Characterization of prion strains and peripheral prion infectivity patterns in E200K genetic CJD patients

The mutation E200K in the prion protein gene (PRNP) is the most common variant in genetic Creutzfeldt-Jakob disease (gCJD). The clinical and pathological features observed in patients with E200K gCJD led to the hypothesis that the prion strains responsible for this form of the disease may be related to those involved in sporadic CJD (sCJD). In this study, we characterized the prion strains responsible for E200K gCJD cases from Slovakia (n = 12), Spain (n = 9), and France (n = 3) using transgenic mouse models expressing human prion protein (PrP). The cohort included patients with various PRNP genotypes: E200K-Met₁₂₉/Met₁₂₉, E200K-Met₁₂₉/E200K-Met₁₂₉, E200K-Met₁₂₉/Val₁₂₉, and E200K-Val₁₂₉/Val₁₂₉. Prion strain characterization revealed that the strains isolated from E200K gCJD cases corresponded to the two most common strains identified in sCJD cases: M1^CJD and V2^CJD. Depending on the individual, these strains were either present as pure M1^CJD or V2^CJD, or as a mixture of both (M1^CJD + V2^CJD). Additionally, peripheral tissues from E200K-Met₁₂₉/Met₁₂₉ patients (n = 4) and one E200K-Met₁₂₉/Val₁₂₉ case were analyzed for prion infectivity and seeding activity. Similar to sCJD patients, low but detectable levels of prions were found in various peripheral tissues of E200K gCJD cases. Overall, our findings suggest that the prion strains and their distribution in the body are highly similar between E200K gCJD and sCJD patients. These similarities indicate that individuals carrying the E200K mutation may serve as a valuable model for understanding CJD pathogenesis during the preclinical phase of the disease.