Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein
kind regards, terry
Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein
Wen-Quan Zou, MD, PhD 1 *, Gianfranco Puoti, MD, PhD 1, Xiangzhu Xiao, PhD 1, Jue Yuan, BA 1, Liuting Qing, PhD 1, Ignazio Cali, MSc 1, Miyuki Shimoji, PhD 1, Jan P.M. Langeveld, PhD 2, Rudy Castellani, MD 3, Silvio Notari, PhD 1, Barbara Crain, MD 4, Robert E. Schmidt, MD 5, Michael Geschwind, MD 6, Stephen J. DeArmond, MD, PhD 6, Nigel J. Cairns, MD 7, Dennis Dickson, MD 8, Lawrence Honig, MD 9, Juan Maria Torres, PhD 10, James Mastrianni, MD, PhD 11, Sabina Capellari, MD 12, Giorgio Giaccone, MD 13, Ermias D. Belay, MD 14, Lawrence B. Schonberger, MD, MPH 14, Mark Cohen, MD 1, George Perry, PhD 15, Qingzhong Kong, PhD 1, Piero Parchi, MD, PhD 12, Fabrizio Tagliavini, MD 13, Pierluigi Gambetti, MD 1 * 1Department of Pathology, National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, OH 2Central Veterinary Institute of Wageningen, Lelystad, the Netherlands 3Department of Neuropathology, University of Maryland Medical Center, Baltimore, MD 4Department of Neuropathology, Johns Hopkins University, Baltimore, MD 5Department of Neuropathology, Washington University, St. Louis, MO 6Department of Pathology, University of California at San Francisco, San Francisco, CA 7Departments of Neurology, Pathology, and Immunology, Washington University, St. Louis, MO 8Department of Neuropathology, Mayo Clinic-Jacksonville, Jacksonville, FL 9New York Presbyterian Hospital, Columbia University, New York, NY 10Centro de Investigación en Sanidad Animal, Madrid, Spain 11Department of Neurology, University of Chicago, Chicago, IL 12Department of Neurological Sciences, University of Bologna, Dipartimento di Scienze Neurologiche, Università di Bologna, Bologna, Italy 13IRCCS Foundation, National Neurological Institute, Instituto Nazionale Neurologico Carlo Besta, Milan, Italy 14Center of Investigation on Animal Health, Centers for Disease Control and Prevention, Atlanta, GA 15College of Science, University of Texas at San Antonio, San Antonio, TX
email: Wen-Quan Zou (email@example.com) Pierluigi Gambetti (firstname.lastname@example.org)
*Correspondence to Wen-Quan Zou, Department of Pathology, National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, OH
*Correspondence to Pierluigi Gambetti, Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44106
Potential Conflicts of Interest Nothing to report.
Funded by: NIH; Grant Number: NIA AG14359, AG08702 NINDS; Grant Number: R01NS062787 Centers for Disease Control and Prevention; Grant Number: CCU 515004 Britton Fund CJD Foundation Alliance BioSecure University Center on Aging and Health with the support of the McGregor Foundation and President's Discretionary Fund (Case Western Reserve University) National Institute on Aging; Grant Number: AG05681
Objective: The objective of the study is to report 2 new genotypic forms of protease-sensitive prionopathy (PSPr), a novel prion disease described in 2008, in 11 subjects all homozygous for valine at codon 129 of the prion protein (PrP) gene (129VV). The 2 new PSPr forms affect individuals who are either homozygous for methionine (129MM) or heterozygous for methionine/valine (129MV).
Methods: Fifteen affected subjects with 129MM, 129MV, and 129VV underwent comparative evaluation at the National Prion Disease Pathology Surveillance Center for clinical, histopathologic, immunohistochemical, genotypical, and PrP characteristics.
Results: Disease duration (between 22 and 45 months) was significantly different in the 129VV and 129MV subjects. Most other phenotypic features along with the PrP electrophoretic profile were similar but distinguishable in the 3 129 genotypes. A major difference laid in the sensitivity to protease digestion of the disease-associated PrP, which was high in 129VV but much lower, or altogether lacking, in 129MV and 129MM. This difference prompted the substitution of the original designation with variably protease-sensitive prionopathy (VPSPr). None of the subjects had mutations in the PrP gene coding region.
Interpretation: Because all 3 129 genotypes are involved, and are associated with distinguishable phenotypes, VPSPr becomes the second sporadic prion protein disease with this feature after Creutzfeldt-Jakob disease, originally reported in 1920. However, the characteristics of the abnormal prion protein suggest that VPSPr is different from typical prion diseases, and perhaps more akin to subtypes of Gerstmann-Sträussler-Scheinker disease. ANN NEUROL 2010;68:162-172
Received: 9 March 2010; Revised: 5 May 2010; Accepted: 19 May 2010
Digital Object Identifier (DOI)
10.1002/ana.22094 About DOI
>>> Because 8 out of 10 patients had a positive family history of dementia in the original study, a genetic cause was suspected. Although all cases were homozygous for valine at codon 129 of the PrP gene, NO mutations were detected.<<<
Protease-sensitive prionopathy (PSPr) is a neurodegenerative disorder caused by an abnormal isoform of the prion protein. Contrary to the prions in Creutzfeldt-Jakob disease (CJD), the prions in this condition are sensitive to protease activity. PSPr was first described in an abstract for a conference on prions in 2006, and this study was published in a 2008 report on 11 cases. The study was conducted by Gambetti P. and coworkers from the United States National Prion Disease Pathology Surveillance Center.
