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

A neurological syndrome involving progressive action tremor with ataxia, cognitive decline and generalized brain atrophy has been described recently in some adult males with pre-mutation alleles of the fragile X syndrome (FXS) fragile X mental retardation gene (FMR1). Neurohistological studies have now been performed on the brains of four elderly premutation carriers, not reported previously, who displayed the neurological phenotype. Eosinophilic, intranuclear inclusions were present in both neuronal and astrocytic nuclei of the cortex in all four individuals. Systematic analysis of the brains of two of these carriers demonstrated the presence of the intranuclear inclusions throughout the cerebrum and brainstem, being most numerous in the hippocampal formation. The cerebellum displayed marked dropout of Purkinje cells, Purkinje axonal torpedoes and Bergmann gliosis. Intranuclear inclusions were absent from Purkinje cells, although they were present in a small number of neurones in the dentate nucleus and diffusely in cerebellar astrocytes. The presence of inclusions in the brains of all four FXS carriers with the neurological findings provides further support for a unique clinical entity associated with pre-mutation FMR1 alleles. The origin of the inclusions is unknown, although elevated FMR1 mRNA levels in these pre-mutation carriers may lead to the neuropathological changes.
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PMID:Neuronal intranuclear inclusions in a new cerebellar tremor/ataxia syndrome among fragile X carriers. 1213 67

Fragile X premutation carriers do not have typical fragile X syndrome (FXS) although late-onset progressive action tremor and gait disorder with CNS atrophy was recently reported in male carriers. We compared tremor, gait disorder and parkinsonian signs in FXS premutation subjects (age 50 or more) and a similar control population, using a standardized videotaping protocol. Videotapes were rated using standard scales for tremor (CRST), ataxia (ICARS), and parkinsonian signs (UPDRS) by an investigator blinded to premutation status. Compared to all other groups pooled (n = 30), the male premutation carrier group (n = 7) had significantly higher scores on the CRST (p = 0.0008), ICARS (p = 0.001), and UPDRS (p = 0.0094). On the CRST, rest, postural and kinetic tremor scores were all higher in the male carriers. The elevated total UPDRS and ICARS scores mainly resulted from markedly higher scores for tremor and limb ataxia, respectively. The female carrier (n = 14) and control groups (n = 8) did not differ on any measure. The FMR1 premutation is associated with increased levels of CGG repeat-containing FMR1 mRNA, which may predispose to these symptoms by interfering with nuclear mechanisms. Given the relatively high population frequency of the FMR1 premutation, this mutation may be a significant cause of late-onset "idiopathic" progressive tremor.
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PMID:Tremor and ataxia in fragile X premutation carriers: blinded videotape study. 1273 Sep 95

Recently it has been reported that late-onset tremor, gait unsteadiness and dementia can be associated with brain atrophy in males of normal intelligence and the pre-mutation carrier state of the fragile X syndrome. We have shown, by means of a telephone survey, that this association is probably causal rather than coincidental. These findings have uncovered another testable cause of late-onset neurological symptoms in males, which also has serious genetic implications for their daughters who are at risk of having sons with full mutations causing mental handicap - the fragile X syndrome.
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PMID:Tremor, ataxia and dementia in older men may indicate a carrier of the fragile X syndrome. 1279 Oct 39

The FMR1 gene is involved in three different syndromes, the Fragile X syndrome, premature ovarian failure (POF) and the Fragile X-associated tremor/ataxia syndrome (FXTAS) at older age. Fragile X syndrome is caused by an expanded 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/or translation that plays a role in synaptic maturation and function. POF 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 all patients suggests that these syndromes may represent a gain-of-function effect from the elevated message levels. The level of FMR1 mRNA is in fragile balance and is therefore critical for normal functioning.
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PMID:A fragile balance: FMR1 expression levels. 1295 62

Fragile X syndrome is a neurodevelopmental disorder that is not known to have any progressive neurological sequelae in adulthood. However, a neurological condition involving intention tremor, ataxia, and cognitive decline has recently been identified among older male carriers of premutation alleles of the FMR1 gene. This condition is clinically distinct from fragile X syndrome and arises through a different molecular mechanism involving the same gene (FMR1). Characteristic findings on magnetic resonance imaging include cerebral and cerebellar volume loss and altered signal intensities of the middle cerebellar peduncles. A striking feature of this fragile X-associated tremor/ataxia syndrome is the presence of ubiquitin-positive neuronal and astroglial intranuclear inclusions. Unlike the CAG repeat expansion diseases, which lead to altered protein products, there is no known protein abnormality among FMR1 premutation carriers. Thus, inclusion formation may reflect a gain-of-function effect of the FMR1 mRNA or the CGG repeat itself. Finally, since this syndrome may represent one of the more common single-gene causes of tremor, ataxia, and dementia among older males, FMR1 DNA testing should be considered when evaluating adult patients with tremor/ataxia.
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PMID:A cerebellar tremor/ataxia syndrome among fragile X premutation carriers. 1452 82

