Thursday, January 31, 2008

Evaluation of the Human Transmission Risk of an Atypical Bovine Spongiform Encephalopathy Prion Strain

J. Virol. doi:10.1128/JVI.02561-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Evaluation of the Human Transmission Risk of an Atypical Bovine Spongiform Encephalopathy Prion Strain

Qingzhong Kong*, Mengjie Zheng, Cristina Casalone, Liuting Qing, Shenghai Huang, Bikram Chakraborty, Ping Wang, Fusong Chen, Ignazio Cali, Cristiano Corona, Francesca Martucci, Barbara Iulini, Pierluigi Acutis, Lan Wang, Jingjing Liang, Meiling Wang, Xinyi Li, Salvatore Monaco, Gianluigi Zanusso, Wen-Quan Zou, Maria Caramelli, and Pierluigi Gambetti*
Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA; CEA, Istituto Zooprofilattico Sperimentale, 10154 Torino, Italy; Department of Neurological and Visual Sciences, University of Verona, 37134 Verona, Italy

* To whom correspondence should be addressed. Email:


Bovine spongiform encephalopathy (BSE), the prion disease in cattle, was widely believed to have only one strain (BSE-C). BSE-C causes the fatal prion disease named new variant Creutzfeldt-Jacob disease in humans. Two atypical BSE strains, BASE (or BSE-L) and BSE-H, have been discovered in several countries since 2004; their transmissibility and phenotypes in humans are unknown. We investigated the infectivity and human phenotype of BASE by inoculating transgenic (Tg) mice expressing the human prion protein with brain homogenates from two BASE-affected cattle. Sixty percent of the inoculated Tg mice became infected after 20-22 months incubation, a transmission rate higher than those reported for BSE-C. A quarter of BASE-infected Tg mice, but none of the Tg mice infected with a sporadic human prion disease, showed presence of pathogenic prion protein isoforms in the spleen, indicating that the BASE prion is intrinsically lymphotropic. The pathological prion protein isoforms in BASE-infected humanized Tg mouse brains are different from those of the original cattle BASE or sporadic human prion disease. Minimal brain spongiosis and long incubation time are observed in the BASE-infected Tg mice. These results suggest that, in humans, BASE is a more virulent BSE strain and likely lymphotropic.

Thursday, January 31, 2008

meeting held on 14th December 2007




40. The Chair explained that the purpose of the question and answer
session was to give members of the public an opportunity to ask
questions related to the work of SEAC. Mr Terry Singeltary
(Texas, USA) had submitted a question prior to the meeting,
asking: “With the Nor-98 now documented in five different states so
far in the USA in 2007, and with the two atypical BSE H-base

© SEAC 2007

cases in Texas and Alabama, with both scrapie and chronic
wasting disease (CWD) running rampant in the USA, is there any
concern from SEAC with the rise of sporadic CJD in the USA from
''unknown phenotype'', and what concerns if any, in relations to
blood donations, surgery, optical, and dental treatment, do you
have with these unknown atypical phenotypes in both humans and
animals in the USA? Does it concern SEAC, or is it of no concern
to SEAC? Should it concern USA animal and human health

41. A member considered that this question ............

snip... please see full text, sources, and comments here ;

APHIS-2006-0041-0006 TSE advisory committee for the meeting December 15,

[Docket No. FSIS-2006-0011] FSIS Harvard Risk Assessment of Bovine
Spongiform Encephalopathy (BSE)

[Docket No. 03-025IFA] FSIS Prohibition of the Use of Specified Risk Materials for Human Food and Requirement for the Disposition of Non-Ambulatory Disabled Cattle

Attachment to Singletary comment

January 28, 2007

Greetings APHIS,

I would kindly like to submit the following to ;

[Docket No. APHIS-2006-0041] RIN 0579-AC01

[Federal Register: January 9, 2007 (Volume 72, Number 5)]
[Proposed Rules]
[Page 1101-1129]
From the Federal Register Online via GPO Access []

DERIVED FROM BOVINES [Docket No. APHIS-2006-0041] RIN 0579-AC01
Date: January 9, 2007 at 9:08 am PST

Diagnosis and Reporting of Creutzfeldt-Jakob Disease

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

Diagnosis and Reporting of Creutzfeldt-Jakob Disease

Since this article does not have an abstract, we have provided the first 150 words of the full text and any section headings.

To the Editor:

In their Research Letter, Dr Gibbons and colleagues1 reported that the annual US death rate due to Creutzfeldt-Jakob disease (CJD) has been stable since 1985. These estimates, however, are based only on reported cases, and do not include misdiagnosed or preclinical cases. It seems to me that misdiagnosis alone would drastically change these figures. An unknown number of persons with a diagnosis of Alzheimer disease in fact may have CJD, although only a small number of these patients receive the postmortem examination necessary to make this diagnosis. Furthermore, only a few states have made CJD reportable. Human and animal transmissible spongiform encephalopathies should be reportable nationwide and internationally.

Terry S. Singeltary, Sr
Bacliff, Tex

1. Gibbons RV, Holman RC, Belay ED, Schonberger LB. Creutzfeldt-Jakob disease in the United States: 1979-1998. JAMA. 2000;284:2322-2323. FREE FULL TEXT

File Format: PDF/Adobe Acrobat -Page 1. J Freas, William From: Sent:
Terry S. SingeltarySr. []
Monday, January 08,200l 3:03 PM freas ...

