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)

Autosomal dominant cerebellar ataxia type I is the most common form of dominant ataxia. A genetic heterogeneity has been identified with five different loci (SCA1, 2, 3, 4, and 6). A pathological expansion of a CAG sequence has been identified in SCA1, 2, 3, and 6. We performed molecular analysis in 51 families with autosomal dominant cerebellar ataxia type I, mainly originating from southern Italy and Sicily. Thirty families carry an expanded CAG sequence within SCA2 gene. The mean number of repeats was 39.9 +/- 3.3 in 85 expanded alleles, with a range of 34-52. The number of triplets was inversely correlated with age at onset and explained 76% of the variance. The best fit was obtained with an exponential relationship between variables. Expanded alleles were unstable when transmitted from parents to offspring. Expansions were more common than contractions, accounting for 59% of the total meioses and for 80% of the father-child transmissions. The mean intergenerational variation was 1.9 repeats (range -3 to +15) with higher values for male transmissions. Bulbar and autonomic signs were related to disease duration, pyramidal signs to CAG size, cerebellar features and peripheral neuropathy to both. Among the remaining 21 families, three carried the SCA1 and one the SCA6 mutation. This study suggests that SCA2 is the prevalent mutation in southern Italy.
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PMID:Spinocerebellar ataxia type 2 in southern Italy: a clinical and molecular study of 30 families. 1043 73

Different aspects of expanded polyglutamine tracts and of their pathogenetic role are taken into consideration here. (i) The (CAG)n length of wild-type alleles of the Huntington disease gene was analysed in instability-prone tumour tissue from colon cancer patients to test whether the process leading to the elongation of alleles towards the expansion range involves single-unit stepwise mutations or larger jumps. The analysis showed that length changes of a single unit had a relatively low frequency. (ii) The observation of an expanded spinocerebellar ataxia (SCA)1 allele with an unusual pattern of multiple CAT interruptions showed that cryptic sequence variations are critical not only for sequence length stability but also for the expression of the disease phenotype. (iii) Small expansions of the (CAG)n sequence at the CACNA1A gene have been reported as causing SCA6. The analysis of families with SCA6 and episodic ataxia type 2 showed that these phenotypes are, in fact, expressions of the same disorder caused either by point mutations or by small (CAG)n expansions. A gain of function has been hypothesized for all proteins containing an expanded polyglutamine stretch, including the alpha 1A subunit of the voltage-gated calcium channel type P/Q coded by the CACNA1A gene. Because point mutations at the same gene with similar phenotypic consequences are highly unlikely to have this effect, an alternative common pathogenetic mechanism for all these mutations, including small expansions, can be hypothesized.
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PMID:CAG repeat instability, cryptic sequence variation and pathogeneticity: evidence from different loci. 1043 11

Autosomal dominant cerebellar ataxias (ADCA) are a clinically heterogeneous group of neurodegenerative disorders caused by unstable CAG repeat expansions encoding polyglutamine tracts. Five spinocerebellar ataxia genes (SCA1, SCA2, SCA3, SCA6 and SCA7) and another related dominant ataxia gene (DRPLA) have been cloned, allowing the genetic classification of these disorders. We present here the molecular analysis of 87 unrelated familial and 60 sporadic Spanish cases of spinocerebellar ataxia. For ADCA cases 15% were SCA2, 15% SCA3, 6% SCA1, 3% SCA7, 1% SCA6 and 1% DRPLA, an extremely rare mutation in Caucasoid populations. About 58% of ADCA cases remained genetically unclassified. All the SCA1 cases belong to the same geographical area and share a common haplotype for the SCA1 mutation. The expanded alleles ranged from 41 to 59 repeats for SCA1, 35 to 46 [corrected] for SCA2, 67 to 77 for SCA3, and 38 to 113 for SCA7. One SCA6 case had 25 repeats and one DRPLA case had 63 repeats. The highest CAG repeat variation in meiotic transmission of expanded alleles was detected in SCA7, this being of +67 units in one paternal transmission and giving rise to a 113 CAG repeat allele in a patient who died at 3 years of age. Meiotic transmissions have also shown a tendency to more frequent paternal transmission of expanded alleles in SCA1 and maternal in SCA7. All SCA1 and SCA2 expanded alleles analyzed consisted of pure CAG repeats, whereas normal alleles were interrupted by 1-2 CAT trinucleotides in SCA1, except for three alleles of 6, 14 and 21 CAG repeats, and by 1-3 CAA trinucleotides in SCA2. No SCA or DRPLA mutations were detected in the 60 sporadic cases of spinocerebellar ataxia, but one late onset patient was identified as a recessive form due to GAA-repeat expansions in the Friedreich's ataxia gene.
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PMID:Spinocerebellar ataxias in Spanish patients: genetic analysis of familial and sporadic cases. The Ataxia Study Group. 1045 42

