Phenotypic diversity of genetic Creutzfeldt–Jakob disease: a histo-molecular-based classification

• DOI: 10.1007/s00401-021-02350-y
• Publication Date: 2021-07-29T08:02:52Z
• Authors: Simone Baiardi; Marcello Rossi; Angela Mammana; Brian S. Appleby; Marcelo A. Barria; Ignazio Calì; Pierluigi Gambetti; Ellen Gelpi; Armin Giese; Bernardino Ghetti; Jochen Herms; Anna Ladogana; Jacqueline Mikol; Suvankar Pal; Diane L. Ritchie; Viktoria Ruf; Otto Windl; Sabina Capellari; Piero Parchi
• Keywords: PRNP

Abstract The current classification of sporadic Creutzfeldt–Jakob disease (sCJD) includes six major clinicopathological subtypes defined by the physicochemical properties protease-resistant core pathologic prion protein (PrP Sc ), defining two PrP types (i.e., 1 and 2), methionine (M)/valine (V) polymorphic codon 129 gene ( PRNP ). How these sCJD relate to well-documented phenotypic heterogeneity genetic CJD (gCJD) is not fully understood. We analyzed molecular features in 208 individuals affected gCJD, carrying 17 different mutations, compared them with those a large series cases. identified groups gCJD based on combination type genotype mutated allele, each showing distinctive histopathological characteristics, irrespectively associated mutation. Five groups, named M1, M2C, M2T, V1, V2, largely reproduced previously described subtypes. sixth group shared traits V2 was only detected patients E200K-129M haplotype association intermediate size (“i”) between 2. Additional mutation-specific effects involved pattern deposition (e.g., “thickened” synaptic E200K carriers, cerebellar “stripe-like linear granular deposits” insertion intraneuronal globular dots E200K-V2 or -M”i”). A few isolated cases linked rare haplotypes T183A-129M), showed atypical features, which prevented their into groups. variability mostly consistent that found sCJD. As sCJD, significantly correlated gCJD. most common mutations appear have variable overall less significant effect phenotype, but they influence susceptibility often strain-specific manner. criteria currently used for can be expanded adapted provide an updated basis.