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From: TSS ()
Opinion of the BIOHAZ Panel on classification of atypical Transmissible Spongiform Encephalopathy (TSE) cases in Small Ruminants* Opinion Since the introduction of active monitoring in small ruminants in January 2002 (Chapter A.II of Annex III to Regulation (EC) No 999/2001) several Member States (MS) have detected atypical scrapie cases. However there appeared to be differences in the way individual member states were assessing and reporting such cases. To facilitate harmonisation within the EU, the European Commission requested that the European Food Safety Authority (EFSA) assess whether it is possible to propose a definition for atypical scrapie and whether different types of atypical scrapie exist. The Scientific Panel on Biological Hazards further requested that the implications for TSE surveillance also be considered. They concluded that an operational definition of atypical scrapie in small ruminants is possible (annex 1 of the opinion); this definition is provided in juxtaposition with similar definitions for scrapie and BSE in small ruminants. Sub-categorisation of scrapie and atypical scrapie is premature although this may become possible when more data are available. The implications of atypical scrapie, as distinct from scrapie, are difficult to quantify in terms of its impact on animal health due to insufficient data. If investigations are to progress to the point where advice can be given on issues such as means of transmission of atypical scrapie within and between flocks, the value of flock slaughter and the implications of atypical scrapie for breeding for TSE resistance programmes, it is essential that statistically valid surveillance should continue in the immediate future. Surveillance programmes should use appropriate combinations of tests and sampling to ensure that atypical cases continue to be identified. Wherever possible samples of brain tissue should be as large as possible and include brain stem and cerebellum as a minimum. Furthermore, collection of whole carcases should be encouraged. This will enable the biological characterisation of isolates to continue, and facilitate transmission experiments in the natural hosts (sheep and goats) and the preparation of reference material for future test evaluations. ______________ *For citation purposes: Opinion of the Scientific Panel on Biological Hazards on the request from the European Commission on classification of atypical Transmissible Spongiform Encephalopathy (TSE) cases in Small Ruminants. The EFSA Journal (2005), 276, 1-30 http://www.efsa.eu.int/science/biohaz/biohaz_opinions/1216_en.html http://www.efsa.eu.int 1 of 2 Opinion of the Scientific Panel on Biological Hazards on classification of atypical Transmissible Spongiform Encephalopathy (TSE) cases in Small Ruminants1 (Question number EFSA-Q-2005-073) Adopted on 26 October 2005 SUMMARY Since the introduction of active monitoring in small ruminants in January 2002 (Chapter A.II of Annex III to Regulation (EC) No 999/2001) several Member States (MS) have detected atypical scrapie cases. However there appeared to be differences in the way individual member states were assessing and reporting such cases. To facilitate harmonisation within the EU, the European Commission requested that the European Food Safety Authority (EFSA) assess whether it is possible to propose a definition for atypical scrapie and whether different types of atypical scrapie exist. The Scientific Panel on Biological Hazards further requested that the implications for TSE surveillance also be considered. They concluded that an operational definition of atypical scrapie in small ruminants is possible (annex 1 of the opinion); this definition is provided in juxtaposition with similar definitions for scrapie and BSE in small ruminants. Sub-categorisation of scrapie and atypical scrapie is premature although this may become possible when more data are available. The implications of atypical scrapie, as distinct from scrapie, are difficult to quantify in terms of its impact on animal health due to insufficient data. If investigations are to progress to the point where advice can be given on issues such as means of transmission of atypical scrapie within and between flocks, the value of flock slaughter and the implications of atypical scrapie for breeding for TSE resistance programmes, it is essential that statistically valid surveillance should continue in the immediate future. Surveillance programmes should use appropriate combinations of tests and sampling to ensure that atypical cases continue to be identified. Wherever possible samples of brain tissue should be as large as possible and include brain stem and cerebellum as a minimum. Furthermore, collection of whole carcases should be encouraged. This 1 For citation purposes: Opinion of the Scientific Panel on Biological Hazards on the request from the European Commission on classification of atypical Transmissible Spongiform Encephalopathy (TSE) cases in Small Ruminants. The EFSA Journal (2005), 276, 1-30 Summary of the Opinion http://www.efsa.eu.int 2 of 2 will enable the biological characterisation of isolates to continue, and facilitate transmission experiments in the natural hosts (sheep and goats) and the preparation of reference material for future test evaluations. Key words: TSE, scrapie, atypical, definition, surveillance, sheep. http://www.efsa.eu.int/science/biohaz/biohaz_opinions/1216/biohaz_op_ej_276_atypicalscrapiedefinition_summary_en1.pdf FULL TEXT OPINION 30 PAGES ; The EFSA Journal (2005) 276, 1-30. Opinion