We estimated the relative contributions of known ataxia genes (SCA1, 2, 3, 6, 7 and X25) in the patient population sent to our DNA diagnostic laboratory for diagnostic testing. Approximately 28% of these patients had an abnormal triplet repeat expansion in one of these ataxia genes (3% for SCA1, 8% for SCA2, 11% for SCA3/MJD, 2% for SCA6, 3% for SCA7, and 1.5% for X25). The lack of abnormal repeat expansions in the majority of ataxis patients tested suggests that the molecular defects associated with most ataxia cases are currently undetermined and that this population includes both familial and sporadic cases. In contrast, of the patients submitted for genetic testing for Friedrich's ataxia (FRDA), 44% (69/157) showed at least one expansion in the X25 gene, indicating that FRDA accounts for a significant proportion of the recessively inherited ataxias and appears to have a high rate of accurate clinical diagnosis. On the basis of our DNA studies, we propose a comprehensive and efficient approach for molecular analysis of ataxia patients.
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PMID:Estimated contribution of known ataxia genes in ataxia patients undergoing DNA testing. 1046 57

Inherited, autosomal-dominant cerebellar ataxia (ADCA) comprises a genetically and clinically heterogenous group of neurodegenerative disorders. Clinical classification of these disorders was an important step [2] in differentiation among several types, the most common one being ADCA-I, accompanied with supranuclear ophthalmoplegia, optic nerve atrophy, symptoms of the basal ganglia lesions, dementia and amyotrophia. Molecular-genetic studies indicated genetic heterogeneity of ADCA-I with mutations of genetic loci on chromosome 6p (spinocerebellar ataxia type 1; SCA1), 12q (SCA2), 14q (SCA3), 19p (SCA6) and 16q (SCA4) [3]. Spinocerebellar ataxia type 1 (SCA1) is characterized by cerebellar ataxia, ophthalmoplegia and pyramidal signs [4], but also with other neurological findings that tend to prevent clinical differentiation among patients with SCA1, SCA2 and SCA3. The mutation inducing SCA1 is an instable expansion of trinucleotide (CAG) repeats in the coding region on chromosome 6 [5]. Herein, we report clinical features in patients from two families with SCA1: family I with 15 and family II with 8 affected members in 4 consecutive generations. The acceptable data (history, examination and/or insight into medical records) were obtained for 9 patients in family I and 7 patients in family II. The age at the onset of the disease was 37.8 +/- 11.3 years (mean value +/- SD) (range: 27-60) for all the patients, or 31.8 +/- 10.7 years (range: 7-60) for family I and 45.0 +/- 8.4 years (range: 35-55) for family II. Duration of the disease was 8.9 +/- 4.6 years (range: 3-15); 10.8 +/- 4.1 (range 5-15) and 5.7 +/- 3.8 years (range: 3-10) for families I and II, respectively. The mean number of CAG repeats in the mutated allele for SCA1 of the affected individuals was 50.5 +/- 6.2 (range 45-64). A significant inverse correlation (p < 0.05) was noted between the number of CAG repeats and the age at the onset of the disease (Figure 3). Similarity of initial symptoms in SCA1 was noted. They include simultaneous gait-related problems and dysarthria (usually slurred speech). Occurrence of other neurological signs (Table 3) was also predictable in most cases and depended on the phase of SCA1 at the time of examination. Generally, it is believed that intra- and interfamilial phenotypic heterogeneity in SCA1 is lower than in SCA2 and SCA3 [12]). In conclusion, typical clinical manifestations of SCA1, at least in early phases of the disease, according to our study, include gait ataxia, dysarthria, brisk muscle reflexes and marked hand ataxia; the age at the onset of the disease was inverse, and clinical progression was directly related to the number of CAG repeats in the mutated allele on chromosome 6. Nevertheless, significant differences in clinical properties of this inherited disease are possible among different affected families.
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PMID:[Clinico-genetic study of type I spinocerebelllar ataxia]. 1050 Apr 22

