MM2-thalamic Creutzfeldt-Jakob disease: neuropathological, biochemical and transmission studies identify a distinctive prion strain
Fabio Moda1,†, Silvia Suardi1,†, Giuseppe Di Fede1, Antonio Indaco1, Lucia Limido1, Chiara Vimercati1, Margherita Ruggerone1, Ilaria Campagnani1, Jan Langeveld2, Alessandro Terruzzi3, Antonio Brambilla4, Pietro Zerbi5, Paolo Fociani5, Matthew T. Bishop6, Robert G. Will6, Jean C. Manson7, Giorgio Giaccone1, Fabrizio Tagliavini1
DOI: 10.1111/j.1750-3639.2012.00572.x
© 2012 The Authors; Brain Pathology © 2012 International Society of Neuropathology
In Creutzfeldt-Jakob disease (CJD), molecular typing based on the size of the protease resistant core of the disease-associated prion protein (PrPSc) and the M/V polymorphism at codon 129 of the PRNP gene correlates with the clinico-pathologic subtypes. Approximately 95% of the sporadic 129MM CJD patients are characterized by cerebral deposition of type 1 PrPSc and correspond to the classic clinical CJD phenotype. The rare 129MM CJD patients with type 2 PrPSc are further subdivided in a cortical and a thalamic form also indicated as Sporadic Fatal Insomnia.
We observed two young patients with MM2-thalamic CJD. Main neuropathological features were diffuse, synaptic PrP immunoreactivity in the cerebral cortex and severe neuronal loss and gliosis in the thalamus and olivary nucleus. Western blot analysis showed the presence of type 2A PrPSc. Challenge of transgenic mice expressing 129MM human PrP, showed that MM2-thalamic sCJD was able to transmit the disease, at variance with MM2-cortical sCJD. The affected mice showed deposition of type 2A PrPSc, a scenario that is unprecedented in this mouse line. These data indicate that MM2-thalamic sCJD is caused by a prion strain distinct from the other sCJD subtypes including the MM2-cortical form.
Case report Sporadic fatal insomnia in a young woman: A diagnostic challenge: Case Report
Karen M Moody1*, Lawrence B Schonberger2, Ryan A Maddox2, Wen-Quan Zou3, Laura Cracco3 and Ignazio Cali3
Karen M Moody1*, Lawrence B Schonberger2, Ryan A Maddox2, Wen-Quan Zou3, Laura Cracco3 and Ignazio Cali3
Case Presentation We report a case of a 33-year-old female who died of a prion disease for whom the diagnosis of sFI or FFI was not considered clinically. Following death of this patient, an interview with a close family member indicated the patient's illness included a major change in her sleep pattern, corroborating the reported autopsy diagnosis of sFI. Genetic tests identified no prion protein (PrP) gene mutation, but neuropathological examination and molecular study showed protease-resistant PrP (PrPres) in several brain regions and severe atrophy of the anterior-ventral and medial-dorsal thalamic nuclei similar to that described in FFI.
Conclusions
In patients with suspected prion disease, a characteristic change in sleep pattern can be an important clinical clue for identifying sFI or FFI; polysomnography (PSG), genetic analysis, and nuclear imaging may aid in diagnosis.
snip...
For the patient described in this report, her long duration of illness and young age at onset are unusual for the most common subtype of prion disease, sporadic CJD [17]. Other forms of CJD were considered but determined to be extremely unlikely. Although this young patient showed signs of psychiatric illness at the beginning of her disease consistent with variant CJD (vCJD), these signs did not precede her noticeable deficits in attention and memory and she had not traveled to any country where transmission of vCJD was known to occur.
snip...
Recently a case of alleged sFI has been reported showing the presence of PrPres type 1 (rather than type 2 as in the present and other cases of sFI); the largest amount of PrPres in the mediodorsal thalamic nucleus, and a glycoform ratio characterized by the relative prevalence of the diglycosylated PrPres isoform similar to that of FFI [23]. If confirmed, this case indicates that, as in sCJD in general, occasional and unexplained phenotypic variations have to be expected in sFI. Finally, the severe neuronal loss of the anterior ventral and mediodorsal thalamic nuclei which contained relatively low amounts of PrPres raises the issue of whether other isoforms of neurotoxic PrP such as protease-sensitive PrP are present in the thalamic nuclei in sFI.
