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)

Hereditary dentatorubral-pallidoluysian atrophy (DRPLA) is a rare autosomal-dominant neurodegenerative disease characterized by variable clinical phenotypes. Its characteristic clinical manifestations include ataxia, choreoathetotic movements, seizures, myoclonus and dementia, but cervical dystonia has been rarely reported. Here we report a family with DRPLA who presented with cervical dystonia. The proband was a 66-year-old woman. Cervical dystonia was the initial and the most prominent symptom, and mild cerebellar signs and choreic movements were also observed. DNA analysis revealed expanded trinucleotide repeats within the DRPLA gene. The daughter of the proband, a 29-year-old woman, also had cervical dystonia for 3 years. Cranial magnetic resonance imaging showed a mild atrophy of the brainstem and the cerebellum in both of these patients. DRPLA should be considered in the differential diagnosis of patients presenting with cervical dystonia.
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PMID:Cervical dystonia in dentatorubral-pallidoluysian atrophy. 1295 64

We report a three-generation Caucasian family of Macedonian origin with dentatorubral-pallidoluysian atrophy (DRPLA), manifesting as very mild elderly onset, severe young adult onset, and severe childhood onset presentations in the three generations. The grandparental trinucleotide expansion size (52 repeats) is the smallest overtly pathogenic mutation yet reported. This 67-year-old man displayed only subtle neurological and cognitive deficits on formal examination and very slight signs on MRI. His son had developed a choreiform disorder at age 32 years, and by his 40s suffered severe dementia and motor decline. The grandson, the proband, presented as a teenager with progressive myoclonic epilepsy, dysarthria, ataxia, and cognitive decline, having manifesting learning difficulties from the age 5 years. Atrophin-1 expansion sizes of 52, 57, and 66 repeats were demonstrated in the three patients, respectively. Given an absence of any other indicative history in the family, we speculate that the mutation may have expanded from a 'high-end' normal allele to a pathogenic size at the grandfather's conception, or that one of his parents may have had a pathogenic mutation at the lowest end of the expanded range.
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PMID:Dentatorubral-pallidoluysian atrophy in three generations, with clinical courses from nearly asymptomatic elderly to severe juvenile, in an Australian family of Macedonian descent. 1594 86

We describe a unique condition affecting two siblings with a form of progressive spinocerebellar ataxia. After a period of very slowly progressive ataxia, the patients developed an extremely accelerated progression of the condition which consisted of cerebellar ataxia, seizure, progressive dementia and spastic tetraparesis. Age of onset was variable at 7 to 18 years. Brain magnetic resonance image (MRI) showed marked atrophy of the cerebellum and cerebrum with strikingly preserved brainstem dimensions. Biochemical or molecular genetic analysis was performed in an elder sister and her parents to exclude known forms of familial spinocerebellar ataxia, dentatorubral-pallidoluysian atrophy (DRPLA), progressive myoclonic epilepsy, and some metabolic disorders which could have a similar phenotype. The mode of inheritance appears to be autosomal recessive. We think that the affected siblings may have a new type of autosomal recessive cerebellar ataxia.
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PMID:Unique cerebellar-cerebral form of autosomal recessive ataxia. 1608 59

