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From: TSS (
Subject: Re: Human Prion Protein with Valine 129 Prevents Expression of Variant CJD Phenotype
Date: November 12, 2004 at 2:25 pm PST

-------- Original Message --------
Subject: Re: Human Prion Protein with Valine 129 Prevents Expression of Variant CJD Phenotype
Date: Fri, 12 Nov 2004 16:24:22 -0600
From: "Terry S. Singeltary Sr."
Reply-To: Bovine Spongiform Encephalopathy
References: <>

Hello Ingrid, Ralph and all,

Ingrid Schuett-Abraham writes;

> whether there has been an increase in sCJD cases in humans with MV and
> VV genotypes in countries with BSE, especially in those which also
> showed an increase in CJD during recent years.

THIS would be difficult to do in the USA under present surveillance
circumstances or the lack of (autopsy). some states have it reportable,
some dont, some states with different age brackets, nothing uniform, no
mandatory CJD questionnaire asking any real questions etc. i could
go on. In fact, we have young people dying at early age 26 that was
MM2 but the death certificate and autopsy from Gambetti et al
stated it was sporadic CJD. why is it in the UK if you are MM2
and young, you are nv/v CJD, but here in the USA you are sporadic CJD?

Collinge/Asante et al 2004;

> Until now it has been a mystery why everyone
> that has developed vCJD is of the MM type and one possibility is that
> they are simply the first to develop the disease when infected with BSE

> Remarkably, when these novel prions were used to infect mice of the MM
> genetic type, the mice either developed a disease very like vCJD, or
> else a pattern of disease that looks like so-called sporadic CJD the
> classical form of CJD.

and from 2002;

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

> A common polymorphism at codon 129 of the human PrP gene (PRNP), where
> either methionine (M) or valine (V) can be encoded, is a key
> determinant of susceptibility to sporadic and acquired prion diseases,
> and may affect age at onset in inherited prion disease (Baker et al.,
> 1991
> ;
> Collinge et al., 1991
> ;
> Palmer et al., 1991
> ).
> To date, all patients recognized with vCJD have been of the PRNP 129MM
> genotype (Collinge et al., 1996a
> ;
> Zeidler et al., 1997
> ;
> our unpublished data). PrP polymorphisms are known to affect prion
> strain propagation in mice and sheep (Bruce, 1993
> ).
> Similarly, codon 129 genotype may play a role in human prion strain
> propagation, since certain PrPSc types are closely associated with
> codon 129 genotypes. To date, we have found types 1 and 4 PrPSc only
> in individuals of the PRNP 129MM genotype and type 3 PrPSc only in
> genotypes MV or VV, while type 2 PrPSc is seen in association with all
> three genotypes (Collinge et al., 1996b
> ;
> Wadsworth et al., 1999
> ;
> our unpublished data). We have previously reported that
> Tg(HuPrP129V+/+ Prnp0/0)-152 mice, which express only human PrP V129
> (129VV Tg152 mice), are highly susceptible to infection with human
> prions from patients with sporadic and iatrogenic forms of CJD,
> regardless of patient genotype at polymorphic codon 129 (Collinge et
> al., 1995
> ;
> Hill et al., 1997
> ).
> However, these mice are much less susceptible to prions from patients
> with vCJD. Indeed, the transmission properties of vCJD closely
> resembled those of BSE, and these experiments form part of the
> extensive data arguing that vCJD is caused by a BSE-like prion strain
> (Collinge et al., 1996b
> ;
> Bruce et al., 1997
> ;
> Hill et al., 1997
> ).
> These mice lacked a species or transmission barrier to classical CJD
> prions and were also used to model the transmission barrier between
> cattle and humans (Collinge et al., 1995
> ;
> Hill et al., 1997
> ).
> These data were relatively reassuring, in that transmission of BSE to
> transgenic mice expressing only human PrP was inefficient, with <40%
> of intracerebrally inoculated mice succumbing to prion disease after
> prolonged incubation periods, consistent with the presence of a
> substantial transmission barrier. However, an important caveat with
> respect to public health considerations was that vCJD was occurring in
> humans of the PRNP 129MM genotype, while these mice expressed human
> PrP 129V (Collinge et al., 1995
> ;
> Hill et al., 1997
> ).
> Although classical CJD from patients with all three PRNP codon 129
> genotypes (MM, VV and MV) transmitted efficiently to these mice, it is
> possible that part of the transmission barrier to vCJD infection of
> these mice resided in the mismatch at codon 129 between inoculum and
> host (Hill et al., 1997
> ).
> Using the same inocula, we have now extended these studies to mice
> expressing human PrP M129 to further study both the bovine-to-human
> species barrier and the propagation of human and BSE prion strains.
> Detailed study of the relative transmission barriers to BSE in
> transgenic mice expressing human PrP M129 and V129 will be published
> elsewhere. Here we report the unexpected finding that BSE prion
> inoculation can induce replication of two distinct prion strains in
> mice expressing human prion protein.


