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Human prion diseases encompass a family of rare neurodegenerative diseases, including, in order of their original clinical recognition, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker syndrome (GSS), kuru, fatal familial insomnia (FFI), and variant CJD (vCJD) [1, 2]. These disorders are all linked by the common feature of inexorably progressive clinical and pathological central nervous system (CNS) injury associated with the accumulation of a pathological isoform (PrPSC) of the cellular prion protein (PrPC). A small percentage of human prion diseases, encompassing 5%–15% of cases of CJD and virtually all known cases of the exceedingly rare disorders GSS and FFI, are inherited and are unequivocally associated with a variety of mutations in the gene encoding PrPC (PRNP) [3]. However, the overwhelming majority of human prion diseases are sporadic rather than inherited. For a small subset of this group, transmission results from inadvertent inoculation of a host with contaminated tissue derived from infected donors. Dramatic examples of this type of “iatrogenic” transmission include cases of CJD due to administration of contaminated pituitary-derived human growth hormone or, less commonly, gonadotropins; transplantation of infected cadaveric dural grafts or corneas; or the use of contaminated neurosurgical instruments [4]. It is important to recognize that the total number of such recognized iatrogenic causes accounts for only a tiny fraction of the total number of cases of “sporadic” prion disease. As a result, one of the central issues in understanding the pathogenesis of prion diseases has been to determine how these diseases are transmitted and how PrPSc spreads and replicates in the infected host.

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Centennial Perspective
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