1208 Proposed link between transmissible spongiform encephalopathies of man and animals Summary A link between scrapie and Creutzfeldt-Jakob disease (CJD) is likely to exist. Based on old observations on scrapie, new experiments on bovine spongiform encephalopathy, and modern reviews on CJD, my proposal fits general rules of virus transmission. Background Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler- Scheinker syndrome (GSS), and kuru are fatal diseases of the central nervous system known as transmissible subacute spongiform encephalopathies.’°2 CJD mainly occurs sporadically, but about 10% of cases have a familial genetic disposition. CJD has also occurred after treatment with cadaveric growth hormone and dura mater graft.2 GSS is regarded as a familial variant of CJD.’ Kuru is restricted to a small area of New Guinea and used to be transmitted with very high frequency during cannibalistic mourning rites.’ 1 After kuru and CJD were shown to be transmissible diseases,3,4 epidemiological studies looked for a link with scrapie, a common disease of sheep. However, no such connection was found.5-7 I suggest that such a link is highly likely, but that the early retrospective epidemiological studies could not possibly have detected it. Pathogenesis All these extremely rare human diseases, as well as scrapie (which is common in sheep), and bovine spongiform encephalopathy (BSE) in cattle, are pathogenetically indistinguishable and can be understood as virus-induced amyloidoses.8 According to this concept, an as yet unidentified virus induces the process of amyloidosis. In principle, this process has been elucidated. It is associated with a single critical host gene (sinc, sip, prion), which codes for an amyloidogenic glycoprotein located predominantly on the surfaces of nerve cells.9 All the familial forms of these diseases are linked to mutations in this gene. The observation that mice without the gene do not develop the disease" fully accords with this concept. Routes of transmission There is no evidence that any transmissible spongiform encephalopathy in man or animal spreads by simple contact between infected and non-infected individuals. Pattison and colleagues" recognised the importance of the oral uptake of infectious fetal membranes for the natural spread of scrapie among sheep or to other ruminant species such as goats. They reported that contact spread Robert Koch-Institut, Nordufer 20, D-13353 Berlin, Germany (Prof H Diringer PhD) of scrapie was never observed during 18 years of experimentation in sheep and goats, because only males or non-pregnant females were used as scrapie-affected donor animals." In 1883,’ more than 50 years before the first reported natural case of scrapie in a goat, 13 a case of BSE in a cow was recognised. Primary transmission of scrapie from sheep to cattle is likely to escape conventional histopathological diagnosis. 14,15 In the late 1970s scrapie was unintentionally and unexpectedly transmitted orally to cattle by way of contaminated meat and bone-meal supplements. Subsequently, oral recycling of infectious cattle material led to an epidemic of BSE in the UK.’6 Subsequent observations,17 as well as comparative transmission and histopathological" studies, are in full agreement with the concept that the BSE agent was transmitted accidentally to other ruminants and to phylogenetically very distant species, such as members of the cat family, by oral infection (figure). According to strain typing techniques commonly used to identify strains of the scrapie agent, the BSE agent has acquired a new quality. It retains this new quality when passaged into antelopes and cats, experimentally by parenteral routes into pigs, or even in back-passage into Figure: Proposed links between scrapie in sheep and human transmissible spongiform encephalopathy A=oral transmission occurs naturally. B=oral transmission proposed. C=oral or parenteral secondary transmission. B, C=proposed very early primary transmission from unknown ruminant source, but nowadays always presents as secondary transmission. Kuru now always presents as secondary transmission; it could have originated from CJD."
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