The autosomal dominant spinocerebellar ataxias (SCA) are a heterogeneous group of degenerative diseases presenting with ataxic gait, limbs ataxia, dysarthria and cerebellar oculomotor disturbances. Usually, cerebellar signs are associated with pyramidal signs, extra-pyramidal signs, spinal signs and signs of peripheral neuropathy. Neuropathological studies have disclosed an involvement of the cerebellum and its afferent/efferent pathways, of the brainstem and of the spinal cord. Distinct entities are now recognized: SCA1, SCA2, SCA3/Machado-Joseph disease, SCA4, SCA5,SCA6, SCA7 and dentatorubropillidoluysian atrophy (DRPLA). In most cases, a CAG trinucleotide repeat expansion has been demonstrated by genetic investigations. Moreover, recent studies have shown that autosomal dominant spinocerebellar ataxias are characterized by intra-nuclear inclusions containing polyglutamine in affected cells. These complexes might pl ay a determinant role in the neurodegenerative process. Cell death could be due to accumulation of a polyglutamine as a result of trinucleotide repeats.
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PMID:[Autosomal dominant spinocerebellar ataxia]. 1067 73

The autosomal dominant spinocerebellar ataxias (SCAs) are a group of late-onset, neurodegenerative disorders for which 10 loci have been mapped (SCA1, SCA2, SCA4-SCA8, SCA10, MJD, and DRPLA). The mutant proteins have shown an expanded polyglutamine tract in SCA1, SCA2, MJD/SCA3, SCA6, SCA7, and DRPLA; a glycine-to-arginine substitution was found in SCA6 as well. Recently, an untranslated (CTG)n expansion on chromosome 13q was described as being the cause of SCA8. We have now (1) assessed the repeat size in a group of patients with ataxia and a large number of controls, (2) examined the intergenerational transmission of the repeat, and (3) estimated the instability of repeat size in the sperm of one patient and two healthy controls. Normal SCA8 chromosomes showed an apparently trimodal distribution, with classes of small (15-21 CTGs), intermediate (22-37 CTGs), and large (40-91 CTGs) alleles; large alleles accounted for only0.7% of all normal-size alleles. No expanded alleles (>/=100 CTGs) were found in controls. Expansion of the CTG tract was found in five families with ataxia; expanded alleles (all paternally transmitted) were characterized mostly by repeat-size contraction. There was a high germinal instability of both expanded and normal alleles: in one patient, the expanded allele (152 CTGs) had mostly contraction in size (often into the normal range); in the sperm of two normal controls, contractions were also more frequent, but occasional expansions into the upper limit of the normal size range were also seen. In conclusion, our results show (1) no overlapping between control (15-91) and pathogenic (100-152) alleles and (2) a high instability in spermatogenesis (both for expanded and normal alleles), suggesting a high mutational rate at the SCA8 locus.
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PMID:High germinal instability of the (CTG)n at the SCA8 locus of both expanded and normal alleles. 1071 99