Asante/Collinge et al, 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;

DER SPIEGEL (9/2001) - 24.02.2001 (9397 Zeichen)USA: Loch in der MauerDie BSE-Angst erreicht Amerika: Trotz strikter Auflagen gelangte in Texas verbotenes Tiermehl ins Rinderfutter - die Kontrollen der Aufsichtsbehördensind lax.Link auf diesen Artikel im Archiv:

"Its as full of holes as Swiss Cheese" says Terry Singeltary of the FDA regulations. ...

2 January 2000

British Medical Journal

U.S. Scientist should be concerned with a CJD epidemic in the U.S., as well

15 November 1999

British Medical Journal

vCJD in the USA * BSE in U.S.

please notice Texas 2006 ;

† Confirmed in United Kingdom and reported to Texas Department of State
Health Services
through Centers for Disease Control and Prevention.

Only 1 case of variant
CJD has ever been diagnosed in Texas.
The patient was a former resident of the
United Kingdom, where the exposure
was likely to have occurred. Texas has a
population of 23 million, and since the
national rate of sporadic CJD is about 1
per million, it is expected that
approximately 23 cases of CJD would
occur each year in the state. Therefore,
it is believed that CJD is currently underreported
in Texas. ...END...TSS

also see ;

Creutzfeldt-Jakob Disease in Northeast Texas,

J.A. Rawlings,*1 K.A.
Hendricks1, O.M. Nuno1, D.A. Brown1, D.A. Evans2, Texas Department of
Health, 1Austin and 2Tyler, Texas

Creutzfeldt-Jacob Disease (CJD), a transmissible spongiform
encephalopathy, is caused by prions composed of proteinaceous material
devoid of nucleic acid. CJD occurs sporadically (generally 1
case/1,000,000 population per year) in older patients (average age of
65) and is characterized by rapidly progressive dementia, accompanied by
severe muscle spasms and incoordination. Death usually occurs within 3
to 12 months (average 7 months). CJD activity in Texas, which has a
population of nearly 19 million, appeared to be typical. The statewide
death rate for 1995 and 1996 was just under 1/1,000,000. In April of
1997, the Texas Department of Health became aware of an increased number
of possible CJD cases in a 23-county area of NE Texas with a population
of just over one million. After review of medical and pathology records,
four patients were identified with definite classic CJD and three were
identified with probable CJD. Dates of death for the eight patients were
from April, 1996 through mid-July 1997. The patients were from 46
through 65 years of age; four were male and three were female. A
case-control study to identify risks for CJD in NE Texas has been initiated.

Division of Neuropathology
Pierluigi Gambetti, M.D.,



March 30, 1998

Dr. Gerald A, Campbell

The University of Texas
Medical Branch at Galveston
Division of Neuropathology
Department of Pathology
Galveston, Texas

Dear Dr Campbell,

We performed Western immunoblot analysis on the frozen tissue from your case
#AU97-435 (our #098-28). The Immunoblot reveals the presence of
protease-resistant prion protein (PrPres) confirming the diagnosis of prion
disease. The immunoblot pattern of PrPres is consistent with the diagnosis
of Creutzfeldt-Jakob disease.

Thank you for referring to us this interesting case.


Piero Parchi, M.D.

Pierluigi Gambetti, M.D.

PP:sbDivision of Neuropathology

Pierluigi Gambetti, M.D.,


Case Western Reserve University


see full text ;

Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in
the United States

Creutzfeldt Jakob Disease

Creutzfeldt-Jakob Disease, Prion Protein Gene Codon 129VV, and a Novel PrPSc Type in a Young British Woman




Friday, January 11, 2008


Friday, January 25, 2008
January 2008 Update on Feed Enforcement Activities to Limit the Spread of BSE



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

Saturday, January 12, 2008

Prominent and Persistent Extraneural Infection in Human PrP Transgenic Mice Infected with Variant CJD

Prominent and Persistent Extraneural Infection in Human PrP Transgenic Mice Infected with Variant CJD

Vincent Béringue1*, Annick Le Dur1, Philippe Tixador1, Fabienne Reine1, Laurence Lepourry2, Armand Perret-Liaudet3, Stéphane Haïk4,5, Jean-Luc Vilotte2, Michel Fontés6, Hubert Laude1*

1 Institut Scientifique de Recherche Agronomique (INRA), UR892, Virologie Immunologie Moléculaires, Jouy-en-Josas, France, 2 Institut Scientifique de Recherche Agronomique (INRA), UR339, Génétique Biochimique et Cytogénétique, Jouy-en-Josas, France, 3 Service de Neurobiologie, Centre de Biologie et Pathologie Est (CBPE), Groupement Hospitalier Est des Hôpitaux de Lyon, Bron, France, 4 INSERM, Equipe Avenir, Maladies à Prions chez l'Homme, Paris, France, 5 Assistance Publique - Hôpitaux de Paris (AP-HP), Laboratoire de Neuropathologie R. Escourolle, Groupe Hospitalier Pitié- Salpétrière, Paris, France, 6 INSERM UMR 491-IPHM, Faculté de médecine de la Timone, Marseille, France



The evolution of the variant Creutzfeldt-Jakob disease (vCJD) epidemic is hazardous to predict due to uncertainty in ascertaining the prevalence of infection and because the disease might remain asymptomatic or produce an alternate, sporadic-like phenotype.

