Thursday, November 14, 2013

A Novel Prion Disease Associated with Diarrhea and Autonomic Neuropathy

Original Article

 

A Novel Prion Disease Associated with Diarrhea and Autonomic Neuropathy

 

Simon Mead, M.D., Sonia Gandhi, M.D., Jon Beck, B.Sc., Diana Caine, Ph.D., Dillip Gallujipali, M.D., Christopher Carswell, M.D., Harpreet Hyare, M.D., Susan Joiner, M.Sc., Hilary Ayling, B.Sc., Tammaryn Lashley, Ph.D., Jacqueline M. Linehan, B.Sc., Huda Al-Doujaily, M.Sc., Bernadette Sharps, B.Sc., Tamas Revesz, M.D., Malin K. Sandberg, Ph.D., Mary M. Reilly, M.D., Martin Koltzenburg, M.D., Alastair Forbes, M.D., Peter Rudge, M.D., Sebastian Brandner, M.D., Jason D. Warren, M.D., Jonathan D.F. Wadsworth, Ph.D., Nicholas W. Wood, M.D., Janice L. Holton, M.D., and John Collinge, M.D.

 

N Engl J Med 2013; 369:1904-1914November 14, 2013DOI: 10.1056/NEJMoa1214747

 

Background

 

Human prion diseases, although variable in clinicopathological phenotype, generally present as neurologic or neuropsychiatric conditions associated with rapid multifocal central nervous system degeneration that is usually dominated by dementia and cerebellar ataxia. Approximately 15% of cases of recognized prion disease are inherited and associated with coding mutations in the gene encoding prion protein (PRNP). The availability of genetic diagnosis has led to a progressive broadening of the recognized spectrum of disease.

 

Methods

 

We used longitudinal clinical assessments over a period of 20 years at one hospital combined with genealogical, neuropsychological, neurophysiological, neuroimaging, pathological, molecular genetic, and biochemical studies, as well as studies of animal transmission, to characterize a novel prion disease in a large British kindred. We studied 6 of 11 affected family members in detail, along with autopsy or biopsy samples obtained from 5 family members.

 

Results

 

We identified a PRNP Y163X truncation mutation and describe a distinct and consistent phenotype of chronic diarrhea with autonomic failure and a length-dependent axonal, predominantly sensory, peripheral polyneuropathy with an onset in early adulthood. Cognitive decline and seizures occurred when the patients were in their 40s or 50s. The deposition of prion protein amyloid was seen throughout peripheral organs, including the bowel and peripheral nerves. Neuropathological examination during end-stage disease showed the deposition of prion protein in the form of frequent cortical amyloid plaques, cerebral amyloid angiopathy, and tauopathy. A unique pattern of abnormal prion protein fragments was seen in brain tissue. Transmission studies in laboratory mice were negative.

 

Conclusions

 

Abnormal forms of prion protein that were found in multiple peripheral tissues were associated with diarrhea, autonomic failure, and neuropathy. (Funded by the U.K. Medical Research Council and others.)

 

Supported by grants from the U.K. Medical Research Council (MRC) (in part to Dr. Reilly), the Reta Lila Weston Institute of Neurological Studies (to Dr. Holton and Ms. Ayling), Alzheimer's Research UK (to Drs. Holton, Revesz, and Lashley), the Multiple System Atrophy Trust (to Drs. Holton and Revesz), the National Institute for Health Research (NIHR) Biomedical Research Centre at the University College London Hospitals NHS Foundation Trust and University College London, the NIHR Dementia Biomedical Research Unit, the National Institutes of Neurological Diseases and Stroke and Office of Rare Diseases Research (U54NS065712, to Dr. Reilly), a Wellcome Trust Senior Clinical Fellowship (to Dr. Warren), and a Wellcome Trust/MRC Neurodegeneration award (WT089698).

 

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

 

Drs. Mead and Gandhi and Drs. Holton and Collinge contributed equally to this article.

