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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