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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three neurodegenerative diseases, Huntington's disease (HD), Kennedy's disease (hereditary spinobulbar muscular atrophy, SBMA), and type 1 spinocerebellar ataxia (SCA-1) have been found to share a common genetic defect: an unstable region of repeated CAG trinucleotides which are thought to be translated into a polyglutamine moiety. The unstable repeat regions occur near the N-termini of the predicted proteins for HD and SBMA, but the location of the CAG repeat region is not known for SCA-1. Each disease is notable for a relatively circumscribed region of central nervous system pathology, and the lack of predicted similarity of the abnormal proteins makes a common mechanism related to the function of each protein unlikely. In order to reconcile the similar genetic abnormalities with the disparities in phenotypes, we suggest a common thread with regard to the pathogenesis of neuronal death. We hypothesize that the mechanism of neurotoxicity in these diseases occurs not through the production of abnormal proteins, but by the generation of abnormal posttranslational cleavage products. These products, in part consisting of abnormally large polyglutamine moieties, act to disturb the cellular and mitochondrial milieu such that energy metabolism is impaired, rendering specific regions of the nervous system vulnerable, and resulting in the clinical phenotypes of HD, SBMA, and SCA-1. We offer this interpretation of recent genetic findings from a neurobiologic perspective, in addition to suggesting testable hypotheses concerning potential disease mechanisms.
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PMID:Trinucleotide repeats in neurologic diseases: an hypothesis concerning the pathogenesis of Huntington's disease, Kennedy's disease, and spinocerebellar ataxia type I. 819 20

Expansion of trinucleotide repeats has now been associated with eight inherited diseases: X-linked spinal and bulbar muscular atrophy, two fragile X syndromes, myotonic dystrophy, Huntington's disease, spinocerebellar ataxia type I, dentatorubral pallidoluysian atrophy and Machado-Joseph disease. It has been shown that these expanded DNA repeats are unstable in number when transmitted from parents to offspring ("meiotic instability"), while somatic variation in repeat number has also been found in the fragile X syndrome and myotonic dystrophy. Moderate meiotic instability has been demonstrated in X-linked spinal and bulbar muscular atrophy (SBMA, Kennedy's disease). In order to determine if the expanded CAG repeat in SBMA also shows somatic instability, we compared different tissues from two patients with SBMA. We then examined the in vitro stability of the CAG repeat expansion by analyzing fibroblast cell cultures. Length comparison of expanded CAG repeats from all these materials clearly demonstrates that the CAG trinucleotide repeat in SBMA does not exhibit somatic variation.
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PMID:Somatic stability of the expanded CAG trinucleotide repeat in X-linked spinal and bulbar muscular atrophy. 880 33

Several human disorders are now known to be caused by expansion of unstable trinucleotide repeat sequences, including fragile X syndrome (FRAX), myotonic dystrophy (DM), spinal and bulbar muscular atrophy (SBMA, also known as Kennedy disease), Huntington disease (HD), dentatorubral-pallidoluysian atrophy (DRPLA), spinocerebellar ataxia type 1 (SCA1), Machado-Joseph disease (MJD), and Friedreich ataxia. As these diseases are studied in more detail, important differences have emerged in the nature of the unstable repeats and the mechanism by which the repeat expansions cause disease symptoms. There are already animal models of some of these disorders, and these are important resources for studying pathology and therapeutic strategies. Diagnostic procedures for these disorders are only beginning to be standardized, and effective therapy will have to wait for further information on disease mechanisms. Much has been learned since discovery of the fragile X syndrome gene in 1991, but much remains to be done.
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PMID:Trinucleotide repeat disorders in humans: discussions of mechanisms and medical issues. 900 50

Dynamic mutations in human genes result from unstable trinucleotide repeats which are expanded within the genome. These expansions of trinucleotide repeats have been shown to be the etiological factors in various neuropsychiatric diseases and other genetic disorders. This hypothesis is supported by various independent studies showing large expansion of trimeric repeats, such as CAG/CTG/CCG/CGG/AAG, in patient DNA samples. These repeats are also identified in other disease loci not clearly related to particular diseases, which indicates that such expansions are one of the general forms of evolution occurring throughout the human genome. The trinucleotide repeat expansions occur during meiosis and are generally irreversible. Accumulation of these repeats over generations eventually ends in a deficiency of replication. There is evidence that certain ethnic groups in the human population have predispositions for expanded repeats related to neuropsychiatric diseases. It is likely that racial/ethnic differences reflect variations, which suggests the possibility of an underlying complex biological process. The present review highlights the importance of repeat expansions in some neuropsychiatric diseases, such as spinal and bulbular atrophy (SBMA), spinocerebellar ataxia (SCA), Huntington's disease (HD), schizophrenia, myotonic dystrophy (DM) and fragile-X syndrome.
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PMID:DNA trinucleotide repeat expansion in neuropsychiatric patients. 1296 Sep 39

