Genetic Mutations and Epigenetic Mechanisms Influencing Disease Phenotype in fCJD and GSS Syndrome

Abstract

This literature review explores the intersection of genotype and phenotype in prion diseases, specifically familial Creutzfeldt–Jakob disease (fCJD) and Gerstmann–Sträussler–Scheinker syndrome (GSS). The relationship between pathogenic PRNP variants and their clinical manifestations, including symptoms, disease severity, and age at onset, remains largely unknown. This review identifies mutations within the PRNP gene associated with both diseases and examines how these genetic differences may influence prion protein misfolding. The presence of mutation-specific phenotypes highlights the sensitivity of prion structure to sequence changes, complicating diagnosis when variants produce overlapping phenotypes. In addition, this review evaluates the role of the PRNP codon 129 polymorphism in disease progression. In certain cases, heterozygosity for methionine and valine at codon 129 is associated with slower neurodegeneration and later disease onset, while homozygosity is associated with faster disease progression and earlier onset. However, these effects appear to depend on the specific pathogenic mutation and genetic background. For example, some patients heterozygous for the D178N variant of fCJD exhibited similar disease duration and severity as homozygous patients, suggesting that additional genetic factors may act as additional disease modifiers. Overall, this synthesis provides a basis for future research into the genetic factors behind prion disease.