Classic scrapie in sheep with the ARR/ARR prion genotype in Germany and France

Transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative diseases in sheep and goats (scrapie), cattle (bovine spongiform encephalopathy [BSE]), and humans (Creutzfeldt-Jakob disease [CJD]). A variant form of CJD (1) was discovered in 1996 and was linked to the BSE epidemic in the United Kingdom and elsewhere. Classic scrapie is caused by a variety of prion strains that can be distinguished from one another by their biologic and biochemical features (2). Recently, so-called atypical scrapie strains that have remarkably different biochemical and transmission characteristics have been discovered (3,4). Although the transmissibility of a particular sheep scrapie isolate to nonhuman primates has been demonstrated (5), no epidemiologic data have linked scrapie in small ruminants to human CJD cases (6). TSE susceptibility in sheep is controlled mainly by polymorphisms in the monocistronic PRNP gene that encodes for normal cellular protein (PrPC). Three major mutations are associated with sheep susceptibility or resistance to classic scrapie and BSE: at codons 136 (A or V), 154 (R or H), and 171 (R, Q, or H) (7). Animals with genotypes V136R154Q171/VRQ, ARQ/VRQ, ARQ/ARQ , and VRQ/ARH PrP are most susceptible to scrapie (8). In the past 20 years, no TSE cases have been found in ARR/ARR sheep in Europe, although thousands of scrapie-diseased animals have been genotyped. However, 1 report, albeit heavily questioned, has been made in the literature of a possible case in an ARR/ARR sheep in Japan (9). Therefore, this genotype was considered to confer full resistance to BSE and scrapie (7) (for a full review see [10]). To minimize the risk of humans acquiring TSE by consuming animal products, massive breeding programs involving PrP-genotyping of millions of sheep were initiated in the European Union (EU). However, the successful transmission of BSE prions to ARR/ARR sheep showed that the resistance of this genotype toward the TSE agent was not absolute (11). Recently, the identification of previously unrecognized so-called atypical scrapie in sheep of various genotypes, including ARR/ARR, has reinforced this statement (4). We report here the identification and characterization of 2 natural classic scrapie cases in sheep of the ARR/ARR genotype, which are clearly different from BSE and atypical scrapie.