Phenotypic Heterogeneity of Variably Protease-Sensitive Prionopathy: A Report of Three Cases Carrying Different Genotypes at Codon 129.

Variably protease-sensitive prionopathy is an exceedingly rare, likely underestimated, sporadic prion disease that is characterized by heterogeneous and often non-specific clinical and pathological features posing diagnostic challenges. We report the results of a comprehensive analysis of three emblematic cases carrying different genotypes at the methionine (M)/valine (V) polymorphic codon 129 in the prion protein gene (). Clinical, biochemical, and neuropathological findings highlighted the prominent role of the host genetic background as a phenotypic modulator.

The characterization of AD/PART co-pathology in CJD suggests independent pathogenic mechanisms and no cross-seeding between misfolded Aβ and prion proteins.

Current evidence indicating a role of the human prion protein (PrP) in amyloid-beta (Aβ) formation or a synergistic effect between Aβ and prion pathology remains controversial. Conflicting results also concern the frequency of the association between the two protein misfolding disorders and the issue of whether the apolipoprotein E gene (APOE) and the prion protein gene (PRNP), the major modifiers of Aβ- and PrP-related pathologies, also have a pathogenic role in other proteinopathies, including tau neurofibrillary degeneration. Here, we thoroughly characterized the Alzheimer's disease/primary age-related tauopathy (AD/PART) spectrum in a series of 450 cases with definite sporadic or genetic Creutzfeldt-Jakob disease (CJD).