Methodology/Principal Findings

Transgenic mice were produced that overexpress human prion protein with methionine at codon 129, the only allele found so far in vCJD-affected patients. These mice were infected with prions derived from variant and sporadic CJD (sCJD) cases by intracerebral or intraperitoneal route, and transmission efficiency and strain phenotype were analyzed in brain and spleen. We showed that i) the main features of vCJD infection in humans, including a prominent involvement of the lymphoid tissues compared to that in sCJD infection were faithfully reproduced in such mice; ii) transmission of vCJD agent by intracerebral route could lead to the propagation of either vCJD or sCJD-like prion in the brain, whereas vCJD prion was invariably propagated in the spleen, iii) after peripheral exposure, inefficient neuroinvasion was observed, resulting in an asymptomatic infection with life-long persistence of vCJD prion in the spleen at stable and elevated levels.


Our findings emphasize the possibility that human-to-human transmission of vCJD might produce alternative neuropathogical phenotypes and that lymphoid tissue examination of CJD cases classified as sporadic might reveal an infection by vCJD-type prions. They also provide evidence for the strong propensity of this agent to establish long-lasting, subclinical vCJD infection of lymphoreticular tissues, thus amplifying the risk for iatrogenic transmission.

Citation: Béringue V, Le Dur A, Tixador P, Reine F, Lepourry L, et al. (2008) Prominent and Persistent Extraneural Infection in Human PrP Transgenic Mice Infected with Variant CJD. PLoS ONE 3(1): e1419. doi:10.1371/journal.pone.0001419

Academic Editor: Adam Ratner, Columbia University, United States of America

Received: September 20, 2007; Accepted: December 17, 2007; Published: January 9, 2008

Copyright: © 2008 Beringue et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This work was supported by INRA, Institut de Veille Sanitaire (InVS) and the Ministry of Research, France. The sponsors of this study had no role in study conduct, collection analysis, interpretation of the data, writing of the report or approval of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

* To whom correspondence should be addressed. E-mail: (HL); (VB)



In this study we used tg650 mice, a newly developed transgenic line expressing human PrPC, to investigate some aspects of the pathogenesis of vCJD infection. As main findings, we demonstrate that prion strain divergence can occur upon transmission of human, primary vCJD to such mice, and that peripheral challenge leads to an asymptomatic, life-long infection of the lymphoid compartment. A feature of tg650 mice is that following primary intracerebral vCJD challenge they developed a neurological disease with typically 100% attack rate, unlike for previously established PrP129Met, including overexpressing lines [16], [19]. The mean survival time – typically around 500 days in homozygous mice - did not change notably on subpassaging, implying that vCJD agent might clinically infect the tg650 mice with little or no transmission barrier. This discrepant result may reflect the use of different constructs and genetic backgrounds (Text S1), and the transgene expression levels, although the latter does not seem to greatly differ as far as the tg650+/− and tg45 mice [16] are concerned.

A surprising result of these studies is the alternate pattern of disease that was induced by one of the inoculated vCJD cases, a WHO reference case here designated vCJD no. 4. Indeed, while vCJD strain features were faithfully propagated in the majority of tg650 mice, almost half of the vCJD 4-inoculated mice were found to propagate a prion replicating faster than vCJD agent, and exhibiting sCJD-like PrPres and neuropathological features. Although strain divergence upon transmission of BSE/vCJD agent to mice was reported to occur in earlier studies [16], [24], it was unprecedented within a context of homotypic transmission, i.e. full matching between the donor and receiver PrP sequences. To address the issue of a possible contamination, we performed independent transmission experiments, involving separate inoculum batches of the incriminated case, which all produced consistent results. Therefore, we consider the data inconsistent with contamination of the VCJD no. 4 material by a sCJD infectious source within our laboratory. An alternate possibility, i.e. a cross-contamination of the source material, was judged highly improbable owing to the procedures applied during the collect of the specimen and the preparation of the homogenates ([25] and P. Minor, personal communication). On the other hand, our observation intriguingly parallels the phenotypic disjunction observed upon transmission of BSE agent to human PrP129Met mice (tg35 line [16]). Together, these findings lend support to the hypothesis that a minor strain component might be created upon cattle-to-human transmission of BSE agent and could emerge upon subsequent human-to–human transmission. It is also worth mentioning that, while the probability to detect such a variant through mouse bioassay would be expected to depend on the amount - and possibly the regions - of brain tissue taken to establish the source material, the vCJD-4 homogenate was prepared using a larger amount of tissue from the same brain than for the other homogenates analyzed in this study (i.e. 100 mg instead of 1 mg of frontal cortex [25]).

The above finding has obvious implications in terms of public health as it raises the concern that some humans iatrogenically infected by vCJD agent may develop a clinical disease that would not be recognized as of vCJD origin [17], [26]. Strikingly however, all vCJD-4-inoculated mice, notwithstanding the strain phenotype divergence propagated bona fide vCJD agent in their spleen, based on the PrPres pattern and the disease phenotype produced by secondary transmission to tg650 mice. This result is of direct relevance to the diagnosis of variant and sporadic CJD. Indeed, looking for peripheral lymphoreticular deposition of abnormal PrP on cases diagnosed as sporadic CJD might reveal a vCJD infection resulting from human-to-human, or cattle-to-human transmission. In this respect, it would be of interest to examine whether BSE-inoculated tg35 mice showing discordant PrPres signatures [16], or vCJD-challenged PrP129Val transgenic mice producing ‘type 5’ prion in their brain [17] do accumulate PrPvCJD in their spleens. In any case, our findings provide clear evidence that, as a consequence of strain-related tropism disparities, the same mouse can propagate different prions in different tissues following a single infection event.

