Atypical/Nor98 scrapie: properties of the agent, genetics, and epidemiology

Vet. Res. (2008) 39:19 DOI: 10.1051/vetres:2007056

Atypical/Nor98 scrapie: properties of the agent, genetics, and epidemiology

Sylvie L. Benestad1, Jean-Noël Arsac2, Wilfred Goldmann3 and Maria Nöremark4

1 National Veterinary Institute, PO Box 8156 Dep., Oslo, Norway 2 Agence Française de Sécurité Sanitaire des Aliments, 31 av. Tony Garnier, 69364 Lyon Cedex 07, France 3 Neuropathogenesis Unit, Roslin Institute, Ogston Bldg, West Mains Rd, Edinburgh, EH9 3JF, UK 4 National Veterinary Institute, 75189 Uppsala, Sweden

(Received 23 July 2007; accepted 23 October 2007 ; published online 11 January 2008)

Abstract - Atypical/Nor98 scrapie cases in sheep were diagnosed for the first time in Norway in 1998. They are now identified in small ruminants in most European countries and represent an increasingly large proportion of the scrapie cases diagnosed in Europe. Atypical/Nor98 scrapie isolates have shown to be experimentally transmissible into transgenic mice and sheep but the properties of the TSE agent involved, like its biological and biochemical features, are so clearly distinct from the agent involved in classical scrapie that they have provided a challenging diagnostic for many years. No strain diversity has yet been identified among the atypical/Nor98 scrapie sample cases. The genetic predisposition of the sheep affected by atypical/Nor98 scrapie is almost inverted compared to classical scrapie, and the exact origin of this sporadic TSE strain is still speculative, but a spontaneous, non-contagious origin, like sporadic Creutzfeldt-Jakob disease in humans, can not be excluded. Further transmission and epidemiological studies are needed to better address this hypothesis.

Key words: atypical scrapie / Nor98 / transmissible spongiform encephalopathies TSE / genetics / epidemiology

Corresponding author: sylvie.benestad@vetinst.no

© INRA, EDP Sciences 2008

http://www.vetres.org/index.php?option=article&access=doi&doi=10.1051/vetres:2007056


The genetic predisposition of the sheep affected by atypical/Nor98 scrapie is almost inverted compared to classical scrapie, and the exact origin of this

sporadic TSE strain is still speculative, but a spontaneous, non-contagious origin, like sporadic Creutzfeldt-Jakob disease in humans, can not be excluded.

there are 26790 hits on 'sporadic' at pub-med.

there are 12830 hits on 'sporadic disease' at pub-med.

with the first few being ;

Comparison Analysis of Gene Expression Patterns between Sporadic Alzheimer's and Parkinson's Disease.

http://www.ncbi.nlm.nih.gov/pubmed/18198416?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum


Sporadic ALS with early onset respiratory failure is not associated with IGHMBP2 gene mutations.

http://www.ncbi.nlm.nih.gov/pubmed/18187479?ordinalpos=10&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum


Sporadic Multiple Cerebral Cavernomatosis: Report of a Case and Review of Literature

http://www.ncbi.nlm.nih.gov/pubmed/18195658?ordinalpos=7&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum


A sporadic disease is one that occurs only occasionally in a population (i.e., prevalence is zero).

http://mansfield.osu.edu/~sabedon/biol2045.htm


sporadic CJD is NOT a single strain, phenotype.

sporadic CJD is simply a human TSE, which routes, sources, strains, are unknown.

there are 6 different documented phenotypes of the sporadic CJD, with 'UNKNOWN' sub-types growing.

spontaneous TSE in the field ??? never has been proven, and highly unlikely that 85%+ of all human TSE i.e. sporadic CJD, just happen without route and source.

Volume 12, Number 12–December 2006

Perspective

On the Question of Sporadic or Atypical Bovine Spongiform Encephalopathy and Creutzfeldt-Jakob Disease

Paul Brown,* Lisa M. McShane,† Gianluigi Zanusso,‡ and Linda Detwiler§

*Bethesda, Maryland, USA; †National Institutes of Health, Bethesda, Maryland, USA; ‡University of Verona, Verona, Italy; and §Virginia-Maryland Regional College of Veterinary Medicine, College Park, Maryland, USA

snip...

