# Genetic Creutzfeldt-Jakob disease linked to the E200K mutation: a large cohort study

## TL;DR

This study examines how a genetic mutation (E200K) in the prion protein gene affects the features of a fatal brain disease called genetic Creutzfeldt-Jakob disease.

## Contribution

The study identifies five subtypes of E200K-linked CJD based on genetic and pathological differences, using the largest cohort of cases to date.

## Key findings

- Codon 129 polymorphism influences histopathological and clinical features of E200K-linked CJD.
- Five distinct E200K subtypes were identified based on PrPSc types and haplotype combinations.
- Some E200K cases showed mixed pathological features of different 129 haplotypes.

## Abstract

Creutzfeldt-Jakob disease (CJD), the most common human prion disease, is an invariably fatal neurodegenerative disorder affecting 1.5 cases per million individuals per year. About 10–15% of the human prion diseases are caused by a pathogenic variant in the prion protein (PrP) gene (PRNP), and the most common genetic human prion disease is CJD (gCJD) linked to a glutamic acid to lysine substitution at codon 200 (E200K) of PRNP. The polymorphic codon 129 methionine (M)/valine (V) genotype has a strong effect on disease phenotype. In the present study, we retrospectively evaluated many features of gCJD E200K cases with respect to the 129MV polymorphism, type of scrapie prion protein (PrPSc), demographic, clinical, laboratory, histopathology, and molecular features, including western blot examination and real-time quaking-induced conversion assay. Analyses were also performed to determine statistically significant features between E200K haplotypes (e.g., codon 129 genotype in cis with the mutated allele) and codon 129 genotypes. This study found that codon 129 polymorphism affects several disease features of gCJD E200K. Specifically, histopathologic differences were found between patients with different 129 haplotypes and genotypes. We have identified five groups or subtypes of E200K associated with either PrPSc type 1 or 2. Other E200K cases showed mixed (i) PrPSc types or (ii) pathological features of 129 M and 129 V haplotypes. To our knowledge, this study describes the largest cohort of 177 E200K cases and provides new insight into the wide range of phenotypes associated with this common CJD genetic variant.

The online version contains supplementary material available at 10.1007/s00401-026-02975-x.