 Symptoms of PSPr are behavioral and psychiatric abnormalities with progressive decline in cognitive and motor functions (including dementia, ataxia, parkinsonism, psychosis, aphasia and mood disorders). This is similar to what occurs in other spongiform encephalopathies, and the condition can be mistaken for Alzheimer's dementia. Contrary to what is the case in CJD, there were no cases with a positive 14-3-3 protein test in the cerebrospinal fluid, no periodic complexes on electroencephalography (EEG), and no pathognomonic changes on diffusion-weighted magnetic resonance images. The mean age of onset in the original 11 patients was 62 years. Patients progressed to death in 20 months on average. PSPr accounted for three percent of prion disease cases evaluated by the U.S. National Prion Disease Pathology Surveillance Center (prion diseases occur in the order of magnitude of 1 case per million people).
 The diagnosis can be made on pathological examination. There are unique microscopic and immunohistochemical features, and the prions cannot be digested using proteases. Because 8 out of 10 patients had a positive family history of dementia in the original study, a genetic cause was suspected. Although all cases were homozygous for valine at codon 129 of the PrP gene, no mutations were detected. How these protease-resistant prions lead to neurological disease remains incompletely understood. For instance, protein-resistant prions have been found in normal human brains.
 1.^ Gambetti P, Dong Z, Yuan J, et al. (June 2008). "A novel human disease with abnormal prion protein sensitive to protease". Ann. Neurol. 63 (6): 697–708. doi:10.1002/ana.21420. PMID 18571782. 2.^ Will R, Head M (June 2008). "A new prionopathy". Ann. Neurol. 63 (6): 677–8. doi:10.1002/ana.21447. PMID 18570344. 3.^ Yuan J, Xiao X, McGeehan J, et al. (November 2006). "Insoluble aggregates and protease-resistant conformers of prion protein in uninfected human brains". J. Biol. Chem. 281 (46): 34848–58. doi:10.1074/jbc.M602238200. PMID 16987816.
no mad cow disease in the USA, no human TSE there from, it's all sporadic genetic now, with no family mutation link there from ???
p l e a s e !
the first 10 humans in the UK in 1995 = BSE to nvCJD in humans. now, 2010, similarly, the 10+ in the USA, = genetic make up same as the g-h-BSEalabama bovine case, but it's all a _sporadic_ genetic disease, that NO mutations were found in family members, BUT is not related to the g-h-BSEalabama case either, even though those mutations are the same? just happens out of thin air. my oh my, how political junk science works $$$
either the UK BSE nvCJD only theory was wrong, or Gambetti's theory is wrong.
which is it ? you can't have your cake and eat it too. just my opinion. ...tss
Genetic Creutzfeldt-Jakob disease associated with the E200K mutation: characterization of a complex proteinopathy
Journal Acta Neuropathologica Publisher Springer Berlin / Heidelberg ISSN 0001-6322 (Print) 1432-0533 (Online) Category Original Paper DOI 10.1007/s00401-010-0713-y Subject Collection Medicine SpringerLink Date Wednesday, June 30, 2010 Gabor G. Kovacs1, 2 , Jérémie Seguin3, Isabelle Quadrio3, Romana Höftberger1, István Kapás2, Nathalie Streichenberger3, Anne Gaëlle Biacabe4, David Meyronet3, Raf Sciot5, Rik Vandenberghe6, Katalin Majtenyi2, Lajos László7, Thomas Ströbel1, Herbert Budka1 and Armand Perret-Liaudet3 (1) Institute of Neurology, Medical University of Vienna, and Austrian Reference Center for Human Prion Diseases, AKH 4J, Währinger Gürtel 18-20, 1097 Vienna, Austria (2) Neuropathology and Prion Disease Reference Center, Hungarian Reference Center for Human Prion Diseases, Semmelweis University, Budapest, Hungary (3) Prion Disease Laboratory, Pathology and Biochemistry, Groupement Hospitalier Est, Hospices Civils de Lyon/Claude Bernard University, Lyon, France (4) Agence Française de Sécurité Sanitaire des AlimentsˆLyon, Unité ATNC, Lyon Cedex 07, France (5) Department of Pathology, University Hospital, Catholic University of Leuven, Leuven, Belgium (6) Neurology Department, University Hospital Gasthuisberg, Leuven, Belgium (7) Department of Anatomy, Cell and Developmental Biology, Eotvos Lorand University of Sciences, Budapest, Hungary Received: 1 April 2010 Revised: 10 June 2010 Accepted: 20 June 2010 Published online: 1 July 2010
The E200K mutation is the most frequent prion protein gene (PRNP) mutation detected worldwide that is associated with Creutzfeldt-Jakob disease (CJD) and thought to have overlapping features with sporadic CJD, yet detailed neuropathological studies have not been reported. In addition to the prion protein, deposition of tau, a-synuclein, and amyloid-ß has been reported in human prion disease. To describe the salient and concomitant neuropathological alterations, we performed a systematic clinical, neuropathological, and biochemical study of 39 individuals carrying the E200K PRNP mutation originating from different European countries. The most frequent clinical symptoms were dementia and ataxia followed by myoclonus and various combinations of further symptoms, including vertical gaze palsy and polyneuropathy. Neuropathological examination revealed relatively uniform anatomical pattern of tissue lesioning, predominating in the basal ganglia and thalamus, and also substantia nigra, while the deposition of disease-associated PrP was more influenced by the codon 129 constellation, including different or mixed types of PrPres detected by immunoblotting. Unique and prominent intraneuronal PrP deposition involving brainstem nuclei was also noted. Systematic examination of protein depositions revealed parenchymal amyloid-ß in 53.8%, amyloid angiopathy (Aß) in 23.1%, phospho-tau immunoreactive neuritic profiles in 92.3%, neurofibrillary degeneration in 38.4%, new types of tau pathology in 33.3%, and Lewy-type a-synuclein pathology in 15.4%. TDP-43 and FUS immunoreactive protein deposits were not observed. This is the first demonstration of intensified and combined neurodegeneration in a genetic prion disease due to a single point mutation, which might become an important model to decipher the molecular interplay between neurodegeneration-associated proteins. Electronic supplementary material The online version of this article (doi:10.1007/s00401-010-0713-y) contains supplementary material, which is available to authorized users.