on classification of atypical Transmissible Spongiform Encephalopathy (TSE) cases in Small Ruminants BACKGROUND Since the introduction of active monitoring in small ruminants in January 2002 (Chapter A.II of Annex III to Regulation (EC) No 999/2001) several Member States have detected atypical scrapie cases. These cases seem to differ from classical scrapie in several ways, such as an unusual sensitivity of associated PrPSc to proteinase K treatment, the pattern of deposition in the brain of the abnormal form of the prion protein, the pathology, the epidemiology and the unusual occurrence in sheep with genotypes previously associated with resistance to scrapie. It was however not clear if all of these cases were really different from classical scrapie, and for those that were, whether there were different groups of atypical cases. Atypical scrapie cases often show similarity to the Norwegian Nor98 cases. Harmonisation between Member States is needed in order to decide which cases should be considered atypical. An overview of TSE cases considered as atypical in different Member States was provided by the European Commission services in the mandate and is attached. The Scientific Panel on Biological Hazards of the European Food Safety Authority (EFSA) has considered the first cases of atypical scrapie in an earlier opinion (EFSA, 2003). Furthermore, an expert Panel on strain-typing, coordinated by the Community Reference Laboratory (CRL), evaluated the nature and the significance of atypical cases in its report to SANCO (CRL report, 2004) and underlined the heterogeneous nature of atypical cases and finally, several scientific papers have been published on atypical cases. The experts of the (EFSA) are requested to evaluate, in collaboration with the CRL and its expert group on strain-typing, the most recent updated scientific information and data on atypical cases in order to indicate criteria to define atypical cases or to identify certain groups of atypical cases taking into account the statements of the CRL panel of experts. TERMS OF REFERENCE REPORT snip... http://www.efsa.eu.int 6 of 30 b) Atypical TSEs in small ruminants In 1998, the molecular and histopathological spectrum of TSEs in sheep was extended by the discovery in Norway of an experimentally-transmissible, PrP-related, neurological disease of sheep that was distinguishable from classical scrapie and was therefore considered to be an "atypical" form of scrapie (Benestad et al., 1999, and 2003). These Nor98 cases, the prototypes of "atypical" TSE, have little or no vacuolation or abnormal PrP at the obex5, but in most cases exhibit an intense cerebellar PrPSc deposition/accumulation characterised at a molecular level by a smaller and less stable protease-resistant core of PrPSc. Nor98 and other "atypical" cases subsequently identified are more often but not uniquely, found in animals carrying alleles not usually associated with classical scrapie (Annex 2). For Nor98, this genotype correlation has been further refined recently to implicate another dimorphic codon in the PrP open reading frame, L141F (Moum et al., 2005). Other "atypical" TSE phenotypes , including those that are similar to or the same as Nor98 have now been published or in press/submitted from France (Buschmann et al., 2004b), Germany (Buschmann et al., 2004a; 2004b), Sweden (Gavier-Widen et al. 2004), Ireland (Onnasch et al., 2004), Portugal (Orge et al., 2004), Belgium (De Bosschere et al., 2004) and the UK (Simmons et al., 2005; Everest et al., 2005). Table 1: Atypical TSE cases reported to the European Commission Member State Number of atypical cases Comment France 69 7 ARR/ARR sheep; 6 goats Spain 17 5 cases found on herds with other atypical cases United Kingdom 87 14 ARR/ARR sheep Germany 64 82 % of all cases; 4 ARR/ARR sheep Portugal 29 All cases atypical (23 Nor98); 5 ARR/ARR Sweden 6 All cases atypical (Nor98 like) Ireland 4 Nor98 like, 3x clinical signs Belgium 2 1 ARR/ARR sheep Norway 45 Nor98 : 80% of TSE cases; 1 ARR/ARR Finland 1 Nor98 Netherlands 1 Nor98 Table 1 above shows the number of cases reported in these and other EU member states at 30th June 2005. Further data from individual member states are provided in 5 IHC does now reveal minimal amounts of immunostaining in the nucleus of the spinal tract of the trigeminal nerve at the level of the obex in many "atypical" cases. However, immunostaining of the dorsal motor nucleus of the vagus (which is consistently involved in ‘classical’ scrapie) would appear to be distinctively not involved in ‘atypicals’. snip... http://www.efsa.eu.int 11 of 30 CONCLUSIONS The Scientific Panel on Biological Hazards concludes that: 1. An operational definition of atypical scrapie in small ruminants is possible (see Annex 1). This definition is provided in juxtaposition with similar definitions for scrapie and BSE in small ruminants. Sub-categorisation of scrapie and atypical scrapie is premature although this may become possible when more data are available. 2. The implications of atypical scrapie, as distinct from scrapie, are difficult to quantify in terms of its impact on animal health due to insufficient data. If investigations are to progress to the point where advice can be given on issues such as means of transmission within and between flocks, the value of flock slaughter, its implications for breeding for TSE resistance programmes, it is essential that statistically valid surveillance should continue in the immediate future. 