Dentatorubral-pallidoluysian atrophy (DRPLA) is a progressive neurodegenerative disease caused by polyglutamine expansion within the Atrophin-1 protein. To study the mechanism of this disease and to test potential therapeutic methods, we established Atro-118Q transgenic mice, which express in neurons a mutant human Atrophin-1 protein that contains an expanded stretch of 118 glutamines. Consistent with the results from previous studies on transgenic mice that expressed mutant Atrophin-1 with 65 glutamines, Atro-118Q mice exhibited several neurodegenerative phenotypes that are commonly seen in DRPLA patients, including ataxia, tremors, and other motor defects. Overexpression of wild-type human Atrophin-1 could not rescue the motor and survival defects in Atro-118Q mice, indicating that the mutant protein with polyglutamine expansion does not simply function in a dominant negative manner. Biochemical analysis of Atro-118Q mice revealed hypoacetylation of histone H3 in brain tissues and thus suggested that global gene repression is an underlying mechanism for neurodegeneration in this mouse model. We further show that intraperitoneal administration of sodium butyrate, a histone deacetylase inhibitor, ameliorated the histone acetylation defects, significantly improved motor performance, and extended the average life span of Atro-118Q mice. These results support the hypothesis that transcription deregulation plays an important role in the pathogenesis of polyglutamine expansion diseases and suggest that reversion of transcription repression with small molecules such as sodium butyrate is a feasible approach to treating DRPLA symptoms.
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PMID:Sodium butyrate ameliorates histone hypoacetylation and neurodegenerative phenotypes in a mouse model for DRPLA. 1640 96

The molecular bases of autosomal dominant cerebellar ataxia (ADCA) have been increasingly elucidated, but 17-50% of ADCA families still remain genetically undefined in Japan. In this study we investigated 67 genetically undefined ADCA families from the Nagano prefecture, and found that 63 patients from 51 families possessed the -16C>T change in the puratrophin-1 gene, which was recently found to be pathogenic for 16q22-linked ADCA. Most patients shared a common haplotype around the puratrophin-1 gene. All patients with the -16C>T change had pure cerebellar ataxia with middle-aged or later onset. Only one patient in a large, -16C>T positive family did not have this change, but still shared a narrowed haplotype with, and was clinically indistinguishable from, the other affected family members. In Nagano, 16q22-linked ADCA appears to be much more prevalent than either SCA6 or dentatorubral-pallidoluysian atrophy (DRPLA), and may explain the high frequency of spinocerebellar ataxia.
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PMID:A -16C>T substitution in the 5' UTR of the puratrophin-1 gene is prevalent in autosomal dominant cerebellar ataxia in Nagano. 1661 95

Autosomal dominant spinocerebellar ataxias (AD-SCAs) form a clinically and genetically heterogeneous group of neurodegenerative disorders. Recently, a single nucleotide substitution in the 5'-untranslated region of the puratrophin-1 gene was found to be associated with one type of AD-SCA linked to chromosome 16q (16q-SCA). To obtain further insight into the contribution of the C-to-T substitution in the puratrophin-1 gene to the clinical and genetic characteristics of patients with 16q-SCA, we analyzed 686 families with 719 individuals diagnosed with progressive ataxia. We found C-to-T substitution in the puratrophin-1 gene in 57 unrelated families with 65 affected individuals. The mean age at onset in the patients with 16q-SCA was 59.1 (range, 46-77). Ataxia is the most common initial symptom. The elderly patients over 65 occasionally showed other accompanying clinical features including abnormalities in tendon reflexes, involuntary movements, and reduced vibration sense. We also examined the frequency of the AD-SCA subtype, considering the effects of age at onset. In the 686 AD-SCA families, SCA6 and Machado-Joseph disease/SCA3 are frequent subtypes, followed by dentatorubral-pallidoluysian atrophy and 16q-SCA. 16q-SCA is not a rare subtype of Japanese AD-SCA, particularly in patients with ages at onset over 60.
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PMID:Clinical and genetic characterizations of 16q-linked autosomal dominant spinocerebellar ataxia (AD-SCA) and frequency analysis of AD-SCA in the Japanese population. 1735 32

