UK Iatrogenic Creutzfeldt-Jakob disease: investigating human prion transmission across genotypic barriers using human tissue-based and molecular approaches.
Creutzfeldt-Jakob disease (CJD) is the prototypic human prion disease that occurs most commonly in sporadic and genetic forms, but it is also transmissible and can be acquired through medical procedures, resulting in iatrogenic CJD (iCJD). The largest numbers of iCJD cases that have occurred worldwide have resulted from contaminated cadaveric pituitary-derived human growth hormone (hGH) and its use to treat primary and secondary growth hormone deficiency. We report a comprehensive, tissue-based and molecular genetic analysis of the largest series of UK hGH-iCJD cases reported to date, including in vitro kinetic molecular modelling of genotypic factors influencing prion transmission. The results show the interplay of prion strain and host genotype in governing the molecular, pathological and temporal characteristics of the UK hGH-iCJD epidemic and provide insights into the adaptive mechanisms involved when prions cross genotypic barriers. We conclude that all of the available evidence is consistent with the hypothesis that the UK hGH-iCJD epidemic resulted from transmission of the V2 human prion strain, which is associated with the second most common form of sporadic CJD.
National CJD Research & Surveillance Unit, Centre for Clinical Brain Sciences, Deanery of Clinical Sciences, The University of Edinburgh, Edinburgh, UK.
Diane L
DL
Ritchie
National CJD Research & Surveillance Unit, Centre for Clinical Brain Sciences, Deanery of Clinical Sciences, The University of Edinburgh, Edinburgh, UK.
Marcelo A
MA
Barria
National CJD Research & Surveillance Unit, Centre for Clinical Brain Sciences, Deanery of Clinical Sciences, The University of Edinburgh, Edinburgh, UK.
Alexander H
AH
Peden
National CJD Research & Surveillance Unit, Centre for Clinical Brain Sciences, Deanery of Clinical Sciences, The University of Edinburgh, Edinburgh, UK.
Helen M
HM
Yull
National CJD Research & Surveillance Unit, Centre for Clinical Brain Sciences, Deanery of Clinical Sciences, The University of Edinburgh, Edinburgh, UK.
James
J
Kirkpatrick
University College London Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK.
Peter
P
Adlard
National CJD Research & Surveillance Unit, Centre for Clinical Brain Sciences, Deanery of Clinical Sciences, The University of Edinburgh, Edinburgh, UK.
James W
JW
Ironside
National CJD Research & Surveillance Unit, Centre for Clinical Brain Sciences, Deanery of Clinical Sciences, The University of Edinburgh, Edinburgh, UK. m.w.head@ed.ac.uk.|National CJD Research & Surveillance Unit, University of Edinburgh, Bryan Matthews Building, Western General Hospital, Edinburgh, EH4 2XU, UK. m.w.head@ed.ac.uk.
Mark W
0000-0003-2034-8613
MW
Head
D000328:Adult; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D015331:Cohort Studies; D007562:Creutzfeldt-Jakob Syndrome / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism / Q000635:transmission*; D058872:Epidemics; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007049:Iatrogenic Disease; D007150:Immunohistochemistry; D007700:Kinetics; D008297:Male; D008822:Mice, Transgenic; D008875:Middle Aged; D008958:Models, Molecular; D000072002:Prion Proteins / Q000235:genetics / Q000378:metabolism; D006113:United Kingdom / Q000453:epidemiology
C512656:PRNP protein, human; D000072002:Prion Proteins
Agent strain; Creutzfeldt–Jakob disease; Disease phenotype; Growth hormone; Iatrogenic; Prion