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)

Fragile X Syndrome is the most common heritable form of mental retardation caused by silencing of the FMR1 gene, which arises from intergenerational trinucleotide repeat expansion leading to full mutation. An intermediary carrier condition, known as the premutation, is characterized by expansion up to 200 repeats without concomitant gene silencing. This prevalent allelic variant was initially thought to be free of phenotypic effects. However, recent reports have identified a degenerative disease, Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) in older men as well as premature ovarian failure in women. Previously reports are inconsistent regarding the neuropsychiatric phenotype associated with premutation due to small sample sizes, ascertainment bias, lack of adequate control groups, administration of measures with poor psychometric properties, and the confounding effects of FXTAS. We addressed these problems by conducting a controlled study of male carriers (n = 40) of the premutation without manifest symptoms of FXTAS, comparing their responses on specific, reliable, and valid measures of neuropsychiatric functioning to those of individuals with shared family environment (n = 22) and non-carrier comparison males (n = 43). Multivariate analyses revealed that the premutation confers significant risk for working memory difficulties, an associated feature of Attention-Deficit Disorder. Furthermore, both the family controls and men with premutation exhibited higher rates of Alcohol Abuse as compared to non-carrier control men. These findings highlight the importance of recognizing the distinct phenotypic outcomes that characterize the Fragile X premutation and the subtle risk factors that can act as precursors to more significant psychiatric impairment.
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PMID:Impact of the Fragile X mental retardation 1 (FMR1) gene premutation on neuropsychiatric functioning in adult males without fragile X-associated Tremor/Ataxia syndrome: a controlled study. 1816 71

Fragile X syndrome is the most common cause of mental retardation in the male. Historically, fragile X premutation was considered to be phenotypically silent. In recent reports the premutation has been associated with premature ovarian failure and fragile X-associated tremor/ataxia syndrome. This case describes a 24-year-old woman who presented with irregular menstrual cycles secondary to premature ovarian failure. Subsequent genetic analysis confirmed that she has a premutation for fragile X with 70 CGG trinucleotide repeats.
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PMID:Premature ovarian failure: a phenotypic expression of fragile X premutation. 1832 8

Fragile X syndrome is the most common form of hereditary mental retardation. The molecular basis of this syndrome is mainly a CGG expansion in the 5' untranslated region of the FMR1 gene. Expansions with more than 200 CGG repeats abolish gene expression causing the classical fragile X phenotype. Premutation carriers (55-200 CGG) have normal cognitive function with increased risk of developing premature ovarian failure and fragile X-associated tremor-ataxia syndrome (FXTAS). Some clinical features associated with FXTAS, such as tremor, gait ataxia, cognitive decline, and generalized brain atrophy, are also seen in other movement disorders. Ninety-five patients referred for HD, who tested negative for the expansion in the IT15 gene, were screened for FMR1 CGG-repeat expansion. One FMR1 premutation male carrier was detected, giving an FXTAS frequency of 1.6%. Our results highlight that FXTAS is still not well diagnosed; therefore, we recommend FMR1 premutation screenings in all patients with late-onset tremor, ataxia, and cognitive dysfunction.
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PMID:Screening for FXTAS in 95 Spanish patients negative for Huntington disease. 1837 10

Movement disorders other than late onset tremor-ataxia in association with fragile X syndrome, the most common identifiable cause of inherited mental retardation, seem to be rare. Here we describe five male patients from three unrelated families with fragile X syndrome that presented with motor and phonic tics. Clinically, 4 patients fulfilled diagnostic criteria for Gilles de la Tourette syndrome (GTS) while 1 patient would have been diagnosed with an adult onset tic disorder. However, in all patients onset of tics was considerably later than in typical GTS. Three patients had atypical tics and two patients reported waxing and waning of tic intensity over time. Four of the 5 patients showed clinical signs typical of fragile X syndrome, in particular dysmorphic features, learning difficulties and speech and language problems that required special treatment. All patients had co-morbidities common to both GTS and fragile X syndrome. We suggest considering fragile X syndrome in GTS complicated by co-morbidity with late onset of atypical tics, in particular when learning disability and dysmorphic features are present.
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PMID:Fragile X syndrome associated with tic disorders. 1838 11

