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From: TSS ()
Subject: Cross-sequence transmission of sporadic Creutzfeldt-Jakob disease creates a new prion strain
Date: August 25, 2007 at 12:42 pm PST

J Biol Chem. 2007 Aug 20; : 17709374

Cross-sequence transmission of sporadic Creutzfeldt-Jakob disease creates a
new prion strain.

[My paper] Atsushi Kobayashi , Masahiro Asano , Shirou Mohri , Tetsuyuki

The genotype (methionine or valine) at polymorphic codon 129 of the human
prion protein (PrP) gene and the type (type 1 or type 2) of abnormal isoform
of PrP (PrP(Sc)) are major determinants of the clinicopathological
phenotypes of sporadic Creutzfeldt-Jakob disease (sCJD). Here we found that
transmission of sCJD prions from a patient with valine homozygosity (129V/V)
and type 2 PrP(Sc) (sCJD-VV2 prions) to mice expressing human PrP with
methionine homozygosity (129M/M) generated unusual PrP(Sc) intermediate in
size between type 1 and type 2. The intermediate type PrP(Sc) was seen in
all examined dura mater graft-associated CJD cases with 129M/M and
plaque-type PrP deposits (p-dCJD). p-dCJD prions and sCJD-VV2 prions
exhibited similar transmissibility and neuropathology, and the identical
type of PrP(Sc) when inoculated into PrP-humanized mice with 129M/M or
129V/V. These findings suggest that p-dCJD could be caused by cross-sequence
transmission of sCJD-VV2 prions.


In this study, the strain-dependent traits of sCJDMM1
prions were inherited through cross-sequence
transmission without any modification. The
humanized mice with 129V/V produced type 1 PrPres
after inoculation with sCJD-MM1 prions. Because
sCJD-VV1 cases are extremely rare (at most 1-2%
of the total number of sCJD cases) and characterized
by early onset (mean age at onset: 39.3 years) (5),
our results raise the possibility that CJD cases
classified as VV1 may include cases caused by
iatrogenic transmission of sCJD-MM1 prions or
food-borne infection by type 1 prions from animals,
e.g., chronic wasting disease prions in cervid. In fact,
two CJD-VV1 patients who hunted deer or
consumed venison have been reported (40, 41). The
results of the present study emphasize the need for
traceback studies and careful re-examination of the
biochemical properties of sCJD-VV1 prions.
In conclusion, cross-sequence transmission of
sCJD-VV2 prions generates a new prion strain with
altered conformational properties and disease
phenotypes as p-dCJD prions. Furthermore, the
newly generated prions have unique transmissibility
including the traceback phenomenon. In the future, if
atypical prion strains emerge through cross-sequence
transmission, especially from animals, traceback
studies will enable us to identify the origin of the



Re: Colorado Surveillance Program for Chronic Wasting Disease
Transmission to Humans (TWO SUSPECT CASES)

Sporadic and familial CJD: classification and

Pierluigi Gambetti*, Qingzhong Kong*, Wenquan Zou*,
Piero Parchi† and Shu G Chen*
*Division of Neuropathology, Institute of Pathology, Case Western Reserve University, Cleveland,
Ohio, USA and †Department of Neurological Sciences, University of Bologna, Bologna, Italy
Prion diseases are unique transmissible neurodegenerative diseases that have
diverse phenotypes and can be familial, sporadic, or acquired by infection.
Recent findings indicate that the PrP genotype and the PrPSc type have a major
influence on the disease phenotype in both sporadic and familial human prion
diseases. This review attempts to classify and characterise sporadic and familial
Creutzfeldt-Jakob disease (CJD) as a function of these two disease determinants.
Based on the genotype at codon 129 on both PRNP alleles, the size of protease
resistant PrPSc fragments and disease phenotype, we divide sporadic CJD into six
subtypes: sCJDMM1/sCJDMV1, sCJDVV2, sCJDMV2, sCJDMM2, sCJDVV1, and
sporadic fatal insomnia (sFI). Familial CJD is classified into many haplotypes
based on the PRNP mutation and codon 129 (and other polymorphic codons) on
the mutant allele. The clinical and pathological features are summarised for
each sporadic CJD subtype and familial CJD haplotype.

