The spectrum of transmissible spongiform encephalopathies

Since the first description by A.M. Jakob and H.G. Creutzfeldt, five human diseases have been identified as transmissible spongiform encephalopathies (TSE). The disease bearing these authors' name, Creutzfeldt-Jakob disease (CJD) occurs sporadically, may be transmitted and has a genetic basis in 10-15% of all cases. Genetic diseases are the Gerstmann-Straussler-Scheinker syndrome and fatal familial insomnia. The latest form of CJD in humans, variant CJD (vCJD), was first described in 1996 and may be considered as evidence for a link between human TSEs and those in the animal kingdom. The putative agent of all TSEs is a proteinaceous infectious agent or prion. The gene for the physiological isoform of this protein (prion related protein or PrPc) is encoded on the short arm of chromosome 20 in humans. The role of the physiological isoform of PrPc is unknown. The physiological isoform PrPc is protease-sensitive and thus designated as PrP-sen, while the pathological isoform is protease-resistant and thus called PrP-res. The pathological isoform PrP-res is invariably associated with TSEs and has given rise to the term prion diseases. PrP-sen and PrP-res have an identical amino acid sequence and have identical posttranslational modifications as assessed by currently available methodology but differ in their tertiary and quaternary structure. These structural differences are thought to be propagated by interaction of PrP-res with PrP-sen, appear to be governed by the polymorphism of PrPc and have been shown to be invariably associated with disease. PrP-sen has a high content of alpha-helical structures, PrP-res consists predominantly of beta-pleated sheets. These physicochemical characteristics of PrP-res cause it to behave like amyloid. The neuropathological hallmarks of TSEs or prion diseases are spongiform change, astrocytic gliosis, neuronal loss and PrP-positive plaques. A nucleic acid has never consistently been shown in any TSE. Diagnosis of TSE can be reliably made only postmortem.