Another salient finding emerging from this study was the remarkable ability of vCJD agent to establish asymptomatic infection despite sustained, life-long propagation in extraneural tissues. When challenged peripherally, tg650 mice remained asymptomatic over the whole observation period, and did not accumulate PrPres at detectable levels in their brain before 750 days pi, near the life end-stage. In the spleen of these mice however, PrPres accumulation reached its maximum at an early stage of infection, and remained at stable and substantial levels until death. Plateauing of prion infection in the spleen is consistent with earlier observations, and has been suggested to reflect an exhaustion of target cells (for review [22]) Importantly, the spleen tissue was highly infectious as it killed 100% of intracerebrally challenged mice within the minimal mean incubation time (~500 days). Altogether these data support the view that the sustained multiplication of the vCJD prion in lymphoid tissues was not accompanied by an efficient neuroinvasion in tg650 mice. Such an extremely delayed neuroinvasion appears to be rare in TSE rodent models, and to our knowledge was only reported for the mouse-adapted strain 87V on IM mice infected intraperitoneally with diluted inoculum [27]. Clearly, while early accumulation of prions in lymphoid tissues may be essential for efficient neuroinvasion [22], efficient lymphoinvasion does not inevitably lead to rapid neuroinvasion. This finding strengthens the notion that humans infected by vCJD from a human source – including individuals of the MM genotype – might remain clinically asymptomatic for a very prolonged period of time while harboring relatively high levels of prion infectivity in their lymphoid tissues from an early stage of infection on, thereby amplifying the risk of iatrogenic transmission. It also supports the view that the large-scale survey of lymphoreticular tissues [28] may lead to a reliable assessment of the actual prevalence of vCJD infection in the UK population.

Finally, the human PrP transgenic model described in this study may help to further our understanding of peripheral vCJD pathogenesis, for instance in trying to identify factors that might enhance neuroinvasion efficiency, or modulate the shedding of prion infectivity from the lymphoreticular to the blood compartment. Moreover, preliminary results indicate that the search for abnormal PrP in the spleen of such mice culled at time intervals post infection [29], [30] could allow the detection of low levels of vCJD infectivity within a reasonably short time scale.

snip...full text ;


MARCH 26, 2003

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?

Asante/Collinge et al, 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;

Friday, January 11, 2008


Diagnosis and Reporting of Creutzfeldt-Jakob Disease

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

vCJD case study highlights blood transfusion risk

vCJD transfusion-associated Fourth Case UK

risk factors for sporadic CJD

Creutzfeldt-Jakob Disease, Prion Protein Gene Codon 129VV, and a Novel PrPScType in a Young British Woman

BSE (Mad Cow) Update: Do Reports of sCJD Clusters Matter?

snip... see full text ;

Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease inthe United States

Creutzfeldt Jakob Disease




Friday, January 11, 2008


Euro Surveill 2008;13(2) Published online January 2008
Unusual brain disease death in the United Kingdom: possible implications for variant Creutzfeldt-Jacob disease

Euro Surveill 2008;13(2) Published online January 2008 Unusual brain disease death in the United Kingdom: possible implications for variant Creutzfeldt-Jacob disease

Editorial team (, Eurosurveillance editorial office


A British woman who died of a brain disease with similarities to variant Creutzfeldt-Jacob disease (vCJD) in 2000 had a different genetic marker from all previous vCJD patients, according to researchers from the National Hospital for Neurology and Neurosurgery in the United Kingdom (UK) in a case report published in Archives of Neurology [1].

Cases of vCJD were first seen in the UK in 1996 following an epidemic of bovine spongiform encephalopathy (BSE) in cattle, sparking fears of a possible pandemic. The European Commission's Scientific Steering Committee - specially convened as a result of such fears - stated in 1999 that as many as 500,000 people could have been exposed to BSE from each single infected bovine, leading to speculation that millions of people could be at risk [2]. Such estimations have since appeared overly pessimistic; according to the European and Allied Countries Collaborative Study Group of CJD, 163 people have died of confirmed or probable vCJD in the UK to date [3].

Until the case described in this latest paper, all vCJD patients tested were homozygous for methionine (MM) at codon 129 of the prion protein gene (PRNP). This patient had the valine-homozygous (VV) form of the prion protein (PrP), that was previously believed to confer protection against vCJD.

The scrapie isoform of PrP (PrPSc) isolated from her brain tissue was similar to the molecular strain (PrPSc type 4) typical for vCJD, but showed an altered protease cleavage pattern in the presence of a metal chelator. This therefore raises the possibility of a new form of the disease. However, the article's authors stressed that such a conclusion cannot be drawn from one case alone.



Mead S, Joiner S, Desbruslais M, Beck JA, O'Donoghue M, Lantos P, Wadsworth JD, Collinge J. Creutzfeldt-Jakob disease, prion protein gene codon 129VV, and a novel PrPSc type in a young British woman. Arch Neurol. 2007 Dec;64(12):1780-4. Opinion of the Scientific Steering Committee on the human exposure risk (HER) via food with respect to BSE. 10 December 1999. Available from: The European And Allied Countries Collaborative Study Group Of CJD. Cases of vCJD worldwide. December 2007. Available from:

Possible vCJD case in UK may signal more to come Lisa Schnirring Staff Writer

Jan 9, 2008 (CIDRAP News) – A British woman who died of a brain disease suggestive of variant Creutzfeld-Jacob disease (vCJD) had a genetic marker not seen in any previous vCJD patients, raising the possibility that her illness represented a new form of the disease that could signal a new wave of infections, according to a recent research report.

The researchers, who reported their findings in the December 2007 issue of Archives of Neurology, found that the 39-year-old woman carried the VV (valine-homozygous) version of the prion protein gene (PRNP), a type previously thought to confer protection against vCJD.

