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

Microsatellites, simple tamdem repeats of 2 to 4 nucleotide sequences, are widely distributed throughout the genome. Trinucleotide repeats are found every 300 to 500 kb. Recently, a new type of mutation was described involving a specific expansion of triplets within or in close proximity to a gene. Expanded triplets have been found in the genes causing six different neurological disorders: fragile X syndrome (FRAXA), spinal and bulbar muscular atrophy (SBMA), myotonic dystrophy (DM), Huntington's disease (HD), spinocerebellar ataxia type 1 (SCA1), and dentato-rubra-pallidoluysian atrophy (DRPLA). These neurological disorders have in common a variable age of onset and clinical severity, as well as a decrease in the age of onset over generations, known as anticipation. These unusual characteristics are related to the observation that expanded repeats are unstable both in meioses and mitoses. A younger age of onset and an increase in severity correlate with a higher number of repeats. Interestingly, particular haplotypes are in disequilibrium with the mutation for FRAXA, DM and HD, suggesting instability for selected chromosomes. How expanded triplets affect the expression and the function of genes is still unknown. Since neurodegenerative disorders are often variable in age of onset and clinical severity, the list of expanding triplet mutations should increase in the very near future.
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PMID:Genes with triplet repeats: a new class of mutations causing neurological diseases. 799 79

Trinucleotide repeat expansions are now a well-established mutational mechanism in human genetic disease. An unstable CAG repeat is known to be responsible for three neurodegenerative disorders: Huntington's disease, spinal and bulbar muscular atrophy and spinocerebellar ataxia type 1. Similarities in the genetics of these diseases, the size of the repeat expansions and the position of the unstable repeat within the gene (when known) suggest a common basis to the observed phenotypes. The cloning of two regions at which chromosome breakage can be induced (FRAXA and FRAXE) has in each case uncovered an unstable CG-rich triplet repeat which becomes methylated when fully expanded. In addition to these two classes of mutation, the presence of an expanded CTG repeat in the 3' untranslated region of a protein kinase causes myotonic dystrophy. The size of the respective expansions, repeat stability, mutational origins and possible mechanisms of action are discussed.
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PMID:Trinucleotide repeat expansions and human genetic disease. 803 5

We describe 54 members of eight families with a distinct autosomal dominant cerebellar ataxia associated with visual failure secondary to a pigmentary macular dystrophy. The presenting symptom was ataxia in two-thirds of patients and visual failure or both in the remainder. The macular abnormalities were often subtle in early cases, even in some with moderately reduced visual acuity. Other neurological features included pyramidal tract signs and a supranuclear ophthalmoplegia with progressive saccadic palsy. Ages of onset and clinical course were very variable, even within families, and included a rapidly progressive, infantile-onset phenotype. Pedigree analysis showed the existence of non-manifesting obligate carriers and anticipation in the offspring of affected fathers; transmission of the disease to severe, infantile-onset cases was always from an affected father. Similar genetic phenomena have been reported in myotonic dystrophy and Huntington's disease and it is likely that the gene mutation in this condition will similarly consist of an unstable trinucleotide repeat expansion.
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PMID:Autosomal dominant cerebellar ataxia with pigmentary macular dystrophy. A clinical and genetic study of eight families. 803 56

Dentatorubropallidoluysian atrophy (DRPLA) has been described chiefly in Japan and appears to be rare in Europe. It is of autosomal dominant inheritance. We report the first British family with DRPLA, which contains four affected individuals in two generations. The diagnosis was made at autopsy in one case. The age of onset of symptoms ranged from 15 to 38 years, and clinical features included ataxia, dementia, chorea, and dystonia; three patients had generalized seizures. The three living patients resemble those with early Huntington's disease clinically. Three main phenotypes of DRPLA have been proposed: an ataxo-choreoathetoid type, a pseudo-Huntington type, and a myoclonic epilepsy type. The variation in clinical presentation in our family demonstrates the difficulty in applying such classifications to this and other dominantly inherited disorders with phenotypic variation. DRPLA is likely to be confused with Huntington's disease in European families.
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PMID:Autosomal-dominant dentatorubropallidoluysian atrophy in the United Kingdom. 804 69

Huntington's disease (HD) has recently been found to be caused by expansion of a trinucleotide (CAG) repeat within the putative coding region of a gene with an unknown function. We report here an analysis of HD mutation and the characteristics of its transmission in 36 HD families. CAG repeats on HD chromosomes were unstable when transmitted from parent to offspring. Instability appeared more frequent and stronger upon transmission from a male than from a female, with a clear tendency towards increased size. We have also found a significant inverse correlation (p = 0.0001) between the age of onset and the CAG repeat length. The observed scatter would, however, not allow an accurate individual prediction of age of onset. Three juvenile onset cases analysed had an HD mutation of paternal origin. In at least two of these cases a large expansion of the HD allele upon paternal transmission may explain the major anticipation observed. Our results suggest that several features of the expansion mutation in HD are similar to those previously observed for mutations of similar size in spinobulbar muscular atrophy and in myotonic dystrophy, and to those observed more recently in spinocerebellar ataxia type 1 and in dentatorubropallidoluysian atrophy, four diseases also caused by expansion of CAG repeats.
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PMID:Instability of CAG repeats in Huntington's disease: relation to parental transmission and age of onset. 806 15