Angelman syndrome (AS) is a childhood-onset neurogenetic disorder characterized by functionally severe developmental delay with mental retardation, deficits in expressive language, ataxia, appendicular action tremors and unique behaviors such as inappropriate laughter and stimulus-sensitive hyperexcitibility. Most cases of AS are caused by mutations which disrupt expression of maternal UBE3A. Although some progress has been made in understanding hippocampal-related memory and learning aspects of the disorder using Ube3a deficient mice, the numerous motoric abnormalities associated with AS (ataxia, action tremor, dysarthria, dysphagia, sialorrhea and excessive chewing/mouthing behaviors) have not been fully explored with mouse models. Here we use a novel quantifiable analysis of fluid consumption and licking behavior along with a battery of motor tests to examine cerebellar and other motor system defects in Ube3a deficient mice. Mice with a maternally inherited Ube3a deficiency (Ube3a(m-/p+)) show defects in fluid consumption behavior which are different from Ube3a(m-/p-) mice. The rhythm of fluid licking and number of licks per visit were significantly different among the three groups (m-/p-, m-/p+, m+/p+) and indicate that not only was fluid consumption dependent on Ube3a expression in the cerebellum, but may also depend on low levels of Ube3a expression in other brain regions. Additional neurological testing revealed defects in both Ube3a(m-/p+) and Ube3a(m-/p-) mice in rope climbing, grip strength, gait and a raised-beam task. Long-term observation of fluid consumption behavior is the first phenotype reported that differentiates between mice with a maternal loss of function versus complete loss of Ube3a in the brain. The neuronal and molecular mechanisms underlying mouse fluid consumption defects specifically associated with maternally inherited Ube3a deficiency may reveal important new insights into the pathobiology of AS in humans.
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PMID:Analysis of cerebellar function in Ube3a-deficient mice reveals novel genotype-specific behaviors. 1841 22

The human FMR1 gene contains an unstable CGG-repeat in its 5' untranslated region. The repeat length in the normal population is polymorphic (5-54 CGG-repeats). Individuals carrying lengths beyond 200 CGGs (i.e. the full mutation) show hypermethylation and as a consequence gene silencing of the FMR1 gene. The absence of the gene product FMRP causes the fragile X syndrome, the most common inherited form of mental retardation. Elderly carriers of the premutation (PM), which is defined as a repeat length between 55 and 200 CGGs, can develop a progressive neurodegenerative syndrome: fragile X-associated tremor/ataxia syndrome (FXTAS). The high FMR1 mRNA levels observed in cells from PM carriers have led to the hypothesis that FXTAS is caused by a pathogenic RNA gain-of-function mechanism. Apart from tremor/ataxia, specific psychiatric symptoms have been described in PM carriers with or without FXTAS. Since these symptoms could arise from elevated stress hormone levels, we investigated hypothalamic-pituitary-adrenal (HPA) axis regulation using a knock-in mouse model with an expanded CGG-repeat in the PM range (>98 repeats) in the Fmr1 gene, which shows repeat instability, and displays biochemical, phenotypic and neuropathological characteristics of FXTAS. We show elevated levels of corticosterone in serum and ubiquitin-positive inclusions in both the pituitary and adrenal gland of 100-week-old animals. In addition, we demonstrate ubiquitin-positive inclusions in the amygdala from aged expanded CGG-repeat mice. We hypothesize that altered regulation of the HPA axis and the amygdala and higher stress hormone levels in the mouse model for FXTAS may explain associated psychological symptoms in humans.
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PMID:Altered hypothalamus-pituitary-adrenal gland axis regulation in the expanded CGG-repeat mouse model for fragile X-associated tremor/ataxia syndrome. 1847 27

Premutation carriers of repeat expansions in the fragile X mental retardation (FMR1) gene develop kinetic tremor and ataxia or the 'fragile X associated tremor/ataxia syndrome' (FXTAS). Affected FMR1 premutation carriers also have parkinsonism, but have not been reported to meet criteria for Parkinson disease. This case series illustrates that some patients who are FMR1 premutation carriers may appear by history and examination to have idiopathic Parkinson disease. Based on previous studies, it is likely that the genetic mutation and parkinsonism are associated. Although screening all PD patients is likely to be low yield, genetic testing of FMR1 in individuals with PD and a family history of fragile X syndrome, autism or developmental delay, or other related FMR1 phenotypes is warranted.
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PMID:Parkinsonism in FMR1 premutation carriers may be indistinguishable from Parkinson disease. 1856 83