J Neurol Neurosurg Psychiatry. Published Online First: 23 May 2007.
© 2007 by BMJ Publishing Group Ltd
Original articles

Sporadic creutzfeldt-jakob disease in two adolescents

K Murray 1, D L Ritchie 1, M Bruce 2, C A Young 3, M Doran 3, J W Ironside 4
and R G Will 4*
1 NationalCJD Surveillance Unit, United Kingdom
2 Neuropathogenesis Unit, United Kingdom
3 Walton Centre for Neurology and Neurosurgery, United Kingdom
4 National CJD Surveillance Unit, United Kingdom
* To whom correspondence should be addressed. E-mail: [log in to unmask]
Accepted 15 April 2007


Background: Sporadic Creutzfeldt-Jakob disease (CJD) is a condition
predominantly affecting older age groups, with cases aged less than 45 years
rare and an age at onset or death of less than 20 years exceptional.
Methods: Data from the systematic study of sporadic CJD in the UK are
available from 1970 onwards. Clinical and pathological data are reviewed in
order to identify atypical cases, including those at the extremes of the age
range of sporadic CJD. Detailed analysis of atypical cases is undertaken and
in selected cases laboratory transmission studies are carried out in order
to provide information on the characteristics of the infectious agent.
Results: In the UK two cases of sporadic CJD in adolescents have been
identified, dying aged 16 and 20 years. The first case predated the epidemic
of bovine spongiform encephalopathy and the characteristics of the second
case, including laboratory transmission studies, are consistent with a
diagnosis of sporadic rather than variant CJD.
Conclusion: The cases in this report indicate that sporadic CJD can develop
at a very young age, that variant CJD is not the only form of CJD occurring
in this age group and that neuropathological examination is essential to
accurate diagnosis of human prion disease.

Coexistence of multiple PrPSc types in individuals with Creutzfeldt-Jakob disease

Magdalini Polymenidou, Katharina Stoeck, Markus
Glatzel, Martin Vey, Anne Bellon, and Adriano Aguzzi


The molecular typing of sporadic
Creutzfeldt-Jakob disease (CJD) is based on the size
and glycoform ratio of protease-resistant prion protein (PrPSc), and
on PRNP haplotype. On digestion with proteinase K, type
1 and type 2 PrPSc display unglycosylated core fragments of
21 kDa and 19 kDa, resulting from cleavage around amino
acids 82 and 97, respectively.
We generated anti-PrP monoclonal antibodies to
epitopes immediately preceding the differential proteinase
K cleavage sites. These antibodies, which were
designated POM2 and POM12, recognise type 1, but not
type 2, PrPSc.


We studied 114 brain samples from 70 patients
with sporadic CJD and three patients with variant CJD.
Every patient classified as CJD type 2, and all variant
CJD patients, showed POM2/POM12 reactivity in the
cerebellum and other PrPSc-rich brain areas, with a
typical PrPSc type 1 migration pattern.
The regular coexistence of multiple
PrPSc types in patients with CJD casts doubts on the
validity of electrophoretic PrPSc mobilities as surrogates for
prion strains, and questions the rational basis of
current CJD classifications.


The above results set the existing CJD classifications
into debate and introduce interesting questions about
human CJD types. For example, do human prion types
exist in a dynamic equilibrium in the brains of affected
individuals? Do they coexist in most or even all CJD
cases? Is the biochemically identified PrPSc type simply
the dominant type, and not the only PrPSc species?
Published online October 31, 2005

Detection of Type 1 Prion Protein in Variant
Creutzfeldt-Jakob Disease

Helen M. Yull,* Diane L. Ritchie,*
Jan P.M. Langeveld,? Fred G. van Zijderveld,?
Moira E. Bruce,? James W. Ironside,* and
Mark W. Head*
From the National CJD Surveillance Unit,* School of
and Clinical Medicine, University of Edinburgh, Edinburgh,
United Kingdom; Central Institute for Animal Disease
(CIDC)-Lelystad, ? Lelystad, The Netherlands; Institute
for Animal
Health, Neuropathogenesis Unit, ? Edinburgh, United Kingdom

Molecular typing of the abnormal form of the prion
protein (PrPSc) has come to be regarded as a powerful
tool in the investigation of the prion diseases. All
thus far presented indicates a single PrPSc molecular
type in variant Creutzfeldt-Jakob disease (termed
type 2B), presumably resulting from infection with a
single strain of the agent (bovine spongiform
Here we show for the first time that the PrPSc
that accumulates in the brain in variant Creutzfeldt-
Jakob disease also contains a minority type 1 component.
This minority type 1 PrPSc was found in all 21
cases of variant Creutzfeldt-Jakob disease tested,
of brain region examined, and was also
present in the variant Creutzfeldt-Jakob disease tonsil.
The quantitative balance between PrPSc types was maintained
when variant Creutzfeldt-Jakob disease was
transmitted to wild-type mice and was also found in
bovine spongiform encephalopathy cattle brain, indicating
that the agent rather than the host specifies their
relative representation. These results indicate that PrPSc
molecular typing is based on quantitative rather than
qualitative phenomena and point to a complex relationship
between prion protein biochemistry, disease phenotype
and agent strain. (Am J Pathol 2006, 168:151-157;
DOI: 10.2353/ajpath.2006.050766)



