Abstract
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.
Highlights
Prion disease (PrD) can be sporadic, genetic, or acquired
This paper presents a new collection of 2-octapeptide repeat insertions (OPRIs) cases in subjects with autopsy-confirmed prion disease and clinical features that satisfy criteria for the classification of probable Creutzfeldt–Jakob disease (CJD)
Three national prion disease surveillance centers replied that they had subjects with the 2-OPRI variant in their database and agreed to partake in this study
Summary
Prion disease (PrD) can be sporadic, genetic, or acquired. Genetic prion disease (gPrD). Associated with 2-OPRI patients and to determine the risk for Creutzfeldt–Jakob disease (CJD) in carriers of the 2-OPRI variant. The first case of the 2-OPRI in the setting of CJD was reported in 1993 [5]. Genetic studies revealed a 2-OPRI variant with valine homozygosity at codon 129 of PRNP. A third case of 2-OPRI in the setting of dementia was reported in 2004 [4]. Genetic studies demonstrated heterozygosity at codon 129 of PRNP. These reports have not provided a conclusion as to the significance of the 2-OPRI genetic variant. This paper presents a new collection of 2-OPRI cases in subjects with autopsy-confirmed prion disease and (or) clinical features that satisfy criteria for the classification of probable CJD. The hypothesis at the outset was that 2-OPRI was not a high penetrance mutation but rather a genetic variant that may modify the risk or phenotype of sCJD
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