Spinal and bulbar muscular atrophy (SBMA or Kennedy's disease) is a fatal neurodegenerative disease characterized by the selective loss of motor neurons in the bulbar region of the brain and in the anterior horns of the spinal cord. The disease has been associated to an expansion of a CAG triplet repeat present in the first coding exon of the androgen receptor (AR) gene. SBMA was the first identified member of a large class of neurodegenerative diseases now known as CAG-related diseases, which includes Huntington's disease (HD), several types of spinocerebellar ataxia (SCAs), and dentatorubral and pallidoluysian atrophy (DRPLA). The expanded CAG tract is translated to an aberrantly long polyglutamine tract (ARpolyQ) in the N-terminal region of the AR protein. The elongated polyQ tract seems to confer a neurotoxic gain-of-function to the mutant AR, possibly via the generation of aberrant conformations (misfolding). Protein misfolding is thought to be a trigger of neurotoxicity, since it perturbs a wide variety of motor neuronal functions. The first event is the accumulation of the ARpolyQ into ubiquitinated aggregates in a ligand (testosterone) dependent manner. The mutant ARpolyQ also impairs proteasome functions. The autophagic pathway may be activated to compensate these aberrant events by clearing the mutant ARpolyQ from motor neuronal cells. This review illustrates the mechanisms at the basis of ARpolyQ degradation via the proteasomal and autophagic systems.
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PMID:Proteasomal and autophagic degradative activities in spinal and bulbar muscular atrophy. 2062 Nov 88

Polyglutamine (polyQ) diseases are a group of neurodegenerative conditions, induced from CAG trinucleotide repeat expansion within causative gene respectively. Generation of toxic proteins, containing polyQ-expanded tract, is the key process to cause neurodegeneration. Till now, although polyQ diseases remain uncurable, numerous therapeutic strategies with great potential have been examined and have been proven to be effective against polyQ diseases, including diverse small biological molecules and many pharmacological compounds mainly through prevention on formation of aggregates and inclusions, acceleration on degradation of toxic proteins and regulation of cellular function. We review promising therapeutic strategies by using Drosophila models of polyQ diseases including HD, SCA1, SCA3 and SBMA.
Cerebellum Ataxias 2014
PMID:Alleviating neurodegeneration in Drosophila models of PolyQ diseases. 2633 Oct 33

Spinal and bulbar (bulbospinal) muscular atrophy (BSMA, SBMA, Kennedy's disease) is a progressive motor neuron disease with rare involvement of structures other than the lower motor neuron, such as the endocrine system and the central nervous system (CNS). Aim of the review was to study type and frequency of clinical, imaging, and functional (CNS) abnormalities in SBMA patients. The most frequent clinical CNS manifestations in SBMA are postural or kinetic tremor predominantly of the hands and mild cognitive impairment. The most frequent instrumental CNS abnormality in SBMA patients are white matter lesions, visible on voxel-based morphometry, magnetic resonance spectroscopy, or diffusion tensor imaging. Single patients with enlarged pituitary volume, or diminished somato-sensory representation in the cortex have been also reported. Seizures, epilepsy, ataxia, spasticity, dystonia, or migraine have not been found in SBMA patients. Only supportive treatment is available for CNS manifestations in SBMA. It is concluded that the most frequent CNS abnormalities in SBMA are tremor, cognitive impairment, and white matter lesions on new imaging modalities. CNS involvement in SBMA should not be neglected as a phenotypic manifestation of SBMA and, apart from cognitive involvement, may help to differentiate clinically SBMA from other types of motor neuron disease.
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PMID:Central nervous system abnormalities in spinal and bulbar muscular atrophy (Kennedy's disease). 3135 Dec 15

Dozens of incurable neurological disorders result from expansion of short repeat sequences in both coding and non-coding regions of the transcriptome. Short repeat expansions underlie microsatellite repeat expansion (MRE) disorders including myotonic dystrophy (DM1, CUG50-3,500 in DMPK; DM2, CCTG75-11,000 in ZNF9), fragile X tremor ataxia syndrome (FXTAS, CGG50-200 in FMR1), spinal bulbar muscular atrophy (SBMA, CAG40-55 in AR), Huntington's disease (HD, CAG36-121 in HTT), C9ORF72- amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD and C9-ALS/FTD, GGGGCC in C9ORF72), and many others, like ataxias. Recent research has highlighted several mechanisms that may contribute to pathology in this heterogeneous class of neurological MRE disorders - bidirectional transcription, intranuclear RNA foci, and repeat associated non-AUG (RAN) translation - which are the subject of this review. Additionally, many MRE disorders share similar underlying molecular pathologies that have been recently targeted in experimental and preclinical contexts. We discuss the therapeutic potential of versatile therapeutic strategies that may selectively target disrupted RNA-based processes and may be readily adaptable for the treatment of multiple MRE disorders. Collectively, the strategies under consideration for treatment of multiple MRE disorders include reducing levels of toxic RNA, preventing RNA foci formation, and eliminating the downstream cellular toxicity associated with peptide repeats produced by RAN translation. While treatments are still lacking for the majority of MRE disorders, several promising therapeutic strategies have emerged and will be evaluated within this review.
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PMID:Repeat RNA expansion disorders of the nervous system: post-transcriptional mechanisms and therapeutic strategies. 3317 4