Past research has linked vCJD to eating meat products contaminated with brain and spinal cord material from cattle infected with bovine spongiform encephalopathy (BSE), or mad cow disease. Normal prion proteins in the brain are corrupted after contact with the BSE agent, eventually causing death in both cattle and humans. BSE, vCJD, and sporadic CJD—a rare disease of unknown cause that closely resembles vCJD—are all prion diseases, also known as transmissible spongiform encephalopathies.

Cases of vCJD began surfacing in the United Kingdom in 1996, in the wake of a BSE epidemic in cattle. According to the most recent update from the National CJD Surveillance Unit (NCJDSU) based at the Western General Hospital in Edinburgh, Scotland, the number of patients in the UK who have died of confirmed or probable vCJD stands at 163. Until the case described, all vCJD patients who had been tested had the MM (methionine-homozygous) version of PRNP.

In early 1999 the patient described started having visual symptoms, followed by a host of other neurological problems, such as memory and gait impairments, according to the report. Polymerase chain reaction testing revealed that the patient had the VV variant of the PRNP gene. The patient died 14 months later.

Brain autopsy findings included severe gray- and white-matter degeneration and extensive prion protein deposits in the cortex and white matter, which the authors wrote is atypical for sporadic CJD. Molecular analysis of the pathologic prion protein (PrPSc) from the woman's cerebellar tissue showed a novel type of PrPSc that was similar in some, but not all, respects to type 4, which is seen in vCJD.

The authors wrote that it wasn't clear if the PrPSc typing points to a BSE cause of the patient's illness or if the finding represents another form of sporadic CJD.

Though a single case can't be the basis for connecting a novel PrPSc type to BSE, "it will be important to see whether other similar cases occur in the United Kingdom and other BSE-exposed countries," the researchers wrote.

Studies in transgenic mice are under way to explore transmission characteristics related to the woman's case, according to the report.

Simon Mead, the study's lead author, said the findings shouldn't cause alarm, according to a Jan 5 New Scientist report. "The final conclusion remains open. It is waving the flag for neurologists to watch for other cases," said Mead, who is at the Medical Research Council Prion Unit at University College London.

Mead told New Scientist that patterns of prion disease seem to vary among people depending on the prion gene variant they have, and incubation period could be one aspect in which the variants differ. Experts have said CJD is known to have a long incubation period, perhaps as long as 50 years.

In 2006, another group of British researchers analyzed DNA from three surgical samples that had previously tested positive in immunohistochemical studies of vCJD prevalence in the UK (though the patients had no clinical signs of the disease). Genotype analysis of the patients' PRNP at codon 129 found that two of the samples were of the VV type, providing the first evidence that patients from this subgroup could be infected. (DNA could not be extracted from the third sample.) Previously, people who carried at least one copy of the V variant of PRNP were thought to have no risk of contracting vCJD.

The authors of the 2006 study suggested their findings might mean that people who are infected with vCJD and have a VV type may have a prolonged incubation period, during which the disease could spread either via blood donations or from contaminated surgical instruments used on the individuals during the asymptomatic phase of the illness.

Will Hueston, DVM, PhD, director of the University of Minnesota Center for Animal Health and Food Safety in St. Paul, told CIDRAP News that it's too soon to say whether the DNA findings from the woman are associated with BSE. "I think that neurologists are probably attempting to be more cautious," he said. "This is most likely not BSE, but they [the researchers] want to be very clear that similar cases should be thoroughly evaluated."

The results of the study could also signify another variant of CJD, which is already known to occur in various forms, "but they don't know what box to put it in," said Hueston, adding that classifying prion disease types is often difficult.

Mead S, Joiner S, Desbruslais S, et al. Creutzfeldt-Jakob disease, prion protein gene codon 129VV, and a novel PrPSc type in a young British woman. Arch Neurol 2007 Dec;64(12):1780-74 [Abstract]

Creutzfeldt-Jakob Disease, Prion Protein Gene Codon 129VV, and a Novel PrPSc Type in a Young British Woman Simon Mead, PhD, MRCP; Susan Joiner, MSc; Melanie Desbruslais, BSc; Jonathan A. Beck, BSc; Michael O’Donoghue, PhD; Peter Lantos, FRCP; Jonathan D. F. Wadsworth, PhD; John Collinge, FRS

Arch Neurol. 2007;64(12):1780-1784.

Background Variant Creutzfeldt-Jakob disease (vCJD) is an acquired prion disease causally related to bovine spongiform encephalopathy that has occurred predominantly in young adults. All clinical cases studied have been methionine homozygotes at codon 129 of the prion protein gene (PRNP) with distinctive neuropathological findings and molecular strain type (PrPSc type 4). Modeling studies in transgenic mice suggest that other PRNP genotypes will also be susceptible to infection with bovine spongiform encephalopathy prions but may develop distinctive phenotypes.

Objective To describe the histopathologic and molecular investigation in a young British woman with atypical sporadic CJD and valine homozygosity at PRNP codon 129.

Design Case report, autopsy, and molecular analysis.

Setting Specialist neurology referral center, together with the laboratory services of the MRC [Medical Research Council] Prion Unit.

Subject Single hospitalized patient.

Main Outcome Measures Autopsy findings and molecular investigation results.

Results Autopsy findings were atypical of sporadic CJD, with marked gray and white matter degeneration and widespread prion protein (PrP) deposition. Lymphoreticular tissue was not available for analysis. Molecular analysis of PrPSc (the scrapie isoform of PrP) from cerebellar tissue demonstrated a novel PrPSc type similar to that seen in vCJD (PrPSc type 4). However, this could be distinguished from the typical vCJD pattern by an altered protease cleavage site in the presence of the metal ion chelator EDTA.

