|
||||||||||||||||||
 |
From: TSS ()
Monthly Creutzfeldt Jakob disease statistics The Department of Health is today issuing the latest information about the numbers of known cases of Creutzfeldt Jakob disease. This includes cases of variant Creutzfeldt Jakob disease (vCJD) - the form of the disease thought to be linked to BSE. The position is as follows: Definite and probable CJD cases in the UK: As at 6 January 2006 Summary of vCJD cases Deaths Deaths from definite vCJD (confirmed): 109 Deaths from probable vCJD (without neuropathological confirmation): 43 Deaths from probable vCJD (neuropathological confirmation pending): 1 Number of deaths from definite or probable vCJD (as above): 153 Alive Number of probable vCJD cases still alive: 6 Total number of definite or probable vCJD (dead and alive): 159 The next table will be published on Monday 6th February 2006 Referrals: a simple count of all the cases which have been referred to the National CJD Surveillance Unit for further investigation in the year in question. CJD may be no more than suspected; about half the cases referred in the past have turned out not to be CJD. Cases are notified to the Unit from a variety of sources including neurologists, neuropathologists, neurophysiologists, general physicians, psychiatrists, electroencephalogram (EEG) departments etc. As a safety net, death certificates coded under the specific rubrics 046.1 and 331.9 in the 9th ICD Revisions are obtained from the Office for National Statistics in England and Wales, the General Register Office for Scotland and the General Register Office for Northern Ireland. Deaths: All columns show the number of deaths that have occurred in definite and probable cases of all types of CJD and GSS in the year shown. The figures include both cases referred to the Unit for investigation while the patient was still alive and those where CJD was only discovered post mortem (including a few cases picked up by the Unit from death certificates). There is therefore no read across from these columns to the referrals column. The figures will be subject to retrospective adjustment as diagnoses are confirmed. Definite cases: this refers to the diagnostic status of cases. In definite cases the diagnosis will have been pathologically confirmed, in most cases by post mortem examination of brain tissue (rarely it may be possible to establish a definite diagnosis by brain biopsy while the patient is still alive). Probable vCJD cases: are those who fulfil the ‘probable’ criteria set out in the Annex and are either still alive, or have died and await post mortem pathological confirmation. Those still alive will always be shown within the current year's figures. Sporadic: Classic CJD cases with typical EEG and brain pathology. Sporadic cases appear to occur spontaneously with no identifiable cause and account for 85% of all cases. Probable sporadic: Cases with a history of rapidly progressive dementia, typical EEG and at least two of the following clinical features; myoclonus, visual or cerebellar signs, pyramidal/extrapyramidalsigns or akinetic mutism. Iatrogenic: where infection with classic CJD has occurred accidentally as the result of a medical procedure. All UK cases have resulted from treatment with human derived pituitary growth hormones or from grafts using dura mater (a membrane lining the skull). Familial: cases occurring in families associated with mutations in the PrP gene (10 - 15% of cases). GSS: Gerstmann-Straussler-Scheinker syndrome - an exceedingly rare inherited autosomal dominant disease, typified by chronic progressive ataxia and terminal dementia. The clinical duration is from 2 to 10 years, much longer than for CJD. vCJD: Variant CJD, the hitherto unrecognised variant of CJD discovered by the National CJD Surveillance Unit and reported in The Lancet on 6 April 1996. This is characterised clinically by a progressive neuropsychiatric disorder leading to ataxia, dementia and myoclonus (or chorea) without the typical EEG appearance of CJD. Neuropathology shows marked spongiform change and extensive florid plaques throughout the brain. Definite vCJD cases still alive: These will be cases where the diagnosis has been pathologically confirmed (by brain biopsy). DIAGNOSTIC CRITERIA FOR VARIANT CJD I A) PROGRESSIVE NEUROPSYCHIATRIC DISORDER B) DURATION OF ILLNESS > 6 MONTHS C) ROUTINE INVESTIGATIONS DO NOT SUGGEST AN ALTERNATIVE DIAGNOSIS D) NO HISTORY OF POTENTIAL IATROGENIC EXPOSURE II A) EARLY PSYCHIATRIC SYMPTOMS * B) PERSISTENT PAINFUL SENSORY SYMPTOMS ** C) ATAXIA D) MYOCLONUS OR CHOREA OR DYSTONIA E) DEMENTIA III A) EEG DOES NOT SHOW THE TYPICAL APPEARANCE OF SPORADIC CJD *** (OR NO EEG PERFORMED) B) BILATERAL PULVINAR HIGH SIGNAL ON MRI SCAN IV A) POSITIVE TONSIL BIOPSY DEFINITE: IA (PROGRESSIVE NEUROPSYCHIATRIC DISORDER) and