Irrespective of whether this proves to be the case, the results shown
here point to further complexities in the relationship between
the physico-chemical properties of the prion protein,
human disease phenotype, and prion agent strain.



Type 1 PrPSc in Variant Creutzfeldt-Jakob Disease 157
AJP January 2006, Vol. 168, No. 1 ...TSS
Neuropathology and Applied Neurobiology
, 565-579 doi: 10.1111/j.1365-2990.2005.00697.x
© 2005 Blackwell Publishing Ltd
Blackwell Science, LtdOxford, UKNANNeuropathology and
Applied Neurobiology0305-1846Blackwell Publishing Ltd, 2005

Review article

Phenotypic variability in human prion diseases

J. W. Ironside, D. L. Ritchie and M. W. Head
National Creutzfeldt-Jakob Disease Surveillance Unit,
Division of Pathology, University of Edinburgh,
Edinburgh, UK
J. W. Ironside, D. L. Ritchie and M. W. Head (2005)
Neuropathology and Applied Neurobiology

Phenotypic variability in human prion diseases
Human prion diseases are rare neurodegenerative disorders
that can occur as sporadic, familial or acquired disorders.
Within each of these categories there is a wide range
of phenotypic variation that is not encountered in other
neurodegenerative disorders. The identification of the
prion protein and its key role in the pathogenesis of this
diverse group of diseases has allowed a fuller
of factors that influence disease phenotype. In particular,
the naturally occurring polymorphism at codon 129
in the prion protein gene has a major influence on the
phenotype in sporadic, familial and acquired prion
diseases, although the underlying mechanisms remain
unclear. Recent technical advances have improved our
ability to study the isoforms of the abnormal prion protein
in the brain and in other tissues. This has lead to the
of molecular strain typing, in which different isoforms
of the prion protein are proposed to correspond to
individual strains of the transmissible agent, each with
specific biological properties. In sporadic
disease there are at least six major combinations of codon
129 genotype and prion protein isotype, which appear to
relate to distinctive clinical subgroups of this disease.
However, these relationships are proving to be more complex
than first considered, particularly in cases with more
than a single prion protein isotype in the brain. Further
work is required to clarify these relationships and to
explain the mechanism of neuropathological targeting of
specific brain regions, which accounts for the diversity of
clinical features within human prion diseases.

© 2005 Blackwell Publishing Ltd, Neuropathology and
Applied Neurobiology, 31, 565-579

BSE prions propagate as either variant CJD-like or
sporadic CJD-like prion strains in transgenic mice
expressing human prion protein

The EMBO Journal Vol. 21 No. 23 pp. 6358±6366, 2002
Emmanuel A.Asante, Jacqueline M.Linehan,
Melanie Desbruslais, Susan Joiner,
Ian Gowland, Andrew L.Wood, Julie Welch,
Andrew F.Hill, Sarah E.Lloyd,
Jonathan D.F.Wadsworth and
John Collinge1
MRC Prion Unit and Department of Neurodegenerative Disease,
Institute of Neurology, University College, Queen Square,
London WC1N 3BG, UK
1Corresponding author

Variant Creutzfeldt±Jakob disease (vCJD) has been
recognized to date only in individuals homozygous for
methionine at PRNP codon 129. Here we show that
transgenic mice expressing human PrP methionine
129, inoculated with either bovine spongiform
encephalopathy (BSE) or variant CJD prions, may
develop the neuropathological and molecular phenotype
of vCJD, consistent with these diseases being
caused by the same prion strain. Surprisingly, however,
BSE transmission to these transgenic mice, in
addition to producing a vCJD-like phenotype, can also
result in a distinct molecular phenotype that is indistinguishable
from that of sporadic CJD with PrPSc
type 2. These data suggest that more than one BSEderived
prion strain might infect humans; it is therefore
possible that some patients with a phenotype consistent
with sporadic CJD may have a disease arising
from BSE exposure.