Conclusions Further studies will be required to characterize the prion strain seen in this patient and to investigate its etiologic relationship with bovine spongiform encephalopathy. This case illustrates the importance of molecular analysis of prion disease, including the use of EDTA to investigate the metal dependence of protease cleavage patterns of PrPSc.

Author Affiliations: MRC [Medical Research Council] Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, University College London, National Hospital for Neurology and Neurosurgery, London, England (Drs Mead, Wadsworth, and Collinge; Mss Joiner and Desbruslais; and Mr Beck); and Institute of Psychiatry, King's College London (Dr Lantos). Dr O’Donoghue is now with the Department of Clinical Neurology, Nottingham University Hospitals NHS [National Health Service] Trust, Nottingham, England.

U.K. CJD Figures

These figures show the number of suspect cases referred to the CJD surveillance unit in Edinburgh, and the number of deaths of definite and probable cases in the UK, up to 7th January 2008


*As at 7th January 2008

Summary of vCJD cases


Deaths from definite vCJD (confirmed): 114

Deaths from probable vCJD (without neuropathological confirmation): 48

Deaths from probable vCJD (neuropathological confirmation pending): 1

Number of deaths from definite or probable vCJD: 163


Number of definite/probable vCJD cases still alive: 3

Total number of definite or probable vCJD cases (dead and alive): 166

(Table updated 7th January 2008)

[PLEASE see the rise of sporadic cjd in 1990 of 28 cases, to a high of 79 cases in 2003. the total of sporadic CJD from 1990 to January 7, 2008 is 942 cases documented. ALSO, see chart for Iatrogenic, Familial, GSS, cases. ...TSS]

ALSO PLEASE NOTE, as of Oct 2007 ;

Following this press notice the Department of Health will stop issuing monthly CJD press notices because the same data is also published by the National CJD Surveillance Unit in Edinburgh. Up to date figures for the number of vCJD cases in the UK can be found on the website of the National CJD Surveillance Unit at:

National Prion Disease Pathology Surveillance Center USA

Cases Examined

(October 2007)

Year Total Referrals Prion Disease Sporadic Familial Iatrogenic vCJD

1996 & earlier 42 32 26 4 0 0

1997 115 68 57 9 0 0

1998 93 53 45 7 1 0

1999 114 69 61 8 0 0

2000 151 103 89 14 0 0

2001 208 116 106 9 0 0

2002 257 143 118 23 2 0

2003 274 174 133 41 0 0

2004 335 183 157 22 0 1(1)

2005 350 195 150 39 1 0

2006 377 186 142 33 0 12

2007 254 168 65 10 0 0

TOTAL 2570(3) 1490(4) 1149 219 4 2

1 Acquired in the United Kingdom; 2 Acquired in Saudi Arabia; 3 Includes 20 inconclusive and 37 pending (2 from 2002, 1 from 2003, 1 from 2004, 6 from 2005, 1 from 2006 & 22 from 2007); 4 Includes 18 non-vCJD type unknown (2 from 1996, 2 from 1997, 1 from 2001, 2 from 2002, 2 from 2003, 4 from 2004, 3 from 2005, 3 from 2006 & 2 from 2007) and 79 type pending (2 from 2005, 13 from 2006, 64 from 2007)

Cases are listed based on the year of death where available. If year of death is not available, year of sample receipt is used.

Referrals: Cases with possible or probable prion disease for which brain tissue and/or blood (in the case of familial disease) were submitted.

Inconclusive: Cases in which the samples were not sufficient to make a diagnosis.

Non-vCJD Type Unknown: Cases in which the tissue submitted was adequate to establish the presence but not the type; in all these cases, vCJD could be excluded.


Creutzfeldt-Jakob Disease Surveillance System (CJD-SS)

Referrals of Suspected CJD Reported by CJD-SS(1), 1997-2007(2)

Year of Reporting Numbers of Referrals

1997 4 1998 43 1999 63 2000 82 2001 101 2002 103 2003 75 2004 89 2005 97 2006 78 2007 88

Total 823

1CJD-SS began in April 1998 2Data before April 1998 are retrospective and partial, data from 1999 to 2005 are complete, and data for 2006 and 2007 are provisional As of December 1, 2007

Neuropathology Volume 27 Issue 5 Page 419-428, October 2007

To cite this article: Leora Velásquez-Pérez, Daniel Rembao-Bojorquez, Jorge Guevara, Rosa María Guadarrama-Torres, Araceli Trejo-Contreras (2007) Creutzfeldt-Jakob disease in Mexico

Neuropathology 27 (5), 419–428. doi:10.1111/j.1440-1789.2007.00807.x


Original Article

Creutzfeldt-Jakob disease in Mexico

Leora Velásquez-Pérez,1Departments of 1Epidemiology and Leora Velásquez-Pérez, MD, MSc, Department of Epidemiology, National Institute of Neurology and Neurosurgery, Insurgentes Sur 3877 Col. La Fama Tlalpan 14269, México, DF, Mexico. Email: Daniel Rembao-Bojorquez,22Pathology, and Jorge Guevara,33Neurodegenerative Diseases Laboratory, National Institute of Neurology and Neurosurgery, Mexico DF, Mexico Rosa María Guadarrama-Torres1Departments of 1Epidemiology and and Araceli Trejo-Contreras1Departments of 1Epidemiology and Departments of 1Epidemiology and 2Pathology, and 3Neurodegenerative Diseases Laboratory, National Institute of Neurology and Neurosurgery, Mexico DF, Mexico Leora Velásquez-Pérez, MD, MSc, Department of Epidemiology, National Institute of Neurology and Neurosurgery, Insurgentes Sur 3877 Col. La Fama Tlalpan 14269, México, DF, Mexico. Email:


Creutzfeldt-Jakob disease (CJD) is classified within the group of transmissible spongiform encephalopathies (TSE). It is a rapidly progressive illness that affects mental functions. The average age of onset is 50 years. Various tests can help orient the clinical diagnosis, but the confirmatory test is still the post mortem analysis. The aim of this study was to describe the epidemiological, clinical and histopathological characteristics of patients diagnosed as suffering from CJD, at the National Institute of Neurology and Neurosurgery of Mexico (NINN). An observational, descriptive and transversal study was conducted. We collected information concerning these cases from the Departments of Epidemiology and Pathology, as well as the clinical charts of the patients with a diagnosis of CJD. Fifteen cases were registered of which three CJD cases were definite, five probable cases were identified, and seven were possible. The average age of the patients was 49 years. Two definite cases were female and one was male. It is important to improve the systems for surveillance of this type of disease and, furthermore, to permit greater accessibility to laboratories where the procedures necessary for supporting diagnosis can be followed.


In Mexico there are some deficiencies in the surveillance system, among other reasons due to limited knowledge concerning this disease on the part of administrative and medical staff, which causes a lack of notification of cases and an under-registration of these diseases. On the other hand, the National System of Epidemiological Surveillance has not rigorously integrated and made obligatory the notification and control of TSE, and there are no centers or laboratories of microbiology and genetics where tests to support the diagnosis of the disease can be conducted. Another problem in Mexico is the fact that many of the suspected or probable cases are never confirmed because of the refusal of relatives to allow deceased patients to undergo autopsies.

The aim of this study was to describe and present the epidemiological, clinical, and histopathological characteristics of CJD cases, detected between January 1, 2000 and May 31, 2005 in our institution; this being one of the world’s main neurological institutions.



Between January 1, 2000 and May 31, 2005, three definite CJD cases were identified (20%), five probable cases were identified (33%), and seven were classified as possible (47%). The laboratory investigations used for the patients are presented in Table 1. The year of diagnosis of these patients is shown in Table 2. By the end of May 2005, eight patients were still alive (53%), and seven had died (47%). Of the seven deceased patients, the neurohistophatological study was performed in three patients. Of these, autopsy was carried out in two and stereotactic biopsy was performed in one. Histopathological images of definite cases of CJD are presented in Figure 1. Of these 15 cases,47% were male and 53% were female. The youngest patient was 23 years old, while the oldest was 75 (average: 49 years). The clinical manifestations observed most frequently at the beginning of the disease included cognitive symptoms, behavioral changes, cephalalgia and depression.The rest of the symptoms are shown in Table 2. The elapsed time between the beginning of symptoms and the patient’s arrival at the NINN for medical attention consisted of a mean of 71 days (range: 10–210).The elapsed time from the beginning of clinical manifestations until the date of death and that between their arrival at the NINN and date of death are shown in Table 2. When analyzing their family history with respect to the presence of CJD and any type of dementia, all patients denied having this kind of antecedent. The past medical history of each patient is shown in Table 3. Ten patients (66.6%) were married or lived as couples, four (26.7%) were single, and only one (6.7%) was a widower. Regarding their educational level, nine (60%) had completed elementary education or had taken the first 3 years of courses and knew how to read and write; two (13%) had completed secondary education; three (20%) had completed high school or had at least a technical degree; and one (7%) had a bachelor degree. Concerning their residential locations, it was found that seven patients (47%) lived in Mexico City, five (33%) in the state of Mexico or suburban zones of the City, and three (20%) in other states of the Mexican Republic. The distribution of the cases in Mexico City, according to political divisions of the city, is shown in Figure 2. Regarding patients living in the state of Mexico, two (40%) were from Chalco, one (20%) was from Cuautitlan, one (20%) was from Ecatepec, and one (20%) from San JuanTeotihuacan. The three states of the Mexican Republic from where the other patients came were Guerrero, Hidalgo, and Sonora, each with one case. Regarding the occupational activities of the seven female patients, six (86%) were housewives and one (14%) was a secretary.With respect to the occupational activities of the male patients, two (25%) were retailers, two (25%) were office employees, and the remaining 50% was made up of farmers, drivers, bricklayers, and students, each with one case.


The average age in this study was 49 years, with an age range of 23–75 years. The age range reported by Bateman et al.13 is 45–75 years, and they mentioned that sCJD is extremely rare under age 30. However, in our study we had patients younger than this latter age. Nevertheless, gender frequency was similar, with 53% of female patients and 47% of male patients. Our results are more consistent with the work of Olov et al.32 who reported cases of CJD in younger patients, ranging from 34 to 84 years of age. Of the three definite cases, two were female, an interesting fact, as in 1995, in Mexico, Martínez et al.33 reported three cases, all of them female patients, but only one of them had a brain biopsy result. We are aware that PrP genotyping is important to classify prion diseases. However, in Mexico this technique is not available, a limitation of this study. However, we consider that this study reveals important information about CJD in Mexico. In the future, it would be interesting to perform a retrospective study with genetic analysis. Although seven cases died over a 5-year period, only 43% of them had a confirmed diagnosis. Despite the clinical profile, the laboratory, and the imaging studies that

could be made due to the refusal by the patients’ relatives. Unfortunately, Mexican culture is not oriented towards organ donation and post mortem studies. Besides this fact, specialized centers or laboratories where 14.3.3 protein determinations can be carried out are scarce. In Mexico, only one National Institute of Health conducts this type of analysis, which means blood samples have to be analyzed in foreign countries, making studies more expensive for patients, most of whom have low economic resources.This makes it impossible for them to obtain studies that support the CJD diagnosis. A tendency therefore exists to underestimate the real frequency of the disease, thus it may be more common in Mexico than it appears. In effect, the lack of knowledge among the population and among the medical staff of some institutions, as well as different levels of medical attention provided countrywide, may cause this disease not to be consistently diagnosed. This contrasts greatly with what happens in many European countries, where prompt post mortem studies for BSE have been carried out since January 1, 2001.

