Neuropathologic variants of sporadic Creutzfeldt-Jakob disease and codon 129 of PrP gene.

Objectives: To determine the contribution of methionine/valine (Met/Val) polymorphism at codon 129 of the prion protein (PrP) gene in the neuropathologic pattern and mechanisms of lesion development in sporadic Creutzfeldt-Jakob disease.

Background: Creutzfeldt-Jakob disease is a transmissible spongiform encephalopathy characterized by a conformational change of PrP and a variety of PrP deposits in the brain, some of which aggregate into amyloid plaques.

Methods: The authors semiquantitatively assessed neuropathologic lesions and performed PrP immunolabeling in 70 patients (39 Met/Met, 11 Met/Val, 20 Val/Val) who had died in France between 1994 and 1998.

Results: Met/Met cases (mild lesions mostly involving the occipital areas, low PrP load, few focal PrP nonamyloid deposits, no amyloid plaques) contrasted with Met/Val cases (marked lesions especially in the parahippocampal gyrus, high PrP load, numerous amyloid plaques) and with Val/Val cases (younger patients, longer course of disease: 11.5 +/- 3 months, and distinct neuropathology: severe lesions heavily involving the hippocampal formation and basal ganglia, high PrP load, numerous focal nonamyloid deposits, rare amyloid plaques). The course of Val/Val patients younger than age 55 was particularly long (19.9 +/- 7 months), and the isocortex bore the brunt of the pathology, suggesting a distinct variety.

Conclusions: Polymorphism at codon 129 modulates the phenotype of sporadic Creutzfeldt-Jakob disease. The Val genotype enhances the production of proteinase-resistant PrP, and the Met/Val genotype facilitates its aggregation into amyloid plaques.