Atypical neuropathological sCJD-MM phenotype with abundant white matter
Kuru-type plaques sparing the cerebellar cortex
Ellen Gelpi1,*, Josep Ma Soler Insa2, Piero Parchi8, Daniela Saverioni8,
Jordi Yagüe3, Carlos Nos5, Elena Martínez- Saez6, Teresa Ribalta1,3, Isidre
Ferrer7, Raquel Sanchez-Valle3,4
Article first published online: 5 AUG 2012
DOI: 10.1111/j.1440-1789.2012.01341.x
Keywords:
atypical sCJD; Kuru plaques; mixed PrP; molecular subtypes; white matter
We describe an atypical neuropatholgical phenotype of sporadic
Creutzfeldt-Jakob disease (sCJD) in a 64-year-old man presenting with a 5-month
history of rapidly progressive dementia, comprising behavioral disturbances,
memory complaints, disorientation and language alterations. MRI showed diffuse
atrophy and hyperintensities in parietal, occipital, temporal and frontal
cortices and left caudate nucleus on T2-weighted and fluid-attenuated inversion
recovery images. No typical EEG alterations were observed. Repeated 14-3-3 assay
was positive after a first negative test. Neuropathology showed classical CJD
changes with small cortical foci of large confluent vacuoles and relatively
well-preserved cerebellar cortex. The most striking feature was the presence of
abundant Kuru-type plaques in both cerebral cortex and subcortical white matter.
Sparse Kuru-type plaques were also seen in cerebellum, although only in white
matter. Immunohistochemistry showed, in addition to unicentric plaques, diffuse
synaptic and patchy perivacuolar, as well as plaque-like and periaxonal
pathological prion protein deposits (PrPres). Western blot studies demonstrated
the co-occurrence of PrPres types 1 and 2 in frontal cortex and a relatively
weak type 2 signal in cerebellum. PRNP genotyping revealed methionine
homozygosity at codon 129 and excluded mutations. This case shows a previously
undescribed combination of histopathological features which preclude its
classification according to the current phenotypic and molecular sCJD
classification. The observation demonstrates that Kuru-type amyloid plaques
mainly involving the cerebral white matter may also occur in sCJD cases with
short clinical course and the co-existence of PrPres types 1 and 2. This case
further highlights the complexity of the correlations between histopathological
phenotype and PrPres isotype in prion diseases.
sporadic CJD, a Zoonotic disease, oh let me count the ways. ...
British Medical Journal
15 November 1999
Terry S Singeltary, NA
In reading the recent article in the BMJ about the potential BSE tests
being developed in the U.S. and Bart Van Everbroeck reply. It does not surprize
me, that the U.S. has been concealing vCJD. There have been people dying from
CJD, with all the symptoms and pathological findings that resemble U.K. vCJD for
some time. It just seems that when there is one found, they seem to change the
clarical classification of the disease, to fit their agenda. I have several
autopsies, stating kuru type amyloid plaques, one of the victims was 41 years of
age. Also, my Mom died a most hideous death, Heidenhain Variant Creutzfeldt
Jakob disease. ...see full text ;
British Medical Journal U.S. Scientist should be concerned with a CJD
epidemic in the U.S., as well... 2 January 2000
Letters|February 14, 2001
Diagnosis and Reporting of Creutzfeldt-Jakob Disease Terry S. Singeltary,
Sr
Copyright 2001 American Medical Association. All Rights Reserved.
Applicable FARS/DFARS Restrictions Apply to Government Use.
JAMA. 2001;285(6):733-734.