NEUROPATHOLOGICAL CONFIRMATION OF vCJD **** PROBABLE: I and 4/5 OF II and III A and III B or I and IV A * depression, anxiety, apathy, withdrawal, delusions. ** this includes both frank pain and/ or unpleasant dysaesthesia *** generalised triphasic periodic complexes at approximately one per second ****spongiform change and extensive PrP deposition with florid plaques, throughout the cerebrum and cerebellum. http://www.dh.gov.uk/PublicationsAndStatistics/PressReleases/PressReleasesNotices/fs/en?CONTENT_ID=4126119&chk=joOCEs SEE SPORADIC CJD CASES HERE; http://www.eurocjd.ed.ac.uk/sporadic.htm TOTAL CASES OF FAMILIAL/GENETIC CJD AND IATROGENIC CJD http://www.eurocjd.ed.ac.uk/genetic.htm Creutzfeldt-Jakob Disease Helen M. Yull,* Diane L. Ritchie,* Jan P.M. Langeveld,† Fred G. van Zijderveld,† Moira E. Bruce,‡ James W. Ironside,* and Mark W. Head* From the National CJD Surveillance Unit,* School of Molecular and Clinical Medicine, University of Edinburgh, Edinburgh, United Kingdom; Central Institute for Animal Disease Control (CIDC)-Lelystad, † Lelystad, The Netherlands; Institute for Animal Health, Neuropathogenesis Unit, ‡ Edinburgh, United Kingdom Molecular typing of the abnormal form of the prion protein (PrPSc) has come to be regarded as a powerful tool in the investigation of the prion diseases. All evidence thus far presented indicates a single PrPSc molecular type in variant Creutzfeldt-Jakob disease (termed type 2B), presumably resulting from infection with a single strain of the agent (bovine spongiform encephalopathy). Here we show for the first time that the PrPSc that accumulates in the brain in variant Creutzfeldt- Jakob disease also contains a minority type 1 component. This minority type 1 PrPSc was found in all 21 cases of variant Creutzfeldt-Jakob disease tested, irrespective of brain region examined, and was also present in the variant Creutzfeldt-Jakob disease tonsil. The quantitative balance between PrPSc types was maintained when variant Creutzfeldt-Jakob disease was transmitted to wild-type mice and was also found in bovine spongiform encephalopathy cattle brain, indicating that the agent rather than the host specifies their relative representation. These results indicate that PrPSc molecular typing is based on quantitative rather than qualitative phenomena and point to a complex relationship between prion protein biochemistry, disease phenotype and agent strain. (Am J Pathol 2006, 168:151–157; DOI: 10.2353/ajpath.2006.050766) snip... Discussion In the apparent absence of a foreign nucleic acid genome associated with the agents responsible for transmissible spongiform encephalopathies or prion diseases, efforts to provide a molecular definition of agent strain have focused on biochemical differences in the abnormal, disease-associated form of the prion protein, termed PrPSc. Differences in PrPSc conformation and glycosylation have been proposed to underlie disease phenotype and form the biochemical basis of agent strain. This proposal has found support in the observation that the major phenotypic subtypes of sCJD appear to correlate with the presence of either type 1 or type 2 PrPSc in combination with the presence of either methionine or valine at codon 129 of the prion protein gene.2 Similarly, the PrPSc type associated with vCJD correlates with the presence of type 2 PrPSc and is distinct from that found in sCJD because of a characteristically high occupancy of both N-linked glycosylation sites (type 2B).6,11 The means by which such conformational difference is detected is somewhat indirect; relying on the action of proteases, primarily proteinase K, to degrade the normal Figure 6. Type 1 PrPSc is a stable minority component of PrPSc from the vCJD brain. Western blot analysis of PrP in a sample of cerebral cortex from a case of vCJD during digestion with proteinase K is shown. Time points assayed are indicated in minutes (T0, 5, 10, 30, 60, 120, 180). Duplicate blots were probed with 3F4, which detects both type 1 and type 2 PrPSc, and with 12B2, which detects type 1. The insert shows a shorter exposure of the same time course study from a separate experiment also probed with 3F4. Both blots included samples of cerebral cortex from a case of sporadic CJD MM1 (Type 1) and molecular weight markers (Markers) indicate weights in kd. Figure 7. A minority type 1-like PrPSc is found in vCJD tonsil, vCJD transmitted to mice and in BSE. Western blot analysis of PrPSc in a concentrated sample of tonsil from a case of vCJD (Tonsil), in a concentrated brain sample of a wild-type mouse (C57BL) infected with vCJD and in a sample of cattle BSE brain (BSE) is shown. Tissue extracts were digested with proteinase K. Duplicate blots were probed with either 3F4 or 6H4, both of which detect type 1 and type 2 PrPSc, and with 12B2, which detects type 1. The blots included samples of cerebral cortex from a case of sporadic CJD MM1 (Type 1) and molecular weight markers (Markers) indicate weights in kd. Type 1 PrPSc in Variant Creutzfeldt-Jakob Disease 155 AJP January 2006, Vol. 168, No. 1 cellular form of PrP and produce a protease-resistant core fragment of PrPSc that differs in the extent of its N-terminal truncation according to the original conformation. A complication has recently arisen with the finding that both type 1 and type 2 can co-exist in the brains of patients with sCJD.2,5-8 More recently this same phenomenon has been demonstrated in patients with iatrogenically acquired and familial forms of human prion disease. 