Sporadic CJD

The possibility that at least some cases of apparently sporadic CJD might be due to infection by sporadic cases of BSE cannot be dismissed outright. Screening programs needed to identify sporadic BSE have yet to be implemented, and we know from already extant testing programs that at least a proportion of infected animals have no symptoms and thus would never be identified in the absence of systematic testing. Thus, sporadic BSE (or for that matter, sporadic disease in any mammalian species) might be occurring on a regular basis at perhaps the same annual frequency as sporadic CJD in humans, that is, in the range of 1 case per million animals.

Whether humans might be more susceptible to atypical forms of BSE cannot be answered at this time. Experimentally transmitted BASE shows shorter incubation periods than BSE in at least 1 breed of cattle, bovinized transgenic mice, and Cynomolgus monkeys (12,13). In humanized transgenic mice, BASE transmitted, whereas typical BSE did not transmit (13). Paradoxically, the other major phenotype (H) showed an unusually long incubation period in bovinized transgenic mice (12).

The limited experimental evidence bearing on a possible relationship between BSE and sporadic CJD is difficult to interpret. The original atypical BASE strain of BSE had a molecular protein signature very similar to that of 1 subtype (type 2 M/V) of sporadic CJD in humans (5). In another study, a strain of typical BSE injected into humanized mice encoding valine at codon 129 showed a glycopattern indistinguishable from the same subtype of sporadic CJD (15). In a third study, the glycopatterns of both the H and L strains of atypical BSE evidently did not resemble any of the known sporadic CJD subtypes (12).

To these molecular biology observations can be added the epidemiologic data accumulated during the past 30 years. The hypothesis that at least some cases of apparently sporadic CJD are due to unrecognized BSE infections cannot be formally refuted, but if correct, we might expect by now to have some epidemiologic evidence linking BSE to at least 1 cluster of apparently sporadic cases of CJD. Although only a few clusters have been found (and still fewer published), every proposed cluster that has been investigated has failed to show any common exposure to bovines. For that matter, no common exposure has been shown to any environmental vehicles of infection, including the consumption of foodstuffs from bovine, ovine, and porcine sources, the 3 livestock species known to be susceptible to transmissible spongiform encephalopathies. Additional negative evidence comes from several large case-control studies in which no statistically significant dietary differences were observed between patients with sporadic CJD and controls (16,17).

On the other hand, the difficulty of establishing a link between BSE and CJD may be compounded by our ignorance of the infectious parameters of a sporadic form of BSE (e.g., host range, tissue distribution of infectivity, route of transmission, minimum infectious dose for humans, whether single or multiple). Presumably, these parameters would resemble those of variant CJD; that is, high infectivity central nervous system and lymphoreticular tissues of an infected cow find their way into products consumed by humans. Transmissions that might have occurred in the past would be difficult to detect because meat products are generally not distributed in a way that results in detectable geographic clusters.

Barring the discovery of a specific molecular signature (as in variant CJD), the most convincing clue to an association will come from the observation of trends over time of the incidence of typical and atypical BSE and of sporadic and variant CJD. With 4 diseases, each of which could have increasing, unchanging, or decreasing trends, there could be 81 (34) possible different combinations. However, it is highly likely that the trends for typical BSE and variant CJD will both decrease in parallel as feed bans continue to interrupt recycled contamination. The remaining combinations are thus reduced to 9 (32), and some of them could be highly informative.

For example, if the incidence of atypical BSE declines in parallel with that of typical BSE, its candidacy as a sporadic form of disease would be eliminated (because sporadic disease would not be influenced by current measures to prevent oral infection). If, on the other hand, atypical BSE continues to occur as typical BSE disappears, this would be a strong indication that it is indeed sporadic, and if in addition at least 1 form of what is presently considered as sporadic CJD (such as the type 2 M/V subtype shown to have a Western blot signature like BASE) were to increase, this would suggest (although not prove) a causal relationship (Figure 5).

