Phenotypic variability in human prion diseases.

National Creutzfeldt-Jakob Disease Surveillance Unit, Division of Pathology, University of Edinburgh, UK.
Neuropathology and Applied Neurobiology (Impact Factor: 4.97). 01/2006; 31(6):565-79. DOI: 10.1111/j.1365-2990.2005.00697.x
Source: PubMed

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: 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.