9,10 The existence of this phenomenon is now beyond doubt but its prevalence and its biological significance remain a matter of debate. Conventional Western blot analysis using antibodies that detect type 1 and type 2 PrPSc has severe quantitative limitations for the co-detection of type 1 and type 2 PrPSc in individual samples, suggesting that the prevalence of co-occurrence of the two types might be underestimated. We have sought to circumvent this problem by using an antibody that is type 1-specific and applied this to the sole remaining human prion disease where the phenomenon of mixed PrPSc types has not yet been shown, namely vCJD. These results show that even in vCJD where susceptible individuals have been infected supposedly by a single strain of agent, both PrPSc types co-exist: a situation reminiscent of that seen when similarly discriminant antibodies were used to analyze experimental BSE in sheep.14,17 In sporadic and familial CJD, individual brains can show a wide range of relative amounts of the two types in samples from different regions, but where brains have been thoroughly investigated a predominant type is usually evident.2,6,10 This differs from this report on vCJD, where type 1 is present in all samples investigated but always as a minor component that never reaches a level at which it is detectable without a type 1-specific antibody. It would appear that the relative balance between type 1 and type 2 is controlled within certain limits in the vCJD brain. A minority type-1-like band is also detected by 12B2 in vCJD tonsil, in BSE brain and in the brains of mice experimentally infected with vCJD, suggesting that this balance of types is agent, rather than host or tissue, specific. Interestingly the “glycoform signature” of the type 2 PrPSc found in vCJD (type 2B) is also seen in the type 1 PrPSc components, suggesting that it could legitimately be termed type 1B. PrPSc isotype analysis has proven to be extremely useful in the differential diagnosis of CJD and is likely to continue to have a major role in the investigation of human prion diseases. However, it is clear, on the basis of these findings, that molecular typing has quantitative limitations and that any mechanistic explanation of prion replication and the molecular basis of agent strain variation must accommodate the co-existence of multiple prion protein conformers. Whether or not the different conformers we describe here correlate in a simple and direct way with agent strain remains to be determined. In principle two interpretations present themselves: either the two conformers can be produced by a single strain of agent or vCJD (and, therefore, presumably BSE) results from a mixture of strains, one of which generally predominates. Evidence for the isolation in mice of more than one strain from individual isolates of BSE has been presented previously.18,19 One practical consequence of our findings is that the correct interpretation of transmission studies will depend on a full examination of the balance of molecular types present in the inoculum used to transmit disease, in addition to a thorough analysis of the molecular types that arise in the recipients. Another consequence relates to the diagnostic certainty of relying on PrPSc molecular type alone when considering the possibility of BSE infection or secondary transmission in humans who have a genotype other than methionine at codon 129 of the PRNP gene. In this context it is interesting to note that this minority type 1B component resembles the type 5 PrPSc described previously to characterize vCJD transmission into certain humanized PRNP129VV transgenic mouse models.12,20 This apparently abrupt change in molecular phenotype might represent a selection process imposed by this particular transgenic mouse model. Irrespective of whether this proves to be the case, the results shown here point to further complexities in the relationship between the physico-chemical properties of the prion protein, human disease phenotype, and prion agent strain. Acknowledgments snip... Type 1 PrPSc in Variant Creutzfeldt-Jakob Disease 157 AJP January 