14th ICID International Scientific Exchange Brochure -
Final Abstract Number: ISE.114
Session: International Scientific Exchange
Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North
America update October 2009
T. Singeltary
Bacliff, TX, USA
Background:
An update on atypical BSE and other TSE in North America. Please remember,
the typical U.K. c-BSE, the atypical l-BSE (BASE), and h-BSE have all been
documented in North America, along with the typical scrapie's, and atypical
Nor-98 Scrapie, and to date, 2 different strains of CWD, and also TME. All these
TSE in different species have been rendered and fed to food producing animals
for humans and animals in North America (TSE in cats and dogs ?), and that the
trading of these TSEs via animals and products via the USA and Canada has been
immense over the years, decades.
Methods:
12 years independent research of available data
Results:
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 2009. With all the science to date refuting it, to continue to
validate this old myth, will only spread this TSE agent through a multitude of
potential routes and sources i.e. consumption, medical i.e., surgical, blood,
dental, endoscopy, optical, nutritional supplements, cosmetics etc.
Conclusion:
I would like to submit a review of past CJD surveillance in the USA, and
the urgent need to make all human TSE in the USA a reportable disease, in every
state, of every age group, and to make this mandatory immediately without
further delay. The ramifications of not doing so will only allow this agent to
spread further in the medical, dental, surgical arena's. Restricting the
reporting of CJD and or any human TSE is NOT scientific. Iatrogenic CJD knows NO
age group, TSE knows no boundaries. I propose as with Aguzzi, Asante, Collinge,
Caughey, Deslys, Dormont, Gibbs, Gajdusek, 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.
CJD Singeltary submission to PLOS ;
No competing interests declared.
see full text ;
Wednesday, August 01, 2012
Behavioural and Psychiatric Features of the Human Prion Diseases:
Experience in 368 Prospectively Studied Patients
Saturday, June 25, 2011
Transmissibility of BSE-L and Cattle-Adapted TME Prion Strain to Cynomolgus
Macaque
"BSE-L in North America may have existed for decades"
RE - "BSE-L in North America may have existed for decades" YA THINK ???
Over the next 8-10 weeks, approximately 40% of all the adult mink on the
farm died from TME.
snip...
The rancher was a ''dead stock'' feeder using mostly (>95%) downer or
dead dairy cattle...
***Also, a link is suspected between atypical BSE and some apparently
sporadic cases of Creutzfeldt-Jakob disease in humans. These atypical BSE cases
constitute an unforeseen first threat that could sharply modify the European
approach to prion diseases.
Second threat
snip...
Rural and Regional Affairs and Transport References Committee
The possible impacts and consequences for public health, trade and
agriculture of the Government's decision to relax import restrictions on beef
Final report June 2010
2.65 At its hearing on 14 May 2010, the committee heard evidence from Dr
Alan Fahey who has recently submitted a thesis on the clinical neuropsychiatric,
epidemiological and diagnostic features of Creutzfeldt-Jakob disease.48 Dr Fahey
told the committee of his concerns regarding the lengthy incubation period for
transmissible spongiform encephalopathies, the inadequacy of current tests and
the limited nature of our current understanding of this group of
diseases.49
2.66 Dr Fahey also told the committee that in the last two years a link has
been established between forms of atypical CJD and atypical BSE. Dr Fahey said
that: They now believe that those atypical BSEs overseas are in fact causing
sporadic Creutzfeldt-Jakob disease. They were not sure if it was due to mad
sheep disease or a different form. If you look in the textbooks it looks like
this is just arising by itself. But in my research I have a summary of a
document which states that there has never been any proof that sporadic
Creutzfeldt-Jakob disease has arisen de novo-has arisen of itself. There is no
proof of that. The recent research is that in fact it is due to atypical forms
of mad cow disease which have been found across Europe, have been found in
America and have been found in Asia. These atypical forms of mad cow disease
typically have even longer incubation periods than the classical mad cow
disease.50
snip...see full text ;
Tuesday, June 26, 2012
Creutzfeldt Jakob Disease Human TSE report update North America, Canada,
Mexico, and USDA PRION UNIT as of May 18, 2012
type determination pending Creutzfeldt Jakob Disease (tdpCJD), is on the
rise in Canada and the USA
***+++***
Thursday, July 10, 2008
A Novel Human Disease with Abnormal Prion Protein Sensitive to Protease
update July 10, 2008 Friday, June 20, 2008
Here we go folks. AS predicted. THIS JUST OUT !