> Prion propagation involves recruitment and conversion of host PrPC
> into PrPSc, and the degree of primary structural similarity between
> inoculated PrPSc and host PrPC is thought to be a key component of
> intermammalian transmission barriers (Prusiner et al., 1990
> ).
> It is clear, however, that prion strain type can also be crucial, as
> clearly demonstrated by the very distinctive transmission properties
> of sporadic CJD 129MM and vCJD 129MM prions (of identical PrP primary
> structure) in either 129VV Tg152 (Hill et al., 1997
> ;
> Collinge, 1999
> )
> or 129MM Tg35 mice. Prion strain type may also affect transmission
> barriers via an effect on PrPSc tertiary structure and state of
> aggregation (Hill et al., 1997
> ;
> Collinge, 1999
> ).
> These 129MM Tg35 mice, in which human PrPSc types can be propagated,
> have been used to study the BSE-to-human species barrier. The frequent
> presence of sub-clinical prion disease in vCJD- and BSE-inoculated
> 129MM Tg35 mice further argues for the need to reassess current
> definitions of species or transmission barriers that limit prion
> transmission between different hosts (Hill et al., 2000
> ).
> Such barriers have hitherto been quantitated on the basis of either
> comparative end-point titrations in the two respective hosts, or by
> measuring the fall in incubation period between primary and subsequent
> passage as the prion strain adapts to the new host. Both methods rely
> on measurement of time to onset of a clinical syndrome. Modelling the
> BSE-to-human barrier in 129MM Tg35 mice would lead to the conclusion,
> on the basis of induced clinical disease, that a substantial barrier
> existed. How ever, it is clear that human PrPSc propagation can be
> efficiently induced by inoculation with BSE or vCJD prions, suggesting
> a smaller barrier to infection (but not to clinical disease) than
> hitherto thought (Collinge et al., 1995
> )
> in humans of the PRNP 129MM genotype. Humans infected with BSE prions,
> but who became asymptomatic carriers, may nevertheless pose a threat
> of iatrogenic transmission via medical and surgical procedures.
> Alternatively, it is possible that the lifespan of the laboratory
> mouse is insufficient to allow expression of clinical disease in most
> inoculated mice, whereas a higher proportion of infected humans might
> survive the incubation period to develop clinical signs of disease.
> Serial passage studies and titration of prions in these mice are in
> progress to study this further.
> These studies further strengthen the evidence that vCJD is caused by a
> BSE-like prion strain. Also, remarkably, the key neuropathological
> hallmark of vCJD, the presence of abundant florid PrP plaques, can be
> recapitulated on BSE or vCJD transmission to these mice. However, the
> most surprising aspect of the studies was the finding that an
> alternate pattern of disease can be induced in 129MM Tg35 mice from
> primary transmission of BSE, with a molecular phenotype
> indistinguishable from that of a sub-type of sporadic CJD. This
> finding has important potential implications as it raises the
> possibility that some humans infected with BSE prions may develop a
> clinical disease indistinguishable from classical CJD associated with
> type 2 PrPSc. This is, in our experience, the commonest molecular
> sub-type of sporadic CJD. In this regard, it is of interest that the
> reported incidence of sporadic CJD has risen in the UK since the 1970s
> (Cousens et al., 1997
> ).
> This has been attributed to improved case ascertainment, particularly
> as much of the rise is reported from elderly patients and similar
> rises in incidence were noted in other European countries without
> reported BSE (Will et al., 1998
> ).
> However, it is now clear that BSE is present in many European
> countries, albeit at a much lower incidence than was seen in the UK.
> While improved ascertainment is likely to be a major factor in this
> rise, that some of these additional cases may be related to BSE
> exposure cannot be ruled out. It is of interest in this regard that a
> 2-fold increase in the reported incidence of sporadic CJD in 2001 has
> recently been reported for Switzerland, a country that had the highest
> incidence of cattle BSE in continental Europe between 1990 and 2002
> (Glatzel et al., 2002
> ).
> No epidemiological casecontrol studies with stratification of CJD
> cases by molecular sub-type have yet been reported. It will be
> important to review the incidence of sporadic CJD associated with
> PrPSc type 2 and other molecular sub-types in both BSE-affected and
> unaffected countries in the light of these findings. If human BSE
> prion infection can result in propagation of type 2 PrPSc, it would be
> expected that such cases would be indistinguishable on clinical,
> pathological and molecular criteria from classical CJD. It may also be
> expected that such prions would behave biologically like those
> isolated from humans with sporadic CJD with type 2 PrPSc. The
> transmission properties of prions associated with type 2 PrPSc from
> BSE-inoculated 129MM Tg35 mice are being investigated by serial passage.
> We consider these data inconsistent with contamination of some of the
> 129MM Tg35 mice with sporadic CJD prions. These transmission studies
> were performed according to rigorous biosafety protocols for
> preparation of inocula and both the inoculation and care of mice,
> which are all uniquely identified by sub-cutaneous transponders.
> However, crucially, the same BSE inocula have been used on 129VV Tg152
> and 129MM Tg45 mice, which are highly sensitive to sporadic CJD but in
> which such transmissions producing type 2 PrPSc were not observed.
> Furthermore, in an independent experiment, separate inbred lines of
> wild-type mice, which are highly resistant to sporadic CJD prions,
> also propagated two distinctive PrPSc types on challenge with either
> BSE or vCJD. No evidence of spontaneous prion disease or PrPSc has
> been seen in groups of uninoculated or mock-inoculated aged 129MM Tg35
> mice.
> While distinctive prion isolates have been derived from BSE passage in
> mice previously (designated 301C and 301V), these, in contrast to the
> data presented here, are propagated in mice expressing different prion
> proteins (Bruce et al., 1994
> ).
> It is unclear whether our findings indicate the existence of more than
> one prion strain in individual cattle with BSE, with selection and
> preferential replication of distinct strains by different hosts, or
> that mutation of a unitary BSE strain occurs in some types of host.
> Western blot analysis of single BSE isolates has not shown evidence of
> the presence of a proportion of monoglycosylated dominant PrPSc type
> in addition to the diglycosylated dominant pattern (data not shown).
> Extensive strain typing of large numbers of individual BSE-infected
> cattle either by biological or molecular methods has not been reported.
> Presumably, the different genetic background of the different inbred
> mouse lines is crucial in determining which prion strain propagates on
> BSE inoculation. The transgenic mice described here have a mixed
> genetic background with contributions from FVB/N, C57BL/6 and 129Sv
> inbred lines; each mouse will therefore have a different genetic
> background. This may explain the differing response of individual
> 129MM Tg35 mice, and the difference between 129MM Tg35 and 129MM Tg45
> mice, which are, like all transgenic lines, populations derived from
> single founders. Indeed, the consistent distinctive strain propagation
> in FVB and C57BL/6 versus SJL and RIIIS lines may allow mapping of
> genes relevant to strain selection and propagation, and these studies
> are in progress.
> That different prion strains can be consistently isolated in different
> inbred mouse lines challenged with BSE prions argues that other
> species exposed to BSE may develop prion diseases that are not
> recognizable as being caused by the BSE strain by either biological or
> molecular strain typing methods. As with 129MM Tg35 mice, the prions
> replicating in such transmissions may be indistinguishable from
> naturally occurring prion strains. It remains of considerable concern
> whether BSE has transmitted to, and is being maintained in, European
> sheep flocks. Given the diversity of sheep breeds affected by scrapie,
> it has to be considered that some sheep might have become infected
> with BSE, but propagated a distinctive strain type indistinguishable
> from those of natural sheep scrapie.
Brain, Vol. 126, No. 6, 1333-1346, June 2003
© 2003 Guarantors of Brain
doi: 10.1093/brain/awg125