Approximately 44% of cases of spinocerebellar ataxia (SCA) in Hokkaido, the northernmost island of Japan, were estimated to be inherited. To determine the prevalence of triplet repeat expansion in hereditary SCA patients, we genotyped seven genetically defined dominant SCAs in 349 patients, including 266 patients from 77 families, 78 probands from unrelated families with hereditary late-onset SCA, and five patients in whom a family history of SCA was not demonstrated. The frequency of each disorder in a total of 155 unrelated families was 23.9% for Machado-Joseph disease (MJD), 29.0% for SCA6, 9.7% for SCA1, 7.7% for SCA2, and 2.6% for dentatorubral-pallidoluysian atrophy. Abnormal expansion of triplet repeats for SCA7 and SCA8 was not detected. A total of 27.1% of the patients had still unknown SCA mutations. In addition, the GAA repeat in the frataxin gene was not abnormally expanded in 13 early-onset SCA patients with clinical features similar to those of Friedreich ataxia. Comparison of our results with those from other centers handling SCA showed that MJD is prevalent throughout Japan, but the frequencies of other dominant SCAs differ considerably even within Japan.
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PMID:Prevalence of triplet repeat expansion in ataxia patients from Hokkaido, the northernmost island of Japan. 1078 56

Two hundred and forty-eight patients from 116 Italian families with dominant ataxia were studied for CAG expansion within SCA1, 2, 3, 6, 7 (spinocerebellar ataxia) and DRPLA (dentatorubropallidoluysian atrophy) genes. Fifty-six percent of the families originated from Southern, 19% from Central and 25% from Northern Italy. SCA2 was the commonest mutation, accounting for 47% of the families, followed by SCA1 (24%), SCA6 (2%), SCA7 (2%) and DRPLA (1%). No SCA3 family was found. Twenty-four percent of the families carried a still unidentified mutation. When occurrence of mutations was evaluated according to the geographic origin, SCA1 was the commonest in Northern (72%), whereas SCA2 was prevalent (63%) in Southern Italy. The number of CAG repeats in SCA1 normal alleles was higher in Northern than in Central-Southern Italy.
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PMID:Relative frequencies of CAG expansions in spinocerebellar ataxia and dentatorubropallidoluysian atrophy in 116 Italian families. 1089 92

Autosomal-dominant cerebellar ataxias (ADCA) may present as progressive or paroxysmal disorders. While the progressive ataxias have been named spinocerebellar ataxias (SCA), the paroxysmal disorders are designated episodic ataxias (EA). Until now, three different mutational mechanisms resulting in distinctive pathogenesis have been identified. The first type of mutation present in SCA1, SCA2, SCA3, and SCA7 is an expanded CAG repeat in genes of unknown function that are translated into proteins with expanded polyglutamine tracts. A common ultrastructural feature of these disorders is the formation of neuronal intranuclear inclusions (NII) harboring the expanded disease proteins and a variety of other proteins. The pathogenic role of these inclusions has yet to be clarified. A second group of disorders is the result of mutations in genes that code for ion channels. In EA-1, a disorder characterized by episodes of ataxia provoked by movement and startle, missense mutations in a potassium channel gene, KCNA1, have been found. Patients with EA-2, another form of paroxysmal ataxia, carry nonsense mutations of the gene encoding the alpha1A voltage-dependent calcium channel subunit, CACNA1A, that are predicted to result in truncated channel proteins. In SCA6, a progressive ataxia, an expanded CAG repeat in the 3' translated region of the CACNA1A gene, has been found. The third type of mutation is an untranslated CTG expansion resembling the mutation found in myotonic dystrophy. It is associated with a progressive ataxia, SCA8.
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PMID:The molecular biology of the autosomal-dominant cerebellar ataxias. 1092 70


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