 

We thank the patients and their families, caregivers, and physicians for providing medical histories and assessments for use in the patient reports; Ray Young for assistance with the original figures; Kerrie Venner for assistance with electron microscopy; and Prof. Bernardino Ghetti for helpful discussions.

 

 Source Information

 

From the Medical Research Council (MRC) Prion Unit (S.M., J.B., C.C., S.J., J.M.L., H.A.-D., B.S., M.K.S., S.B., J.D.F.W., J.C.), Department of Molecular Neuroscience (S.G., N.W.W.), and Dementia Research Centre, Department of Neurodegenerative Disease (J.D.W.), and MRC Centre for Neuromuscular Diseases (M.M.R.), University College London (UCL) Institute of Neurology; the National Prion Clinic (S.M., D.C., D.G., H.H., P.R., J.C.), National Hospital for Neurology and Neurosurgery (M.K.), UCL Hospitals National Health Service Trust (A.F.); and the Queen Square Brain Bank (H.A., T.L., T.R., J.L.H.) — all in London.

 

Address reprint requests to Dr. Collinge at the MRC Prion Unit, UCL Institute of Neurology, Queen Sq., London WC1N 3BG, United Kingdom, or at j.collinge@prion.ucl.ac.uk.

 


 

 Wednesday, November 13, 2013

 

Spontaneous Generation of Infectious Prion Disease in Transgenic Mice

 


 

Wednesday, November 13, 2013

 

Atypical Scrapie Prions from Sheep and Lack of Disease in Transgenic Mice Overexpressing Human Prion Protein

 


 

CJD Mark Tami: To ask the Secretary of State for Health (1) what steps his Department has put in place to monitor the number of people who carry the abnormal prion protein which causes variant Creutzfeldt-Jakob disease; [174628]

 

(2) when he plans that screening of the abnormal prion protein which causes variant Creutzfeldt-Jakob disease will be introduced; [174631]

 

(3) what assessment he has made of the number of people who carry the abnormal prion protein which causes variant Creutzfeldt-Jakob disease. [174633]

 

12 Nov 2013 : Column 615W

 

Jane Ellison: The presence of abnormal prion protein is currently taken as a marker for asymptomatic carriage of variant Creutzfeldt-Jakob disease or for symptomatic infection. A recent study to assess carriage by looking at stored appendix tissue samples, first published in the Health Protection Report in August 2012, found abnormal prion protein in 16 appendices out of 32,441 samples. This suggests a prevalence of about 1 in 2,000.

 

There is no monitoring of people who may carry the abnormal prion protein; all appendix prevalence studies are anonymised.

 

No routine screening can yet take place as there are no suitable validated screening tests for abnormal prion protein available. The Department, together with the United Kingdom Blood Services, continues to monitor, scientific research and development in this area.

 


 

Monday, October 14, 2013

 

Researchers estimate one in 2,000 people in the UK carry variant CJD proteins

 


 

Tuesday, October 29, 2013

 

VARIANT CJD PRESENTS DIFFERENTLY IN OLDER PATIENTS

 


 

Wednesday, October 09, 2013

 

*** WHY THE UKBSEnvCJD ONLY THEORY IS SO POPULAR IN IT'S FALLACY, £41,078,281 in compensation REVISED

 


 

Thursday, October 10, 2013

 

CJD REPORT 1994 increased risk for consumption of veal and venison and lamb

 


 

Friday, August 16, 2013

 

*** Creutzfeldt-Jakob disease (CJD) biannual update August 2013 U.K. and Contaminated blood products induce a highly atypical prion disease devoid of PrPres in primates

 


 

WHAT about the sporadic CJD TSE proteins ?