Molecular classification of sporadic CreutzfeldtJakob disease

Andrew F. Hill1,4, Susan Joiner1, Jonathan D. F. Wadsworth1, Katie C. L.
Sidle1, Jeanne E. Bell2, Herbert Budka3, James W. Ironside2 and John

1 MRC Prion Unit, Department of Neurodegenerative Disease, Institute of
Neurology, National Hospital for Neurology and Neurosurgery, London, 2
National CJD Surveillance Unit, University of Edinburgh, Western General
Hospital, Edinburgh, UK and 3 Institute of Neurology, University of
Vienna, Vienna, Austria 4 Present address: Department of Biochemistry
and Molecular Biology, University of Melbourne, Parkville, Victoria,

Correspondence to: Professor John Collinge, MRC Prion Unit, Department
of Neurodegenerative Disease, Institute of Neurology, Queen Square,
London WC1N 3BG, UK E-mail:

According to the protein-only hypothesis of prion propagation, an
abnormal isoform (designated PrPSc) of the cellular prion protein (PrPC)
is the principal or sole component of transmissible prions. However, the
existence of multiple prion strains has been difficult to accommodate
within this hypothesis. We have previously reported the identification
of four types of human PrPSc associated with sporadic and acquired human
prion diseases. These PrPSc types are distinguished by differing
molecular mass of fragments following limited proteinase K digestion and
by differing ratios of di-, mono- and unglycosylated PrPSc. That these
discrete biochemical features of PrPSc are serially transmissible to
human PrP in transgenic mice following experimental transmission
suggests that they may be responsible for encoding prion strain
diversity. Here we present detailed clinical, pathological and molecular
data from a large number of sporadic CreutzfeldtJakob disease (CJD)
cases. We show that PrPSc types are associated with codon 129 status,
duration of illness and neuropathological phenotype. A novel PrPSc type
is presented, illustrating further heterogeneity in CJD, and suggesting
that further molecular subtypes of CJD may exist at lower frequencies. A
molecular classification of sporadic CJD is proposed.


Strange how 2 highly respected research centers differ with this
terminology of science, if i understand all this correctly?


