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From: TSS ()
Variant Creutzfeldt-Jakob disease: prion protein genotype analysis of positive appendix tissue samples from a retrospective prevalence study James W Ironside, Matthew T Bishop, Kelly Connolly, Doha Hegazy, Suzanne Lowrie, Margaret Le Grice, Diane L Ritchie, Linda McCardle, David A Hilton Abstract Objective To perform prion protein gene (PRNP) codon 129 analysis in DNA extracted from appendix tissue samples that had tested positive for disease associated prion protein. Design Reanalysis of positive cases identified in a retrospective anonymised unlinked prevalence study of variant Creutzfeldt-Jakob disease (vCJD) in the United Kingdom. Study samples 3 positive appendix tissue samples out of 12 674 samples of appendix and tonsil tested for disease associated prion protein. The patients from whom these samples were obtained were aged 20-29 years at the time of surgery, which took place in 1996-9. Setting Pathology departments in two tertiary centres in England and Scotland. Results Adequate DNA was available for analysis in two of the three specimens, both of which were homozygous for valine at codon 129 in the PRNP. Conclusions This is the first indication that the valine homozygous subgroup at codon 129 in the PRNP is susceptible to vCJD infection. All tested clinical cases of vCJD have so far occurred in the methionine homozygous subgroup, and a single case of probable iatrogenic vCJD infection has been identified in one patient who was a methionine/valine heterozygote at this genetic locus. People infected with vCJD with a valine homozygous codon 129 PRNP genotype may have a prolonged incubation period, during which horizontal spread of the infection could occur either from blood donations or from contaminated surgical instruments used on these individuals during the asymptomatic phase of the illness. snip... Discussion These results give the first indication that PRNP codon 129 valine homozygotes may be susceptible to vCJD infection. Though the immunohistochemical technique used in our earlier study seems to be specific for disease associated prion protein,6 it is unlikely to be 100% sensitive, suggesting that the true prevalence of vCJD infection in the UK population may be even higher than earlier estimated (3/12 674).2 Genetic studies of kuru, another orally transmitted human prion disease, found that PRNP codon 129 MV and VV genotypes were associated with longer incubation periods than the MM genotype.7 As the ethical approval for our study placed restraints on the identification of individual cases, we are not able to state with certainty the age of the patients in the positive cases at the time of surgery.We can, however, state that they were aged 20-29 years at the time of surgery, which took place in 1996-9. No clinical cases of vCJD at any age have yet been identified in PRNP codon 129 valine homozygotes, indicating the need for continued surveillance of all cases of vCJD in the UK. Though it is inadvisable to overinterpret the data from only three positive cases in this study, it is perhaps surprising (given the relative prevalences of PRNP codon 129 genotypes in the general population) that both the positive cases analysed here were valine homozygotes. Though this may represent a chance finding, we should consider the possibility of differences in the peripheral pathogenesis of vCJD that depend on the PRNP codon 129 genotype. The patient who developed asymptomatic vCJD infection after red blood cell transfusion was a codon 129 heterozygote in whom both tonsil and appendix tissues were negative on staining for disease associated prion protein with methods identical to those used in this study, though the spleen and lymph nodes gave positive results.3 PRNP polymorphisms in sheep infected with scrapie also have a major influence on the incubation period and timing and distribution of disease associated prion protein in lymphoid tissues during the incubation period.8 A prolonged incubation period after infection with vCJD is likely to result in an asymptomatic carrier state (which cannot yet be identified), which represents a potential risk for horizontal transmission of vCJD infection by blood transfusion, blood products, or contaminated surgical instruments. These uncertainties further underline the need for continued surveillance of vCJD in the UK (including surveillance for subclinical or asymptomatic infection9), a requirement to continue to reduce the possibility of secondary iatrogenic transmission, and the inclusion of carrier states and susceptibility to vCJD infection in all PRNP codon 129 genotypes in future disease modelling. Contributors: JWI and DAH were responsible for the prevalence study and the analysis of the results, including the selection of the cases for analysis, and drafted and modified the manuscript.MTB established the methods for DNA extraction and analysis, designed and executed the validation study, and drafted and modified the manuscript. KC and DH performed the DNA extraction on the test materials and in the validation study, and modified the manuscript. MLeG, SL, DLR, and LMcC identified cases for the validation study and prepared the paraffin sections for DNA analysis and modified the manuscript. JWI is guarantor. Funding: The prevalence study was funded by the Department of Health (1216963 DAH; 1216982 JWI). Competing interest: None declared. Ethical approval: The prevalence study received approval from the South and West multi-centre research ethics committee (MREC reference 99/6/32) and for each of the centres included, appropriate local research ethics committee approval. http://bmj.bmjjournals.com/cgi/rapidpdf/bmj.38804.511644.55v1 TSS
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