Polyglutamine diseases are hereditary neurodegenerative disorders caused by an abnormal expansion of a trinucleotide CAG repeat, which encodes a polyglutamine tract. To date, nine polyglutamine diseases are known: Huntington's disease (HD), spinal and bulbar muscular atrophy (SBMA), dentatorubral-pallidoluysian atrophy (DRPLA) and six forms of spinocerebellar ataxia (SCA). The diseases are inherited in an autosomal dominant fashion except for SBMA, which shows an X-linked pattern of inheritance. Although the causative gene varies with each disorder, polyglutamine diseases share salient genetic features as well as molecular pathogenesis. CAG repeat size correlates well with the age of onset in each disease, shows both somatic and germline instability, and has a strong tendency to further expand in successive generations. Aggregation of the mutant protein followed by the disruption of cellular functions, such as transcription and axonal transport, has been implicated in the etiology of neurodegeneration in polyglutamine diseases. Although animal studies have provided promising therapeutic strategies for polyglutamine diseases, it remains difficult to translate these disease-modifying therapies to the clinic. To optimize "proof of concept", the process for testing candidate therapies in humans, it is of importance to identify biomarkers which can be used as surrogate endpoints in clinical trials for polyglutamine diseases.
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PMID:Molecular genetics and biomarkers of polyglutamine diseases. 1847 21

Polyglutamine (polyQ) diseases are a group of hereditary neurodegenerative disorders caused by expansion of a glutamine repeat in responsible gene products. To date, the pathogenesis of polyQ diseases is still not very clear, but many researches suggest that phosphorylation of mutant proteins plays a critical role on the process of Huntington's disease, dentatorubral-pallidoluysian atrophy, spinal bulbar muscular atrophy, spinocerebellar ataxia1 and spinocerebellar ataxia 3/Machado-Joseph disease.
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PMID:[The advances in research on phosphorylation of polyglutamine disease]. 1868 39

It has been reported that patients with spinocerebellar degenerations (SCDs) have cognitive dysfunction as well as limb and truncal ataxia, dysarthria and dysphagia. We review cognitive dysfunction in common types of SCD, including spinocerebellar ataxia types 1, 2, 3, 6, and 17, dentatorubral-pallidoluysian atrophy, Friedreich's ataxia, and multiple system atrophy. There are few studies that address cognitive function in SCD. Although there are few comparison studies among the various SCDs, cognitive dysfunction may be more common and severe in spinocerebellar ataxia type 17 and dentatorubral-pallidoluysian atrophy. While cognitive dysfunction in SCD appears to represent frontal dysfunction, the mechanisms of cognitive dysfunction have not been directly clarified. Nevertheless, various lesions, including those in the cerebrocerebellar circuitry, cortico-striatal-thalamocortical circuitry, and the frontal lobe, may influence cognitive function to various degrees for each disease.
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PMID:Cognitive impairment in spinocerebellar degeneration. 1929 12

Repeat expansion has been implicated in 10 out of 17 candidate genes identified for autosomal dominant cerebellar ataxias (ADCAs)-commonly referred as spinocerebellar ataxias (SCAs). Though genetically distinct, the SCAs share a large number of features that confound their clinical classification. In addition, there is a difference in the prevalence and phenotypic expression of ataxias between different ethnic groups. We have created a new SCA-locus-specific variation database (LSVD) that aims to catalog and integrate information on SCAs associated with trinucleotide repeat expansion (SCA1, SCA 2, SCA 3, SCA 6, SCA 7, SCA 8, SCA 12, SCA 17, Friedreich's ataxia [FRDA], and dentatorubral-pallidoluysian atrophy [DRPLA]) from all over the world. The database has been developed using the Leiden Open (source) Variation Database (LOVD) software (Leiden University Medical Center, Leiden, the Netherlands). The database houses detailed information on clinical features, such as age and symptom at onset, mode of inheritance, and genotype information, pertaining to the SCA patients from more than 400 families across India. All the compiled genotype data conforms to the HGVS Nomenclature guidelines. This would be a very useful starting point for understanding the molecular correlates of phenotypes in ataxia-a multilocus disease in which related molecular mechanisms converge to overlapping phenotypes.
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PMID:SCA-LSVD: a repeat-oriented locus-specific variation database for genotype to phenotype correlations in spinocerebellar ataxias. 1937 Jul 69


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