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)

Carriers of premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene are spared the major neurodevelopmental symptomatology of fragile X syndrome patients carrying a full mutation (>200 repeats). In a proportion of premutation carriers, the repeat expansion is associated with a specific neurological profile involving intention tremor, ataxia, intellectual decline compatible with dementia syndrome, Parkinsonism and autonomic dysfunction at older age, commonly referred to as fragile-X-associated tremor/ataxia syndrome (FXTAS). Typical CNS changes include hyperintense signals on T2 weighted magnetic resonance images and the presence of ubiquitin-positive intranuclear neuronal inclusions. A knock-in mouse model with a (CGG)98 repeat in the premutation range has been generated and shown to exhibit elevated Fmr1 mRNA levels and ubiquitin-positive intranuclear neuronal inclusions, suggesting it may be a valid model for the human disease. Given the specific clinical profile of FXTAS patients, the expanded CGG repeat model was assessed for cognitive, behavioural and neuromotor performance at different ages (20, 52 and 72 weeks). The Morris water maze task exposed age-dependent decline of visual-spatial memory. Open field recordings revealed decreased exploration of the centre of the arena in the oldest group of expanded CGG repeat mice, potentially reflecting increased anxiety. Neuromotor tasks primarily showed decline of performance on the accelerating rotarod with age in the premutation carriers but not in control littermates. The age-dependent cognitive decline and neuromotor disturbances may be related to the progressive cognitive and behavioural difficulties observed in FXTAS patients.
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PMID:Cognitive decline, neuromotor and behavioural disturbances in a mouse model for fragile-X-associated tremor/ataxia syndrome (FXTAS). 1587 60

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.
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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.
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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.
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PMID:Genetic counseling for fragile x syndrome: updated recommendations of the national society of genetic counselors. 1604 89

The FMR1 gene is involved in two different syndromes: Fragile X syndrome and Fragile X-associated tremor/ataxia syndrome (FXTAS). Fragile X syndrome is a childhood disease and is associated with mental retardation as the main clinical characteristic, whereas FXTAS develops in men and women over 50 years of age. FXTAS represents a new form of inclusion disorder with a high prevalence in the general population. The neurologic phenotype of FXTAS includes intention tremor and ataxia. Associated features are dementia, parkinsonism, neuropathy, and autonomic dysfunction. Elevated FMR1 transcripts have been proposed as the molecular basis of the pathogenic mechanism leading to FXTAS. This review discusses recent developments in the clinical phenotype, prevalence and screening, animal models, and molecular mechanisms of RNA-based pathogenesis in FXTAS.
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PMID:FXTAS: a progressive neurologic syndrome associated with Fragile X premutation. 1613 24

A 75-year-old man had progressive difficulty with walking, intention tremor, ataxia, and mild cognitive deficits. MRI scan ofthe brain showed symmetrical hyperintensities in the middle cerebellar peduncles. DNA analysis ofthe fragile-X gene revealed an expansion of 150-200 repetitions in the FMR1-gene, compatible with a premutation in the fragile-X gene. Two years later, after progression of the symptoms, the patient was admitted to a nursing home. The clinical picture of intention tremor, parkinsonism and ataxia with white matter lesions and atrophy on MRI occurs in carriers of this premutation and has recently been described as the fragile-X-associated tremor/ataxia syndrome. Recognition of this clinical picture is important for the patient but also for the relatives, since female carriers of the premutation have an increased risk of offspring with the fragile-X syndrome.
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PMID:[Progressive ataxia and cognitive deficits caused by premutation in the fragile-X-mental retardation gene]. 1627 33

The fragile X mental retardation 1 gene (FMR1) mutation causes two disorders: fragile X syndrome (FXS) in those with the full mutation and the fragile X-associated tremor/ataxia syndrome (FXTAS) in some older individuals with the premutation. FXS is caused by a deficiency of the FMR1 protein (FMRP) leading to dysregulation of many genes that create a phenotype with ADHD, anxiety, and autism. FXTAS is caused by the elevation of FMR1-mRNA to levels 2 to 8 times normal in the premutation. This causes an RNA gain of function toxicity leading to brain atrophy, white matter disease, neuronal and astrocytic inclusion formation, and subsequent ataxia, intention tremor, peripheral neuropathy, and cognitive decline. The neurobiology and pathophysiology of FXS and FXTAS are described in detail.
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PMID:Lessons from fragile X regarding neurobiology, autism, and neurodegeneration. 1651 73

The FRAXA trinucleotide repeat at Xq27.3 gives rise to fragile X syndrome when fully expanded, and both premature ovarian failure (POF) and fragile X tremor and ataxia syndrome (FXTAS) when in the premutation range. Reports of phenotypic effects extending into the intermediate repeat range are inconsistent but some studies suggest that these smaller expansions predispose to special educational needs (SEN). This study utilises the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort to investigate cognitive and behavioural variables that might be associated with FRAXA intermediate alleles. The current study failed to find any strong evidence of association of FRAXA intermediate alleles with SEN, behavioural problems or cognitive difficulties. However, our findings illustrate some of the difficulties encountered in identifying individuals with SEN. The power to identify specific components of cognitive and behavioural difficulties was reduced due to elective drop-out, which is characteristic of longitudinal studies. Our findings demonstrate the non-random loss of participants from this cohort and highlight problems that may arise when such data are used in genetic association studies.
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PMID:An investigation of FRAXA intermediate allele phenotype in a longitudinal sample. 1662 28

Disorders associated with fragile X syndrome involve a trinucleotide (CGG) repeat expansion in the FMR1 gene. Recently, a progressive movement disorder (fragile X-associated tremor/ataxia syndrome [FXTAS]) has been identified in premutation carriers, persons with 55 to 200 CGG repeats. In addition to ataxia, action tremor, and Parkinsonism, early case reports suggested that FXTAS involves impaired cognition, but the precise nature of the impairment has not been elucidated. In this first, preliminary study of the subject, circumscribed aspects of cognitive functioning were examined in 25 men with FXTAS. Subjects' performance on the cognitive tests was compared with normative data. Scores on two measures of executive cognitive functioning showed a high prevalence of substantial impairment. Capacity for inhibition was severely affected in one-quarter of this highly educated sample; information processing speed was profoundly impaired in most subjects. Although mean verbal and performance IQ scores were not significantly different from the general population, they were quite low given the sample's educational level. Cognitive and functional impairment was greater for men with more CGG repeats, although number of repeats was not associated with age of onset of either tremor or ataxia. The results provide evidence that FXTAS involves marked impairment of executive cognitive abilities.
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PMID:Impairment in the cognitive functioning of men with fragile X-associated tremor/ataxia syndrome (FXTAS). 1678 Aug 89

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


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