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

Genetic anticipation--increasing severity and a decrease in the age of onset with successive generations of a pedigree--is clearly present in autosomal dominant cerebellar ataxia (ADCA). Anticipation is correlated with expansion of the CAG/CTG repeat sequence to sizes above those in the normal range through the generations of a pedigree. Genetic heterogeneity has been demonstrated for ADCA, with four cloned genes (SCA1, SCA2, SCA3/MJD, and SCA6) and three mapped loci (SCA4, SCA5 and SCA7). Another related dominant ataxia, dentatorubral-pallidoluysian atrophy (DRPLA), presents anticipation with CAG/CTG repeat expansions. We had previously analysed ADCA patients who had not shown repeat expansions in cloned genes for CAG/CTG repeat expansions by the repeat expansion detection method (RED) and had detected expansions of between 48 and 88 units in 17 unrelated familial cases. We present here an analysis of 13 genes and expressed sequence tags (ESTs) containing 10 or more CAG/CTG repeat sequences selected from public databases in the 17 unrelated ADCA patients. Of the 13 selected genes and ESTs, 9 were found to be polymorphic with heterozygosities ranging between 0.09 and 0.80 and 2 to 17 alleles. In ADCA patients none of the loci showed expansions above the normal range of the CAG/CTG repeat sequences, excluding them as the mutation causing ADCA.
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PMID:Polymorphisms at 13 expressed human sequences containing CAG/CTG repeats and analysis in autosomal dominant cerebellar ataxia (ADCA) patients. 938 62

Autosomal dominant spinocerebellar ataxias (SCAs) are clinically and genetically a heterogeneous group of neurodegenerative disorders. Recently, mild CAG repeat expansion in the alpha1A voltage-dependent calcium channel gene has been found to be associated with a type of autosomal dominant SCA (SCA6). We analyzed 98 Japanese families with autosomal dominant SCAs, for whom CAG repeat expansions of the SCA1, SCA2, Machado-Joseph disease/SCA3, and dentatorubral-pallidoluysian atrophy genes were excluded, and 5 apparently sporadic cases of cortical cerebellar atrophy. The diagnosis of SCA6 was confirmed in 30 families (31%) comprising 47 affected individuals and 1 sporadic case. The size of expanded CAG repeats ranged from 21 to 26 repeat units and was found to be correlated inversely with age at onset. We identified 2 SCA6 patients homozygous for expanded CAG repeats, whose ages at onset were earlier than the 95% lower confidence level, suggesting the presence of a gene dosage effect of expanded CAG repeat. Ataxia is the most common initial symptom found in 45 of the 48 patients. Patients with a prolonged disease course showed other accompanying clinical features including dystonic postures, involuntary movements, and abnormalities in tendon reflexes.
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PMID:Spinocerebellar ataxia type 6: CAG repeat expansion in alpha1A voltage-dependent calcium channel gene and clinical variations in Japanese population. 940 80

In some neurodegenerative diseases, genetic anticipation correlates with expansions of the CAG/CTG repeat sequence above the normal range through the generations of a pedigree. Among these neurodegenerative diseases are late onset autosomal dominant cerebellar ataxias (ADCA). ADCA are genetically heterogeneous disorders with different cloned genes for spinocerebellar ataxia type 1 (SCA1), type 2 (SCA2), type 3 or Machado-Joseph disease (SCA3/MJD), and type 6 (SCA6). Another related dominant ataxia, dentatorubral-pallidoluysian atrophy (DRPLA), also shows CAG/CTG repeat expansions. Genetic anticipation has been reported for all of them except for the recently cloned SCA6 gene. Other, as yet undetected SCA genes may show the same features. We have used the repeat expansion detection (RED) method to detect repeat expansions directly in DNA samples from ADCA patients not resulting from known genes. Our sample consists of 19 affected index cases, corresponding to 52.8% of our ADCA families without CAG/CTG repeat expansions in the SCA1, SCA2, SCA3/MJD, SCA6, or DRPLA genes. Eighty-nine percent of the index cases had expansions of a CAG/CTG sequence greater than 40 repeats by RED, while these were observed in only 26.9% of 78 healthy subjects from the general population (p < 0.0001). The distribution of RED fragments in controls and ADCA patients also shows significant differences with the Mann-Whitney U test (U = 376.5, p = 0.0007). Moreover, there was a significant inverse correlation between the size of expansion and the age of onset (r = -0.54, p = 0.018). These results show CAG/CTG repeat expansions of over 40 repeats in our sample of ADCA families not resulting from known SCA genes.
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PMID:Uncloned expanded CAG/CTG repeat sequences in autosomal dominant cerebellar ataxia (ADCA) detected by the repeat expansion detection (RED) method. 950 87