> [P06.039] Two Cases of Early Onset Sporadic Creutzfeld-Jakob Disease
> in Michigan
> Amanda C. Peltier, Patience H. Reading, Karen Kluin, Sharin Sakurai,
> Ahmad Beydoun, Jonathan Edwards, Pierluigi Gambetti, Norman L. Foster
> Ann Arbor , MI; Cleveland, OH
> OBJECTIVE: To describe the clinical, pathological and genetic features
> in two young men who developed sporadic Creutzfeldt-Jakob disease
> (CJD) concurrently in Michigan.
> BACKGROUND: Sporadic CJD typically occurs in the 6th and 7th decades
> of life and is rarely reported in persons younger than 30, except with
> exposure to bovine spongiform encephalopathy (BSE) or pituitary
> extract derived human growth hormone (HGH). BSE has not been found in
> the US.
> DESIGN/METHODS: Case Reports.
> RESULTS: Two young men, ages 26 and 28, who were unknown to each other
> and had lived their entire lives in Michigan, developed rapidly
> progressive dementia and were simultaneously evaluated in our
> hospital. Neither had traveled to countries with known BSE, received
> HGH, eaten venison or elk, or had a family history of dementia. The
> first patient had a 2 month history of progressive aphasia, social
> withdrawal and memory difficulties. An EEG performed on admission
> revealed waxing and waning rhythmic spike and wave discharges. He was
> treated for nonconvulsive status epilepticus, which became convulsive
> during his hospital course. His seizures were refractory to medical
> therapy despite multiple anticonvulsants, including midazolam coma.
> His EEG became more periodic and he never recovered responsiveness
> even as medication was tapered. A brain biopsy and subsequent
> postmortem examination following his death 5 months after the onset of
> symptoms showed spongiform changes. The scrapie prion protein (PrPsc)
> was distributed in a cluster pattern as revealed by
> immunohistochemistry. Genetic analysis and immunoblot established that
> this patient had the MM2 subtype of sporadic CJD. Treatment with
> quinacrine had no benefit. The second patient had a 10 month history
> of progressive memory loss, inappropriate behavior, violent outbursts,
> and difficulty performing his job. He had bradykinesia and rigidity on
> examination. There were no periodic discharges on EEG and CSF protein
> 14-3-3 was negative. Following a brain biopsy showing spongiform
> changes he developed startle myoclonus. The presence of PrPsc type 1
> was confirmed with immunoblot and immunostaining. Both patients had
> abnormal MRI scans with increased signal in the basal ganglia and
> cerebral cortex on T2- and diffusion-weighted images.
> CONCLUSIONS: These cases expand the spectrum of sporadic CJD to
> include younger age of onset than previously suspected and cases
> presenting as non-convulsive status epilepticus. The appearance of CJD
> in 2 individuals within a few months of each other in southeastern
> Michigan may indicate that very early-onset CJD is more common than
> previously believed. Alternatively, other unrecognized risk factors
> may exist. It is important to consider CJD in young people with
> progressive behavioral and cognitive disturbances, even in the absence
> of typical EEG or CSF abnormalities.
> Supported By: This study was supported by NIH grant AG14359 and grant
> CCU 515004 to the National Prion Disease Pathology Surveillance Center
> and the Michigan Alzheimers Disease Research Center (NIH grant
> P50-AG0871).
> Category - Infection/AIDS/Prion Disease
> SubCategory - Epidemiology
> ====================
> A recent epidemiologic and laboratory investigation
> of three unusually young patients with CJD who regularly
> consumed venison did not identify convincing evidence
> for a causal link between CWD and the patients
> illness.5 Two of the patients, aged 28 and 30 years at
> death, were hunters, and the third patient, aged 28
> years, consumed venison harvested by family members.
> None of the patients was reported to have consumed
> deer meat obtained from the known CWDendemic
> areas of Colorado and Wyoming. The patients
> disease phenotype and the prion protein gene polymorphism
> at codon 129 were heterogeneous, possibly indicating
> lack of exposure to a similar agent. This was
> unlike patients with vCJD in whom the disease phenotype
> and codon 129 polymorphism had some homogeneity,
> owing to infection of the patients by the same
> agent of BSE. In addition, brain tissues from over
> 1,000 deer and elk harvested in the areas where the
> venison consumed by the three patients originated
> from tested negative for CWD...


Risk for Transmission to Humans

Epidemiologic Studies

The increasing detection of CWD in a wider geographic area and the
presumed foodborne transmission of BSE to humans, resulting in cases of
vCJD, have raised concerns about the possible zoonotic transmission of
CWD (32 ). In the
late 1990s, such concerns were heightened by the occurrence of CJD among
three patients 30 years of age who were deer hunters or ate deer and elk
meat harvested by family members (Table 2
). However,
epidemiologic and laboratory investigations of these case-patients
indicated no strong evidence for a causal link between CWD and their CJD
illness (33 ).
None of the patients were reported to have hunted deer or eaten deer
meat harvested in the CWD-endemic areas of Colorado and Wyoming. Such a
history in unusually young CJD patients, if present, would have
supported a causal link with CWD. Moreover, the testing of brain tissues
from >1,000 deer and elk harvested from areas where the patients hunted
or their venison originated did not show any evidence of CWD (33
). In addition,
the lack of homogeneity in the clinicopathologic manifestation and codon
129 of the prion protein gene among the three patients suggested that
their illnesses could not be explained by exposure to the same prion
strain. In vCJD, homogeneity of the genotype at codon 129 and the
clinical and pathologic phenotype were attributed to the patients'
exposure to the same prion strain, the agent of BSE.

In 2001, the case of a 25-year-old man who reportedly died of a prion
disease after an illness lasting ?22 months was investigated (Table 2
). Although
this man had hunted deer only rarely, his grandfather hunted deer and
elk throughout much of the 1980s and 1990s and regularly shared the
venison with the case-patient's family. The grandfather primarily hunted
in southeastern Wyoming, around the known CWD-endemic area. The
case-patient's illness began with a seizure and progressed to fatigue,
poor concentration, and depression. Memory loss, ataxia, speech
abnormalities, combative behavior, and recurrent seizures also
developed. Histopathologic, immunohistochemical, and Western blot
testing of brain autopsy samples confirmed a prion disease diagnosis.
Analysis of the prion protein gene indicated a P102L mutation coupled
with valine at the polymorphic codon 129 in the mutant allele,
confirming a diagnosis of Gerstmann-Sträussler-Scheinker syndrome (GSS).
This case-patient was unusually young even for a person with a GSS P102L
mutation. It remains unknown whether the possible exposure of the
case-patient to CWD-infected venison potentially contributed to the
early onset of his prion disease.