3. Surveillance programmes should use appropriate combinations of tests and sampling to ensure that atypical cases continue to be identified. Wherever possible samples of brain tissue should be as large as possible and include brain stem and cerebellum as a minimum. Furthermore, collection of whole carcases should be encouraged. This will enable the biological characterisation of isolates to continue, and facilitate transmission experiments in the natural hosts (sheep and goats) and the preparation of reference material for future test evaluations. The EFSA Journal (2005) 276, 1-30. Opinion on classification of atypical Transmissible Spongiform Encephalopathy (TSE) cases in Small Ruminants RECOMMENDATIONS The Scientific Panel on Biological Hazards recommends: 1. The classification system at Annex 1 is adopted by all MS until further notice. It represents no more than the current state of knowledge, and will require to be updated as scientific knowledge advances. 2. Surveillance programmes, including tests and sampling arrangements, be used so as to enable detection of all forms of TSEs in small ruminants 3. Analysis of data arising from EU surveillance programmes in small ruminants and any investigations specifically established to study the epidemiology of "atypical scrapie" is reviewed in order to ensure that surveillance and test methodologies are appropriate. SNIP...FULL TEXT 30 PAGES; http://www.efsa.eu.int/science/biohaz/biohaz_opinions/1216/biohaz_op_ej_276_atypicalscrapiedefinition_en_vf1.pdf Infected and Source Flocks As of August 31, 2005, there were 115 scrapie infected and source flocks (figure 3). There were 3 new infected and source flocks reported in August (Figure 4) with a total of 148 flocks reported for FY 2005 (Figure 5). The total infected and source flocks that have been released in FY 2005 are 102 (Figure 6), with 5 flocks released in August. The ratio of infected and source flocks released to newly infected and source flocks for FY 2005 = 0.69 : snip... full text ; http://www.aphis.usda.gov/vs/nahps/scrapie/monthly_report/monthly-report.html AS of July 31, 2005, there were 120 scrapie infected soure flocks (figure 3). There were 16 new infected and source flocks reorted in July (Figure 4) with a total of 143 flocks reported for FY 2005 (Figure 5). The total infected and source flocks that have been released in FY 2005 are 89 (Figure 6), with 8 flocks released in July. The ratio of infected and source flocks released to newly infected and source flocks for FY = 0.62 : 1. IN addition, as of July 31, 2005, 524 scrapie cases have been confirmed and reported by the National Veterinary Services Laboratories (NVSL), of which 116 were RSSS cases (Figure 7). This includes 76 newly confirmed cases in July 2005 (Figure 8). Fifteen cases of scrapie in goats have been reported since 1990 (Figure 9). The last goat case was reported in May 2005. ........... snip... http://www.aphis.usda.gov/vs/nahps/scrapie/monthly_report/monthly-report.html SCRAPIE USA MONTHLY REPORT 2005 AS of March 31, 2005, there were 70 scrapie infected source flocks (Figure FULL TEXT ; http://www.aphis.usda.gov/vs/nahps/scrapie/monthly_report/monthly-report.html Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0502296102 A newly identified type of scrapie agent can naturally infect sheep with resistant PrP genotypes ( sheep prion | transgenic mice ) Annick Le Dur *, Vincent Béringue *, Olivier Andréoletti , Fabienne Reine *, Thanh Lan Laï *, Thierry Baron , Bjørn Bratberg ¶, Jean-Luc Vilotte ||, Pierre Sarradin **, Sylvie L. Benestad ¶, and Hubert Laude * Scrapie in small ruminants belongs to transmissible spongiform encephalopathies (TSEs), or prion diseases, a family of fatal neurodegenerative disorders that affect humans and animals and can transmit within and between species by ingestion or inoculation. Conversion of the host-encoded prion protein (PrP), normal cellular PrP (PrPc), into a misfolded form, abnormal PrP (PrPSc), plays a key role in TSE transmission and pathogenesis. The intensified surveillance of scrapie in the European Union, together with the improvement of PrPSc detection techniques, has led to the discovery of a growing number of so-called atypical scrapie cases. These include clinical Nor98 cases first identified in Norwegian sheep on the basis of unusual pathological and PrPSc molecular features and "cases" that produced discordant responses in the rapid tests currently applied to the large-scale random screening of slaughtered or fallen animals. Worryingly, a substantial proportion of such cases involved sheep with PrP genotypes known until now to confer natural resistance to conventional scrapie. Here we report that both Nor98 and discordant cases, including three sheep homozygous for the resistant PrPARR allele (A136R154R171), efficiently transmitted the disease to transgenic mice expressing ovine PrP, and that they shared unique biological and biochemical features upon propagation in mice. These observations support the view that a truly infectious TSE agent, unrecognized until recently, infects sheep and goat flocks and may have important implications in terms of scrapie control and public health. -------------------------------------------------------------------------------- Author contributions: H.L. designed research; A.L.D., V.B., O.A., F.R., T.L.L., J.-L.V., and H.L. performed research; T.B., B.B., P.S., and S.L.B. contributed new reagents/analytic tools; V.B., O.A., and H.L. analyzed data; and H.L. wrote the paper. A.L.D. and V.B. contributed equally to this work. To whom correspondence should be addressed. Hubert Laude, E-mail: laude@jouy.inra.fr www.pnas.org/cgi/doi/10.1073/pnas.0502296102
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