Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We describe the first Danish family with dentatorubral-pallidoluysian atrophy (DRPLA), containing 16 clinically affected individuals in five generations. Inheritance is autosomal dominant. The disorder was diagnosed as Huntington's disease (HD), but analysis of the IT15 gene for HD revealed normal alleles. The diagnosis of DRPLA was based on the finding of elongated CAG repeats in the B37 gene on chromosome 12 in affected individuals. The age at onset ranged from 13 to 60 years, with the most severe clinical picture being associated with onset in childhood. Clinical features included varying combinations of dementia, euphoria, visuomotor disturbances, speech problems, ataxia, tremor, epilepsy and involuntary movements presenting as chorea, athetosis, and dystonia. We discuss characteristics of DRPLA that may enable the differentiation from HD on a clinical basis. In conclusion, DRPLA should be considered and DNA analysis is recommended in patients manifesting varying combinations of extrapyramidal and cerebellar symptoms, especially when clinical features show pronounced intrafamilial variability, and dyscoordination, tremor, myoclonus, epilepsy, and euphoria are part of the syndrome.
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PMID:Dentatorubral-pallidoluysian atrophy. Clinical features of a five-generation Danish family. 886 94

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

The autosomal dominant cerebellar ataxias are a heterogeneous group of neurodegenerative disorders characterized by slowly progressive cerebellar ataxia. Recently, among the ataxias, spinocerebellar ataxia type 1 (SCA1), Machado-Joseph disease (MJD) and dentatorubral-pallidoluysian atrophy have been found to be caused by expansion of a CAG trinucleotide repeat in the coding region of the disease genes. We have analyzed the CAG repeats of 67 patients from 47 families with dominantly inherited ataxia who lived in the Kinki area of Japan. The following results were obtained. First, 31 patients from 22 families were found to be positive for the MJD repeat expansion, indicating that MJD is the most common dominantly inherited ataxia in the Kinki area of Japan. Second, no SCA1 repeat expansion was found among the families studied. This presents a striking contrast to the fact that there are many families with SCA1 in Hokkaido and the Tohoku area of Japan. These findings suggest geographic variation in autosomal dominant cerebellar ataxias in Japan.
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PMID:Autosomal dominant cerebellar ataxias in the Kinki area of Japan. 908 10

We report a family with autosomal recessive spastic paraplegia. Patient 1 was a 37-year-old woman and patient 2 was her 35-year-old sister. They showed spastic paraplegia with mild truncal ataxia and dysarthria but no dementia, epilepsy, myoclonus, or other involuntary movements. They were the products of a consanguineous marriage but the parents were neurologically normal. We analyzed the CAG repeats of the dentatorubral-pallidoluysian atrophy (DRPLA) gene in the family members. The patients were homozygous for an allele carrying an intermediate size of CAG repeats (41 or 40 repeats) in the DRPLA gene; the parents were heterozygous for an intermediate allele and a normal allele in this gene. Homozygosity for an intermediate allele in the DRPLA gene appears to have resulted in spastic paraplegia different from any DRPLA phenotype.
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PMID:Homozygosity for an allele carrying intermediate CAG repeats in the dentatorubral-pallidoluysian atrophy (DRPLA) gene results in spastic paraplegia. 910 5

Three autosomal dominant spinocerebellar ataxias, dentatorubral-pallidoluysian atrophy (DRPLA), Machado-Joseph disease (MJD), and spinocerebellar ataxia type 1 (SCA1), are associated with the expansion of a CAG repeat in the respective genes. To investigate the association between CAG repeat expansion and neuropathological findings, we analyzed several brain regions from 9 cases of DRPLA, 3 cases of MJD, and 1 case of SCA1. We found that the expanded alleles were smaller in the cerebellar cortex than in other brain regions, such as the frontal cortex, in these three diseases. The discrepancy in the expanded CAG repeat length between cerebellar cortex and other tissues was most prominent in DRPLA, and especially in cases of adult-onset DRPLA. A significant correlation was found between the age at onset of DRPLA and the size of the CAG repeat expansion. Cerebella of DRPLA patients were microscopically dissected into three layers, the molecular and granular layers and the white matter, which were analyzed separately. The lower level of CAG repeat expansion in DRPLA cerebella was representative of CAG repeat expansion in the granule cells. The microdissected samples of the granular layer of the hippocampal formation, which is densely packed with neuronal cells, revealed that the degree of CAG repeat expansion in this layer was similar to that in the cerebellum. These observations suggest that granule cells in the cerebellum and hippocampus have low levels of CAG repeat expansion, and that other types of cells exhibit a higher level of CAG repeat expansion, in spinocerebellar ataxias.
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PMID:Brain regional differences in the expansion of a CAG repeat in the spinocerebellar ataxias: dentatorubral-pallidoluysian atrophy, Machado-Joseph disease, and spinocerebellar ataxia type 1. 912 8

Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3, is a neurodegenerative disorder which is associated with a CAG repeat expansion in the MJD1 gene on chromosome 14q32.1. A recent study reported an excess of transmission of disease chromosomes relative to normal chromosomes from affected fathers, while this phenomenon was not observed in female meioses. These data were compatible with meiotic drive. We investigated the transmission of alleles with larger versus smaller CAG repeat numbers in the MJD1 gene in normal heterozygotes from the 40 CEPH families. Our data suggest that there was no segregation distortion in male meioses, while the smaller CAG allele was inherited in 57% of female meioses (p < 0.016). The pattern of inheritance of smaller versus larger CAG alleles at this locus was significantly different when male and female meioses were compared (p = 0.0139). While previous data suggest that meiotic drive may be a feature of certain human diseases, including the trinucleotide diseases MJD, myotonic dystrophy, and dentatorubral-pallidoluysian atrophy, these data are compatible with meiotic drive also occurring among non-disease associated CAG sizes.
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PMID:Non-Mendelian transmission at the Machado-Joseph disease locus in normal females: preferential transmission of alleles with smaller CAG repeats. 913 96

We have genotyped unrelated French Alsatian schizophrenic and bipolar I disorder (BPD) patients and matched controls for the polymorphic CAG repeats within the genes for spinocerebellar ataxia type 1 (SCA1) and dentatorubral-pallidoluysian atrophy (B37), in order to test their possible involvement in these disorders. No alleles with abnormally expanded repeats were found in either gene in patients and controls. Differences in allele and genotype frequencies for the SCA1 CAG repeat between patients and controls were not significant, thus providing no support for its role as a possible positional candidate gene for schizophrenia and BPD in our patients. Chi square testing revealed a significant result (P = 0.019) for an association between the B37 CAG repeat on chromosome 12p and schizophrenia. This result was more significant when only schizophrenics with a positive family history were compared with controls (P = 0.0001). The frequencies of alleles with 14, 12, and 15 CAG repeats differed the most, respectively, between schizophrenics and controls. When choosing the median of the B37 allele distribution (15 CAG repeats) as a threshold, there were significantly more controls than schizophrenics in the group with longer alleles (15 or more repeats) and more schizophrenics with shorter alleles (P = 0.002 by Fisher exact test). No particular genotype was associated with schizophrenia. This result possibly indicates linkage disequilibrium with another locus on chromosome 12p and therefore deserves further attention. No association was found between the B37 CAG repeat and patients with BPD.
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PMID:Analysis of the CAG repeats in the SCA1 and B37 genes in schizophrenic and bipolar I disorder patients: tentative association between B37 and schizophrenia. 918 18

