Understanding the Phenotypic Heterogeneity Within the Sporadic Creutzfeldt-Jakob Disease MV1 Subtype

The MV1 subtype of sporadic Creutzfeldt-Jakob disease (sCJD) is one of the least studied. Cases are defined by the presence of the methionine/valine (MV) polymorphism at codon 129 of the PRNP gene and a type 1 immunoblot pattern of pathological prion protein (PrP^D), where the unglycosylated PrP^D fragment migrates at ~21 kDa (T²¹). Because the originally described MV1 cases had T²¹ plus brain pathology indistinguishable from MM1 cases (small vacuoles), the MV1 subtype has historically been grouped with MM1. However, the recent identification of MV1 cases with immunoblot and pathological features similar to the VV1 subtype (T^21-20 doublet, larger vacuoles, ballooned neurons) has raised the possibility that the MV1 subtype is more heterogeneous than originally proposed. Here, we report three MV1 cases that further reveal the heterogeneity of this subtype. All cases were atypical in that they had persistent T²⁰ fragments, in isolation or combination with T²¹ or T¹⁹, when typed at pH 6.9, a finding that would have been missed if typing were undertaken at pH 8.0 only. Fragment proportions differed in different brain regions, and further examination found that the cases had mixed MM1/VV1 features, predominant VV1-like characteristics or features of the MV2C subtype. Two cases had small to intermediate-sized vacuoles and synaptic PrP staining. The third case had intermediate vacuolation, weak synaptic staining and coarse PrP deposits. We also describe, for the first time, the application of asymmetric-flow field-flow fractionation as a novel tool to discriminate sCJD subtypes based on size distributions of protease-resistant and protease-sensitive PrP^D. Overall, we propose that MV1 is a more heterogeneous subtype than previously appreciated, potentially existing along a spectrum from MM1-like to VV1-like phenotypes. Importantly, this biochemical heterogeneity may be underrepresented when subtyping is done at pH 8.0, so we recommend CJD subtyping be performed at pH 6.9 to avoid missing atypical or mixed cases.