Fragile X syndrome, the most common form of inherited mental retardation, is caused by hyperexpansion and hypermethylation of a CGG repeat tract in the 5' untranslated region of the FMR1 gene. This methylation causes the gene to be transcriptionally silenced. In addition to the common allele form with less than 41 repeats, there are two other allelic forms of the FMR1 gene that are unmethylated: premutation (61-200 CGG repeats) and intermediate (41-60 CGG repeats). Recently, premutation-specific phenotypes not related to fragile X syndrome have been reported: a 20-fold increased risk for premature ovarian failure (POF) among female carriers and an increased risk for a tremor ataxia syndrome (TAS) primarily among older male carriers. At the molecular level, increased levels of FMR1 transcript have been observed among premutation carriers. Increased levels of transcript may be causally related to the POF or TAS phenotypes or may be a surrogate of some other allelic property. In this report, we have examined the distributional properties of transcript levels by repeat size and gender among 238 individuals. We have confirmed a significant linear relationship between transcript level and repeat size in males and females. The evidence for the linear effect is primarily within the premutation size alleles.
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PMID:A study of the distributional characteristics of FMR1 transcript levels in 238 individuals. 1475 38

Carriers of fragile X mental retardation 1 (FMR1) premutation alleles (55 to 200 CGG repeats) are generally spared the more serious neurodevelopmental problems associated with the full-mutation carriers (>200 repeats) of fragile X syndrome. However, some adult male premutation carriers (55-200 repeats) develop a neurological syndrome involving intention tremor, ataxia, dementia, parkinsonism, and autonomic dysfunction. In excess of one-third of male premutation carriers over 50 years of age develop the fragile X-associated tremor/ataxia syndrome (FXTAS). FXTAS also represents a new form of inclusion disease, with eosinophilic intranuclear inclusions found throughout the brain in both neurons and astrocytes. Because FXTAS appears to be relatively specific to male premutation carriers, who are known to possess elevated levels of FMR1 mRNA, the neuropathology may arise as a consequence of a toxic gain-of-function of the mRNA itself, although this proposal requires additional direct testing. One of the critical needs at present is a better estimate for the prevalence of this disorder, because FXTAS is likely to be underdiagnosed in the adult movement disorders clinics.
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PMID:Fragile X-associated tremor/ataxia syndrome (FXTAS). 1499 85

Individuals with fragile X mental retardation 1 (FMR1) premutation (55 to 200 CGG repeats) are typically unaffected by fragile X syndrome. However, a subgroup of older males with the premutation have developed a neurological syndrome, which usually begins between 50 and 70 years and is associated with a progressive intention tremor and/or ataxia manifested by balance problems, frequent falling, and Parkinsonian symptoms, such as masked facies, intermittent resting tremor, and mild rigidity. This finding has been termed the fragile X-associated tremor/ataxia syndrome (FXTAS) and has brought focus to the aging process in individuals with the FMR1 mutation. The premutation is associated with elevated messenger RNA levels leading to the formation of intranuclear inclusions in neurons and astrocytes associated with FXTAS. This review is a summary of our experience with FXTAS in male carriers of the premutation.
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PMID:Aging in individuals with the FMR1 mutation. 1500 Jun 74

Carriers of premutation alleles (55-200 CGG repeats) of the fragile-X mental retardation 1 (FMR1) gene are often regarded as being clinically uninvolved. However, it is now apparent that such individuals can present with one (or more) of three distinct clinical disorders: mild cognitive and/or behavioral deficits on the fragile-X spectrum; premature ovarian failure; and a newly described, neurodegenerative disorder of older adult carriers, fragile-X-associated tremor/ataxia syndrome (FXTAS). Awareness of these clinical presentations is important for proper diagnosis and therapeutic intervention, not only among families with known cases of fragile-X syndrome but also more broadly for adults with tremor, gait ataxia, and parkinsonism who are seen in movement-disorders clinics.
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PMID:The fragile-X premutation: a maturing perspective. 1505 36

It is currently thought that fragile X syndrome (FraX; the most common inherited form of learning disability) results from having more than 200 cytosine-guanine-guanine (CGG) trinucleotide repeats, with consequent methylation of the fragile X mental retardation (FMR1) gene and loss of FMR1 protein (FMRP). It was also considered that premutation carriers (with 55-200 CGG repeats) are unaffected, although a tremor/ataxia syndrome has recently been described in older adult male carriers. We reported that premutation expansion of CGG trinucleotide repeats affects brain anatomy, which, together with other studies, indicates that the molecular model for FraX needs modification. However, there are few studies on the cognitive ability of adult male premutation carriers. Thus, we selected 20 male premutation carriers on the basis of their genetic phenotype, and compared them to 20 male controls matched on age, IQ and handedness. We investigated intellectual functioning, executive function, memory, attention, visual and spatial perception, and language and pragmatics. The premutation carriers had significant impairments on tests of executive function (Verbal Fluency, Trail Making Test and Tower of London) and memory (Names sub-test of the Doors and People, Verbal Paired Associates Immediate Recall and Visual Paired Associates Delayed Recall sub-tests of the WMS-R, and Category Fluency Test for natural kinds). We therefore suggest that CGG trinucleotide repeats in the premutation range affect specific neuronal circuits that are concordant with specific neuropsychological deficits; and that these deficits reflect an emerging neuropsychological phenotype of premutation FraX.
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PMID:A neuropsychological investigation of male premutation carriers of fragile X syndrome. 1538 Oct 24


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