Recognition of the different forms of BSE and CJD depends upon continuing systematic testing for both bovines and humans, but bovine testing will be vulnerable to heavy pressure from industry to dismantle the program as the commercial impact of declining BSE cases ceases to be an issue. Industry should be aware, however, of the implications of sporadic BSE. Its occurrence would necessitate the indefinite retention of all of the public health measures that exclude high-risk bovine tissues from the animal and human food chains, whereas its nonoccurrence would permit tissues that are now destroyed to be used as before, once orally acquired BSE has disappeared.

http://www.cdc.gov/ncidod/EID/vol12no12/06-0965.htm


THE USDA JUNE 2004 ENHANCED BSE SURVEILLANCE PROGRAM WAS TERRIBLY FLAWED ;

CDC DR. PAUL BROWN TSE EXPERT COMMENTS 2006

The U.S. Department of Agriculture was quick to assure the public earlier this week that the third case of mad cow disease did not pose a risk to them, but what federal officials have not acknowledged is that this latest case indicates the deadly disease has been circulating in U.S. herds for at least a decade.

The second case, which was detected last year in a Texas cow and which USDA officials were reluctant to verify, was approximately 12 years old.

These two cases (the latest was detected in an Alabama cow) present a picture of the disease having been here for 10 years or so, since it is thought that cows usually contract the disease from contaminated feed they consume as calves. The concern is that humans can contract a fatal, incurable, brain-wasting illness from consuming beef products contaminated with the mad cow pathogen.

"The fact the Texas cow showed up fairly clearly implied the existence of other undetected cases," Dr. Paul Brown, former medical director of the National Institutes of Health's Laboratory for Central Nervous System Studies and an expert on mad cow-like diseases, told United Press International. "The question was, 'How many?' and we still can't answer that."

Brown, who is preparing a scientific paper based on the latest two mad cow cases to estimate the maximum number of infected cows that occurred in the United States, said he has "absolutely no confidence in USDA tests before one year ago" because of the agency's reluctance to retest the Texas cow that initially tested positive.

USDA officials finally retested the cow and confirmed it was infected seven months later, but only at the insistence of the agency's inspector general.

"Everything they did on the Texas cow makes everything USDA did before 2005 suspect," Brown said. ...snip...end

http://www.upi.com/

CDC - Bovine Spongiform Encephalopathy and Variant Creutzfeldt ... Dr. Paul Brown is Senior Research Scientist in the Laboratory of Central Nervous System ... Address for correspondence: Paul Brown, Building 36, Room 4A-05, ...

http://www.cdc.gov/ncidod/eid/vol7no1/brown.htm


PAUL BROWN COMMENT TO ME ON THIS ISSUE

Tuesday, September 12, 2006 11:10 AM

"Actually, Terry, I have been critical of the USDA handling of the mad cow issue for some years, and with Linda Detwiler and others sent lengthy detailed critiques and recommendations to both the USDA and the Canadian Food Agency." ........

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

PRION DISEASE UPDATE 2007 (07)

snip...

[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]

http://www.promedmail.org/pls/askus/f?p=2400:1001:6833194127530602005::NO::F2400_P1001_BACK_PAGE,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.

http://www.fda.gov/ohrms/dockets/ac/06/transcripts/1006-4240t1.htm


http://www.fda.gov/ohrms/dockets/ac/06/transcripts/2006-4240t1.pdf


JOURNAL OF NEUROLOGY

MARCH 26, 2003

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

disease in the United States

Email Terry S. Singeltary:

flounder@wt.net

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?

http://www.neurology.org/cgi/eletters/60/2/176#535


Diagnosis and Reporting of Creutzfeldt-Jakob Disease

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

http://jama.ama-assn.org/http://www.neurology.org/cgi/eletters/60/2/176#535


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

http://cjdusa.blogspot.com/


Creutzfeldt Jakob Disease

http://creutzfeldt-jakob-disease.blogspot.com/


CJD QUESTIONNAIRE

http://cjdquestionnaire.blogspot.com/


SEAC 99th meeting on Friday 14th December 2007

http://seac992007.blogspot.com/


16 January 2008 - The final minutes of the 98th SEAC meeting have been published.

PUBLIC QUESTION AND ANSWER SESSION 2© SEAC 2007SEAC considered a question about possible links between CJD cases and animal TSEs in the United States of America (USA).

http://www.seac.gov.uk/summaries/seac99_summary.pdf


vCJD case study highlights blood transfusion risk

http://vcjdblood.blogspot.com/


vCJD transfusion-associated Fourth Case UK

http://vcjdtransfusion.blogspot.com/


risk factors for sporadic CJD

http://creutzfeldt-jakob-disease.blogspot.com/2008/01/risk-factors-for-sporadic-creutzfeldt.html