Tuesday, August 03, 2010
Variably protease-sensitive prionopathy: A new sporadic disease of the
prion protein
Monday, August 9, 2010
Variably protease-sensitive prionopathy: A new sporadic disease of the
prion protein or just more PRIONBALONEY ?
snip...see full text ;
O.K. let's compare some recent cases of this prionpathy in other countries
besides Gambetti's first 10 recently, that he claims is a spontaneous event,
from a genetic disorder, that is not genetic, but sporadic, that is related to
no animal TSE in North America, or the world. ...
Wednesday, October 27, 2010
A novel variant of human disease with a protease-sensitive prion protein
and heterozygosity methionine/valine at codon 129: Case report
Sunday, August 09, 2009
CJD...Straight talk with...James Ironside...and...Terry Singeltary... 2009
Tuesday, August 18, 2009
BSE-The Untold Story - joe gibbs and singeltary 1999 – 2009
====================================
The familial mutations, Gajdusek proposed, lowered the barrier to such
accidental conversion. "Thus," he wrote in 1996, "with these mutations, this
ordinarily rare event becomes a ... dominant inherited trait." But Weissmann's
qualification still remained to be refuted: the mutations might simply allow
easier entry to a lurking virus. ...page 202 Deadly Feast
===================================
something to think about for sure.
but i interpret this as (1st not the gold standard, just my opinion;-), as
because of certain gene mutations, one or a family, would be more susceptible to
the many different strains of TSE, and the many different proven routes and
sources, (which will cause different symptoms, different incubation periods from
onset of clinical symptoms to death, different parts of the brain infected,
etc.). in other words, it's NOT the gene mutation that CAUSES the disease, but
the fact that it makes you more SUSCEPTIBLE, to the TSEs from the surrounding
environment, and PLUS accumulation, i think this plays a critical role. maybe
there is a one dose scenario, but i think there is more of the 'accumulators'
that go clinical, than the 'one dose'. and what is the threshold to sub-clinical
to clinical ?
anyway, just pondering out loud here.
also, for anyone interested, there are some studies with links to follow
here ;
Thursday, June 21, 2012
Clinical and Pathologic Features of H-Type Bovine Spongiform Encephalopathy
Associated with E211K Prion Protein Polymorphism
let's take a closer look at this new prionpathy or prionopathy, and then
let's look at the g-h-BSEalabama mad cow.
This new prionopathy in humans? the genetic makeup is IDENTICAL to the
g-h-BSEalabama mad cow, the only _documented_ mad cow in the world to date like
this, ......wait, it get's better. this new prionpathy is killing young and old
humans, with LONG DURATION from onset of symptoms to death, and the symptoms are
very similar to nvCJD victims, OH, and the plaques are very similar in some
cases too, bbbut, it's not related to the g-h-BSEalabama cow, WAIT NOW, it gets
even better, the new human prionpathy that they claim is a genetic TSE, has no
relation to any gene mutation in that family. daaa, ya think it could be related
to that mad cow with the same genetic make-up ??? there were literally tons and
tons of banned mad cow protein in Alabama in commerce, and none of it
transmitted to cows, and the cows to humans there from ??? r i g h t $$$
ALABAMA MAD COW g-h-BSEalabama
In this study, we identified a novel mutation in the bovine prion protein
gene (Prnp), called E211K, of a confirmed BSE positive cow from Alabama, United
States of America. This mutation is identical to the E200K pathogenic mutation
found in humans with a genetic form of CJD. This finding represents the first
report of a confirmed case of BSE with a potential pathogenic mutation within
the bovine Prnp gene. We hypothesize that the bovine Prnp E211K mutation most
likely has caused BSE in "the approximately 10-year-old cow" carrying the E221K
mutation.
her healthy calf also carried the mutation (J. A. Richt and S. M. Hall PLoS
Pathog. 4, e1000156; 2008).