Some transcription factors contain stretches of polyglutamine encoded by repeats of the trinucleotide CAG. Expansion of the CAG repeat in the androgen receptor (AR) has been correlated with the incidence and severity of X-linked spinal and bulbar muscular atrophy (Kennedy's disease). In order to understand the relationship of this mutation to AR function, we constructed ARs that varied in the position and size of the polyglutamine tract, and assayed for the abilities of these mutant receptors to bind androgen and to activate transcription of several different AR-responsive reporter genes. Elimination of the tract in both human and rat AR resulted in elevated transcriptional activation activity, strongly suggesting that the presence of the polyglutamine tract is inhibitory to transactivation. Progressive expansion of the CAG repeat in human AR caused a linear decrease of transactivation function. Importantly, expansion of the tract did not completely eliminate AR activity. We postulate that this residual AR activity may be sufficient for development of male primary and secondary sex characteristics, but may fall below a threshold level of activity necessary for normal maintenance of motor neuron function. This functional abnormality may be representative of other genetic diseases that are associated with CAG expansion mutations in open reading frames, such as spinocerebellar ataxia type I and Huntington's disease.
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PMID:The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. 806 34

The triplet repeat sequences (CGG)n, (GCT)n, and (CAG)n, which naturally occur in the human genome, can be autonomously expanded in human DNA by an as yet unknown mechanism. These in part excessive expansions have been causally related to human genetic diseases, the fragile X (Martin-Bell) syndrome, to myotonic dystrophy (Curschmann-Steinert), to spinal and bulbar muscular atrophy (Kennedy disease), and recently to Huntington disease. A GCC trinucleotide repeat was found to be expanded and methylated in the fragile site FRAXE on the human X chromosome. These findings were associated with mental retardation (Knight et al., 1993). In spinocerebellar ataxia type 1 (SCA1), a polymorphic CAG repeat was found to be unstable and expanded in individuals with that disease (Orr et al., 1993). We have demonstrated in in vitro experiments that the synthetic oligodeoxyribonucleotides (CGG)17, (CGG)12, (GCC)17, (CG)25, (CTG)17, or (CAG)17 plus (GTC)17, in the absence of added natural DNA, can be expanded with Taq polymerase in the polymerase chain reaction (PCR). Some expansion can already be detected after 4 PCR cycles. The E. coli Klenow DNA polymerase also functions in a similar amplification and expansion reaction performed at 37 degrees C without cycling. Other oligodeoxyribonucleotides, like, (CGG)7, (CGGT)13, or (TAA)17, are devoid of this property or have very low activity. The cytidine-methylated polymers (GCC)17 or (CG)25 yield expansion products of considerably reduced chain lengths. The expansion of the polymer (CGG)17 is affected by cytidine methylation to a lesser degree. A specific sequence and/or secondary structure and high CG content appear to be requirements for this expansion reaction by a possible slippage mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Enzymatic amplification of synthetic oligodeoxyribonucleotides: implications for triplet repeat expansions in the human genome. 811 62

The recent observation that the mutation underlying a number of genetic diseases including fragile sites, FRAXA and FRAXE (associated with mental retardation), myotonic dystrophy, spinal and bulbar muscular atrophy (Kennedy's disease), Huntington's disease and spinocerebellar ataxia type 1 are caused by the expansion of a trinucleotide repeat sequence will lead to interest in the identification of such sequences in regions related to other diseases. We report here the identification of all ten classes of trinucleotide repeats within a 2 Mbp region of 4p16.3 containing the Huntington's disease (HD) gene. Fifty one triplet repeats were identified and localised on a high resolution restriction map of a cosmid contig covering this region. This included the triplet repeat (CAG)n, which has subsequently been shown to be expanded in Huntington's disease patients.
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PMID:Distribution of trinucleotide repeat sequences across a 2 Mbp region containing the Huntington's disease gene. 816 55

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

Genetic considerations in movement disorders are described. 1) Familial parkinsonisms are heterogeneous; genes for two of them, 'Lubag' and Waisman syndrome have been mapped to X chromosome, though genes for others do not have been mapped. 2) The responsible gene for Huntington's disease has been cloned recently and named huntingtin. A (CAG)n repeat longer than the normal range was observed in huntingtin gene. The (CAG)n repeat appears to be located within the coding sequence of a predicted approximately 348 kD protein that is widely expressed but unrelated to any known gene. The expansion of an unstable trinucleotide CAG repeat are also the causes of hereditary neurodegenerative diseases such as X-linked bular and spinal muscular atrophy and spinocerebellar ataxia type 1. 3) There are various forms in hereditary dystonia. Although the responsible gene for idiopathic torsion dystonia, inherited as an autosomal dominant pattern, has been mapped to 9q 32-34, genes for others do not have been mapped. 4) The Gilles des la Tourette syndrome (GTS) is a hereditary, neuropsychiatric-neurobehavioral disorder with childhood onset that is characterized by motor and vocal tics. About 80% of the human genome could be excluded as possible site for the GTS gene by studies with over 600 DNA markers in an international collaborative effort, but actual localization has not yet been accomplished.
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PMID:[Genetics in movement disorders]. 827 74


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