 

WE now know that some cases of sporadic CJD are linked to atypical BSE and atypical Scrapie, so why are not MORE concerned about the sporadic CJD, and all it’s sub-types $$$

 

Creutzfeldt-Jakob Disease CJD cases rising North America updated report August 2013

 

*** Creutzfeldt-Jakob Disease CJD cases rising North America with Canada seeing an extreme increase of 48% between 2008 and 2010 ***

 


 

Sunday, October 13, 2013

 

CJD TSE Prion Disease Cases in Texas by Year, 2003-2012

 


 

Saturday, November 2, 2013

 

Recommendation of the Swiss Expert Committee for Biosafety on the classification of activities using prion genes and prion protein January 2013

 


 

Saturday, November 2, 2013

 

APHIS Finalizes Bovine Import Regulations in Line with International Animal Health Standards while enhancing the spread of BSE TSE prion mad cow type disease around the Globe

 


 

I AGREE WITH MR. BULLARD, it’s all about trade and money, BSE TSE PRION aka mad cow type disease and sound science there from, was thrown out the window by the USDA et al that fateful day in December 23, 2003, when the USDA lost it’s ‘gold card’ of supposedly being BSE FREE, (that was and still is a sad joke though), that’s when mad cow junk science was adopted by the USDA...

 

see why below...kind regards, terry

 

Monday, November 4, 2013

 

*** R-CALF Bullard new BSE rule represents the abrogation of USDA’s responsibility to protect U.S. consumers and the U.S. cattle herd from the introduction of foreign animal disease

 


 

*** Saturday, November 2, 2013 ***

 

Exploring the risks of a putative transmission of BSE to new species

 


 

Wednesday, September 25, 2013

 

Presence of subclinical infection in gene-targeted human prion protein transgenic mice exposed to atypical BSE

 


 

I ask Professor Kong ; Thursday, December 04, 2008 3:37 PM

 

Subject: RE: re--Chronic Wating Disease (CWD) and Bovine Spongiform Encephalopathies (BSE): Public Health Risk Assessment ''IS the h-BSE more virulent than typical BSE as well, or the same as cBSE, or less virulent than cBSE? just curious.....'' Professor Kong reply ;

 

.....snip

 

''As to the H-BSE, we do not have sufficient data to say one way or another, but we have found that H-BSE can infect humans. I hope we could publish these data once the study is complete. Thanks for your interest.''

 

Best regards, Qingzhong Kong, PhD Associate Professor Department of Pathology Case Western Reserve University Cleveland, OH 44106 USA END...TSS

 

Thursday, December 04, 2008 2:37 PM

 

"we have found that H-BSE can infect humans."

 

personal communication with Professor Kong. ...TSS

 

BSE-H is also transmissible in our humanized Tg mice. The possibility of more than two atypical BSE strains will be discussed.

 

Supported by NINDS NS052319, NIA AG14359, and NIH AI 77774.

 


 


 

please see below from PRION2013 ;

 

*** This study imply the possibility that the novel BSE prions with high virulence in cattle will be emerged during intraspecies transmission.

 

AD.56: The emergence of novel BSE prions by serial passages of H-type BSE in bovinized mice

 

Kentaro Masujin, Naoko Tabeta, Ritsuko Miwa, Kohtaro Miyazawa, Hiroyuki Okada, Shirou Mohri and Takashi Yokoyama National Institute of Animal Health; Tsukuba, Japan

 

H-type bovine spongiform encephalopathy (BSE) is an atypical form of BSE, and has been detected in several European countries, and North America. Transmission studies of H-type BSE led to the emergence of the classical BSE (C-BSE) phenotypes during passages in inbred wild type and bovinized PrP-overexpressing transgenic mice. In this study, we conducted serial passages of Canadian H-type BSE isolate in bovinized PrP-overexpressing transgenic mice (TgBoPrP). H-type BSE isolate was transmitted to TgBoPrP with incubation periods of 320 ± 12.2 d at primary passage. The incubation period of 2nd and 3rd passage were constant (~= 220 d), no clear differences were observed in their biological and biochemical properties. However, at the forth passage, 2 different BSE phenotypes were confirmed; one is shorter survival times (109 ± 4 d) and the other is longer survival times. TgBoPrP mice with longer incubation period showed the H-type phenotype of PrPsc profile and pathology. However, those of shorter incubation period were different phenotypes from previously existed BSE prions (C-BSE, L-type BSE, and H-type BSE).

