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From: TSS ()
Subject: vCJD: PrP genotype analysis of positive appendix tissue samples from a retrospective prevalence study
Date: April 11, 2006 at 7:13 am PST

Variant Creutzfeldt-Jakob disease: prion protein genotype analysis of

positive appendix tissue samples from a retrospective prevalence


James W Ironside, Matthew T Bishop, Kelly Connolly, Doha Hegazy, Suzanne Lowrie, Margaret Le Grice, Diane L

Ritchie, Linda McCardle, David A Hilton


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.



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


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.


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