We studied the frequency and characteristics of brainstem and thalamic lesions in dentatorubral-pallidoluysian atrophy using MRI. Of 15 subjects diagnosed by DNA analysis, 13 had lesions in the pontine base, nine in the midbrain, and five in the thalamus. Lesions were correlated positively with the patient's age, but not with neurologic features or numbers of CAG repeats. Patients with Machado-Joseph disease or spinocerebellar ataxia 1 did not show these characteristic lesions.
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PMID:The brainstem and thalamic lesions in dentatorubral-pallidoluysian atrophy: an MRI study. 963 53

CAG repeat expansions cause spinocerebellar ataxia type 1 (SCA1), SCA2, SCA3, SCA6 and dentatorubral-pallidoluysian atrophy (DRPLA). So far these expansions have been examined mainly in ataxia patients with a family history. However, some sporadic cases with SCA have recently been reported. To elucidate the frequency and characteristics of sporadic SCAs, we screened 85 Japanese ataxia patients without a family history for the SCA1, SCA2, SCA3, SCA6 and DRPLA mutations. As a result, 19 patients (22%) were found to have expanded CAG repeats. Among sporadic SCAs, the SCA6 mutation was most frequently observed. The sporadic SCA6 patients had smaller CAG repeats and a later age of onset than SCA6 patients with an established family history. We also identified one father-child pair in which intermediate sized CAG repeats expanded into the SCA2 disease range during transmission. These findings suggest that patients with ataxia even without a family history should be examined for a CAG repeat expansion.
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PMID:CAG repeat expansions in patients with sporadic cerebellar ataxia. 969 28

Autosomal dominant hereditary spastic paraplegia (HSP) is genetically classified into three types, all of which are characterized by insidiously progressive spasticity of the lower extremities. Patients with a complicated form of autosomal recessive HSP associated with hypoplasia of the corpus callosum have been reported by Iwabuchi et al. Here we report a 64-year-old patient with a pure form of autosomal dominant HSP with thinning of the corpus callosum. He had been well until 12 years of age, when spasticity and weakness of the lower extremities began to develop. His symptoms gradually worsened and he had difficulty in walking at the age of 44. When he was 56 years old, he visited our hospital. Eleven family members over five generations have been affected, and anticipation, i.e., an apparent decrease in age of onset, has been observed. On admission, he had mild cataracts, equinovarus and pes cavus, and neurological examination revealed spastic paraplegia. However, the intelligence test was normal, and nystagmus, ataxia of the extremities, involuntary movement, orthostatic hypotension or urinary disturbance was not observed. Trinucleotide repeat diseases, such as Huntington's disease, spinocerebellar ataxia type 1, spinocerebellar ataxia type 2, Machado-Joseph disease and dentatorubral-pallidoluysian atrophy, were excluded by DNA analysis. Brain MRI at the age of 64 revealed marked thinning of the corpus callosum. We considered this patient had a pure form of HSP. However, thinning of the corpus callosum has never been reported in autosomal dominant HSP.
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PMID:[A case of autosomal dominant, pure form spastic paraplegia with thinning of the corpus callosum]. 980 90

