Molecular Genetics of Creutzfeldt–Jakob Disease and Gerstmann– Sträussler– Scheinker Disease

Abstract

Abstract Creutzfeldt–Jakob disease (CJD) and Gerstmann–Sträussler–Scheinker disease (GSS) are distinct clinicopathological phenotypes of human prion diseases or transmissible spongiform encephalopathies (TSEs). TSEs arise either spontaneously (sporadic disease forms such as sporadic CJD/sCJD or sporadic fatal insomnia/sFI), by genetic aberration (genetic CJD/gCJD, GSS, fatal familial insomnia/FFI) or acquired by contact with infectious prions from bovine spongiform encephalopathy (BSE), causing variant CJD (vCJD), or – more or less historically – as iatrogenic CJD (iCJD) from invasive medical procedures such as dural or corneal transplantations, cadaveric pituitary hormone preparations or surgical instruments, or from blood and blood products with vCJD prions. Genetic forms constitute about 10–15% of human prion diseases and result from more than 30 mutations, insertions or rarely deletions in the prion protein (PrP) gene, PRNP . A polymorphism at PRNP codon 129 is an important susceptibility factor and relevant for phenotypic heterogeneity. Other genes have not convincingly been shown to be involved. Key Concepts Prion diseases are invariably lethal and transmissible neurological disorders that affect humans and animals. In humans, they occur sporadically and can also be acquired or inherited. The infectious agent is considered to be solely an abnormal conformer of the host‐encoded prion protein (PrP). Genetic disease forms constitute about 10–15%, result from aberrations in the PrP gene, PRNP , and are inherited as autosomal dominant trait with variable penetrance. There is a broad clinical and neuropathological phenotypic spectrum, which is modulated by molecular factors including PRNP polymorphisms and PrP strains. Creutzfeldt–Jakob disease (CJD) and Gerstmann–Sträussler–Scheinker disease (GSS) are distinct clinicopathological phenotypes. CJD occurs mostly sporadically (sCJD), more rarely by genetic aberration (gCJD), whereas GSS is always of genetic origin. There is no effective treatment yet.