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

http://creutzfeldt-jakob-disease.blogspot.com/2008/01/creutzfeldt-jakob-disease-prion-protein.html


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

snip... see full text ;

http://cjdtexas.blogspot.com/


THE PATHOLOGICAL PROTEIN Hardcover, 304 pages plus photos and illustrations. ISBN 0-387-95508-9 June 2003 BY Philip Yam

CHAPTER 14 LAYING ODDS

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.

http://www.thepathologicalprotein.com/


doi:10.1016/S1473-3099(03)00715-1Copyright © 2003 Published by Elsevier Ltd.

Newsdesk

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." ...

http://www.thelancet.com/journals/laninf/article/PIIS1473309903007151/fulltext


http://download.thelancet.com/pdfs/journals/1473-3099/PIIS1473309903007151.pdf


ANIMAL HEALTH REPORT 2006 (BSE h-BASE EVENT IN ALABAMA, Scrapie, and CWD)

http://animalhealthreport2006.blogspot.com/


P03.141

Aspects of the Cerebellar Neuropathology in Nor98

Gavier-Widén, D1; Benestad, SL2; Ottander, L1; Westergren, E11National Veterinary Insitute, Sweden; 2National Veterinary Institute, Norway

Nor98 is a prion disease of old sheep and goats. This atypical form of scrapie was first described in Norway in 1998. Several features of Nor98 were shown to be different from classical scrapie including the distribution of disease associated prion protein (PrPd) accumulation in the brain. The cerebellum is generally the most affected brain area in Nor98. The study here presented aimed at adding information on the neuropathology in the cerebellum of Nor98 naturally affected sheep of various genotypes in Sweden and Norway. A panel of histochemical and immunohistochemical (IHC) stainings such as IHC for PrPd, synaptophysin, glial fibrillary acidic protein, amyloid, and cell markers for phagocytic cells were conducted. The type of histological lesions and tissue reactions were evaluated. The types of PrPd deposition were characterized. The cerebellar cortex was regularly affected, even though there was avariation in the severity of the lesions from case to case. Neuropil vacuolation was more marked in the molecular layer, but affected also the granular cell layer. There was a loss of granule cells. Punctate deposition of PrPd was characteristic. It was morphologically and in distribution identical with that of synaptophys in, suggesting that PrPd accumulates in the synaptic structures. PrPd was also observed in the granule cell layer and in the white matter. The pathology features of Nor98 in the cerebellum of the affected sheep showed similarities with those of sporadic Creutzfeldt-Jakob disease in humans.

http://www.prion2007.com/pdf/Prion%20Book%20of%20Abstracts.pdf


NOR-98 ATYPICAL SCRAPIE USA UPDATE AS AT OCT 2007

typical scrapie transmits to primates by there NON-FORCED ORAL CONSUMPTION ;

76/10.12/4.6

http://www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf


http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=6997404&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus


full text ;

http://nor-98.blogspot.com/


http://scrapie-usa.blogspot.com/


CREUTZFELDT JAKOB DISEASE MAD COW BASE UPDATE USA

http://cjdmadcowbaseoct2007.blogspot.com/


Transmissible Mink Encephalopathy TME

http://transmissible-mink-encephalopathy.blogspot.com/


CHRONIC WASTING DISEASE

http://chronic-wasting-disease.blogspot.com/


ONE other question from Confucius,

IF we are to believe as some has so persistently tried to claim without any proof, if we are to believe that these TSE just happen spontaneous, then why have there been NO other cases of TME in the USA ???

WHERE are these cases of spontaneous BSE/BASE in the USA ???

WHAT about the FSE cases, none in the USA either, no feline spongiform encephalopathy in USA documented to date ???

IF the spontaneous TSE truely exist, would we have not seen these species with TSE here in the USA ???

WHAT about Europe, if the spontanous TSE truely happened, would CWD, TME, not happen in the EU countries as well ???

OR is it just the USDA certified BASE mad cows that are spontaneous ;-) $$$

Saturday, December 01, 2007

Phenotypic Similarity of Transmissible Mink Encephalopathy in Cattle and L-type Bovine Spongiform Encephalopathy in a Mouse Model

http://transmissible-mink-encephalopathy.blogspot.com/


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