, symptoms unrelated to FXS. To further investigate the phenotype consequence of high repeat alleles, we have analyzed Wechsler adult intelligence scales-III (WAIS-III) measures on 66 males and 217 females with a wide range of repeat sizes. Among females only, we found that FMR1 repeat size and transcript level significantly explained approximately 4% of the variance in the Verbal IQ summary measure, suggesting that this polymorphism is one of many factors that influence variation in cognitive performance. Because of the well established association of increasing repeat size with decreasing age at menopause, we also investigated the reproductive stage and use of hormone replacement therapy (HRT) as a covariate to model verbal intelligence quotient (VIQ). We found that it explained an additional 5% of the variance in VIQ, but did not interact with FMR1 repeat and transcript level.
 ...
PMID:Examination of the effect of the polymorphic CGG repeat in the FMR1 gene on cognitive performance. 1597 Oct 24

Carriers of premutation within the FMR1 gene are typically normal intellectually, although a limited number of them have been reported to have either learning disabilities or mild dysmorphic features. A neurological condition involving intention tremor, ataxia and cognitive decline has recently been identified among older males carrying premutation alleles of the FMR1 gene, including grandfathers of children affected with fragile X syndrome. Characteristic findings from magnetic resonance imaging include cerebral and cerebellar volume loss and altered signal intensities of the middle cerebellar peduncles. This syndrome may represent one of the more common causes of tremor, ataxia and dementia among older males. The diagnosis of FXTAS is straightforward if a family at high genetic risk could be identified. Thus genetic counseling should be offered to such family.
 ...
PMID:[Fragile X-associated tremor/ataxia syndrome]. 1598 Nov 62

These recommendations describe the minimum standard criteria for genetic counseling and testing of individuals and families with fragile X syndrome, as well as carriers and potential carriers of a fragile X mutation. The original guidelines (published in 2000) have been revised, replacing a stratified pre- and full mutation model of fragile X syndrome with one based on a continuum of gene effects across the full spectrum of FMR1 CGG trinucleotide repeat expansion. This document reviews the molecular genetics of fragile X syndrome, clinical phenotype (including the spectrum of premature ovarian failure and fragile X-associated tremor-ataxia syndrome), indications for genetic testing and interpretation of results, risks of transmission, family planning options, psychosocial issues, and references for professional and patient resources. These recommendations are the opinions of a multicenter working group of genetic counselors with expertise in fragile X syndrome genetic counseling, and they are based on clinical experience, review of pertinent English language articles, and reports of expert committees. These recommendations should not be construed as dictating an exclusive course of management, nor does use of such recommendations guarantee a particular outcome. The professional judgment of a health care provider, familiar with the facts and circumstances of a specific case, will always supersede these recommendations.
 ...
PMID:Genetic counseling for fragile x syndrome: updated recommendations of the national society of genetic counselors. 1604 89

Some carriers of a "premutation" allele of the FMR1 gene develop late-onset tremor/ataxia. We conducted a magnetic resonance imaging volumetric study in an unselected sample of eight older male premutation carriers. Volumetric measures, including total brain volume, and the volumes of cerebrum, cerebellum, and cerebral cortex all were significantly reduced in premutation carriers compared with similar data from 21 age-matched normal controls. Total brain and cerebral volumes were significantly related to the number of CGG repeats in the FMR1 gene. Moreover, increased hippocampal volume indicates this premutation may account for both neurodegenerative and neurodevelopmental changes.
 ...
PMID:Magnetic resonance imaging study in older fragile X premutation male carriers. 1604 24


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>