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)

To study gene loci and disease phenotypes, 18 families with dominant OPCA were subjected for linkage analysis to SCA1- or SCA2-linked microsatellites. Total individuals consisted of 190. Among them, 77 were affected. Consequently, 10 families were 6p-linked, 7 were 12q-linked, and one was type-undetermined. These results indicate that the majority of dominant OPCA in Japan are composed with these two genotypes. Clinically, these two disorders show progressive ataxia, Babinski reflexes, and terminal amyotrophy. Other common features in SCA1 were hyperreflexia, spasticity, mild nystagmus at early stage, slow saccade, and external ophthalmoparesis (EOP) at advanced stage. In contrast SCA2 showed progressive hyporeflexia and slow saccade from early stage. Moreover, choreiform movement, tremor, and rhythmic myoclonus were more frequent in the latter. Neuropathologically, dentate nucleus, brainstem motor nuclei, spinocerebellar tract were involved more severely in SCA1 than SCA2. Degeneration of substantia nigra is more marked in SCA2 than SCA1. These observations strongly indicate that there are correlations between genotypes and phenotypes in dominant OPCAs. Conversely, it is possible to diagnose these two genetic disorders from the clinico-pathological findings.
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PMID:[Linkage study of hereditary spinocerebellar ataxia, and probable correlation for the loci to the disease phenotypes]. 817 26

The autosomal dominant cerebellar ataxias (ADCA) are a group of neurodegenerative disorders characterized by onset with gait ataxia, dysarthria, dysmetria and dysdiadochokinesia. We have demonstrated previously genetic heterogeneity within these disorders by excluding the disease locus from the documented spinocerebellar ataxia locus (SCA1) on chromosome 6p in a large Cuban founder population. We now report the assignment of a second locus for ADCA (SCA2) to chromosome 12q23-24.1 following linkage analyses carried out for the Cuban pedigrees, with probable flanking markers D12S58 and phospholipase A2. Investigation of linkage to the interval containing SCA2 for seven French ADCA families, previously excluded from linkage to SCA1, provides preliminary data suggesting the existence of a third ADCA locus (SCA3).
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PMID:Chromosomal assignment of the second locus for autosomal dominant cerebellar ataxia (SCA2) to chromosome 12q23-24.1. 835 38

Hereditary spinocerebellar degeneration consist of a cluster of heterogenous disorders. Based on clinical features, neuropathological findings and inheritance mode, these disorders have been classified into several entities. In the Japanese, olivo-ponto-cerebellar atrophy (OPCA), Machado-Joseph disease (MJD) and dominant cortical cerebellar atrophy (CCA) are the most popular forms of ataxia. Recent linkage analyses have revealed the locations of these genes; OPCA maps either on 6p23 (SCA1) or on 12q23 (SCA2), and MJD on 14q. The chromosomal assignment of these genes has resulted in development of a new classification of ataxia and has opened a new era of ataxia research.
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PMID:[Recent progress of research on hereditary spinocerebellar degeneration]. 841 30

Eight human genetic diseases have been associated with the expansion of CTG or CGG triplet repeats. The molecular etiology behind expansion is unknown but may involve participation of an unusual DNA structure in replication, repair, or recombination. We show that DNA fragments containing CTG triplet repeats derived from the human myotonic dystrophy gene migrate up to 20% faster than expected in nondenaturing polyacrylamide gels, suggesting the presence of an unusual DNA helix structure within the CTG triplet repeats. The anomalous migration is dependent upon the number of triplet repeats, the length of the flanking DNA, and the percentage and temperature of the polyacrylamide. The effect could be reduced by the addition of actinomycin D. Applying a reptation model for electrophoresis, the results are consistent with a 20% increase in persistence length of the DNA. PCR products containing CTG or CGG repeats from the spinocerebellar ataxia type I gene (SCA1) or the fragile X FMR1 gene, respectively, also showed higher electrophoretic mobility. These are the first sequences of defined length for which a dramatic increase in mobility can be attributed to sequence-dependent structural elements in DNA.
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PMID:Anomalous rapid electrophoretic mobility of DNA containing triplet repeats associated with human disease genes. 851 69