In 2001, two additional CJD patients 26 and 28 years of age were
reported from a single state (Table 2
) (34
). The patients
grew up in adjacent counties and had illness onset within several months
of each other. As a result of this fact and their unusually young age, a
possible environmental source of infection, including exposure to
CWD-infected venison, was considered. One of the patients died after an
illness lasting 56 months that was characterized by progressive
aphasia, memory loss, social withdrawal, vision disturbances, and
seizure activity leading to status epilepticus and induced coma.
Histopathologic, immunohistochemical, and Western blot testing of brain
biopsy and autopsy samples confirmed a CJD diagnosis. The patient's
disease phenotype corresponded to the MM2 sporadic CJD subtype reported
by Parchi et al. (35
). This patient
did not hunt, and family members provided no history of regularly eating
venison. The patient may have occasionally eaten venison originating
from the Upper Peninsula of Michigan while away from home during his
college years. However, ongoing surveillance has not detected CWD in
Michigan deer (36 ).

The second patient died from an illness lasting <16 months. The
patient's illness began with behavioral changes, including unusual
outbursts of anger and depression. Confusion, memory loss, gait
disturbances, incontinence, headaches, and photophobia also developed.
Western blot analysis of frozen brain biopsy tissue confirmed a prion
disease diagnosis. Immunohistochemical analysis of brain tissue obtained
after the patient's death showed prion deposition consistent with GSS. A
prion protein gene analysis could not be performed because appropriate
samples were lacking. However, prion protein gene analysis of a blood
sample from one of the patient's parents indicated a GSS P102L mutation.
The patient did not hunt but may have eaten venison from Michigan once
when he was 12 years old. The GSS diagnosis greatly reduced the
likelihood that the two patients reported from adjacent counties had
disease with a common origin.

Recently, rare neurologic disorders resulting in the deaths of three men
who participated in "wild game feasts" in a cabin owned by one of the
decedents created concern about the possible relationship of their
illnesses with CWD (Table 2
) (37
). Two of the
patients reportedly died of CJD, and the third died from Pick's disease.
More than 50 persons were identified as possibly participating in these
feasts; the three patients were the only participants reported to have
died of a degenerative neurologic disorder. Reanalysis of autopsy brain
tissues from the three patients at the National Prion Disease Pathology
Surveillance Center indicated that two of them had no evidence of a
prion disease by immunohistochemical analysis. CJD was confirmed in the
third patient, who had clinicopathologic, codon 129, and prion
characteristics similar to the most common sporadic CJD subtype
(MM1/MV1) (35 ).
This patient participated in the feasts only once, perhaps in the
mid-1980s. In addition, the investigation found no evidence that the
deer and elk meat served during the feasts originated from the known
CWD-endemic areas of Colorado and Wyoming.

In 2003, CJD in two deer and elk hunters (54 and 66 years of age) was
reported (38 ).
The report implied that the patients had striking neuropathologic
similarities and that their illness may represent a new entity in the
spectrum of prion diseases. A third patient (63 years of age), who was
also purported to have been a big game hunter, was subsequently reported
from the same area. However, none of the three patients were reported to
have eaten venison from the CWD-endemic areas of the western United
States. The 66-year-old patient hunted most of his life in Washington
State. Although information about the 54-year-old patient was limited,
there was no evidence that he hunted in CWD-endemic areas. The third
patient was not a hunter but ate venison harvested from Pennsylvania and
Washington. The neuropathologic changes, Western blot profile, and
genotype at codon 129 of the three patients each fit the MM1, VV1, or
VV2 sporadic CJD subtype, indicating absence of phenotypic similarity
among the cases or atypical neuropathologic features (35

To date, only two nonfamilial CJD cases with a positive history of
exposure to venison obtained from the known CWD-endemic areas have been
reported. One of the patients was a 61-year-old woman who grew up in an
area where this disease is known to be endemic, and she ate venison
harvested locally. She died in 2000, and analysis of autopsy brain
specimens confirmed that the patient's CJD phenotype fit the MM1
subtype, with no atypical neuropathologic features. The second patient
was a 66-year-old man who was reported to have eaten venison from two
deer harvested in a CWD-endemic area. Both deer tested negative for CWD,
and the patient's illness was consistent with the MM1 CJD phenotype.

Ann Neurol. 1999 Aug;46(2):224-33.

Classification of sporadic Creutzfeldt-Jakob disease based on molecular
and phenotypic analysis of 300 subjects.

Parchi P, Giese A, Capellari S, Brown P, Schulz-Schaeffer W, Windl O,
Zerr I, Budka H, Kopp N, Piccardo P, Poser S, Rojiani A, Streichemberger
N, Julien J, Vital C, Ghetti B, Gambetti P, Kretzschmar H.

Division of Neuropathology, Institute of Pathology, Case Western Reserve
University, Cleveland, OH 44106, USA.