To date, eight neurodegenerative diseases, including Huntington's disease, dentatorubral-pallidoluysian atrophy, spinal and bulbar muscular atrophy, and spinocerebellar ataxia (SCA) types 1, 2, 3, 6, and 7, have been proven to be caused by an expanded trinucleotide repeat (CAG)n located within a specific gene for each of these diseases. Except in SCA 6, the CAG repeat is present in approximately 7 to 35 copies in the normal population, whereas patients have CAG expansions of 40 to approximately 75 repeats. Sizing of the repeat length enables molecular diagnosis in affected patients and presymptomatic persons carrying a mutated allele. A molecular protocol for the diagnosis of these diseases was developed based on polymerase chain reaction, denaturing polyacrylamide gel electrophoresis and staining with silver nitrate, and adapted to each disease. This simple and rapid method gives a sensitivity of detection equal to current procedures but avoids isotopic manipulations. Therefore, shorter turnaround time, decreased cost per sample, and simplified screening of these neurodegenerative diseases by PCR-based assays may be attainable using this protocol.
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PMID:Simple nonisotopic assays for detection of (CAG)n repeats expansions associated with seven neurodegenerative disorders. 983 74

A 44-year-old Japanese man was diagnosed as having late adult-onset dentatorubral-pallidoluysian atrophy (DRPLA), whose CAG repeats in the DRPLA gene were 60 and 15. He developed gait disturbance, limb ataxia, pyramidal tract signs, dementia, and psychiatric symptoms including character changes within a few years of the above diagnosis. His T 2-weighted brain MRI showed symmetric high-signal lesions in the cerebral white matter and brain stem, in addition to cerebellar, brain stem, and cerebral cortical atrophy. Since the results of RI cisternography indicated that he manifested the clinical features of normal pressure hydrocephalus (NPH), V-P shunt operation was done. In a week after the operation, his gait disturbance, pyramidal tract signs, dementia and psychiatric symptoms were remarkably improved. White matter lesions have been thought to be concomitant with late adult-onset DRPLA patients, but some of these patients may have characteristics of NPH pathophysiology.
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PMID:[A case of late adult-onset dentatorubral-pallidoluysian atrophy (DRPLA) successfully treated with V-P shunt operation]. 984 69

The discovery of unstable DNA sequences as the cause of genetic disease is a fascinating new area in human genetics, raising a number of important questions addressing the understanding of both the mechanisms and the effects of this new type of mutation. Trinucleotide repeat expansion mutations have been identified in a number of neurodegenerative diseases, including spinal and bulbar muscular atrophy (SBMA), fragile X syndrome (FRAXA and FRAXE), myotonic dystrophy (DM), Huntington's disease (HD), spinocerebellar ataxia types 1, 2, 3, 6, 7 (SCA1, SCA2, SCA3, SCA6, SCA7), dentatorubral-pallidoluysian atrophy (DRPLA), Friedreich's ataxia (FRDA) and autosomal dominant pure spastic paraplegia (ADPSP). They have been traced to genetic variation in the length of (CTG)n/(CAG)n, (CGG)n/(CCG)n, or (GAA)n/(TTC)n triplet repeats in DNA. In normal individuals these loci contain a short length of triplet repeats (usually 5-40), which is polymorphic within the population. Increases in the lengths of the translated triplet repeats to 40-100 are associated with disease symptoms, whereas the untranslated triplet repeats to 200-3000 are associated with the disease. We concentrated on repeat expansions in myotonic dystrophy. In this symposium, we outline the molecular aspects of myotonic dystrophy including DNA diagnosis and anticipation, and review the similarities and differences among these triplet repeat diseases.
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PMID:[Genomic instability and neurodegenerative disease]. 1006 64

Segregation ratio distortion (SRD) with preferential transmission of expanded CAG alleles has been reported in Machado-Joseph disease (MJD/SCA3), spinocerebellar ataxia type I (SCA1), and dentatorubral-pallidoluysian atrophy (DRPLA). We have examined the transmission frequencies of alleles in normal heterozygotes at these disease loci in 377 pairs of twins and their parents and find no evidence for SRD.
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PMID:Mendelian segregation of normal CAG trinucleotide repeat alleles at three autosomal loci. 1020 58


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