Keywords Alpha-synuclein - Amyloid-beta - Prion protein - Tau - Neurodegeneration
Molecular Features of the Protease-resistant Prion Protein (PrPres) in H-type BSE
Biacabe, A-G1; Jacobs, JG2; Gavier-Widén, D3; Vulin, J1; Langeveld, JPM2; Baron, TGM1 1AFSSA, France; 2CIDC-Lelystad, Netherlands; 3SVA, Sweden
Western blot analyses of PrPres accumulating in the brain of BSE-infected cattle have demonstrated 3 different molecular phenotypes regarding to the apparent molecular masses and glycoform ratios of PrPres bands. We initially described isolates (H-type BSE) essentially characterized by higher PrPres molecular mass and decreased levels of the diglycosylated PrPres band, in contrast to the classical type of BSE. This type is also distinct from another BSE phenotype named L-type BSE, or also BASE (for Bovine Amyloid Spongiform Encephalopathy), mainly characterized by a low representation of the diglycosylated PrPres band as well as a lower PrPres molecular mass. Retrospective molecular studies in France of all available BSE cases older than 8 years old and of part of the other cases identified since the beginning of the exhaustive surveillance of the disease in 20001 allowed to identify 7 H-type BSE cases, among 594 BSE cases that could be classified as classical, L- or H-type BSE. By Western blot analysis of H-type PrPres, we described a remarkable specific feature with antibodies raised against the C-terminal region of PrP that demonstrated the existence of a more C-terminal cleaved form of PrPres (named PrPres#2 ), in addition to the usual PrPres form (PrPres #1). In the unglycosylated form, PrPres #2 migrates at about 14 kDa, compared to 20 kDa for PrPres #1. The proportion of the PrPres#2 in cattle seems to by higher compared to the PrPres#1. Furthermore another PK–resistant fragment at about 7 kDa was detected by some more N-terminal antibodies and presumed to be the result of cleavages of both N- and C-terminal parts of PrP. These singular features were maintained after transmission of the disease to C57Bl/6 mice. The identification of these two additional PrPres fragments (PrPres #2 and 7kDa band) reminds features reported respectively in sporadic Creutzfeldt-Jakob disease and in Gerstmann-Sträussler-Scheinker (GSS) syndrome in humans.
BASE Transmitted to Primates and MV2 sCJD Subtype Share PrP27-30 and PrPSc C-terminal Truncated Fragments
Zanusso, G1; Commoy, E2; Fasoli, E3; Fiorini, M3; Lescoutra, N4; Ruchoux, MM4; Casalone, C5; Caramelli, M5; Ferrari, S3; Lasmezas, C6; Deslys, J-P4; Monaco, S3 1University of Verona, of Neurological and Visual Sciences, Italy; 2CEA, IMETI/SEPIA, France; 3University of Verona, Neurological and Visual Sciences, Italy; 4IMETI/SEPIA, France; 5IZSPLVA, Italy; 6The Scripps Research Insitute, USA
The etiology of sporadic Creutzfeldt-Jakob disease (sCJD), the most frequent human prion disease, remains still unknown. The marked disease phenotype heterogeneity observed in sCJD is thought to be influenced by the type of proteinase K-resistant prion protein, or PrPSc (type 1 or type 2 according to the electrophoretic mobility of the unglycosylated backbone), and by the host polymorphic Methionine/Valine (M/V) codon 129 of the PRNP. By using a two-dimensional gel electrophoresis (2D-PAGE) and imunoblotting we previously showed that in sCJD, in addition to the PrPSc type, distinct PrPSc C-terminal truncated fragments (CTFs) correlated with different sCJD subtypes. Based on the combination of CTFs and PrPSc type, we distinguished three PrPSc patterns: (i) the first was observed in sCJD with PrPSc type 1 of all genotypes,; (ii) the second was found in M/M-2 (cortical form); (iii) the third in amyloidogenic M/V- 2 and V/V-2 subtypes (Zanusso et al., JBC 2004) . Recently, we showed that sCJD subtype M/V-2 shared molecular and pathological features with an atypical form of BSE, named BASE, thus suggesting a potential link between the two conditions. This connection was further confirmed after 2D-PAGE analysis, which showed an identical PrPSc signature, including the biochemical pattern of CTFs. To pursue this issue, we obtained brain homogenates from Cynomolgus macaques intracerebrally inoculated with brain homogenates from BASE. Samples were separated by using a twodimensional electrophoresis (2D-PAGE) followed by immunoblotting. We here show that the PrPSc pattern obtained in infected primates is identical to BASE and sCJD MV-2 subtype. These data strongly support the link, or at least a common ancestry, between a sCJD subtype and BASE. This work was supported by Neuroprion (FOOD-CT-2004-506579)
Transmission of Italian BSE and BASE Isolates in Cattle Results into a Typical BSE Phenotype and a Muscle Wasting Disease
Zanusso, G1; Lombardi, G2; Casalone, C3; D’Angelo, A4; Gelmetti, D2; Torcoli, G2; Barbieri, I2; Corona, C3; Fasoli, E1; Farinazzo, A1; Fiorini, M1; Gelati, M1; Iulini, B3; Tagliavini, F5; Ferrari, S1; Monaco, S1; Caramelli, M3; Capucci, L2 1University of Verona, Neurological and Visual Sciences, Italy; 2IZSLER, Italy; 3IZSPLVA, Italy; 4University of Turin, Animal Pathology, Italy; 5Isituto Carlo Besta, Italy