Fig. 2 Geographical areas of the Mexican Republic where the studied cases were located.







Table 2 indicates that most of the reported cases applied for medical attention 1–2 months after the appearance of symptoms, due to the limited importance patients give to behavioral and psycho-affective disorders. Early identification of the first symptoms in sporadic CJD, like depression, agitation, irritability, and memory loss, is important for public health reasons and potential timely interventions when treatments become available.34 No similarities were observed among the occupational activities of the studied male patients. Besides this, the fact that most of the female patients were housewives is most probably a reflection of the usual occupation of lowincome Mexican women. Forty-seven percent of the cases died, and the available information indicates that the elapsed time from the initiation of symptoms and the patient’s death is short – less than a year – indicating the damaging and aggressive impact of this disease. In spite of the fact that CJD is sporadic and its frequency of appearance is relatively low, it is necessary to make patients and their relatives aware of the importance of brain donation, to be able to reach more precise diagnoses and avoid many of these cases being classified either as probable or possible. Information about TSE must be widespread, particularly that concerning CJD; epidemiological surveillance and diagnostic systems must be established, so that more precise data concerning the incidence of these diseases are available, allowing for stricter control and prevention to be imposed. The training process should be enriched by increasing the number of autopsies performed in the NINN. From 1998 onwards, an institutional autopsy program has been established; however, proven cases of dementia including prion diseases are still low.35 It is necessary to increase the study of prion diseases by including autopsies as an integral part of medical education programs, along with a participating academic committee that should promote, assess, and evaluate the results obtained.



2007 Japanese Society of Neuropathology

PLEASE NOTE ABOVE CJD MEXICO ''The youngest patient was 23 years old,''... TSS

Published online before print January 2, 2008, 10.1073/pnas.0710824105 PNAS January 8, 2008 vol. 105 no. 1 11-12


Unraveling prion strains with cell biology and organic chemistry

Adriano Aguzzi*

Institute of Neuropathology, UniversitätsSpital Zürich, Schmelzbergstrasse 12, CH-8091 Zürich, Switzerland

Prions are the infectious agents causing transmissible spongiform encephalopathies (TSEs), which comprise human Creutzfeldt–Jakob disease (CJD), scrapie of sheep, bovine spongiform encephalopathy (BSE), and several other rare ailments of various species. According to the protein-only hypothesis (1), prions are composed solely of PrPSc, a misfolded form of the cellular protein PrPC. PrPSc typically forms highly ordered fibrillary aggregates, also termed "amyloid." The term "prion strain" denotes individual prion isolates sharing the same PrP sequence but giving rise to distinct, stable disease traits with different incubation periods and lesion profiles upon serial transmission in congenic hosts. The propagation of different strains in mice congenic with respect to their Prnp allelotypes is difficult to explain by the protein-only hypothesis because the epigenetic strain characteristics of prions appear to dominate over the primary prion protein sequence of the infected host (2, 3).

Circumstantial evidence suggests that strain phenotypes are encoded by distinct conformations of PrPSc (Fig. 1). This was first implied by experiments showing that distinct strains of transmissible mink encephalopathy went along with different protease-exposed sites within PrPSc (4). Great strides have been made since then, yet the final proof that conformational variants of PrPSc represent the biological basis of mammalian prion strains is still elusive. Distinct prion strains may bear highly divergent risks of transmission to humans: Sheep scrapie-derived strains may be mostly innocuous, whereas BSE-derived strains appear to induce variant CJD (vCJD) in humans. Also, two subtypes . . .see full text ;

Archive Number 20071105.3602 Published Date 05-NOV-2007 Subject PRO/AH/EDR> Prion disease update 2007 (07)



[In submitting these data, Terry S. Singeltary Sr. draws attention to the steady increase in the "type unknown" category, which, according to their definition, comprises cases in which vCJD could be excluded. The total of 26 cases for the current year (2007) is disturbing, possibly symptomatic of the circulation of novel agents. Characterization of these agents should be given a high priority. - Mod.CP],F2400_P1001_PUB_MAIL_ID:1010,39963

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 collection.

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


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?

Diagnosis and Reporting of Creutzfeldt-Jakob Disease

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

Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States

Creutzfeldt Jakob Disease


SEAC 99th meeting on Friday 14th December 2007

vCJD case study highlights blood transfusion risk

vCJD transfusion-associated Fourth Case UK

risk factors for sporadic CJD

Creutzfeldt-Jakob Disease, Prion Protein Gene Codon 129VV, and a Novel PrPSc Type in a Young British Woman

BSE (Mad Cow) Update: Do Reports of sCJD Clusters Matter?

snip... see full text ;

THE PATHOLOGICAL PROTEIN 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 population.

doi:10.1016/S1473-3099(03)00715-1Copyright © 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." ...


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