 

*** This study imply the possibility that the novel BSE prions with high virulence in cattle will be emerged during intraspecies transmission.

 


 

www.landesbioscience.com

 

please see ;

 

Thursday, August 15, 2013

 

The emergence of novel BSE prions by serial passages of H-type BSE in bovinized mice

 


 

Sunday, September 1, 2013

 

*** Evaluation of the Zoonotic Potential of Transmissible Mink Encephalopathy

 

We previously described the biochemical similarities between PrPres derived from L-BSE infected macaque and cortical MM2 sporadic CJD: those observations suggest a link between these two uncommon prion phenotypes in a primate model (it is to note that such a link has not been observed in other models less relevant from the human situation as hamsters or transgenic mice overexpressing ovine PrP [28]). We speculate that a group of related animal prion strains (L-BSE, c-BSE and TME) would have a zoonotic potential and lead to prion diseases in humans with a type 2 PrPres molecular signature (and more specifically type 2B for vCJD)

 

snip...

 

Together with previous experiments performed in ovinized and bovinized transgenic mice and hamsters [8,9] indicating similarities between TME and L-BSE, the data support the hypothesis that L-BSE could be the origin of the TME outbreaks in North America and Europe during the mid-1900s.

 


 

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 ;

 


 

Thursday, August 12, 2010

 

Seven main threats for the future linked to prions

 

First threat

 

The TSE road map defining the evolution of European policy for protection against prion diseases is based on a certain numbers of hypotheses some of which may turn out to be erroneous. In particular, a form of BSE (called atypical Bovine Spongiform Encephalopathy), recently identified by systematic testing in aged cattle without clinical signs, may be the origin of classical BSE and thus potentially constitute a reservoir, which may be impossible to eradicate if a sporadic origin is confirmed.

 

***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...

 


 


 


 

 Wednesday, November 13, 2013

 

CJD House of Commons Tuesday 12 November 2013

 


 

 Sunday, December 12, 2010

 

EFSA reviews BSE/TSE infectivity in small ruminant tissues News Story 2 December 2010

 


 

Wednesday, January 18, 2012

 

Selection of Distinct Strain Phenotypes in Mice Infected by Ovine Natural Scrapie Isolates Similar to CH1641 Experimental Scrapie

 

Journal of Neuropathology & Experimental Neurology: February 2012 - Volume 71 - Issue 2 - p 140–147

 


 

Thursday, July 14, 2011

 

Histopathological Studies of "CH1641-Like" Scrapie Sources Versus Classical Scrapie and BSE Transmitted to Ovine Transgenic Mice (TgOvPrP4)

 


 

Wednesday, January 18, 2012

 

BSE IN GOATS CAN BE MISTAKEN FOR SCRAPIE

 

February 1, 2012

 


 

Thursday, December 23, 2010

 

Molecular Typing of Protease-Resistant Prion Protein in Transmissible Spongiform Encephalopathies of Small Ruminants, France, 2002-2009

 

Volume 17, Number 1 January 2011

 


 

Thursday, November 18, 2010

 

Increased susceptibility of human-PrP transgenic mice to bovine spongiform encephalopathy following passage in sheep

 


 

Monday, December 14, 2009

 

Similarities between Forms of Sheep Scrapie and Creutzfeldt-Jakob Disease Are Encoded by Distinct Prion Types

 

(hmmm, this is getting interesting now...TSS)

 

Sporadic CJD type 1 and atypical/ Nor98 scrapie are characterized by fine (reticular) deposits,

 

see also ;

 

All of the Heidenhain variants were of the methionine/ methionine type 1 molecular subtype.