We report a family with 16q-ADCA(16q 22.1 linked autosomal dominant cerebellar ataxia) coexisting with SCA8 repeat expansion. The brothers in this family presented with pyramidal signs, tremor, myoclonus and mental retardation in addition to cerebellar symptom in childhood. They showed both C-to-T substitution puratrophin-1 gene and an expanded allele of the SCA8 gene in the brothers and their father. These siblings presented with atypical symptoms and early onset age as16q-ADCA. Although it remains controversial whether the expanded SCA8 allele is associated with cerebellar symptoms, the coexistence of SCA8 repeat expansion with SCA6 was reported previously. Pure or predominant cerebellar symptoms were found in patients with SCA8, SCA6 and 16q-ADCA. In addition, common findings in neuropathology of SCA8, SCA6 and 16q-ADCA have been reported. We suppose that coexistence of SCA8 repeat expansion with 16q-ADCA may be involved in the pathogenesis and severe symptoms in this family.
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PMID:Severe symptoms of 16q-ADCA coexisting with SCA8 repeat expansion. 1868 74

The 5'untranslated region (UTR) of the FMR1 gene contains a CGG-repeat, which may become unstable upon transmission to the next generation. When repeat length exceeds 200, the FMR1 gene generally undergoes methylation-mediated transcriptional silencing. The subsequent absence of the gene product Fragile X Mental Retardation Protein (FMRP)causes the mental retardation seen in fragile X patients. A CGG-repeat length between 55 and 200 trinucleotides has been termed the premutation (PM). Predominantly elderly male PM carriers are at risk of developing a progressive neurodegenerative disorder: fragile X-associated tremor/ataxia syndrome (FXTAS). All PM carriers have elevated FMR1 mRNA levels, in spite of slightly decreased FMRP levels. The presence of intranuclear ubiquitin-positive inclusions in many brain regions is a neuropathological hallmark of FXTAS. Studies in humans attempting to correlate neuropathological outcomes with molecular measures are difficult because of the limited availability of tissue. Therefore, we have used the expanded CGG-repeat knock-in mouse model of FXTAS to examine the relationship between the molecular and neuropathological parameters in brain. We present Fmr1 mRNA and Fmrp levels and the presence of intranuclear inclusions at different repeat lengths. Contrary to existing hypotheses, our results suggest that inclusion formation may not depend on the elevation per se of Fmr1 transcript levels in aged CGG mice.
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PMID:CGG-repeat length and neuropathological and molecular correlates in a mouse model for fragile X-associated tremor/ataxia syndrome. 1901 69

The 5' untranslated region of the fragile X mental retardation gene, FMR1, contains a polymorphic CGG repeat. Expansions of this repeat are associated with a spectrum of disorders. Full mutation alleles, repeats >or= 200, are associated with fragile X syndrome. Premutation alleles, repeats of approximately 55-199, are associated with a tremor-ataxia syndrome most commonly in older males and primary ovarian insufficiency in females. However, the neuropsychological impact of carrying a premutation allele is presently unclear in younger adults. In this study, we analyzed neuropsychological scores for 138 males and 506 females ascertained from the general population and from families with a history of fragile X syndrome. Subjects were age 18-50 years and had varying repeat lengths. Neuropsychological scores were obtained from measures of general intelligence, memory, and executive functioning, including attention. Principal component analysis followed by varimax rotation was used to create independent factors for analysis. These factors were modeled for males and females separately via a general linear model that accounted for correlation among related subjects. All models were adjusted for potential confounders, including age at testing, ethnicity, and household income. Among males, no repeat length associations were detected for any factor. Among females, only a significant association with repeat length and self-report attention (p < 0.01) was detected, with premutation carriers self-reporting significantly more attention-related problems compared to noncarriers. No significant interactions between repeat length and age were detected. Overall, these results indicate the lack of a global neuropsychological impact of carrying a premutation allele among adults under the age of 50.
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PMID:No evidence for a difference in neuropsychological profile among carriers and noncarriers of the FMR1 premutation in adults under the age of 50. 1902 94


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