CJD Associated with the E200K Mutation with Valine at Codon 129 on the Mutated Allele and Methionine on the Wild Type Allele: Report of Two Cases

The E200K mutation, the most frequent among pathogenic prion protein gene (PRNP) mutations, can be coupled with either methionine (M) or valine (V) at codon 129. Due to their rarity, the CJD phenotype associated with the E200K-129V haplotype has not been fully characterized as yet. We studied two unrelated CJD patients carrying the E200K mutation coupled with valine at codon 129 on the mutated allele and methionine on the wild type allele. Symptoms at onset included disequilibrium which rapidly evolved to severe ataxia, while dementia appeared only late in the course. CSF examination showed pathological levels of 14-3-3 and tau proteins, while a MRI-DWI revealed an hyperintensity in the caudate and putamen nuclei. Neuropathological examination in one of the two cases revealed many features of the VV2 sCJD phenotype, namely the widespread subcortical distribution of lesions, the laminar distribution of spongiform degeneration in the deep cortical layers, and the predominant involvement of the granular layer in the cerebellum. In contrast, the most characteristic histopathologic feature of the MV2 sCJD phenotype, which is the presence of kuru-like amyloid plaques in the cerebellum was completely lacking. In line with this finding, PrP immunohistochemistry revealed a synaptic pattern of PrP deposition without any associated plaque-like deposits. Finally, Western blot analysis of brain homogenates showed PrPSc type 2 with a predominant diglycosylated form (e.g. pattern 2B) in all regions analyzed. The present results will be discussed in relation to current knowledge of the molecular basis of phenotypic variability of human prion diseases.