We report a 60-year-old woman with progressive ataxia, myoclonus, choreoathetosis, and dementia. She was well until 27 years of the age when she noted an onset of gait disturbance and speech disturbance. She noted abnormal involuntary movements in her four limbs at 42 years of the age. Her symptoms had progressively become worse and she fell down frequently by her 52 years of the age. In addition, her family members noted gradual decline in her intelligence. She was admitted to our hospital in February of 1993 when she was 57-year-old. On admission, she showed dementia, scanning speech, ataxic gait, limb ataxia, action myoclonus, and choreic movements which involved her four limbs. Deep tendon reflexes were slightly exaggerated in the lower limbs; no Babinski sign was noted. Sensation was intact. Laboratory findings were unremarkable. Cerebral MRI revealed atrophy of the cerebellar cortex, superior cerebellar peduncle, brain stem, and the cerebral cortex; the third ventricle and the lateral ventricles were dilated; furthermore, T2-high signal lesions were seen in the cerebral white matter and in the pontine base. Her clinical course was one of the progressive deterioration of her ataxia, involuntary movements, and dementia. She expired on April 24, 1996 when she was 60-year-old. She was discussed in a neurologic CPC and the chief discussant arrived at the conclusion that the patient had dentatorubral-pallidoluysian atrophy. A minor opinion was that she might have had myoclonus epilepsy with ragged-red fibers. Postmortem examination revealed atrophy, gliosis, and neuronal loss in the external segment of the globus pallidus, subthalamic nucleus, red nucleus, and in the dentate nucleus. In addition, the gracil and cuneiform nuclei showed neuronal loss and spheroid formation; the spinocerebellar tracts were retained. The substantia nigra and the locus coeruleus were intact. No ragged-red fibers were seen in the muscle biopsy specimen taken in February, 1993. The neuropathologic findings were consistent with the diagnosis of dentatorubral-pallidoluysian atrophy.
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PMID:[(Neurological CPC.55). A 60-year-old woman with progressive cerebellar ataxia, myoclonus, and dementia]. 923 57

CAG repeat expansions have been identified as the disease-causing dynamic mutations in the coding regions of genes in several dominantly inherited neurodegenerative disorders, including spinobulbar muscular atrophy, Huntington's disease, dentatorubral-pallidoluysian atrophy, spinocerebellar ataxia type 1, 2 and 6 and Machado-Joseph disease. The CAG repeat expansions are translated to elongated polyglutamine tracts and an increased size of the polyglutamine tract correlates with anticipation, the cardinal feature, seen in all these diseases. Autosomal dominant pure spastic peraplegia (ADPSP) is a degenerative disorder of the central motor system clinically characterized by slowly progressive and unremitting spasticity of the legs, hyperreflexia and Babinski's sign. Like the established CAG repeat diseases ADPSP is characterized by both inter- and intrafamilial variation and anticipation. Using the Repeat Expansion Detection (RED) method, we have analyzed 21 affected individuals from six Danish families with the disease linked to chromosome 2p21-p24. We found that 20 of 21 affected individuals showed CAG repeat expansions versus two of 21 healthy spouses, demonstrating a strongly statistically significant association between the occurrence of the repeat expansion and the disease (Fisher's test, P < 10(-5)) suggesting that a CAG repeat expansion is involved presumably as a dynamic mutation in ADPSP linked to chromosome 2p21-p24. The size of the expansion is estimated to be > or = 60 CAG repeat copies in the affected individuals. The CAG repeat expansion is very likely translated and expressed as indicated by the detection of a polyglutamine-containing protein in an ADPSP patient.
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PMID:CAG repeat expansion in autosomal dominant pure spastic paraplegia linked to chromosome 2p21-p24. 930 57

The human genome has many nucleotide repeat sequences. These range from a single repeating base to entire duplicated genes. Expansion of repeating triplets of nucleotides in the genome has recently been associated with nine degenerative and developmental neuropsychiatric diseases: fragile X syndrome, fragile X-linked mental retardation, myotonic dystrophy, Friedreich's ataxia, spinal and bulbar muscular atrophy, Huntington's disease, spinocerebellar ataxia type 1, dentatorubral-pallidoluysian atrophy, and Machado-Joseph disease. These diseases are all conditions of the central nervous system; in all of them, the inheritance pattern usually exhibits the phenomenon of anticipation (defined as progressively earlier age of onset or a worsening disease severity over successive generations), and the severity of the phenotypic expression and penetrance appears to be related to the extent of the triplet expansion. Identification of this pathological genetic phenomenon solves several of the mysteries that surrounded these conditions but raises many important questions regarding pathogenic mechanisms that may be shared. There is some indication that triplet expansions may also underlie other neuropsychiatric conditions such as schizophrenia or bipolar disorder.
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PMID:Triplet repeat gene sequences in neuropsychiatric diseases. 938 23


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