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Variably protease-sensitive prionopathy in the UK: a retrospective review 1991-2008
Head, M.W. ; Yull, H.M. ; Ritchie, D.L. ; Langeveld, J.P.M. ; Fletcher, N.A. ; Knight, R.S. ; Ironside, J.W. - \ 2013
Brain 136 (2013)4. - ISSN 0006-8950 - p. 1102 - 1115.
creutzfeldt-jakob-disease - abnormal prion protein - straussler-scheinker-disease - atypical scrapie - phenotype - patient - prp
Variably protease-sensitive prionopathy is a newly described human prion disease of unknown aetiology lying out with the hitherto recognized phenotypic spectrum of Creutzfeldt-Jakob disease. Two cases that conform to the variably protease-sensitive prionopathy phenotype have been identified prospectively in the U.K. since the first description of the condition in 2008 in the U.S.A. To determine the incidence and phenotype of variably protease-sensitive prionopathy within a single well-defined cohort, we have conducted a retrospective review of patients referred to the National Creutzfeldt-Jakob Disease Research & Surveillance Unit during the period 1991-2008. The approach taken was to screen frozen brain tissue by western blotting for the form of protease-resistant prion protein that characterizes variably protease-sensitive prionopathy, followed by neuropathological and clinical review of candidate cases. Cases diagnosed as sporadic Creutzfeldt-Jakob disease with atypical neuropathology were also reviewed. Four hundred and sixty-five cases were screened biochemically, yielding four candidate cases of variably protease-sensitive prionopathy. One was discounted on pathological and clinical grounds, and one was a known case of variably protease-sensitive prionopathy previously reported, leaving two new cases, which were confirmed biochemically and neuropathologically as variably protease-sensitive prionopathy. A third new case that lacked frozen tissue was recognized retrospectively on neuropathological grounds alone. This means that five cases of variably protease-sensitive prionopathy have been identified (prospectively and retrospectively) during the surveillance period 1991-2011 in the U.K. Assuming ascertainment levels equivalent to that of other human prion diseases, these data indicate that variably protease-sensitive prionopathy is a rare phenotype within human prion diseases, which are themselves rare. Biochemical investigation indicates that the abnormal protease-resistant prion protein fragment that characterizes variably protease-sensitive prionopathy is detectable at low levels in some cases of sporadic Creutzfeldt-Jakob disease and conversely, that the form of abnormal prion protein that characterizes sporadic Creutzfeldt-Jakob disease can be found in certain brain regions of cases of variably protease-sensitive prionopathy, indicating molecular overlaps between these two disorders.
Differentiation of ruminant transmissible spongiform encephalopathy isolate types, including bovine spongiform encephalopathy and CH1641 scrapie
Jacobs, J.G. ; Sauer, M. ; Keulen, L.J.M. van; Tang, Y. ; Bossers, A. ; Langeveld, J.P.M. - \ 2011
Journal of General Virology 92 (2011)1. - ISSN 0022-1317 - p. 222 - 232.
creutzfeldt-jakob-disease - abnormal prion protein - natural sheep scrapie - monoclonal-antibodies - molecular analysis - atypical scrapie - prp(d) accumulation - transgenic mice - infected sheep - bse
With increased awareness of the diversity of transmissible spongiform encephalopathy (TSE) strains in the ruminant population, comes an appreciation of the need for improved methods of differential diagnosis. Exposure to bovine spongiform encephalopathy (BSE) has been associated with the human TSE, variant Creutzfeldt–Jakob disease, emphasizing the necessity in distinguishing low-risk TSE types from BSE. TSE type discrimination in ruminants such as cattle, sheep, goats and deer, requires the application of several prion protein (PrP)-specific antibodies in parallel immunochemical tests on brain homogenates or tissue sections from infected animals. This study uses in a single incubation step, three PrP-specific antibodies and fluorescent Alexa dye-labelled anti-mouse Fabs on a Western blot. The usual amount of brain tissue needed is 0.5 mg. This multiplex application of antibodies directed towards three different PrP epitopes enabled differential diagnosis of all established main features of classical scrapie, BSE and Nor98-like scrapie in sheep and goats, as well as the currently known BSE types C, H and L in cattle. Moreover, due to an antibody-dependent dual PrP-banding pattern, for the first time CH1641 scrapie of sheep can be reliably discriminated from the other TSE isolate types in sheep.
