References for this review were identified by searches of PubMed through July 1, 2005 with the terms “prions”, “Creutzfeldt-Jakob disease”, “scrapie”, “chronic wasting disease”, and “bovine spongiform encephalopathy”.
ReviewPrion diseases
Introduction
Creutzfeldt-Jakob disease (CJD), the most common human prion disease, is a rare form of adult dementia; the disease was not widely recognised until the 1960s. In the past decade, CJD has become a prominent consideration in the differential diagnosis of chronic neurological diseases and a popular topic in the public press. The growing interest in the disease is not caused by increasing incidence, which is estimated to be stable at between 0·5 and 1·5 cases per million people per year. This focus on CJD and other prion diseases stems from basic biological studies on the nature of the transmissible agents, which have raised fundamental new questions in microbiology, and from the emergence of bovine spongiform encephalopathy (BSE) in the UK. The highly publicised spread of BSE outside of the UK and the transmission to human beings have had major economic and political repercussions in Europe, Asia, and North America.1
After the experimental transmissions of scrapie from sheep to sheep in the 1930s and 1940s the nature of the transmissible agent remained baffling;2 it was found to be resistant to formaldehyde, ethanol, proteases, nucleases, and even ultraviolet and ionising radiation.3 In 1982 the term prion was proposed to “denote a small proteinaceous infectious particle which is resistant to inactivation by most procedures that modify nucleic acids”.3 Subsequently an isoform of a normal host membrane glycoprotein (prion protein) was found to co-purify with infectivity.4 The normal prion protein is protease sensitive, soluble, and has a high α-helix content. Its normal function is uncertain.5 The prion (the transmissible isoform) is protease resistant, is insoluble, forms amyloid fibrils, and has a high β-sheet content.6 Recent studies support the concept of an infectious protein,7 and no specific nucleic-acid sequence has been identified. Nevertheless, whether the infectious agent or prion is “protein only” remains a subject of debate.8
Prion diseases or transmissible spongiform encephalopathies affect human beings and other mammals (panel). All have long incubation periods followed by chronic neurological disease and fatal outcomes, have similar pathology limited to the CNS, and are experimentally transmissible to some other species.
The nature of prions and their mode of replication or “conversion” still pose fascinating basic questions. Recent reviews have emphasised the pathogenesis of prion diseases and the need for better diagnostic tests and potential treatments.9, 10 In this review, I focus primarily on comparative epidemiology of prion diseases. Knowledge about the modes of transmission or acquisition of prion diseases may help guide rational policy and individual decisions about prevention and abrogation of risk.
Section snippets
Human prion diseases
CJD is the commonest human prion disease and the sporadic form accounts for about 85% of cases; about 10–15% of cases are familial, 1% iatrogenic, and variant CJD is a regional disease limited largely to the UK and France. Kuru was the first spongiform encephalopathy of human beings to be experimentally transmitted to non-human primates. This disease is of importance not only for historical reasons but also because of lessons learned about modes of transmission and incubation periods associated
Scrapie of sheep
Scrapie was the first prion disease to be identified and has been recognised by shepherds for over 200 years.2 The disease is characterised by scraping of fleece, stumbling, and behavioural changes and has a progressive course, leading to death in 3–6 months. Post-mortem examination shows changes only in the CNS with neuronal loss, gliosis, and vacuolisation of neural cells. Early debate between advocates of the genetic or the infectious origin of scrapie was settled by the demonstration of
Risk assessment
Prion diseases show some remarkable similarities. They have long incubation periods; present as progressive fatal neurological diseases with motor, sensory, and cognitive deficits; cause similar spongiform pathology limited to the CNS; result from misfolding of a normal membrane glycoprotein; and evoke no immune response. Despite these shared features predicting risk of acquisition or spread of disease is complicated by the striking differences in mode and ease of transmission, unpredictable
Concluding comments
The first claims of transmission of scrapie were met with incredulity; and almost every event in the prion story since has been equally unlikely and unpredictable—the outbreak of kuru, the unexplained spread of chronic wasting disease, the astonishing epidemic of bovine spongiform encephalopathy, the unpredictable spread to people, and the very nature of the agents themselves. If one lesson has been learned about transmissible spongiform encephalopathies, it is to temper any future predictions;
Search strategy and selection criteria
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