Defining sporadic Creutzfeldt-Jakob disease strains and their transmission properties
Matthew T. Bishopa, Robert G. Willa, and Jean C. Mansonb,1 + Author Affiliations
aNational Creutzfeldt-Jakob Disease Surveillance Unit, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom; and bThe Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Roslin, Midlothian EH25 9PS, United Kingdom Edited* by Reed B. Wickner, National Institutes of Health, Bethesda, MD, and approved May 19, 2010 (received for review April 15, 2010)
Next Section Abstract The biological determinants of the phenotypic variation in sporadic Creutzfeldt-Jakob disease (sCJD) are unknown. To categorize sCJD cases, the prion protein (PrP) codon 129 genotype and the biochemical characteristics of the disease-associated form of PrP (PrPSc) can be combined to form six subgroups (MM1, MM2, MV1, MV2, VV1, and VV2). This classification largely correlates with the known variation in the clinical and pathological features of sCJD, with the MM1 and MV1 cases representing the “classic” phenotype of sCJD. To address how this classification relates to different strains of sCJD we have inoculated each subgroup of sCJD to a panel of mice expressing different forms of the human PRNP gene (129MM, 129VV, and 129MV). We have established that all subtypes are transmissible to at least one genotype of mouse, and both agent and host factors determine transmission efficiency and the form of PrPSc deposited in the brain. Moreover, we have identified four distinct strains of sCJD using our in vivo strain typing panel.
snip...
Evidence in support of these four major strains of sCJD has recently been reported through a very different approach. Using in vitro assays, Uro-Coste et al. (29) examined the protease sensitivity and conformational stability of PrPSc found in 41 patients with sCJD and found groupings identical to those outlined in this study (i.e., MM1 and MV1; MV2 and VV2; MM2; VV1). Because this study was based entirely on in vitro analysis of PrPSc, this suggests that the four strains of agent identified in our study have different conformations of PrPSc. What is perhaps surprising is that only four discrete strains of sCJD have been identified. If the prion protein can exist in many different pathogenic isoforms in a single host, why then do only four different strains of sCJD result in humans? Because the assumption is that each sCJD case arises spontaneously, this would require strong selection factors to be operating for these four strains and against others that may be produced.
There are diverse suggestions as to the origin of sCJD, including proposals that somatic mutations lead to protein misfolding and disease (30) or that sCJD has arisen through infection from an animal source, such as atypical BSE (18, 31).
snip...
Our study evaluated the precise effect host PRNP codon 129 genotype has on defining transmission and propagation of sCJD strains in the three genotypes 129MM, 129MV, and 129VV. There were some specific combinations of host and inoculum within the dataset that showed similar characteristics across the experiments, such as the observation that the HuVV genotype line developed clinical TSE features with most inocula. HuVV mice also had the shortest incubation periods by more than 100 d, seen for sCJD(MV2) and sCJD(VV2) inocula. These data predict that for human iatrogenic spread of sCJD as a whole, this genotype may be the most susceptible or may show shorter incubation periods. It is of note that there is an increased prevalence of young (<50 y) VV genotype sCJD cases across European countries (United Kingdom, Germany, Italy, and France) (10). The second common characteristic among the data was that HuMM and HuMV mice had similar levels of clinical disease, and mean incubation periods, for four of the six inocula [excluding sCJD(MM2) and sCJD(VV1)]. This suggests that the methionine allele of PrPC in the heterozygous HuMV mice may have had a dominant effect over the valine allele PrPC with regard to the transmission properties. This study identifies two areas of risk in terms of developing sCJD. The first is that the highest risk of developing CJD after exposure to infection is from strain M1CJD [sCJD(MM1) or sCJD(MV1)] and that the VV genotype confers the highest risk of acquiring infection. The epidemiological findings in sCJD demonstrate that approximately 80% of patients are diagnosed with “classic CJD” types MM1 and MV1, which might intriguingly suggest an infectious rather than genetic origin for the majority of sCJD cases.
Sunday, September 25, 2011
Clinical Heidenhain Variant Of Sporadic Creutzfeldt-Jakob Disease (CJD) With Co-occurrence Of Prion Protein Types 1 and 2
Poster 52
Monday, January 30, 2012
The First Report of a Patient with Probable Variant Creutzfeldt-Jakob Disease in Turkey
Dement Geriatr Cogn Dis Extra. 2011 Jan-Dec; 1(1): 429–432. Published online 2011 December 24. doi: 10.1159/000332024 PMCID: PMC3265806
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
Friday, February 04, 2011
NMLB and USDA allow scrapie prion infected mutton to enter food chain on the Navajo Reservation in New Mexico
----- Original Message -----
From: Terry S. Singeltary Sr.
To: President.BenShelly
Cc: sroanhorse ; opvp.nelson ; alaughing; georgehardeen; pressoffice
Monday, September 26, 2011
Variably Protease-Sensitive Prionopathy, Prionpathy, Prionopathy, FFI, GSS, gCJD, hvCJD, sCJD, TSE, PRION, update 2011
Wednesday, June 16, 2010
Defining sporadic Creutzfeldt-Jakob disease strains and their transmission properties
Monday, September 26, 2011
L-BSE BASE prion and atypical sporadic CJD
SEE RISE IN cpsCJD i.e. classification pending sporadic CJD ;
CANADA CJD UPDATE 2011
CJD Deaths Reported by CJDSS1, 1994-20112 As of January 31, 2011
3. Final classification of 49 cases from 2009, 2010, 2011 is pending.
snip...
