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From: TSS ()
Subject: A new human genotype prone to variant Creutzfeldt-Jakob disease
Date: May 19, 2006 at 7:38 am PST

A new human genotype prone to variant Creutzfeldt-Jakob disease
New evidence may rekindle fears of a larger epidemic and greater risk of iatrogenic spread

The first 150 words of the full text of this article appear below.

From the initial discovery of variant Creutzfeldt-Jacob disease (vCJD) in the United Kingdom a decade ago, there has been concern about the ultimate extent and magnitude of the epidemic.1 Early estimates varied widely, with one model predicting up to 136 000 cases.2 Fortunately, the magnitude of the epidemic at present seems to match the lower limit of the early estimates, with 161 definite or probable cases in the United Kingdom. However, the article by Ironside and colleagues on p 1186 may rekindle fears that a larger epidemic is an ongoing threat.3

The study reports a genotype analysis that identified the presence of the homozygous valine (VV) genotype in two samples of appendix tissue that harboured prion proteins. The implication of this finding of most concern is that it raises the possibility that ongoing iatrogenic transmission of vCJD may sustain the epidemic.

Why are the findings from . . . [Full text of this article]

Policy implications

Related Articles

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 M McCardle, and David A Hilton
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Predicting susceptibility and incubation time of human-to-human transmission of vCJD
MT Bishop a, P Hart b, L Aitchison b, HN Baybutt b, C Plinston b, V Thomson b, NL Tuzi b, MW Head a, JW Ironside a, RG Will a and JC Manson b

Identification of possible transmission of variant Creutzfeldt-Jakob disease (vCJD) via blood transfusion has caused concern over spread of the disease within the human population. We aimed to model iatrogenic spread to enable a comparison of transmission efficiencies of vCJD and bovine spongiform encephalopathy (BSE) and an assessment of the effect of the codon-129 polymorphism on human susceptibility.

Mice were produced to express human or bovine prion protein (PrP) by direct replacement of the mouse PrP gene. Since the human PrP gene has variation at codon 129, with MM, VV, and MV genotypes, three inbred lines with an identical genetic background were produced to express human PrP with the codon-129 MM, MV, and VV genotypes. Mice were inoculated with BSE or vCJD and assessed for clinical and pathological signs of disease.

BSE was transmitted to the bovine line but did not transmit to the human lines. By contrast, vCJD was transmitted to all three human lines with different pathological characteristics for each genotype and a gradation of transmission efficiency from MM to MV to VV.

Transmission of BSE to human beings is probably restricted by the presence of a significant species barrier. However, there seems to be a substantially reduced barrier for human-to-human transmission of vCJD. Moreover, all individuals, irrespective of codon-129 genotype, could be susceptible to secondary transmission of vCJD through routes such as blood transfusion. A lengthy preclinical disease is predicted by these models, which may represent a risk for further disease transmission and thus a significant public-health issue.



Although the cattle BSE epidemic in the UK has
amounted to more than 180 000 cases since the 1980s,
the extent of the human vCJD epidemic has so far
remained limited with the total number of cases
worldwide currently at 190. One explanation for this
apparent discrepancy is that there exists a significant
species barrier between cattle and human beings, which
limits the susceptibility of the human population to
BSE. The data shown here suggest that this could
indeed be the case since BSE was readily transmissible
to the bovine transgenic mice but not to the human
transgenic mice. However, once BSE has passed
through human beings in the form of vCJD, the
transmissibility of this TSE strain is altered for the
human population.

All the human transgenic lines inoculated with BSE
were negative for TSE transmission, which suggests that
either the human transgenic lines are relatively resistant
to transmission of BSE or the incubation time is longer
than the length of the experiment (approximately
700 days). BSE transmission previously observed by
others, in human transgenic lines overexpressing the
human prion protein, could be due to overexpression of
the PrP gene and may not therefore give a true reflection
of the species barrier between BSE and human
beings.15,25,26 This apparent resistance of human transgenic
mice to BSE could be explained by a large species barrier
and this in turn could explain the low number of vCJD
cases in the human population.