The clinical phenotype of bovine spongiform encephalopathy has been extensively reported in early accounts of the disorder. Following the introduction of statutory active surveillance, almost all BSE cases have been diagnosed on a pathological/molecular basis, in a pre-symptomatic clinical stage. In recent years, the active surveillance system has uncovered atypical BSE cases, which are characterized by distinct conformers of the PrPSc, named high-type (BSE-H) and low-type (BSE-L), whose clinicopathological phenotypes remain unknown. We recently reported two Italian atypical cases with a PrPSc type similar to BSE-L, pathologically characterized by PrP amyloid plaques. Experimental transmission to TgBov mice has recently disclosed that BASE is caused by a distinct prion strain which is extremely virulent. A major limitation of transmission studies to mice is the lack of reliable information on clinical phenotype of BASE in its natural host. In the present study, we experimentally infected Fresian/Holstein and Alpine/Brown cattle with Italian BSE and BASE isolates by i.c. route. BASE infected cattle showed survival times significantly shorter than BSE, a finding more readily evident in Fresian/Holstein, and in keeping with previous observations in TgBov mice. Clinically, BSE-infected cattle developed a disease phenotype highly comparable with that described in field BSE cases and in experimentally challenged cattle. On the contrary, BASE-inoculated cattle developed an amyotrophic disorder accompanied by mental dullness. The molecular and neuropathological profiles, including PrP deposition pattern, closely matched those observed in the original cases. This study further confirms that BASE is caused by a distinct prion isolate and discloses a novel disease phenotype in cattle, closely resembling the phenotype previous reported in scrapie-inoculated cattle and in some subtypes of inherited and sporadic Creutzfeldt-Jakob disease.
Analysis of Bovine Prion Protein Gene Sequence Variation in Animals with Classical and Atypical BSE
Polak, MP; Larska, M; Rola, J; Zmudzinski, JF National Veterinary Research Institute, Department of Virology, Poland B.
Variation within prion protein gene sequence have major impact on the susceptibility to prion diseases in humans and sheep. However no major differences between healthy cattle and bovine spongiform encephalopathy (BSE) affected individuals were identified. Recent studies indicate that susceptibility to bovine spongiform encephalopathy is associated with 23-base pair (bp) and 12-bp indel sequences. Identification of atypical BSE in older cattle in several countries pointed at the possibility of spontaneous origin of this new form of prion disease due to possible mutations within prion gene (PRNP) sequence. A./O. Therefore the aim of the study was to analyze and to compare prion protein gene sequences in animals showing classical and atypical BSE for any genetic traits differentating both forms of the disease. M. Analysis included: octapeptide-repeat polymorphism; sequence analysis of exon 3 region; deletion/insertion polymorphism within the promoter sequence (23-bp), intron 1 (12-bp) and 3’untranslated region - UTR (14-bp) of PRNP gene. R. No major differences were found as for the octapeptide-repeats. Most dominant genotype in both classical and atypical BSE involved 6/6 homozygous animals. Sequence comparison within exon 3 region also showed no differences. Results from indel sequence analysis within three regions of PRNP gene were also quite uniform between both forms of BSE. D. Therefore no genetic traits explaining the appearance of atypical BSE could be found. However, it is too early to reject the hypothesis that genetic makeup is not involved in atypical BSE. Further and more detailed studies including more cases of atypical BSE would be more reliable to draw such a conclusion.
BSE Case Associated with Prion Protein Gene Mutation
Bovine spongiform encephalopathy (BSE) is a transmissible spongiform encephalopathy (TSE) of cattle and was first detected in 1986 in the United Kingdom. It is the most likely cause of variant Creutzfeldt-Jakob disease (CJD) in humans. The origin of BSE remains an enigma. Here we report an H-type BSE case associated with the novel mutation E211K within the prion protein gene (Prnp). Sequence analysis revealed that the animal with H-type BSE was heterozygous at Prnp nucleotides 631 through 633. An identical pathogenic mutation at the homologous codon position (E200K) in the human Prnp has been described as the most common cause of genetic CJD. This finding represents the first report of a confirmed case of BSE with a potential pathogenic mutation within the bovine Prnp gene. A recent epidemiological study revealed that the K211 allele was not detected in 6062 cattle from commercial beef processing plants and 42 cattle breeds, indicating an extremely low prevalence of the E211K variant (less than 1 in 2000) in cattle.
Author Summary Top
Bovine spongiform encephalopathy (BSE or Mad Cow Disease), a transmissible spongiform encephalopathy (TSE) or prion disease of cattle, was first discovered in the United Kingdom in 1986. BSE is most likely the cause of a human prion disease known as variant Creutzfeldt Jakob Disease (vCJD). In this study, we identified a novel mutation in the bovine prion protein gene (Prnp), called E211K, of a confirmed BSE positive cow from Alabama, United States of America. This mutation is identical to the E200K pathogenic mutation found in humans with a genetic form of CJD. This finding represents the first report of a confirmed case of BSE with a potential pathogenic mutation within the bovine Prnp gene. We hypothesize that the bovine Prnp E211K mutation most likely has caused BSE in “the approximately 10-year-old cow” carrying the E221K mutation.