This raises the possibility that the disease could occasionally be genetic
in origin. Indeed, the report of the UK BSE Inquiry in 2000 suggested that the
UK epidemic had most likely originated from such a mutation and argued against
the scrapierelated assumption. Such rare potential pathogenic PRNP mutations
could occur in countries at present considered to be free of BSE, such as
Australia and New Zealand. So it is important to maintain strict surveillance
for BSE in cattle, with rigorous enforcement of the ruminant feed ban (many
countries still feed ruminant proteins to pigs). Removal of specified risk
material, such as brain and spinal cord, from cattle at slaughter prevents
infected material from entering the human food chain. Routine genetic screening
of cattle for PRNP mutations, which is now available, could provide additional
data on the risk to the public. Because the point mutation identified in the
Alabama animals is identical to that responsible for the commonest type of
familial (genetic) CJD in humans, it is possible that the resulting infective
prion protein might cross the bovine–human species barrier more easily. Patients
with vCJD continue to be identified. The fact that this is happening less often
should not lead to relaxation of the controls necessary to prevent future
outbreaks.
Malcolm A. Ferguson-Smith Cambridge University Department of Veterinary
Medicine, Madingley Road, Cambridge CB3 0ES, UK e-mail: maf12@cam.ac.uk Jürgen
A. Richt College of Veterinary Medicine, Kansas State University, K224B Mosier
Hall, Manhattan, Kansas 66506-5601, USA
NATURE|Vol 457|26 February 2009
Wednesday, March 28, 2012
VARIABLY PROTEASE-SENSITVE PRIONOPATHY IS TRANSMISSIBLE, price of prion
poker goes up again $
OR-10 15:25 - 15:40 VARIABLY PROTEASE-SENSITIVE PRIONOPATHY IS
TRANSMISSIBLE IN BANK VOLES Nonno
OR-10: Variably protease-sensitive prionopathy is transmissible in bank
voles
Romolo Nonno,1 Michele Di Bari,1 Laura Pirisinu,1 Claudia D’Agostino,1
Stefano Marcon,1 Geraldina Riccardi,1 Gabriele Vaccari,1 Piero Parchi,2 Wenquan
Zou,3 Pierluigi Gambetti,3 Umberto Agrimi1
1Istituto Superiore di Sanità; Rome, Italy; 2Dipartimento di Scienze
Neurologiche, Università di Bologna; Bologna, Italy; 3Case Western Reserve
University; Cleveland, OH USA
Background. Variably protease-sensitive prionopathy (VPSPr) is a recently
described “sporadic”neurodegenerative disease involving prion protein
aggregation, which has clinical similarities with non-Alzheimer dementias, such
as fronto-temporal dementia. Currently, 30 cases of VPSPr have been reported in
Europe and USA, of which 19 cases were homozygous for valine at codon 129 of the
prion protein (VV), 8 were MV and 3 were MM. A distinctive feature of VPSPr is
the electrophoretic pattern of PrPSc after digestion with proteinase K (PK).
After PK-treatment, PrP from VPSPr forms a ladder-like electrophoretic pattern
similar to that described in GSS cases. The clinical and pathological features
of VPSPr raised the question of the correct classification of VPSPr among prion
diseases or other forms of neurodegenerative disorders. Here we report
preliminary data on the transmissibility and pathological features of VPSPr
cases in bank voles.
Materials and Methods. Seven VPSPr cases were inoculated in two genetic
lines of bank voles, carrying either methionine or isoleucine at codon 109 of
the prion protein (named BvM109 and BvI109, respectively). Among the VPSPr cases
selected, 2 were VV at PrP codon 129, 3 were MV and 2 were MM. Clinical
diagnosis in voles was confirmed by brain pathological assessment and western
blot for PK-resistant PrPSc (PrPres) with mAbs SAF32, SAF84, 12B2 and 9A2.