A single step multiplex immunofluorometric assay for differential diagnosis of BSE and scrapie
Tang, Y. ; Thorne, J. ; Whatling, K.L. ; Jacobs, J.G. ; Langeveld, J.P.M. ; Sauer, M. - \ 2010
Journal of Immunological Methods 356 (2010)1-2. - ISSN 0022-1759 - p. 29 - 38.
bovine spongiform encephalopathy - creutzfeldt-jakob-disease - abnormal prion protein - natural scrapie - immunohistochemical detection - monoclonal-antibodies - molecular analysis - atypical scrapie - small ruminants - sheep
Although there is no evidence that the European sheep population has been infected with bovine spongiform encephalopathy (BSE), distinguishing this from scrapie is paramount, given the association between BSE exposure and the human transmissible spongiform encephalopathy (TSE), variant Creutzfeldt–Jakob disease. The capability to differentially diagnose TSEs in sheep is thus essential in order to safeguard the food chain and human health. Biochemical methods for differentiating BSE and scrapie are largely reliant on assessment by Western blot (WB) analysis of the abnormal disease associated prion protein PrPD following partial proteolytic digestion. WB banding patterns obtained using a panel of antibodies enable different strain specific conformations of PrPD to be distinguished. This approach provides a robust confirmatory test but one which is not appropriate for high throughput screening. A simple, one step, bead array flow cytometry based multiplex immunofluorometric assay has been developed which is suitable for simultaneous screening and confirmation. Using a combination of antibodies directed towards three PrP epitopes enabled differential diagnosis of scrapie and BSE. Proof of principle studies indicated a high predictive value (100%) when applied to brain samples from control animals, BSE infected cattle and sheep naturally infected with scrapie or experimentally infected with BSE.
Incidence and spectrum of sporadic Creutzfeldt-Jakob disease variants with mixed phenotype and co-occurrence of PrPSc types: an updated classification
Parchi, P. ; Strammiello, R. ; Notari, S. ; Giese, A. ; Langeveld, J.P.M. ; Ladogana, A. ; Zerr, I. ; Roncaroli, F. ; Cras, P. ; Ghetti, B. ; Pocchiari, M. ; Kretzschmar, H. ; Capellari, S. - \ 2009
Acta Neuropathologica 118 (2009)5. - ISSN 0001-6322 - p. 659 - 671.
abnormal prion protein - fatal familial insomnia - strain variation - scrapie strains - molecular-basis - brain-tissue - western-blot - cjd - identification - conformations
Six subtypes of sporadic Creutzfeldt-Jakob disease with distinctive clinico-pathological features have been identified largely based on two types of the abnormal prion protein, PrPSc, and the methionine (M)/valine (V) polymorphic codon 129 of the prion protein. The existence of affected subjects showing mixed phenotypic features and concurrent PrPSc types has been reported but with inconsistencies among studies in both results and their interpretation. The issue currently complicates diagnosis and classification of cases and also has implications for disease pathogenesis. To explore the issue in depth, we carried out a systematic regional study in a large series of 225 cases. PrPSc types 1 and 2 concurrence was detected in 35% of cases and was higher in MM than in MV or VV subjects. The deposition of either type 1 or 2, when concurrent, was not random and always characterized by the coexistence of phenotypic features previously described in the pure subtypes. PrPSc type 1 accumulation and related pathology predominated in MM and MV cases, while the type 2 phenotype prevailed in VVs. Neuropathological examination best identified the mixed types 1 and 2 features in MMs and most MVs, and also uniquely revealed the co-occurrence of pathological variants sharing PrPSc type 2. In contrast, molecular typing best detected the concurrent PrPSc types in VV subjects and MV cases with kuru plaques. The present data provide an updated disease classification and are of importance for future epidemiologic and transmission studies aimed to identify etiology and extent of strain variation in sporadic Creutzfeldt-Jakob disease.
A refined method for molecular typing reveals that co-occurrence of PrPSc types in Creutzfeldt-Jakob disease is not the rule
Notari, S. ; Capellari, S. ; Langeveld, J.P.M. ; Giese, A. ; Strammiello, R. ; Gambetti, P. ; Kretzschmar, H.A. ; Parchi, P. - \ 2007
Laboratory Investigation 87 (2007)11. - ISSN 0023-6837 - p. 1103 - 1112.