Archive Number 20100405.1091 Published Date 05-APR-2010
Subject PRO/AH/EDR> Prion disease update 1010 (04)
[Terry S. Singeltary Sr. has added the following comment:
"According to the World Health Organisation, the future public health threat of vCJD in the UK and Europe and potentially the rest of the world is of concern and currently unquantifiable. However, the possibility of a significant and geographically diverse vCJD epidemic occurring over the next few decades cannot be dismissed.
The key word here is diverse. What does diverse mean? If USA scrapie transmitted to USA bovine does not produce pathology as the UK c-BSE, then why would CJD from there look like UK vCJD?"
Wednesday, July 9, 2008
10 people killed by new CJD-like disease USA
Thursday, July 10, 2008
A Novel Human Disease with Abnormal Prion Protein Sensitive to Protease update July 10, 2008
Thursday, July 10, 2008
A New Prionopathy update July 10, 2008
Sunday, August 10, 2008
A New Prionopathy OR more of the same old BSe and sporadic CJD
some additional interesting studies ;
A novel human prion disease affecting subjects with the three prion protein codon 129 genotypes: could it be the sporadic form of Gerstmann-Straussler?
Pierluigi Gambetti Case Western Reserve University, USA
Background: We recently described a novel prion disease, named protease-sensitive prionopathy or PSPr, characterized by the presence of an abnormal prion protein (PrP) that was 60 fold less protease resistant than that of sporadic Creutzfeldt-Jakob disease (sCJD) and on immunoblot generated a distinct ladder-like profile. All affected subjects where homozygous for valine at codon 129 (VV) and had no mutation in the PrP gene.
Methods: We have characterized several new cases in our surveillance and received from Europe.
1) A disease overall similar to that reported in the 129VV subjects also affects subjects that are methionine/valine heterozygous (MV) and methionine homozygous (MM) at codon 129 and have no PrP gene mutation;
2) The clinical and histopathological features of the new MV and MM PSPr cases are similar but distinguishable from those of the original VV cases; 3) The electrophoretic profiles generated by the abnormal PrP isoforms associated with the MV and MM cases are similar to VV cases but show increasing levels of proteaseresistance; 3) abnormal tau is present in all three genotypic forms of PSPr with features apparently similar to those of primary tauopathies placing PSPr at the intersection of tauopathies and prion diseases.
Discussion: Will focus on: 1) the features of the abnormal PrP in the newly discovered 129MV and 129MM PSPr; 2) the effect of the 129 polymorphism on PSPr compared to that on sCJD; 3) the relationship of PSPr with tauopathies; 4) whether PSPr now with the three 129 genotypic forms is the long sought sporadic form of GSS. (Supported by NIH AG-14359, NS052319, CDC UR8/CCU515004).
Wednesday, September 3, 2008
Phenotypic heterogeneity and genetic modification of P102L inherited prion disease in an international series
Brain Advance Access published September 1, 2008
Phenotypic heterogeneity and genetic modification of P102L inherited prion disease in an international series
T. E. F.Webb,1,2 M. Poulter,1 J. Beck,1 J.Uphill,1 G. Adamson,1 T. Campbell,1 J. Linehan,1 C. Powell,1 S. Brandner,1,2 S. Pal,1,2 D. Siddique,1,2 J. D.Wadsworth,1 S. Joiner,1 K. Alner,2 C. Petersen,2 S. Hampson,2 C. Rhymes,2 C. Treacy,2 E. Storey,3 M. D.Geschwind,4 A. H. Nemeth,5 S.Wroe,1,2 J. Collinge1,2 and S. Mead1,2 1MRC Prion Unit and Department of Neurodegenerative Disease,UCL Institute of Neurology, 2National Prion Clinic and National Hospital for Neurology & Neurosurgery, Queen Square, London,WC1N 3BG, 3Department of Medicine (Neuroscience), Monash University, Melbourne, Australia, 4Department of Neurology,University of California, San Francisco (UCSF), San Francisco, CA,USA and 5Department of Clinical Genetics, Churchill Hospital and Weatherall Institute of Molecular Medicine, John Radcliffe Hospital,Oxford,OX3 9DU, UK Correspondence to: Prof. John Collinge, Department of Neurodegenerative Disease and MRC Prion Unit, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, LondonWC1N 3BG, UK E-mail: email@example.com
The largest kindred with inherited prion disease P102L, historically Gerstmann-Stra«ussler-Scheinker syndrome, originates from central England, with e¤migre¤ s now resident in various parts of the English-speaking world. We have collected data from 84 patients in the large UK kindred and numerous small unrelated pedigrees to investigate phenotypic heterogeneity and modifying factors.This collection represents by far the largest series of P102L patients so far reported.Microsatellite and genealogical analyses of eight separate European kindreds support multiple distinct mutational events at a cytosine-phosphate diester-guanidine dinucleotide mutation hot spot. All of the smaller P102L kindreds were linked to polymorphic human prion protein gene codon 129M andwere not connected by genealogy ormicrosatellite haplotype background to the large kindred or each other. While many present with classical Gerstmann-Stra«ussler-Scheinker syndrome, a slowly progressive cerebellar ataxia with later onset cognitive impairment, there is remarkable heterogeneity. A subset of patients present with prominent cognitive and psychiatric features and some have met diagnostic criteria for sporadic Creutzfeldt-Jakob disease. We show that polymorphic human prion protein gene codon 129 modifies age at onset: the earliest eight clinical onsets were all MM homozygotes and overall age at onset was 7 years earlier for MM compared with MV heterozygotes (P=0.02).Unexpectedly, apolipoprotein E4 carriers have a delayed age of onset by10 years (P=0.02).We found a preponderance of female patients comparedwithmales (54 females versus 30 males,P=0.01), which probably relates to ascertainment bias.However, thesemodifiers had no impact on a semi-quantitative pathological phenotype in 10 autopsied patients.These data allow an appreciation of the range of clinical phenotype, modern imaging andmolecular investigation and should inform genetic counselling of at-risk individuals, with the identification of two genetic modifiers.
