Characterization of Prion Disease Associated with a Two-Octapeptide Repeat Insertion

• Published in: Viruses Vol. 13; no. 9; p. 1794
• Main Authors: Brennecke, Nicholas, Cali, Ignazio, Mok, Tze, Speedy, Helen, Hosszu, Laszlo, Stehmann, Christiane, Cracco, Laura, Puoti, Gianfranco, Prior, Thomas, Cohen, Mark, Collins, Steven, Mead, Simon, Appleby, Brian
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 08.09.2021; MDPI
• Subjects: Aged; Aged, 80 and over; Alleles; Alzheimer's disease; Australia; blood; Brain - pathology; Brain research; Creutzfeldt-Jakob disease; Creutzfeldt-Jakob Syndrome; Creutzfeldt-Jakob Syndrome - genetics; Creutzfeldt-Jakob Syndrome - physiopathology; data collection; Datasets; Dementia; Endopeptidase K; Ethics; Family medical history; Female; Fluorides; genetic Creutzfeldt-Jakob disease; Genetic diversity; Genetic screening; genetics; Genomes; Health surveillance; Humans; Infrared imaging systems; Insertion; Male; Methionine - genetics; Middle Aged; monitoring; Mutagenesis, Insertional; Mutation; octapeptide repeat insertion; Oligopeptides - genetics; Pathogenicity; penetrance; peptidase K; Polymorphism; Population genetics; prion disease; Prion Diseases - genetics; Prion Diseases - physiopathology; Prion protein; Prion Proteins - genetics; prions; Prions - genetics; Prions - pathogenicity; Proteinase; Proteins; risk; Western blotting; United Kingdom > UK; United States > US; Australia; octapeptide repeat insertion; genetics; prion disease; Creutzfeldt-Jakob disease; genetic Creutzfeldt-Jakob disease
• ISSN: 1999-4915; 1999-4915
• DOI: 10.3390/v13091794

Genetic prion disease accounts for 10–15% of prion disease. While insertion of four or more octapeptide repeats are clearly pathogenic, smaller repeat insertions have an unclear pathogenicity. The goal of this case series was to provide an insight into the characteristics of the 2-octapeptide repeat genetic variant and to provide insight into the risk for Creutzfeldt–Jakob disease in asymptomatic carriers. 2-octapeptide repeat insertion prion disease cases were collected from the National Prion Disease Pathology Surveillance Center (US), the National Prion Clinic (UK), and the National Creutzfeldt–Jakob Disease Registry (Australia). Three largescale population genetic databases were queried for the 2-octapeptide repeat insertion allele. Eight cases of 2-octapeptide repeat insertion were identified. The cases were indistinguishable from the sporadic Creutzfeldt–Jakob cases of the same molecular subtype. Western blot characterization of the prion protein in the absence of enzymatic digestion with proteinase K revealed that 2-octapeptide repeat insertion and sporadic Creutzfeldt–Jakob disease have distinct prion protein profiles. Interrogation of large-scale population datasets suggested the variant is of very low penetrance. The 2-octapeptide repeat insertion is at most a low-risk genetic variant. Predictive genetic testing for asymptomatic blood relatives is not likely to be justified given the low risk.