The EMBO Journal Vol. 21 No. 23 pp. 6358±6366, 2002
6358 ãEuropean Molecular Biology Organization
J Neuropsychiatry Clin Neurosci 17:489-495, November 2005
doi: 10.1176/appi.neuropsych.17.4.489
© 2005 American Psychiatric Publishing, Inc.

Psychiatric Manifestations of Creutzfeldt-Jakob
Disease: A 25-Year Analysis

Christopher A. Wall, M.D., Teresa A. Rummans, M.D.,
Allen J. Aksamit, M.D.,
Lois E. Krahn, M.D. and V. Shane Pankratz, Ph.D.
Received April 20, 2004; revised September 9, 2004;
accepted September 13,
2004. From the Mayo Clinic, Department of Psychiatry
and Psychology,
Rochester, Minnesota; Mayo Clinic, Department of
Neurology, Rochester,
Minnesota. Address correspondence to Dr. Wall, Mayo
Clinic, Department of
Psychiatry and Psychology, Mayo Building-W11A, 200
First St., SW, Rochester,
MN 55905; (E-mail).

This study characterizes the type and timing of psychiatric manifestations
in sporadic Creutzfeldt-Jakob disease (sCJD). Historically, sCJD has been
characterized by prominent neurological symptoms, while the variant form
(vCJD) is described as primarily psychiatric in presentation and course: A
retrospective review of 126 sCJD patients evaluated at the Mayo Clinic from
1976-2001 was conducted. Cases were reviewed for symptoms of depression,
anxiety, psychosis, behavior dyscontrol, sleep disturbances, and
neurological signs during the disease course. Eighty percent of the cases
demonstrated psychiatric symptoms within the first 100 days of illness, with
26% occurring at presentation. The most commonly reported symptoms in this
population included sleep disturbances, psychotic symptoms, and depression.
Psychiatric manifestations are an early and prominent feature of sporadic
CJD, often occurring prior to formal diagnosis.



Historically, psychiatric manifestations have been described as a relatively
infrequent occurrence in the sporadic form of creutzfeldt-Jakob disease.
However, our findings suggest otherwise. In this study,
a vast majority of the cases were noted to have at least one psychiatric
symptom during the course of illness, with nearly one-quarter occurring in
the prodromal or presenting phase of the illness. After comparing the
frequency of neuropsychiatric symptoms in sporadic CJD to studies
describing the variant form of CJD, we found that there are fewer clinical
differences than previously reported.5-7 While the age of patients
with vCJD presentation is significantly younger and the course of illness is
longer, the type and timing of psychiatric manifestations appear similar
between these two diseases. ...


Polish Journal of Neurology and Neurosurgery 6/2005



Mental disorders in a female patient with probable Creutzfeldt-Jakob disease
Neurol Neurochirur Pol 2005; 39, 6: 520–523
authors: Marek Gronkowski, Bozena Spila, Alina Nowicka, Piotr Machala, Grzegorz
The paper presents an overview of the current knowledge about the etiology,
classification of Creutzfeldt-Jakob disease, abnormalities in the results of the EEG, MR
and laboratory examinations in patients with this disease. The diagnostic value of the
CSF examination for presence of protein 14-3-3 is underlined. The article is based on
both Polish and foreign literature, describing mainly the diagnostics of CJD. The case of
a female patient with dementia, mental disorders and neurological symptoms in the
course of probable CJD, who was hospitalized at the Psychogeriatric Department of the
Neuropsychiatric Hospital in Lublin is described.
Polish Journal of Neurology and Neurosurgery 6/2005
full text of the article:

August 2007

HUMAN and ANIMAL TSE Classifications i.e. mad cow disease and the UKBSEnvCJD
only theory