The need for public health control measures, together with the evident diagnostic challenges that IPD heterogeneity causes, make a strong argument for including PRNP gene analysis in he list of investigations for suspected prion disease of any type and indeed of all undiagnosed familial dementia or cerebellar syndromes. Successful diagnosis allows clinicians to provide more accurate prognostic information to patients, to allow participation in the clinical trials and reduce the risk of iatrogenic transmission of disease. As a consequence of these geographically highly mobile ancestors, and the large number of untraced individuals in the nineteenth century who were clearly at risk of inheriting the P102L mutation, it remains likely that further patients and at-risk individuals exist who have yet to be identified. It is hoped that the data presented here will help to raise awareness of P102L IPD and its associated presentations.
please see also ;
Sunday, August 24, 2008 Sporadic Fatal Insomnia with Unusual Biochemical and Neuropathological Findings
Sporadic Fatal Insomnia with Unusual Biochemical and Neuropathological Findings
Giaccone, G1; Mangieri, M1; Priano, L2; Limido, L1; Brioschi, A2; Albani, G2; Pradotto, L2; Fociani, P3; Orsi, L4; Mortara, P4; Tagliavini, F1; Mauro, A2 1Fondazione IRCCS Istituto Neurologico Carlo Besta, Italy; 2IRCCS Istituto Auxologico Italiano, Italy; 3Università di Milano, Ospedale Luigi Sacco, Italy; 4Università di Torino, Dipartimento di Neuroscienze, Italy
Sporadic fatal insomnia (SFI) is a rare subtype of human prion disease, whose clinical and neuropathological phenotype is very similar to familial fatal insomnia (FFI). SFI patients reported until now were all homozygous for methionine at codon 129 of PRNP with deposition of type 2 PrPres (Parchi classification) in the brain. Here we describe a 56-year-old woman who died after a 10-month illness characterized by progressive drowsiness, cognitive deterioration, autonomic impairment and myoclonus. Polysomnography demonstrated a pattern similar to that described in FFI cases with loss of circadian pattern of sleep-wake cycle. A remarkable finding was that 20 years before the onset of symptoms, the patient had undergone surgery for a colloid cyst of the third ventricle, and two ventricular shunts were placed, one correctly in the left ventricle, while the second ended in the right thalamus. The PRNP gene showed no mutation and methionine homozygosity at codon 129. The neuropathologic examination revealed neuronal loss, gliosis, and spongiosis that were mild in the cerebral cortex, while relevant in the caudate nucleus, putamen, thalamus, hypothalamus and inferior olives. In the thalamus, the mediodorsal nuclei were more severely affected than the ventral ones. PrPres immunoreactivity was consistent in the striatum, thalamus and hypothalamus, patchy and of low intensity in the cerebral cortex and absent in the cerebellum. Western blot analysis confirmed this topographic distribution of PrPres. The bands corresponding to di- glycosylated, monoglycosylated and non-glycosylated PrPres were equally represented. The nonglycosylated PrPres band had an electrophoretic mobility identical to that of type 1 by Parchi classification, in the multiple cortical and subcortical regions examined. These findings demonstrate the existence of further rare molecular subtypes of human prion diseases, whose characterization may provide clues for the elucidation of the relation between biochemical characteristics of PrPres and clinico-pathological features of these disorders.
IT could also be that this sFFI is just another case of iCJD (via friendly fire from the surgery for a colloid cyst of the third ventricle, and two ventricular shunts were placed, one correctly in the left ventricle, while the second ended in the right thalamus), some 20 years before the onset of symptoms of this so called sFFI case, from some sub-type of sporadic CJD, now called sporadic FFI ???
I believe it was Gambetti et al that coined this term sporadic FFI, from some conspicuous sub-type of sporadic CJD possibly? seems they could not tie it to a true FFI by diagnostic standards to date, so it was then termed a sFFI, confusing matters even worse ;
A subtype of sporadic prion disease mimicking fatal familial insomnia
THIS seems to raise more questions than answers, confusing the TSEs even worse.
WHAT is sporadic CJD, and how many sub-types and atypical strains, phenotypes etc. will there be, arising from nothing. a spontaneous happening of sorts???
August 19, 2008, Publish Ahead of Print:
First Report of Creutzfeldt-Jakob Disease Occurring in 2 Siblings Unexplained by PRNP Mutation.
Journal of Neuropathology & Experimental Neurology. POST EDITOR CORRECTIONS, 19 August 2008 Webb, Thomas E.F. MRCP; Pal, Suvankar MRCP; Siddique, Durrenajaf MRCP; Heaney, Dominic C. MRCP; Linehan, Jacqueline M. BSc; Wadsworth, Jonathan D.F. PhD; Joiner, Susan BSc; Beck, Jon BSc; Wroe, Stephen J. FRCP; Stevenson, Valerie MRCP; Brandner, Sebastian MRCPath; Mead, Simon PhD; Collinge, John FRS
Abstract: Sibling concurrence of pathologically confirmed prion disease has only been reported in association with pathogenic mutation of the prion protein gene (PRNP). Here, we report 2 siblings with classic neuropathologic features of sporadic Creutzfeldt-Jakob disease unexplained by PRNP mutation or known risk factors for iatrogenic transmission of prion infection. Possible explanations include coincidental occurrence, common exposure to an unidentified environmental source of prions, horizontal transmission of disease, or the presence of unknown shared genetic predisposition.