Results. To date, 2 VPSPr cases (1 MV and 1 MM) gave positive transmission
in BvM109. Overall, 3 voles were positive with survival time between 290 and 588
d post inoculation (d.p.i.). All positive voles accumulated PrPres in the form
of the typical PrP27–30, which was indistinguishable to that previously observed
in BvM109 inoculated with sCJDMM1 cases. In BvI109, 3 VPSPr cases (2 VV and 1
MM) showed positive transmission until now. Overall, 5 voles were positive with
survival time between 281 and 596 d.p.i.. In contrast to what observed in
BvM109, all BvI109 showed a GSS-like PrPSc electrophoretic pattern,
characterized by low molecular weight PrPres. These PrPres fragments were
positive with mAb 9A2 and 12B2, while being negative with SAF32 and SAF84,
suggesting that they are cleaved at both the C-terminus and the N-terminus.
Second passages are in progress from these first successful transmissions.
Conclusions. Preliminary results from transmission studies in bank voles
strongly support the notion that VPSPr is a transmissible prion disease.
Interestingly, VPSPr undergoes divergent evolution in the two genetic lines of
voles, with sCJD-like features in BvM109 and GSS-like properties in BvI109. The
discovery of previously unrecognized prion diseases in both humans and animals
(i.e., Nor98 in small ruminants) demonstrates that the range of prion diseases
might be wider than expected and raises crucial questions about the epidemiology
and strain properties of these new forms. We are investigating this latter issue
by molecular and biological comparison of VPSPr, GSS and Nor98.
Saturday, August 14, 2010
BSE Case Associated with Prion Protein Gene Mutation (g-h-BSEalabama) and
VPSPr PRIONPATHY
(see mad cow feed in COMMERCE IN ALABAMA...TSS)
P.9.21
Molecular characterization of BSE in Canada
Jianmin Yang1, Sandor Dudas2, Catherine Graham2, Markus Czub3, Tim
McAllister1, Stefanie Czub1 1Agriculture and Agri-Food Canada Research Centre,
Canada; 2National and OIE BSE Reference Laboratory, Canada; 3University of
Calgary, Canada
Background: Three BSE types (classical and two atypical) have been
identified on the basis of molecular characteristics of the misfolded protein
associated with the disease. To date, each of these three types have been
detected in Canadian cattle.
Objectives: This study was conducted to further characterize the 16
Canadian BSE cases based on the biochemical properties of there associated
PrPres. Methods: Immuno-reactivity, molecular weight, glycoform profiles and
relative proteinase K sensitivity of the PrPres from each of the 16 confirmed
Canadian BSE cases was determined using modified Western blot analysis.
Results: Fourteen of the 16 Canadian BSE cases were C type, 1 was H type
and 1 was L type. The Canadian H and L-type BSE cases exhibited size shifts and
changes in glycosylation similar to other atypical BSE cases. PK digestion under
mild and stringent conditions revealed a reduced protease resistance of the
atypical cases compared to the C-type cases. N terminal- specific antibodies
bound to PrPres from H type but not from C or L type. The C-terminal-specific
antibodies resulted in a shift in the glycoform profile and detected a fourth
band in the Canadian H-type BSE.
Discussion: The C, L and H type BSE cases in Canada exhibit molecular
characteristics similar to those described for classical and atypical BSE cases
from Europe and Japan. This supports the theory that the importation of BSE
contaminated feedstuff is the source of C-type BSE in Canada.
*** It also suggests a similar cause or source for atypical BSE in these
countries.