Phenotypic heterogeneity in sporadic Creutzfeldt-Jakob disease (sCJD) is
well documented, but there is not yet a systematic classification of the
disease variants. In a previous study, we showed that the polymorphic
codon 129 of the prion protein gene (PRNP), and two types of
protease-resistant prion protein (PrP(Sc)) with distinct physicochemical
properties, are major determinants of these variants. To define the full
spectrum of variants, we have examined a series of 300 sCJD patients.
Clinical features, PRNP genotype, and PrP(Sc) properties were determined
in all subjects. In 187, we also studied neuropathological features and
immunohistochemical pattern of PrP(Sc) deposition. Seventy percent of
subjects showed the classic CJD phenotype, PrP(Sc) type 1, and at least
one methionine allele at codon 129; 25% of cases displayed the ataxic
and kuru-plaque variants, associated to PrP(Sc) type 2, and valine
homozygosity or heterozygosity at codon 129, respectively. Two
additional variants, which included a thalamic form of CJD and a
phenotype characterized by prominent dementia and cortical pathology,
were linked to PrP(Sc) type 2 and methionine homozygosity. Finally, a
rare phenotype characterized by progressive dementia was linked to
PrP(Sc) type 1 and valine homozygosity. The present data demonstrate the
existence of six phenotypic variants of sCJD. The physicochemical
properties of PrP(Sc) in conjunction with the PRNP codon 129 genotype
largely determine this phenotypic variability, and allow a molecular
classification of the disease variants.

TO add more confusion ;

Sporadic and familial CJD: classification and characterisation

Pierluigi Gambetti*, Qingzhong Kong*, Wenquan Zou*, Piero Parchi{dagger}
and Shu G Chen*

*Division of Neuropathology, Institute of Pathology, Case Western
Reserve University, Cleveland, Ohio, USA
{dagger} 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

Identification of Distinct N-terminal Truncated Forms of Prion
Protein in Different Creutzfeldt-Jakob Disease Subtypes*

Gianluigi Zanusso{ddagger} , Alessia Farinazzo{ddagger} , Frances
Prelli§ , Michele Fiorini{ddagger} , Matteo Gelati{ddagger} , Sergio
Ferrari{ddagger} , Pier Giorgio Righetti¶, Nicolò Rizzuto{ddagger} ,
Blas Frangione§ , and Salvatore Monaco{ddagger} ||

From the {ddagger} Departments of Neurological and Visual Sciences,
Section of Neurology and ¶Agricultural and Industrial Biotechnologies,
University of Verona, 37134 Verona, Italy and the § Department of
Pathology, New York University Medical Center, New York, New York

In prion diseases, the cellular prion protein (PrPC) is converted to an
insoluble and protease-resistant abnormal isoform termed PrPSc. In
different prion strains, PrPSc shows distinct sites of endogenous or
exogenous proteolysis generating a core fragment named PrP27-30.
Sporadic Creutzfeldt-Jakob disease (sCJD), the most frequent human prion
disease, clinically presents with a variety of neurological signs. As
yet, the clinical variability observed in sCJD has not been fully
explained by molecular studies relating two major types of PrP27-30 with
unglycosylated peptides of 21 (type 1) and 19 kDa (type 2) and the amino
acid methionine or valine at position 129. Recently, smaller C-terminal
fragments migrating at 12 and 13 kDa have been detected in different
sCJD phenotypes, but their significance remains unclear. By using
two-dimensional immunoblot with anti-PrP antibodies, we identified two
novel groups of protease-resistant PrP fragments in sCJD brain tissues.
All sCJD cases with type 1 PrP27-30, in addition to MM subjects with
type 2 PrP27-30, were characterized by the presence of unglycosylated
PrP fragments of 16-17 kDa. Conversely, brain homogenates from patients
VV and MV with type 2 PrP27-30 contained fully glycosylated PrP
fragments, which after deglycosylation migrated at 17.5-18 kDa.
Interestingly, PrP species of 17.5-18 kDa matched deglycosylated forms
of the C1 PrPC fragment and were associated with tissue PrP deposition
as plaque-like aggregates or amyloid plaques. These data show the
presence of multiple PrPSc conformations in sCJD and, in addition, shed
new light on the correlation between sCJD phenotypes and
disease-associated PrP molecules.


J. Biol. Chem., Vol. 279, Issue 37, 38936-38942, September 10, 2004

Identification of Distinct N-terminal Truncated Forms of Prion
Protein in Different Creutzfeldt-Jakob Disease Subtypes*

Received for publication, May 17, 2004 , and in revised form, July 7, 2004.

* This work was supported by grants from the Italian Ministry of Health
in collaboration and with the contribution of the Istituto Superiore di
Sanità ("Search for infection-related endogenous or exogenous factors in
the cerebrospinal fluid of patients with transmissible spongiform
encephalopathy" and "Study of pathogenic mechanisms in neurodegenerative
disorders for the diagnosis and development of therapeutic approaches.")
and from National Institutes of Health Grant AR02584 (to B. F.). The
costs of publication of this article were defrayed in part by the
payment of page charges. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section 1734 solely to
indicate this fact.

|| To whom correspondence should be addressed: Dept. of Neurological and
Visual Sciences, Section of Neurology, Policlinico G. B. Rossi, P.le L.
A. Scuro, 10, 37134 Verona, Italy. Tel.: 39-045-8074286; Fax:
39-045-585933; E-mail:

Severe brain atrophy in a case of thalamic variant of sporadic CJD with
plaque-like PrP deposition
Mariko Yamash!ta,1

Toru Yamamoto,1

Kazuto Nishinaka,2

Fukashi Udaka,2

Masakuni Kameyama2

and Tetsuyuki Kitamoto3

A 30-year-old woman presented with ataxic gait and progressive mental
deterioration, and 3 years later developed myoclonus in the limbs.
Subsequently, she lapsed into an akinetic state and died more than 6
years after the onset of disease. The brain weighed 670 g, and
preferential degeneration was found in the medial thalamus and the
inferior olivary nucleus. In the cerebrum and cerebellum, gliosis and
neuronal depletion were only mild and disintegration of the parenchymal
structures was inconspicuous, despite pronounced atrophy. The patient
had methionine homozygosity at codon 129 of the PrP gene and
protease-resistant PrP type 2 in the brain. On PrP immunostaining,
plaque-like deposits were detected in the cerebral and cerebellar
cortices. Severe brain atrophy such as in the present case has never
been described in the thalamic variant of sporadic CJD.;jsessionid=eF7_r2TI1Sx5



FOR ABOUT 15 MONTHS (sporadic CJD?)


sporadic CJD ?