bovine spongiform encephalopathy - fatal familial insomnia - abnormal prion protein - scrapie strains - monoclonal-antibodies - variant cjd - mice - classification - agent - sheep
Molecular typing in Creutzfeldt¿Jakob disease (CJD) relies on the detection of distinct protease-resistant prion protein (PrPSc) core fragments, which differ in molecular mass or glycoform ratio. However, the definition and correct identification of CJD cases with a co-occurrence of PrPSc types remains a challenge. With antibodies recognizing a linear epitope in the octapeptide repeat PrP region, supposed to distinguish between the two major PrPSc isoforms (ie, types 1 and 2), it was recently shown that all type 2 cases display an associated band with a type 1 migration pattern, which led to the conclusion that multiple PrPSc types regularly coexist in CJD. We studied brain samples from 53 sporadic CJD and 4 variant CJD subjects using a high-resolution electrophoresis, a wide range of proteinase K (PK) activities, the 'type 1-selective' antibody 12B2, and several unselective antibodies. We found that the type 1-like band detected by 12B2 in all CJD subtypes associated with PrPSc type 2 is not a PK-resistant PrPSc core but rather matches the physicochemical properties of partially cleaved fragments, which result from the several PK cleavage sites included in the N-terminal portion of PrPSc. Furthermore, using gels with high resolution and a relatively high PK activity, we were able to increase the detection sensitivity of either type 1 or 2, when coexisting, to amount corresponding to 3¿5% of the total PrPSc signal (ie, weak band of one type/total PrPSc). Our results show that there are many pitfalls associated with the use of 'type 1 selective' antibodies for CJD typing studies and that co-occurrence of PrPSc types in CJD is not the rule. The present results further validate the rationale basis of current CJD classification and the qualitative nature of molecular typing in CJD.
Molecular discrimination of atypical bovine spongiform encephalopathy strains from a geographical region spanning a wide area in Europe
Jacobs, J.G. ; Langeveld, J.P.M. ; Biacabe, A.G. ; Acutis, P.L. ; Polak, M.P. ; Gavier-Widen, D. ; Buschmann, A. ; Caramelli, M. ; Casalone, C. ; Mazza, M. ; Groschup, M. ; Erkens, J.H.F. ; Davidse, A. ; Zijderveld, F.G. van; Baron, T. - \ 2007
Journal of Clinical Microbiology 45 (2007)6. - ISSN 0095-1137 - p. 1821 - 1829.
transmissible mink encephalopathy - creutzfeldt-jakob-disease - abnormal prion protein - transgenic mice - monoclonal-antibodies - messenger-rna - scrapie agent - n-glycosidase - brain-stem - prp gene
Transmissible spongiform encephalopathy strains can be differentiated by their behavior in bioassays and by molecular analyses of the disease-associated prion protein (PrP) in a posttranslationally transformed conformation (PrPSc). Until recently, isolates from cases of bovine spongiform encephalopathy (BSE) appeared to be very homogeneous. However, a limited number of atypical BSE isolates have recently been identified upon analyses of the disease-associated proteinase K (PK) resistance-associated moiety of PrPSc (Prp(res)), suggesting the existence of at least two additional BSE PrPres variants. These are defined here as the H type and the L type, according to the higher and lower positions of the nonglycosylated PrPres band in Western blots, respectively, compared to the position of the band in classical BSE (C-type) isolates. These molecular Prpres variants, which originated from six different European countries, were investigated together. In addition to the migration properties and glycosylation profiles (glycoprofiles), the H- and L-type isolates exhibited enhanced PK sensitivities at pH 8 compared to those of the C-type isolates. Moreover, H-type BSE isolates exhibited differences in the binding of antibodies specific for N- and more C-terminal PrP regions and principally contained two aglycosylated PrPres moieties which can both be glycosylated and which is thus indicative of the existence of two PrPres, populations or intermediate cleavage sites. These properties appear to be consistent within each BSE type and independent of the geographical origin, suggesting the existence of different BSE strains in cattle. The choice of three antibodies and the application of two pHs during the digestion of brain homogenates provide practical and diverse tools for the discriminative detection of these three molecular BSE types and might assist with the recognition of other variants.
Bovine spongiform encephalopathy in sheep?
Schreuder, B.E.C. ; Somerville, R.A. - \ 2003
Revue scientifique et technique / Office International des Epizooties 22 (2003)1. - ISSN 0253-1933 - p. 103 - 120.
creutzfeldt-jakob-disease - scrapie-associated fibrils - abnormal prion protein - molecular analysis - strain variation - blood-transfusion - prp accumulation - natural scrapie - infected sheep - great-britain
Bovine spongiform encephalopathy (BSE) in sheep has not been identified under natural conditions at the time of writing and remains a hypothetical issue. However, rumours about the possible finding of a BSE-like isolate in sheep have led to great unrest within the sheep industry, among the general public and within governmental and regulatory bodies. The difficulties of implementing a proper risk assessment and pre-emptive measures, in the absence of a confirmed case, are described. The authors attempt to list what is known about experimental BSE in sheep, the distribution of infectivity in the host, some aspects of risk assessment and management and the most promising methods for differentiating BSE from scrapie in the same host. As for the latter, new and promising methods are being developed and appear suitable for initial screening of isolates of transmissible spongiform encephalopathies, but in the absence of proper validation, use of the 'classical' strain-typing in a mouse panel is still indicated.
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