Diagnosis of Prion Diseases

Prion diseases, or transmissible spongiform encephalopathies (TSEs), are a large group of transmissible, progressive, and invariably fatal neurodegenerative conditions that affect both animals and humans (1–5). Prion diseases are unique in that they can be inherited, occur sporadically, or can be acquired by infection (1, 3–5). As described below, the infectious agent in the prion disease is composed mainly or entirely of an abnormal conformation of a host-encoded glycoprotein called the cellular prion protein (PrPC). The replication of prions involves the recruitment of the normally expressed prion protein (PrPC) structure, which is largely alpha-helical, into a disease-specific conformation (PrPSc) that is rich in beta-sheets and that can adopt a fibrillar aggregated structure that is characteristic of many of the deposits found in the brains of TSE-affected species. In contrast to the protease-sensitive PrPC, the beta-sheet conformation along with the aggregation properties of PrPSc makes this protein partially resistant to proteolytic digestion (6). Furthermore, this posttranslational modification of PrPC into the abnormal, infection-associated isoform, PrPSc, is believed to be the principal molecular basis underlying prion diseases. Animal prion diseases include scrapie of sheep and goats, bovine spongiform encephalopathy (BSE) or mad cow disease, chronic wasting disease (CWD) of cervids (predominantly mule deer and elk), transmissible mink encephalopathy (TME), feline spongiform encephalopathy, exotic ungulate spongiform encephalopathy, and spongiform encephalopathy of nonhuman primates. Although some cases of sporadic atypical scrapie and BSE have also been reported, most animal prion diseases occur via the acquisition of infection from contaminated feed or via exposure to environmental contaminants. Scrapie and CWD are naturally sustaining epidemics. The human prion diseases can be sporadic, inherited, or acquired. Sporadic human prion diseases include Creutzfeldt-Jakob disease (sCJD), fatal insomnia, and variably protease-sensitive prionopathy (VPSPr) (3, 4). Genetic prion diseases are caused by inheritance of autosomal dominant mutations in the host PRNP gene, which encodes the normal cellular PrPC and includes genetic CJD (gCJD), fatal familial insomnia (FFI), and Gerstmann-Sträussler-Scheinker syndrome (GSS) (3, 4). Acquired human prion diseases account for only 5% of cases of human prion disease. They include kuru, iatrogenic CJD (iCJD), and variant CJD (vCJD) (3, 4), which was transmitted to humans from affected cattle via meat consumption. The transmission of BSE to humans has resulted in more than 200 cases of vCJD and has raised serious public health concerns. All prion diseases have long incubation periods but are typically rapidly progressive once clinical symptoms begin. Currently, there are no effective treatments for prion diseases, although increased understanding of their pathogenesis has recently led to the promise of effective therapeutic interventions. Numerous therapeutic approaches are under development both for the prevention of prion disease prior to or shortly after exposure and for treatment of already symptomatic disease (2, 7–10).