vCJD was transmitted to all three human lines with
different pathological characteristics for each genotype,
and a gradation of transmission efficiency from MM to
MV to VV. The greater transmission efficiency in HuMM
mice suggests that homozygosity for methionine at
codon 129 leads to earlier onset of TSE-related
pathological features and clinical disease than for the
other two genotypes. The differences in PrPSc deposition
in the HuMM and HuMV lines suggest that the codon-
129 polymorphism in human beings is likely to affect
the distribution of PrPSc deposition in the brain.
Moreover, the similar numbers that scored positive for
PrP deposition in each of the MM and MV groups (11/15
and 11/13 respectively) suggest that the two genotypes
might be equally susceptible to vCJD, but with different
incubation periods. Titration experiments are needed to
fully compare the susceptibility of each line. The single
HuVV mouse positive for PrPSc shows that VV
individuals may be susceptible to vCJD with very long
incubation times, including a lengthy subclinical phase.
Transmission studies from all three genotype mice are
now underway to examine the infectious nature of the
disease and determine any alterations in the strain
characteristics on passage through human transgenic
mice. By contrast with published data suggesting that
VV individuals cannot propagate the vCJD biochemical
phenotype,15 the data presented here suggest that the

PrPSc type will remain a useful diagnostic feature of
secondary vCJD infection irrespective of codon-129
genotype, as has been observed for the two extant cases
of transfusion-associated vCJD infection. 5,27

Transmission of vCJD to the three lines of human
transgenic mice indicates that the human population
could be at significantly heightened risk of developing
disease after iatrogenic exposure to vCJD. Secondary
transmission of vCJD has partly removed the cattle-to-
human species barrier and has resulted in an agent that
can be transmitted from human to human with relative
efficiency. Transmission studies in cynomolgus macaques
provide further evidence for this agent adaptation as they
show reduction in incubation times after serial passage
of BSE.28 Our BSE inoculation at 10-1 dilution was
compared with vCJD inoculation at 10-2 because the latter
inoculum was found to be toxic to the mice at 10-1. Use of
a higher dose ofvCJD inoculum would have maintained
or increased the transmission efficiency of vCJD and
enhanced the current findings.

Our findings raise concerns relevant to the possibility
of secondary transmission of vCJD through blood
transfusion, fractionated blood products, or contaminated
surgical instruments. For this study mice were injected
intracerebrally, whereas the probable human exposure to
these agents is by peripheral routes (eg, oral or
intravenous), and thus human-to-human exposures
might be significantly less efficient. However, it is difficult
to know for sure what the practical implications might be
in human beings. Peripheral route challenge is in
progress; however, BSE transmission studies in primates
have shown the intravenous route to be as efficient as the
intracerebral route, with an extension of the incubation

Although all cases of vC]D up to now have been
observed in the MM genotype, this model of human-to-
human vCJD transmission suggests that other genotypes
are also susceptible. In our experimental setting, all
PRNP codon-129 genotypes are susceptible to vCJD
infection; however, progressive development of
pathological TSE features (vacuolation and PrP
deposition) is more rapid in the MM-genotype mice. An
explanation for this finding might be provided by in-vitro
conversion of recombinant human PrP by BSE and vCJD
agents, which has shown that PrP with methionine at
position 129 is more efficiently converted than PrP with
valine, and that conversion by vCJD is significantly more
efficient than by BSE.29 Long incubation periods during
which PrPSc is deposited predicts that, in human beings,
infection could be present in all genotypes for a significant
period before clinical onset. Incubation periods of more
than 30 years have been reported in the human TSE
disease kuru.30

The possibility that an MV or VV genotype could result
in a phenotype distinct from that recognised in vCJD
draws attention to the importance of systematic
assessment of the clinical, genetic, pathological, and

biochemical features of all human prion diseases. Our
findings indicate that for human-to-human vCJD infection

it should be assumed that all codon-129
genotype individuals (not just MM) can be infected, that
long incubation times can occur, and that a significant
level of subclinical disease might be present in the population.


MTB, PH, and CP did immunocytochemical and western blot analysis;

JCM, NT, HNB, and LA produced the transgenic mouse lines; JWI
supplied vCJD case material and reviewed the neuropathology; VT did
the mouse inoculations; and MTB, PH, MWH, RGW, JWI, and JCM
prepared the manuscript.

Conflicts of interest

We have no conflicts of interest.




a. National CJD Surveillance Unit, Bryan Matthews Building, Western General Hospital, Edinburgh, UK
b. Institute for Animal Health, Neuropathogenesis Unit, King's Buildings, Edinburgh, UK

Correspondence to: Prof J C Manson, Institute for Animal Health, Neuropathogenesis Unit, Ogston Building, King's Buildings, West Mains Road, Edinburgh EH9 3JF, UK;article=2847


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