Saturday, August 4, 2012
Final Feed Investigation Summary - California BSE Case - July 2012
Summary Report BSE 2012
Executive Summary
Saturday, August 4, 2012
Update from APHIS Regarding Release of the Final Report on the BSE
Epidemiological Investigation
Thursday, March 29, 2012
atypical Nor-98 Scrapie has spread from coast to coast in the USA 2012
NIAA Annual Conference April 11-14, 2011San Antonio, Texas
Monday, June 11, 2012
another atypical Nor-98 Scrapie case documented in Canada for 2012
Monday, October 10, 2011
EFSA Journal 2011 The European Response to BSE: A Success Story
snip...
EFSA and the European Centre for Disease Prevention and Control (ECDC)
recently delivered a scientific opinion on any possible epidemiological or
molecular association between TSEs in animals and humans (EFSA Panel on
Biological Hazards (BIOHAZ) and ECDC, 2011). This opinion confirmed Classical
BSE prions as the only TSE agents demonstrated to be zoonotic so far but the
possibility that a small proportion of human cases so far classified as
"sporadic" CJD are of zoonotic origin could not be excluded. Moreover,
transmission experiments to non-human primates suggest that some TSE agents in
addition to Classical BSE prions in cattle (namely L-type Atypical BSE,
Classical BSE in sheep, transmissible mink encephalopathy (TME) and chronic
wasting disease (CWD) agents) might have zoonotic potential.
snip...
see follow-up here about North America BSE Mad Cow TSE prion risk factors,
and the ever emerging strains of Transmissible Spongiform Encephalopathy in many
species here in the USA, including humans ;
Reasons for Caution
There are several reasons for caution with respect to zoonotic and
interspecies CWD transmission. First, there is strong evidence that distinct CWD
strains exist (36). Prion strains are distinguished by varied incubation
periods, clinical symptoms, PrPSc conformations, and CNS PrPSc depositions
(3,32). Strains have been identified in other natural prion diseases, including
scrapie, BSE, and CJD (3). Intraspecies and interspecies transmission of prions
from CWD-positive deer and elk isolates resulted in identification of >2
strains of CWD in rodent models (36), indicating that CWD strains likely exist
in cervids. However, nothing is currently known about natural distribution and
prevalence of CWD strains. Currently, host range and pathogenicity vary with
prion strain (28,37). Therefore, zoonotic potential of CWD may also vary with
CWD strain. In addition, diversity in host (cervid) and target (e.g., human)
genotypes further complicates definitive findings of zoonotic and interspecies
transmission potentials of CWD.
Intraspecies and interspecies passage of the CWD agent may also increase
the risk for zoonotic CWD transmission. The CWD prion agent is undergoing serial
passage naturally as the disease continues to emerge. In vitro and in vivo
intraspecies transmission of the CWD agent yields PrPSc with an increased
capacity to convert human PrPc to PrPSc (30). Interspecies prion transmission
can alter CWD host range (38) and yield multiple novel prion strains (3,28). The
potential for interspecies CWD transmission (by cohabitating mammals) will only
increase as the disease spreads and CWD prions continue to be shed into the
environment. This environmental passage itself may alter CWD prions or exert
selective pressures on CWD strain mixtures by interactions with soil, which are
known to vary with prion strain (25), or exposure to environmental or gut
degradation.
Given that prion disease in humans can be difficult to diagnose and the
asymptomatic incubation period can last decades, continued research,
epidemiologic surveillance, and caution in handling risky material remain
prudent as CWD continues to spread and the opportunity for interspecies
transmission increases. Otherwise, similar to what occurred in the United
Kingdom after detection of variant CJD and its subsequent link to BSE, years of
prevention could be lost if zoonotic transmission of CWD is subsequently
identified,
SNIP...
*** Chronic Wasting Disease CWD CDC REPORT MARCH 2012 ***
Saturday, February 18, 2012
Occurrence, Transmission, and Zoonotic Potential of Chronic Wasting Disease
CDC Volume 18, Number 3—March 2012
see much more here ;
TSS