TSEs have been rampant in the USA for decades in many species, and they all have been
rendered and fed back to animals for human/animal consumption. I propose that the
current diagnostic criteria for human TSEs only enhances and helps the spreading of
human TSE from the continued belief of the UKBSEnvCJD only theory in 2007.
With all the science to date refuting it, to continue to validate this myth, will only spread
this TSE agent through a multitude of potential routes and sources i.e. consumption,
surgical, blood, medical, cosmetics etc. I propose as with Aguzzi, Asante, Collinge,
Caughey, Deslys, Dormont, Gibbs, Ironside, Manuelidis,
Marsh, et al and many more, that the world of TSE Transmissible Spongiform
Encephalopathy is far from an exact science, but there is enough proven science to
date that this myth should be put to rest once and for all, and that we move forward with a
new classification for human and animal TSE that would properly identify
the infected species, the source species, and then the route.
This would further have to be broken down to strain of species and then the route of
transmission would further have to be broken down. Accumulation and Transmission are
key to the threshold from sub-clinical to clinical disease, and key to all this, is to stop the
amplification and transmission of this agent, the spreading of, no matter what strain. In
my opinion, to continue with this myth that the U.K. strain of BSE (one strain TSE in
cows), and the nv/v CJD (one strain TSE humans) and that all the rest of human
TSE are just one single strain i.e. sporadic CJD (when to date there are 6 different
phenotypes of sCJD, and growing per Gambetti et al), and that no other animal TSE
transmits to humans, to continue with this masquerade will only continue to spread,
expose, and kill, who knows how many more in the years and decades to come. ONE was
enough for me, My Mom, hvCJD i.e. Heidenhain Variant CJD, DOD 12/14/97
confirmed, which is nothing more than another mans name added to CJD, like CJD itself,
Jakob and Creutzfeldt, or Gerstmann-Straussler-Scheinker syndrome, just another CJD or
human TSE, named after another human.

WE are only kidding ourselves with the current diagnostic criteria for human and animal
TSE, especially differentiating between the nvCJD vs the sporadic CJD strains and then
the GSS strains and also the FFI fatal familial insomnia strains or the ones that mimics
one or the other of those TSE? Tissue infectivity and strain typing of the many variants
of the human and animal TSEs are paramount in all variants of all TSE. There must be a
proper classification that will differentiate between all these human TSE in order to do
this. With the CDI and other more sensitive testing coming about, I only hope that my
proposal will some day be taken seriously. ...

Terry S. Singeltary Sr.
P.O. Box 42
Bacliff, Texas USA 77518

1997 TO 2006. SPORADIC CJD CASES TRIPLED, with phenotype
of 'UNKNOWN' strain growing. ...

There is a growing number of human CJD cases, and they were presented last
week in San Francisco by Luigi Gambatti(?) from his CJD surveillance

He estimates that it may be up to 14 or 15 persons which display selectively
SPRPSC and practically no detected RPRPSC proteins.

Diagnosis and Reporting of Creutzfeldt-Jakob Disease

Singeltary, Sr et al. JAMA.2001; 285: 733-734.





MARCH 26, 2003

RE-Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob

disease in the United States

Email Terry S. Singeltary:

I lost my mother to hvCJD (Heidenhain Variant CJD). I would like to

comment on the CDC's attempts to monitor the occurrence of emerging

forms of CJD. Asante, Collinge et al [1] have reported that BSE

transmission to the 129-methionine genotype can lead to an alternate

phenotype that is indistinguishable from type 2 PrPSc, the commonest

sporadic CJD. However, CJD and all human TSEs are not reportable

nationally. CJD and all human TSEs must be made reportable in every

state and internationally. I hope that the CDC does not continue to

expect us to still believe that the 85%+ of all CJD cases which are

sporadic are all spontaneous, without route/source. We have many TSEs in

the USA in both animal and man. CWD in deer/elk is spreading rapidly and

CWD does transmit to mink, ferret, cattle, and squirrel monkey by

intracerebral inoculation. With the known incubation periods in other

TSEs, oral transmission studies of CWD may take much longer. Every

victim/family of CJD/TSEs should be asked about route and source of this

agent. To prolong this will only spread the agent and needlessly expose

others. In light of the findings of Asante and Collinge et al, there

should be drastic measures to safeguard the medical and surgical arena

from sporadic CJDs and all human TSEs. I only ponder how many sporadic

CJDs in the USA are type 2 PrPSc?

Hardcover, 304 pages plus photos and illustrations. ISBN 0-387-95508-9

June 2003

BY Philip Yam


Answering critics like Terry Singeltary, who feels that the U.S. under-
counts CJD, Schonberger conceded that the current surveillance system
has errors but stated that most of the errors will be confined to the older

Copyright © 2003 Published by Elsevier Ltd.

Tracking spongiform encephalopathies in North America

Xavier Bosch

Available online 29 July 2003.

Volume 3, Issue 8, August 2003, Page 463

“My name is Terry S Singeltary Sr, and I live in Bacliff, Texas. I lost my
mom to hvCJD (Heidenhain variant CJD)
and have been searching for answers ever since. What I have found is that we
have not been told the truth. CWD
in deer and elk is a small portion of a much bigger problem.”

see history of cjd questionnaire


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