Genetic causes and modifiers of prion diseases

Prion diseases are transmissible neurodegenerative diseases caused by misfolding of prion protein (PrP). All inherited prion diseases, including genetic Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease, and fatal familial insomnia, are caused by pathogenic mutations in the prion protein gene (PRNP). The mutation partly dictates age at disease onset and clinical phenotype, presumably by its effects on the misfolding of PrP, but the clinical features can be highly variable even within the same pedigree. In sporadic prion diseases, genetic factors also play pivotal roles, as polymorphisms of PrP affect susceptibility, strain specificity, and disease progression. Additionally, emerging evidence highlights genetic modifiers outside PRNP that regulate disease susceptibility, implicating protein trafficking and lipid metabolism. Because individuals at genetic risk can be identified long before symptom onset, a distinctive opportunity exists for early or even presymptomatic therapeutic intervention. The unequivocal and well understood molecular target that is PrP, together with the development of diagnostic biomarkers, could create a favourable research setting for disease-modifying treatments.