USA 2011
USA
National Prion Disease Pathology Surveillance Center
Cases Examined1
(November 1, 2010)
Year Total Referrals2 Prion Disease Sporadic Familial Iatrogenic vCJD
1996 & earlier 51 33 28 5 0 0
1997 114 68 59 9 0 0
1998 87 51 43 7 1 0
1999 121 73 65 8 0 0
2000 146 103 89 14 0 0
2001 209 119 109 10 0 0
2002 248 149 125 22 2 0
2003 274 176 137 39 0 0
2004 325 186 164 21 0 13
2005 344 194 157 36 1 0
2006 383 197 166 29 0 24
2007 377 214 187 27 0 0
2008 394 231 205 25 0 0
2009 425 258 215 43 0 0
2010 333 213 158 33 0 0
TOTAL 38315 22656 1907 328 4 3
1 Listed based on the year of death or, if not available, on year of referral;
2 Cases with suspected prion disease for which brain tissue and/or blood (in familial cases) were submitted;
3 Disease acquired in the United Kingdom;
4 Disease was acquired in the United Kingdom in one case and in Saudi Arabia in the other case;
5 Includes 18 cases in which the diagnosis is pending, and 18 inconclusive cases;
6 Includes 23 (22 from 2010) cases with type determination pending in which the diagnosis of vCJD has been excluded.
Please notice where sporadic CJD cases in 1996 went from 28 cases, to 215 cases in 2009, the highest recorded year to date. sporadic CJD is on a steady rise, and has been since 1996.
I also urge you to again notice these disturbing factors in lines 5 and 6 ;
5 Includes 18 cases in which the diagnosis is pending, and 18 inconclusive cases;
6 Includes 23 (22 from 2010) cases with type determination pending in which the diagnosis of vCJD has been excluded.
========end=====tss=====2011
Monday, August 9, 2010
National Prion Disease Pathology Surveillance Center Cases Examined (July 31, 2010)
(please watch and listen to the video and the scientist speaking about atypical BSE and sporadic CJD and listen to Professor Aguzzi)
THE steady rise of sporadic CJD cases in Canada AND USA, with many unusual cases of ''PENDING CLASSIFICATIONS" which have been pending now FOR 3 YEARS. HOW long can this cover-up continue $$$
The most recent assessments (and reassessments) were published in June 2005 (Table I; 18), and included the categorisation of Canada, the USA, and Mexico as GBR III. Although only Canada and the USA have reported cases, the historically open system of trade in North America suggests that it is likely that BSE is present also in Mexico.
SEE FULL TEXT AND MORE HERE ;
Saturday, March 5, 2011
MAD COW ATYPICAL CJD PRION TSE CASES WITH CLASSIFICATIONS PENDING ON THE RISE IN NORTH AMERICA
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
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
Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North America
14th ICID International Scientific Exchange Brochure -
Final Abstract Number: ISE.114
Session: International Scientific Exchange
Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North America
update October 2009
T. Singeltary
Bacliff, TX, USA
Background:
An update on atypical BSE and other TSE in North America. Please remember, the typical U.K. c-BSE, the atypical l-BSE (BASE), and h-BSE have all been documented in North America, along with the typical scrapie's, and atypical Nor-98 Scrapie, and to date, 2 different strains of CWD, and also TME. All these TSE in different species have been rendered and fed to food producing animals for humans and animals in North America (TSE in cats and dogs ?), and that the trading of these TSEs via animals and products via the USA and Canada has been immense over the years, decades.
Methods:
12 years independent research of available data
Results:
I propose that the current diagnostic criteria for human TSEs only enhances and helps the spreading of human TSE from the continued belief of the UKBSEnvCJD only theory in 2009. With all the science to date refuting it, to continue to validate this old myth, will only spread this TSE agent through a multitude of potential routes and sources i.e. consumption, medical i.e., surgical, blood, dental, endoscopy, optical, nutritional supplements, cosmetics etc.
Conclusion:
I would like to submit a review of past CJD surveillance in the USA, and the urgent need to make all human TSE in the USA a reportable disease, in every state, of every age group, and to make this mandatory immediately without further delay. The ramifications of not doing so will only allow this agent to spread further in the medical, dental, surgical arena's. Restricting the reporting of CJD and or any human TSE is NOT scientific. Iatrogenic CJD knows NO age group, TSE knows no boundaries. I propose as with Aguzzi, Asante, Collinge, Caughey, Deslys, Dormont, Gibbs, Gajdusek, Ironside, Manuelidis, Marsh, et al and many more, that the world of TSE Transmissible Spongiform Encephalopathy is far from an exact science, but there is enough proven science to date that this myth should be put to rest once and for all, and that we move forward with a new classification for human and animal TSE that would properly identify the infected species, the source species, and then the route.
page 114 ;
TSS
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