Patients with spinocerebellar ataxia 3 (SCA3) and Machado-Joseph disease (MJD) carry an expanded CAG repeat in the MJD1 gene. One hundred twenty families of different geographic origin with autosomal dominant cerebellar ataxia (ADCA) type I were tested. Thirty-four families (126 patients) carried an expanded CAG repeat. The expanded and the normal allele did not overlap and the repeat was unstable during transmission, with variation in the size of the CAG length ranging from -8 to +5 and a mean expansion of 0.86 repeats without differences according to the parental sex. There was a combined effect of the number of CAG repeats of the expanded and normal allele on the age at onset, which accounted for 70% of its variability. The length of the CAG repeat influenced the frequency of clinical signs associated with cerebellar ataxia, such as abnormal tendon reflexes or decreased vibration sense, whereas the interindividual variation of supranuclear ophthalmoplegia, sphincter and swallowing difficulties, and amyotrophy was mostly determined by different disease durations. We compared the clinical profile of 91 SCA3/MJD patients with 51 SCA1 and 32 SCA2 patients. There were striking differences between the SCA3/MJD and SCA2 but not with SCA1 groups of patients. Despite their clinical similarities, distinct neuropathological features were observed in 2 SCA3/MJD and 2 SCA1 patients.
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PMID:Spinocerebellar ataxia 3 and Machado-Joseph disease: clinical, molecular, and neuropathological features. 861 27

Hereditary cerebellar ataxias, including spinocerebellar ataxia type I (SCA1), dentato-rubro-pallidoluysian atrophy (DRPLA), and Machado-Joseph disease (MJD), have been associated with unstable CAG repeats. The length of the CAG repeat is a major factor in determining the age of onset of these diseases. In electrophoresis through acrylamide gels with formamide, the CAG repeat length following the polymerase chain reaction (PCR) coincides with the sequence-determined repeat length after subcloning. However, without formamide, PCR products with long CAG repeats appear 1-4 repeats shorter than when electrophoresed with formamide, and the repeat lengths are variable. In addition, the larger the CAG repeats are, the more difficult are the PCR reactions. A mixture containing thermostable Taq and Pwo DNA polymerases (so-called "long PCR") is much more sensitive than that with Taq polymerase alone in detecting- expanded CAG repeats. Therefore, highly denaturing conditions, especially formamide gel electrophoresis, and the "long PCR" protocol should be used to evaluate the exact CAG repeat length. We have used these principles to detect unstable CAG repeats. The normal ranges are 14-34 repeats for MJD, 6-31 repeats for DRPLA, and 21-32 repeats for SCA1.
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PMID:Reevaluation of the exact CAG repeat length in hereditary cerebellar ataxias using highly denaturing conditions and long PCR. 865 36

There are currently some types of autosomal dominant cerebellar ataxias such as Machado-Joseph disease (MJD), spinocerebellar ataxia types 1-5 (SCA1-5), or hereditary dentatorubropallidoluysian atrophy. It is very important for these ataxias to be clinically differentiated, but that is sometimes difficult. In particular, the differential diagnosis between MJD and SCA1 is thought to be the most difficult. Recently, both MJD and SCA1 have been proven to be related to expansions of CAG trinucleotide in their causative genes. In this study, 20 cases of MJD in 13 unrelated Japanese families were genetically and clinically examined in comparison with 20 cases of age at onset- and duration-matched Japanese SCA1. The CAG repeat number of expanded MJD and SCA1 alleles was 72.2 +/- 3.1 (mean +/- SD, n = 20) and 47.3 +/- 4.4 (n = 20), respectively, and each repeat size was inversely correlated with age at onset in both MJD and SCA1. The repeat number in leukocytes increased from parents to children with acceleration of age at onset (anticipation) in MJD. In MJD, the number of CAG repeats in the expanded allele was lower in sperm than that of leukocytes, but was more in SCA1. However, the number of peaks in the expanded allele was greater in sperm than in leukocytes in both MJD and SCA1 (increased mosaicism level). MJD was clinically characterized by a relatively higher frequency of ocular signs such as eyelid retraction, bulging eyes, ophthalmoparesis, and nystagmus, spasticity in lower limbs, and sensory and urinary disturbances in contrast to the SCA1 patients except for slow eye movement. These results indicate that the expanded CAG repeat and clinical features are correlated in both MJD and SCA1, and MJD can be differentiated from SCA1 by clinical characteristics mentioned above as well as DNA analysis.
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PMID:Analysis of CAG trinucleotide expansion associated with Machado-Joseph disease. 881 56