2006, Vol. 168, No. 1 ...TSS http://neurology.thelancet.com Published online October 31, 2005 Creutzfeldt-Jakob disease Magdalini Polymenidou, Katharina Stoeck, Markus Glatzel, Martin Vey, Anne Bellon, and Adriano Aguzzi Summary Background The molecular typing of sporadic Creutzfeldt-Jakob disease (CJD) is based on the size and glycoform ratio of protease-resistant prion protein (PrPSc), and on PRNP haplotype. On digestion with proteinase K, type 1 and type 2 PrPSc display unglycosylated core fragments of 21 kDa and 19 kDa, resulting from cleavage around amino acids 82 and 97, respectively. Methods We generated anti-PrP monoclonal antibodies to epitopes immediately preceding the differential proteinase K cleavage sites. These antibodies, which were designated POM2 and POM12, recognise type 1, but not type 2, PrPSc. Findings We studied 114 brain samples from 70 patients with sporadic CJD and three patients with variant CJD. Every patient classified as CJD type 2, and all variant CJD patients, showed POM2/POM12 reactivity in the cerebellum and other PrPSc-rich brain areas, with a typical PrPSc type 1 migration pattern. Interpretation The regular coexistence of multiple PrPSc types in patients with CJD casts doubts on the validity of electrophoretic PrPSc mobilities as surrogates for prion strains, and questions the rational basis of current CJD classifications. into debate and introduce interesting questions about human CJD types. For example, do human prion types exist in a dynamic equilibrium in the brains of affected individuals? Do they coexist in most or even all CJD cases? Is the biochemically identified PrPSc type simply the dominant type, and not the only PrPSc species? Bovine Spongiform Encephalopathy (BSE) is a prion disease of cattle. Since 1986, when BSE was recognized, over 180,000 cattle in the UK have developed the disease, and approximately one to three million are likely to have been infected with the BSE agent, most of which were slaughtered for human consumption before developing signs of the disease. The origin of the first case of BSE is unknown, but the epidemic was caused by the recycling of processed waste parts of cattle, some of which were infected with the BSE agent and given to other cattle in feed. Control measures have resulted in the consistent decline of the epidemic in the UK since 1992. Infected cattle and feed exported from the UK have resulted in smaller epidemics in other European countries, where control measures were applied later. Compelling evidence indicates that BSE can be transmitted to humans through the consumption of prion contaminated meat. BSE-infected individuals eventually develop vCJD with an incubation time believed to be on average 10 years. As of November 2004, three cases of BSE have been reported in North America. One had been imported to Canada from the UK, one was grown in Canada, and one discovered in the USA but of Canadian origin. There has been only one case of vCJD reported in the USA, but the patient most likely acquired the disease in the United Kingdom. If current control measures intended to protect public and animal health are well enforced, the cattle epidemic should be largely under control and any remaining risk to humans through beef consumption should be very small. (For more details see Smith et al. British Medical Bulletin, 66: 185. 2003.) Chronic Wasting Disease (CWD) is a prion disease of elk and deer, both free range and in captivity. CWD is endemic in areas of Colorado, Wyoming, and Nebraska, but new foci of this disease have been detected in Nebraska, South Dakota, New Mexico, Wisconsin, Mississippi Kansas, Oklahoma, Minnesota, Montana, and Canada. Since there are an estimated 22 million elk and deer in the USA and a large number of hunters who consume elk and deer meat, there is the possibility that CWD can be transmitted from elk and deer to humans. As of November 2004, the NPDPSC has examined 26 hunters with a suspected prion disease. However, all of them appeared to have either typical sporadic or familial forms of the disease. The NPDPSC coordinates with the Centers for Disease Control and state health departments to monitor cases from CWD-endemic areas. Furthermore, it is doing experimental research on CWD transmissibility using animal models. (For details see Sigurdson et al. British Medical Bulletin. 66: 199. 2003 and Belay et al. Emerging Infectious Diseases. 10(6): 977. 2004.) p.s. please note the 47 PENDING CASES to Sept. 2005 p.s. please note the 2005 Prion D. total 120(8) 8=includes 51 type pending, 1 TYPE UNKNOWN ??? p.s. please note sporadic CJD 2002(1) 1=3 TYPE UNKNOWN??? p.s. please note 2004 prion disease (6) 6=7 TYPE UNKNOWN??? snip... http://www.bseinquiry.gov.uk/files/yb/1991/01/04004001.pdf 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
|