(C) 2008 American Association of Neurop
SPORADIC FATAL INSOMNIA IN A FATAL FAMILIAL INSOMNIA PEDIGREE
S. Capellari1a, P. Cortelli1, P. Avoni1, G.P. Casadei2, A. Baruzzi1, E. Lugaresi1, M. Pocchiari3, P. Gambetti4, P. Montagna1, P. Parchi1. 1Department of Neurological Sciences, University of Bologna, Bologna, Italy; 2Department of Cell Biology and Neurosciences, ISS, Roma, Italy; 3Servizio di Anatomia Patologica, Ospedale Maggiore, Bologna, Italy, 4Division of Neuropathology, CWRU, Cleveland, OH, USA. a mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000208/!x-usc:mailto:firstname.lastname@example.org
We describe a case of sporadic fatal insomnia (sFI) occurring in a family in which several members carried the D178N mutation in the PRNP gene and died of fatal familial insomnia (FFI). A 43-year-old woman presented with an 11-month history of diplopia, withdrawal, confusion, memory loss, unsteady gait and inability to sleep with episodes of agitation and dream enactment. After a progressive course characterized by cognitive impairment, marked gait ataxia, signs of autonomic hyperactivity, and myoclonus the patient died 24 months after the onset of symptoms. The patient did not have any personal contact with FFI affected relatives and her closest one was a paternal uncle, the son of her grand-grand mother. Analyses of DNA from various tissues of endo- ecto- and meso-dermal origin, including 5 different regions of the CNS revealed no pathogenic mutations and methionine homozygosity at codon 129 of PRNP. Brain histopathology and PrPSc typing showed typical features of FI such as thalamic and olivary atrophy, focal spongiform degeneration limited to the cerebral cortex, relative sparing of basal ganglia and cerebellum, and relatively low amount of PrPSc type 2A accumulation. sFI represents the rarest among the sporadic human TSE subtypes described to date with less than twenty cases described worldwide and only three cases diagnosed in Italy since the establishment of TSE surveillance. Similarly, only six unrelated FFI families have been observed in Italy to date, making the probability of a chance association between sFI and FFI in the same family extremely low. Thus, we believe that our observation emphasizes the importance of undiscovered factors modulating the susceptibility to human prion diseases. Supported by the EU Network of Excellence "NeuroPrion" (FOOD-CT-2004-506579).
Sunday, August 24, 2008
Sporadic Fatal Insomnia with Unusual Biochemical and Neuropathological Findings P03.121
for those interested, please see ;
14th International Congress on Infectious Diseases H-type and L-type Atypical BSE January 2010 (special pre-congress edition)
18.173 page 189
Experimental Challenge of Cattle with H-type and L-type Atypical BSE
A. Buschmann1, U. Ziegler1, M. Keller1, R. Rogers2, B. Hills3, M.H. Groschup1. 1Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany, 2Health Canada, Bureau of Microbial Hazards, Health Products & Food Branch, Ottawa, Canada, 3Health Canada, Transmissible Spongiform Encephalopathy Secretariat, Ottawa, Canada
Background: After the detection of two novel BSE forms designated H-type and L-type atypical BSE the question of the pathogenesis and the agent distribution of these two types in cattle was fully open. From initial studies of the brain pathology, it was already known that the anatomical distribution of L-type BSE differs from that of the classical type where the obex region in the brainstem always displays the highest PrPSc concentrations. In contrast in L-type BSE cases, the thalamus and frontal cortex regions showed the highest levels of the pathological prion protein, while the obex region was only weakly involved.
Methods:We performed intracranial inoculations of cattle (five and six per group) using 10%brainstemhomogenates of the two German H- and L-type atypical BSE isolates. The animals were inoculated under narcosis and then kept in a free-ranging stable under appropriate biosafety conditions.At least one animal per group was killed and sectioned in the preclinical stage and the remaining animals were kept until they developed clinical symptoms. The animals were examined for behavioural changes every four weeks throughout the experiment following a protocol that had been established during earlier BSE pathogenesis studies with classical BSE.
Results and Discussion: All animals of both groups developed clinical symptoms and had to be euthanized within 16 months. The clinical picture differed from that of classical BSE, as the earliest signs of illness were loss of body weight and depression. However, the animals later developed hind limb ataxia and hyperesthesia predominantly and the head. Analysis of brain samples from these animals confirmed the BSE infection and the atypical Western blot profile was maintained in all animals. Samples from these animals are now being examined in order to be able to describe the pathogenesis and agent distribution for these novel BSE types. Conclusions: A pilot study using a commercially avaialble BSE rapid test ELISA revealed an essential restriction of PrPSc to the central nervous system for both atypical BSE forms. A much more detailed analysis for PrPSc and infectivity is still ongoing.
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
Bacliff, TX, USA
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.
12 years independent research of available data
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.
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.
International Society for Infectious Diseases Web: http://www.isid.org/
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 ;
''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.''