SCA1 is a dominant spinocerebellar ataxia (SCA) and a multi-systemic syndrome caused by abnormal expansion of unstable CAG repeat in a novel gene located on chromosome 6p22-p23. We clinically studied 35 Japanese SCA1 patients who were assumed to have come from a common origin. The age at onset ranged from 15-63 years, and significantly correlated with CAG repeat units of mutant alleles. Ataxia was the initial symptom, and the majority of patients had a similar history of signs and symptoms. Nystagmus was at first minimal, later attenuated, and a slow saccade followed. Limb tendon reflexes were mostly hyperactive and depressed with the development of diffuse amyotrophy. The cardinal feature was ataxia-hyperreflexia-late slow saccade syndrome with terminal amyotrophy. Although the phenotype of SCA1 overlaps with those of other dominant SCAs, some facets of the neurological events differ from either SCA2 with ataxia-hyporeflexia-slow saccade syndrome, or early-onset Machado-Joseph disease with dystonia-bradykinesia-spasticity syndrome.
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PMID:Clinical features and natural history of spinocerebellar ataxia type 1. 882 76

Sixty-five patients suffering from autosomal dominant cerebellar ataxia-I(ADCA-1) were subjected genotype phenotype correlation analysis using molecular genetic assignment to the spinocerebellar ataxia type 1, 2 or 3 (SCA1, -2 or -3) locus, clinical examination, eye movement recording and morphometric analysis of MRIs. Pyramidal tract signs, pale discs and dysphagia were more frequent in SCA1 compared SCA2 and SCA3 patients. Saccade velocity was reduced in 56% of SCA1 and all SCA2, but only in 30% of SCA3 patients. MRIs of SCA2 patients showed atrophy changes typical of severe olivopontocerebellar atrophy (OPCA). The morphological changes in SCA1 were similar but less pronounced. In contrast, SCA3 patients had only mild cerebellar and brain stem atrophy distinct from typical OPCA. The principal finding of this study is that mutations of the SCA2 and SCA3 gene cause phenotypes which can be distinguished in vivo by recording of eye movements and morphometric MRI analysis. Correlative plotting of saccade velocity and diameter of the middle cerebellar peduncle yields a clear separation of SCA2 and SCA3. Spinocerebellar ataxia type I falls into an intermediate range that overlaps with both SCA2 and SCA3. However, the clinical syndrome observed in SCA1 patients is different from that in SCA2 and SCA3.
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PMID:Autosomal dominant cerebellar ataxia type I clinical features and MRI in families with SCA1, SCA2 and SCA3. 893 75

X-linked spinal and bulbar muscular atrophy (SBMA) occurs due to an expansion of the trinucleotide repeat (CAG)n in the androgen receptor gene. Anticipation is relatively rare in SBMA in contrast to spinocerebellar ataxia type 1 (SCAl), and dentatorubral and pallidoluysian atrophy (DRPLA) which show obvious paternal anticipation. The differences in the CAG repeat number were compared among sperm, leukocytes and skeletal muscles of SBMA patients. In SBMA, the sperm of most patients and the skeletal muscle of all patients showed the same repeat number as their leukocytes, whereas the increase in the repeat number from leukocytes to sperm was evident in SCA1 and DRPLA patients. The higher mosaicism level in sperm compared with leukocytes was common in SBMA, SCA1 and DRPLA, and the level of sperm was lower in SBMA than in SCA1 and DRPLA. Thus, spermatogenesis was suggested to be strongly associated with paternal anticipation. The mosaicism level was smaller in SBMA than in other (CAG)n expanded disorders, and smallest in the SBMA carrier females. These findings demonstrate that the CAG repeat in SBMA is relatively stable in mitotic and meiotic, processes, and there is a possibility that the lower mosaicism level of the carrier females compared with the SBMA patients is associated with X-linked recessive inheritance.
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PMID:Mitotic and meiotic stability of the CAG repeat in the X-linked spinal and bulbar muscular atrophy gene. 894 11


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