HOWEVER, even more important should be, what about those farmers in the
80s that died from
sporadic CJD? Exactly what was that?


20 year old died from sCJD in USA in 1980 and a 16 year
old in 1981. A 19 year old died from sCJD in
France in 1985. There is no evidence of an iatrogenic
cause for those cases....

cover-up of 4th farm worker ???


now story changes from;

SEAC concluded that, if the fourth case were confirmed, it would be
worrying, especially as all four farmers with CJD would have had BSE
cases on their farms.


This is not unexpected...

was another farmer expected?

4th farmer, and 1st teenager

2. snip...
Over a 5 year period, which is the time period on which the advice
from Professor Smith and Dr. Gore was based, and assuming a
population of 120,000 dairy farm workers, and an annual incidence
of 1 per million cases of CJD in the general population, a
an individual in the general population to develop CJD. Using the
actual current annual incidence of CJD in the UK of 0.7 per
million, this figure becomes 7.5 TIMES.

3. You will recall that the advice provided by Professor Smith in
1993 and by Dr. Gore this month used the sub-population of dairy
farm workers who had had a case of BSE on their farms -
63,000, which is approximately half the number of dairy farm
workers - as a denominator. If the above sums are repeated using
this denominator population, taking an annual incidence in the general
population of 1 per million the observed rate in this sub-population
is 10 TIMES, and taking an annual incidence of 0.7 per million,
that in the general population...


INDEED these studies bring us closer to explaining the 85%+ of all
CJD 'sporadic', at least it shows they are not as spontaneous as once
thought. However, even more frightening and another snake pit which
someone will have to jump off into sooner hopefully rather than later is;

Prion protein codon 129 polymorphism and risk of Alzheimer disease [FULL
Date: July 29, 2004 at 9:26 am PST

The authors investigated the PRNP Met129Val polymorphism in
1,393 subjects including 482 patients with
Alzheimer disease (AD) and two independent control groups. In patients,
PRNP Met homozygosity conferred increasing risk
with decreasing age at onset (onset: 61 to 70 years, n  151, p  0.02,
odds ratio [OR]  1.72, 95% CI  1.2 to 2.53; onset: 60
years, n  138, p  0.013, OR  1.92, 95% CI  1.31 to 2.87), whereas no
association was obtained in patients with onset at
older than 70 years. The results suggest involvement of the prion
protein in the pathogenesis of early-onset AD.
NEUROLOGY 2004;63:364366

full text;

and here;

Proof Mad Cow Is The Same As Alzheimer's And CJD

How Many Of Them Are Really Mad Cow/vCJD/TSEs ???

How Can Government Claims Of Just 'One In A Million'
Be Accurate

When CJD Is Not A Reportable Disease? And When The Elderly Do
Not Get Routinely Autopsied??

By Terry Singeltary, Sr



Collinge/Asante et al have been right all along, but the fact is the Gov's
involved simply refuse to acknowledge the science due to corporate interest$
and refuse to heed there warnings for years, thus, we are all exposed due to
years .........decades of denial and cover-up. THEY better heed there


> We always have to be cautious about making direct comparison to the
> human condition, but our work strongly suggests that we can not assume
> only those with one genetic profile are vulnerable to BSE infection.
> At this stage it is not possible to say how this should alter estimates
> of those likely to become ill, but our findings do suggest we should be
> taking steps to draw up a more sophisticated system of categorizing the
> disease so that we dont mistake BSE related infection for a version of
> sporadic CJD.

Warnings have been there for a long time;


AS implied in the Inset 25 we must not _ASSUME_ that
transmission of BSE to other species will invariably
present pathology typical of a scrapie-like disease.



ROUND TABLE ON BSE - WASHINGTON - 27 - 28 '''1989'''

The summary does tend to give a particular slant to the epidemiology of BSE
which is not totally sound. IT IS a possibility that the agent of BSE may be
in the cattle population in a number of countries already apart from the
USA and
that clinical cases are occurring on rare occasions...

HOW long must we play this game of Russian Roulette for political purposes,
while the agent continues to spread, expose, infect and kill innocent

AS we delve further into this man made nightmare, I predict that one day
there will be an answer
for all sporadic CJDs and none will be spontaneous (i dont believe in
santa clause or the tooth
fairy anymore either). However, I don't think I will live long enough
for that to be proven beyond
a shadow of a doubt of strain typing all human/animal TSEs with there
many different routes of

I don't see anything getting any better here in the USA anytime soon
under present circumstances.
WE have a government that is not run by a President, but by corporate
interest and all the mad cash
cows that comes with it. Hell, in the USA we cannot even get them to
document the true extent
of TSE in the USA bovine, much less human TSEs.