Qingzhong Kong, PhD Associate Professor Department of Pathology Case Western Reserve University Cleveland, OH 44106 USA
TRANSMISSION OF ATYPICAL BOVINE SPONGIFORM ENCEPHALOPATHY (BSE) IN HUMANIZED MOUSE MODELS
Liuting Qing1, Fusong Chen1, Michael Payne1, Wenquan Zou1, Cristina Casalone2, Martin Groschup3, Miroslaw Polak4, Maria Caramelli2, Pierluigi Gambetti1, Juergen Richt5*, and Qingzhong Kong1 1Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA; 2CEA, Istituto Zooprofilattico Sperimentale, Italy; 3Friedrich-Loeffler-Institut, Germany; 4National Veterinary Research Institute, Poland; 5Kansas State University, Diagnostic Medicine/Pathobiology Department, Manhattan, KS 66506, USA. *Previous address: USDA National Animal Disease Center, Ames, IA 50010, USA
Classical BSE is a world-wide prion disease in cattle, and the classical BSE strain (BSE-C) has led to over 200 cases of clinical human infection (variant CJD). Two atypical BSE strains, BSE-L (also named BASE) and BSE-H, have been discovered in three continents since 2004. The first case of naturally occurring BSE with mutated bovine PrP gene (termed BSE-M) was also found in 2006 in the USA. The transmissibility and phenotypes of these atypical BSE strains/isolates in humans were unknown. We have inoculated humanized transgenic mice with classical and atypical BSE strains (BSE-C, BSE-L, BSE-H) and the BSE-M isolate. We have found that the atypical BSE-L strain is much more virulent than the classical BSE-C. The atypical BSE-H strain is also transmissible in the humanized transgenic mice with distinct phenotype, but no transmission has been observed for the BSE-M isolate so far.
III International Symposium on THE NEW PRION BIOLOGY: BASIC SCIENCE, DIAGNOSIS AND THERAPY 2 - 4 APRIL 2009, VENEZIA (ITALY)
Wednesday, July 28, 2010
re-Freedom of Information Act Project Number 3625-32000-086-05, Study of Atypical BSE UPDATE July 28, 2010
Wednesday, March 31, 2010
Atypical BSE in Cattle North America
*****URGENT NOTE HERE ABOUT OIE AND ATYPICAL BSE*****
To date the OIE/WAHO assumes that the human and animal health standards set out in the BSE chapter for classical BSE (C-Type) applies to all forms of BSE which include the H-type and L-type atypical forms. This assumption is scientifically not completely justified and accumulating evidence suggests that this may in fact not be the case. Molecular characterization and the spatial distribution pattern of histopathologic lesions and immunohistochemistry (IHC) signals are used to identify and characterize atypical BSE. Both the L-type and H-type atypical cases display significant differences in the conformation and spatial accumulation of the disease associated prion protein (PrPSc) in brains of afflicted cattle. Transmission studies in bovine transgenic and wild type mouse models support that the atypical BSE types might be unique strains because they have different incubation times and lesion profiles when compared to C-type BSE. When L-type BSE was inoculated into ovine transgenic mice and Syrian hamster the resulting molecular fingerprint had changed, either in the first or a subsequent passage, from L-type into C-type BSE. In addition, non-human primates are specifically susceptible for atypical BSE as demonstrated by an approximately 50% shortened incubation time for L-type BSE as compared to C-type. Considering the current scientific information available, it cannot be assumed that these different BSE types pose the same human health risks as C-type BSE or that these risks are mitigated by the same protective measures.
The familial mutations, Gajdusek proposed, lowered the barrier to such accidental conversion. "Thus," he wrote in 1996, "with these mutations, this ordinarily rare event becomes a ... dominant inherited trait." But Weissmann's qualification still remained to be refuted: the mutations might simply allow easier entry to a lurking virus. ...page 202 Deadly Feast
SO, cows can transmit BSE to humans as nvCJD in every country but the USA, but here in the USA, it's a new prionpathy that is genetic, not related to cows, even though one of the USA cows has the same type genetics, and even though Kong et al said that same type cow h-BSE is transmissible to humans. interesting isn't it?
IF you consider the many different TSE strains in different species in North America, and then think 'friendly fire' there from. For a few years now there seems to be a rise here in the U.S.A. of sporadic CJD strains of 'unknown phenotype', with ;
5 Includes 28 cases in which the diagnosis is pending, and 17 inconclusive cases;
6 Includes 28 (24 from 2010) cases with type determination pending in which the diagnosis of vCJD has been excluded
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.
2008 - 2010
The statistical incidence of CJD cases in the United States has been revised to reflect that there is one case per 9000 in adults age 55 and older. Eighty-five percent of the cases are sporadic, meaning there is no known cause at present.
CJD TEXAS 38 YEAR OLD FEMALE WORKED SLAUGHTERING CATTLE EXPOSED TO BRAIN AND SPINAL CORD MATTER
>>> Up until about 6 years ago, the pt worked at Tyson foods where she worked on the assembly line, slaughtering cattle and preparing them for packaging. She was exposed to brain and spinal cord matter when she would euthanize the cattle. <<<
CJD TEXAS 38 YEAR OLD FEMALE WORKED SLAUGHTERING CATTLE EXPOSED TO BRAIN AND SPINAL CORD MATTER
Creutzfeldt-Jakob Disease Surveillance in Texas
Friday, February 05, 2010
New Variant Creutzfelt Jakob Disease case reports United States 2010 A Review
Manuscript Draft Manuscript Number: Title: HUMAN and ANIMAL TSE Classifications i.e. mad cow disease and the UKBSEnvCJD only theory Article Type: Personal View Corresponding Author: Mr. Terry S. Singeltary, Corresponding Author's Institution: na First Author: Terry S Singeltary, none Order of Authors: Terry S Singeltary, none; Terry S. Singeltary
Abstract: TSEs have been rampant in the USA for decades in many species, and they all have been rendered and fed back to animals for human/animal consumption. 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 2007.
Saturday, June 13, 2009
Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States 2003 revisited 2009
Saturday, January 2, 2010
Human Prion Diseases in the United States January 1, 2010 ***FINAL***
my comments to PLosone here ;
Friday, November 30, 2007
CJD QUESTIONNAIRE USA CWRU AND CJD FOUNDATION