Intracerebral distribution of the abnormal isoform of the prion protein in sporadic Creutzfeldt-Jakob disease and fatal insomnia.

Molecular genetics and protein chemistry have led to major advances in our understanding of the molecular basis of phenotypic variability of prion diseases. A large body of evidence indicates that a common methionine/valine polymorphism at codon 129 in the prion protein gene (PRNP), alone or in conjunction with PRNP mutations, modulates both disease susceptibility and phenotypic expression of human prion diseases. In addition, there are physicochemical properties of the abnormal isoform of the prion protein (PrP(sc)), such as relative molecular mass and glycosylation, that correlate with distinct phenotypes even in subjects carrying the same PRNP genotype. Different PrP(sc) "type"-PRNP genotype combinations are found associated with pathological phenotypes that differ in the relative severity of lesions among distinct brain regions, the presence and morphology of certain lesions such as amyloid plaques, and the pattern of intracerebral and tissue deposition of PrP(sc). This review summarizes the currently available data on the molecular pathology of sporadic Creutzfeldt-Jakob disease, the most common human prion disease, and fatal insomnia, a more recently defined entity that has rapidly become one of the best characterized of the human prion diseases.