Phenotypic variability in human prion diseases.
ABSTRACT Human prion diseases are rare neurodegenerative disorders that can occur as sporadic, familial or acquired disorders. Within each of these categories there is a wide range of phenotypic variation that is not encountered in other neurodegenerative disorders. The identification of the prion protein and its key role in the pathogenesis of this diverse group of diseases has allowed a fuller understanding of factors that influence disease phenotype. In particular, the naturally occurring polymorphism at codon 129 in the prion protein gene has a major influence on the disease phenotype in sporadic, familial and acquired prion diseases, although the underlying mechanisms remain unclear. Recent technical advances have improved our ability to study the isoforms of the abnormal prion protein in the brain and in other tissues. This has lead to the concept of molecular strain typing, in which different isoforms of the prion protein are proposed to correspond to individual strains of the transmissible agent, each with specific biological properties. In sporadic Creutzfeldt-Jakob disease there are at least six major combinations of codon 129 genotype and prion protein isotype, which appear to relate to distinctive clinical subgroups of this disease. However, these relationships are proving to be more complex than first considered, particularly in cases with more than a single prion protein isotype in the brain. Further work is required to clarify these relationships and to explain the mechanism of neuropathological targeting of specific brain regions, which accounts for the diversity of clinical features within human prion diseases.
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ABSTRACT: Genetic Creutzfeldt-Jakob disease (CJD) due to V180I mutation in the prion protein gene (PRNP) is of great interest because of the differences from sporadic CJD and other genetic prion diseases in terms of clinical features, as well as pathological and biochemical findings. However, few systematic observations about the clinical features in patients with this unique mutation have been published. Therefore, the goal of this study was to relate this mutation to other forms of CJD from a clinical perspective.BMJ Open 04/2014; 4(5). DOI:10.1136/bmjopen-2014-004968 · 2.06 Impact Factor
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ABSTRACT: In our pathologic observation of the cerebral cortex including the neocortex, hippocampus, and limbic cortex in 43 Japanese patients with MM1-type sporadic Creutzfeldt-Jakob disease, the earliest pathologic finding was spongiform change and next was gliosis. Subsequently, neuropil rarefaction appeared, followed by neuron loss. On the basis of these observations, we propose the following cortical pathologic staging: Stage I, spongiform change; Stage II, hypertrophic astrocytosis; Stage III, neuropil rarefaction; Stage IV, neuron loss; Stage V, status spongiosus; and Stage VI, large cavity formation. We also suggest a more simple staging classification: Stages I and II, mild; Stages III and IV, moderate; and Stages V and VI, severe involvement. Based on statistical analysis of the cases, strong correlation coefficients were obtained between the neocortical and limbic pathologic stage and both total disease duration and brain weight. We estimated that the first observation times of cortical hyperintensity on diffusion-weighted images of magnetic resonance imaging, myoclonus, and periodic sharp wave complexes on the electroencephalogram approximately correspond to the early phase of Stage II of the neocortex. The time to reach the akinetic mutism state approximately corresponds to the middle phase of Stage II of the neocortex. Therefore, we think that approximate clinical manifestations at death, total disease duration, and brain weight can be estimated according to the pathologic stage of the neocortex or limbic cortex. Panencephalopathic-type pathology appeared approximately 12months after disease onset, and this time approximately corresponds to the middle phase of Stage III of the neocortex.Journal of the neurological sciences 04/2014; 341(1-2). DOI:10.1016/j.jns.2014.04.011 · 2.32 Impact Factor
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ABSTRACT: Human prion diseases are fatal neurodegenerative diseases caused by the deposition of abnormal, protease-resistant conformers of the prion protein in the brain. They show a great variability in clinical and neuropathological expression and may occur as sporadic, hereditary or infectious diseases. The wide range of phenotypes are paralleled by the existence of different species of prion protein in the various subgroups of the illness that can be identified by western blot analysis on brain homogenates. The spectrum of neuropathological changes ranges from spongiform degeneration, neuronal loss and reactive gliosis to cerebral amyloidosis. Some clinical criteria as well as neurophysiological and neuroradiological analyses are commonly used in practice to diagnose the various forms of prion diseases as possible or prob-able, but only the neuropathological and the biochemical examination of the brain tissue allow the identification of the abnormal isoforms of prion pro-tein and are therefore necessary for a definite diagnosis and a molecular classification of prion diseases.