 


 

see full text ;

 

Monday, December 14, 2009

 

Similarities between Forms of Sheep Scrapie and Creutzfeldt-Jakob Disease Are Encoded by Distinct Prion Types

 


 

Thursday, July 21, 2011

 

A Second Case of Gerstmann-Sträussler-Scheinker Disease Linked to the G131V Mutation in the Prion Protein Gene in a Dutch Patient Journal of Neuropathology & Experimental Neurology:

 

August 2011 - Volume 70 - Issue 8 - pp 698-702

 


 

Friday, March 09, 2012

 

Experimental H-type and L-type bovine spongiform encephalopathy in cattle: observation of two clinical syndromes and diagnostic challenges

 

Research article

 


 

Thursday, June 23, 2011

 

Experimental H-type bovine spongiform encephalopathy characterized by plaques and glial- and stellate-type prion protein deposits

 


 

Thursday, February 14, 2013

 

*** The Many Faces of Mad Cow Disease Bovine Spongiform Encephalopathy BSE and TSE prion disease

 


 

Tuesday, March 5, 2013

 

Use of Materials Derived From Cattle in Human Food and Cosmetics; Reopening of the Comment Period FDA-2004-N-0188-0051 (TSS SUBMISSION)

 

FDA believes current regulation protects the public from BSE but reopens comment period due to new studies

 


 

Tuesday, March 05, 2013

 

A closer look at prion strains Characterization and important implications

 

Prion 7:2, 99–108; March/April 2013; © 2013 Landes Bioscience

 


 

Thursday, January 26, 2012

 

Facilitated Cross-Species Transmission of Prions in Extraneural Tissue

 

Science 27 January 2012: Vol. 335 no. 6067 pp. 472-475 DOI: 10.1126/science.1215659

 


 

Saturday, February 11, 2012

 

Prion cross-species transmission efficacy is tissue dependent

 


 

Thursday, January 26, 2012

 

The Risk of Prion Zoonoses

 

Science 27 January 2012: Vol. 335 no. 6067 pp. 411-413 DOI: 10.1126/science.1218167

 


 

Monday, April 25, 2011

 

Experimental Oral Transmission of Atypical Scrapie to Sheep

 

Volume 17, Number 5-May 2011

 


 

Sunday, April 18, 2010

 

SCRAPIE AND ATYPICAL SCRAPIE TRANSMISSION STUDIES A REVIEW 2010

 


 

Thursday, November 18, 2010

 

Increased susceptibility of human-PrP transgenic mice to bovine spongiform encephalopathy following passage in sheep

 


 

Wednesday, January 19, 2011

 

EFSA and ECDC review scientific evidence on possible links between TSEs in animals and humans Webnachricht 19 Januar 2011

 


 

Monday, June 27, 2011

 

Comparison of Sheep Nor98 with Human Variably Protease-Sensitive Prionopathy and Gerstmann-Sträussler-Scheinker Disease

 


 

Thursday, November 18, 2010

 

Increased susceptibility of human-PrP transgenic mice to bovine spongiform encephalopathy following passage in sheep

 


 

Tuesday, September 24, 2013

 

NORDION (US), INC., AND BIOAXONE BIOSCIENCES, INC., Settles $90M Mad Cow TSE prion Contamination Suit Cethrin(R)

 

Case 0:12-cv-60739-RNS Document 1 Entered on FLSD Docket 04/26/2012 Page 1 of 15

 


 

with great sadness and disgust, I must inform you that our federal government has failed us again, and chose the industry over sound science, with regards to TSE prion disease, aka mad cow type disease...tss

 

Saturday, November 2, 2013

 

APHIS Finalizes Bovine Import Regulations in Line with International Animal Health Standards while enhancing the spread of BSE TSE prion mad cow type disease around the Globe

 


 

Monday, November 4, 2013

 

R-CALF Bullard new BSE rule represents the abrogation of USDA’s responsibility to protect U.S. consumers and the U.S. cattle herd from the introduction of foreign animal disease

 


 

 TSS

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