IT's a loose/loose situation here.

kindest regards,

J Ralph Blanchfield, MBE wrote:

>##################### Bovine Spongiform Encephalopathy #####################
>Dear Terry, Ingrid and Everyone,
>It is interesting to recall that, before the identification of vCJD and its
>characteristics, the first major mouse research experiments, first reported by
>Collinge et al in December 1995 and in follow-ups thereafter, were on
>genetically-modified mice that expressed only human protein and no mouse
>protein, and that the genotype chosen was val/val homozygous at codon 129,
>which was the one they considered (at that time) to be most susceptible to human
>prion diseases. They intracerebrally inoculated the mice with BSE (brain
>homogenate from confirmed BSE-infected cows). It was reported in the paper
>that these remained well at 264 days after inoculation (60 days longer than for
>CJD to develop in mice of this genotype). Published reports on their progress
>appeared from time to time, the most recent being after they had successfully
>passed the 500 day mark in early September 1996. On 10 February 1997, Collinge
>confirmed verbally that the mice were still fit and well, at which point they
>must have been close to dying of old age. There were subsequent uninformative
>reports that the mice had died but I cannot recall any publication of
>post-mortem findings.
>In vitro research [Raymond et al (1997)] suggested that "recruitment" can occur,
>though at a slower rate, even if there is a significant conformational
>difference between the infective prion and the host normal prion. Their finding
>that host prion protein methionine/methionine homozygous at codon 129 is
>converted more rapidly than host prion protein valine/valine homozygous at codon
>129, is consistent with the subsequent fact that all the victims who have died
>of vCJD to date have been met/met homozygous at codon 129. Their findings
>suggested that met/met has a shorter incubation period, rather than that val/val
>or met/val confer immunity.
>Since then, Collinge et al (2001) have shown that codon 129 may not be the only
>significant location and that other genes are likely to play an important role
>in susceptibility to infection. Two different strains of mice with known
>differences in incubation periods for disease were used in the study and the
>mice given a thorough analysis of their whole genome, which allowed the three
>genes to be located that are involved in susceptibility to prion disease in
>mice. As the mouse and human genomes are so similar they concluded that it is
>almost certain that corresponding genes in humans will be found which have the
>same role to play, Thus there could up to three variably-susceptible genetic
>groups and at least three sub-groups in each. All the reported deaths thus far,
>all met/met at codon 129, could be in the most susceptible genetic sub-group of
>the most susceptible group.
>Asante et al (2002) have shown that transgenic mice expressing human PrP
>methionine 129, inoculated with either BSE or vCJD 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 SE-derived 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.
>This latest paper represents a logical progression in the valuable work of the
>Collinge group.
>Collinge J et al (1995) "Unaltered susceptibility to BSE in transgenic mice
>expressing human prion protein", Nature, 378, 21-28 December, 779.
>Raymond G J et al (1997) "Molecular assessment of the potential
>transmissibilities of BSE and scrapie to humans", Nature, 388, 17 July 1997,
>Collinge J et al (2001), Proceedings of the National Academy of Sciences, 14 May
>Asante et al (2002). EMBO Journal, 21 ( 23), 6358-6366.
>Best wishes
>Prof J Ralph Blanchfield, MBE
>Food Science, Food Technology and Food Law Consultant
>Chair, External Affairs, Institute of Food Science and Technology
>Webmaster / Web Editor, Institute of Food Science and Technology
>IFST Web address
>Personal Web address
>Note: All outgoing e-mails have been scanned for all
>known viruses by the latest version of Norton Anti-virus.
>On Thu, 11 Nov 2004 16:18:17 -0600, Terry wrote:

>> Submitted on August 11, 2004
>>Accepted on October 22, 2004
>> Human Prion Protein with Valine 129 Prevents Expression of Variant
>> CJD Phenotype
>>Jonathan D. F. Wadsworth 1, Emmanuel A. Asante 1, Melanie Desbruslais 1,
>>Jacqueline M. Linehan 1, Susan Joiner 1, Ian Gowland 1, Julie Welch 1,
>>Lisa Stone 1, Sarah E. Lloyd 1, Andrew F. Hill 1{dagger} , Sebastian
>>Brandner 1, John Collinge 1*
>>1 Medical Research Council (MRC) Prion Unit and Department of
>>Neurodegenerative Disease, Institute of Neurology, University College
>>London, Queen Square, London WC1N 3BG, UK.
>>* To whom correspondence should be addressed.
>>John Collinge , E-mail:
>>{dagger} Present address: Department of Biochemistry and Molecular
>>Biology and Department of Pathology, University of Melbourne, Parkville,
>>Victoria 3010, Australia.
>>Variant Creutzfeldt-Jakob disease (vCJD) is a unique and highly
>>distinctive clinicopathological and molecular phenotype of human prion
>>disease associated with infection with bovine spongiform encephalopathy
>>(BSE)-like prions. Here, we found that generation of this phenotype in
>>transgenic mice required expression of human prion protein (PrP) with
>>methionine 129. Expression of human PrP with valine 129 resulted in a
>>distinct phenotype and, remarkably, persistence of a barrier to
>>transmission of BSE-derived prions on subpassage. Polymorphic residue
>>129 of human PrP dictated propagation of distinct prion strains after
>>BSE prion infection. Thus, primary and secondary human infection with
>>BSE-derived prions may result in sporadic CJD-like or novel phenotypes
>>in addition to vCJD, depending on the genotype of the prion source and
>>the recipient.
>>Science 10.1126/science.1103932
>>Copyright © 2004 by The American Association for the Advancement of
>>Science. All rights reserved.
>################# #################

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