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Dentatorubral-pallidoluysian Atrophy (dentatorubral-pallidoluysian + atrophy)

Distribution by Scientific Domains

Medical Sciences	83%

Selected Abstracts

Dentatorubral-pallidoluysian atrophy (DRPLA)

NEUROPATHOLOGY, Issue 5 2010
The 50th Anniversary of Japanese Society of Neuropathology
Dentatorubral-pallidoluysian atrophy (DRPLA) is a hereditary spinocerebellar degeneration. Despite the establishment of this disease in 1982, it has been pointed out that DRPLA has an unexplained aspect concerning its clinicopathological features; that is, the discrepancy between the variety of clinical manifestations and the uniformity of the brain lesions. The discovery of a causative gene mutation (abnormal expansion of the CAG repeat in DRPLA gene) triggered the development of novel neuropathology in DRPLA, which has suggested that polyglutamine-related pathogenesis involves a wide range of central nervous system regions far beyond the systems previously reported to be affected. It is now likely that DRPLA has an aspect of neuronal storage disorder and has multiple system degeneration, the lesion distribution of which varies depending on the CAG repeat sizes in the causative gene. [source]

Novel brain 14-3-3 interacting proteins involved in neurodegenerative disease

FEBS JOURNAL, Issue 16 2005
Shaun Mackie
We isolated two novel 14-3-3 binding proteins using 14-3-3 , as bait in a yeast two-hybrid screen of a human brain cDNA library. One of these encoded the C-terminus of a neural specific armadillo-repeat protein, ,-catenin (neural plakophilin-related arm-repeat protein or neurojungin). ,-Catenin from brain lysates was retained on a 14-3-3 affinity column. Mutation of serine 1072 in the human protein and serine 1094 in the equivalent site in the mouse homologue (in a consensus binding motif for 14-3-3) abolished 14-3-3 binding to ,-catenin in vitro and in transfected cells. ,-catenin binds to presenilin-1, encoded by the gene most commonly mutated in familial Alzheimer's disease. The other clone was identified as the insulin receptor tyrosine kinase substrate protein of 53 kDa (IRSp53). Human IRSp53 interacts with the gene product implicated in dentatorubral-pallidoluysian atrophy, an autosomal recessive disorder associated with glutamine repeat expansion of atrophin-1. [source]

Huntington's disease phenocopies are clinically and genetically heterogeneous

MOVEMENT DISORDERS, Issue 5 2008
Edward J. Wild MRCP
Abstract Huntington's disease (HD) classically presents with movement disorder, cognitive dysfunction and behavioral problems but is phenotypically variable. One percent of patients with HD-like symptoms lack the causative mutation and are considered HD phenocopies. Genetic diseases known to cause HD phenocopies include HD-like syndromes HDL1, HDL2, and HDL4 (SCA17). HD has phenotypic overlap with dentatorubral-pallidoluysian atrophy, the spinocerebellar ataxias and neuroferritinopathy. Identifying the genetic basis of HD phenocopies is important for diagnosis and may inform the search for HD genetic modifiers. We sought to identify neurogenetic diagnoses in the largest reported cohort of HD phenocopy patients. Two hundred eighty-five patients with syndromes consistent with HD, who were HD expansion-negative, were screened for mutations in PRNP, JPH3, TBP, DRPLA, SCA1, SCA2, SCA3, FTL and FRDA. Genetic diagnoses were made in 8 subjects: we identified 5 cases of HDL4, 1 of HDL1 and 1 of HDL2. One patient had Friedreich's ataxia. There were no cases of DRPLA, SCA1, SCA2, SCA3, or neuroferritinopathy. HD phenocopies are clinically and genetically diverse and a definitive genetic diagnosis is currently possible in only a minority of cases. When undertaken, it should be clinically directed and patients and clinicians should be prepared for the low probability of reaching a genetic diagnosis in this group of patients. © 2008 Movement Disorder Society [source]

Polyglutamine disease: Recent advances in the neuropathology of dentatorubral-pallidoluysian atrophy

NEUROPATHOLOGY, Issue 4 2006
Mitsunori Yamada
Polyglutamine diseases are hereditary neurodegenerative disorders that are caused by the expansion of a CAG repeat in the causative genes. They comprise at least nine disorders, including DRPLA, HD, and Machado-Joseph disease. Initially, the discovery of neuronal intranuclear inclusions (NIIs) in human brains and in a murine model of HD provided a plausible hypothesis that the expression of expanded polyglutamine stretches leads to NII formation, resulting in neuronal cell death in selective brain regions characteristic to each disease. Recent studies, however, suggest that nuclear dysfunction, especially transcriptional abnormalities caused by the diffuse intranuclear accumulation of mutant proteins, plays a pivotal role in the development and progression of clinical symptoms. Polyglutamine diseases have a similarity with neuronal storage disease, and this pathological process might become a target for the establishment of an effective therapy for these diseases. [source]

The occurrence of dominant spinocerebellar ataxias among 251 Finnish ataxia patients and the role of predisposing large normal alleles in a genetically isolated population

ACTA NEUROLOGICA SCANDINAVICA, Issue 3 2005
V. Juvonen
Objectives,,, Frequency and distribution of dominant ataxias caused by dynamic mutations may vary in different populations, which has been explained on the basis of relative frequency of predisposing normal alleles. The aim of the study was to evaluate the occurrence of spinocerebellar ataxias (SCAs) and dentatorubral-pallidoluysian atrophy (DRPLA) in Finland, and to investigate the role of predisposing normal alleles in a genetically homogenous population. Material and methods,,, Mutation analyses for SCA1, 2, 3, 6, 7, 8, 10, 12, 17, and DRPLA and frataxin genes were performed for 251 unrelated Finnish patients who presented with progressive ataxia disorder. Results,,, Expansions of SCA1, SCA2, SCA6, SCA7, SCA8, and SCA17 genes were detected in 2, 1, 1, 7, 22, and 1 patients, respectively. Altogether, 39 and 7% of dominant and sporadic SCA patients, respectively, harboured expansions at some of the investigated loci. Normal variation, collected from 477 to 502 chromosomes at each disease loci, revealed that Finns were different from the Japanese but largely similar to other Caucasians. Conclusions,,, Lack of SCA3 and excess of SCA8 are characteristic to the Finnish population. Homozygosity for the SCA8 expansion increases penetrance. Frequencies of large normal alleles at the SCA loci predict poorly prevalence of the respective diseases in Finland. Prioritization in DNA testing, based on ethnic origin and geographical location, is recommendable in Finland, and analogous approach may be applied to other countries as well. [source]