New Variant Creutzfeldt-Jacob Disease - Essay Example

Name of writer appears here] [Course name appears here] [Professor’s name appears here] [Date appears here] New Variant CJD Variant Creutzfeldt-Jacob Disease (vCJD): An Introduction Variant CJD (vCJD) is a rare, degenerative, fatal brain disorder in humans. Although experience with this new disease is limited, evidence to date indicates that there has never been a case of vCJD transmitted through direct contact of one person with another. However, a case of probable transmission of vCJD through transfusion of blood components from an asymptomatic donor who subsequently developed the disease has been reported. As of June 2005, a total of 177 cases of vCJD had been reported in the world: 156 from the United Kingdom, 12 from France, 2 from Ireland and 1 each from Canada, Italy, Japan, The Netherlands, Portugal, Saudi Arabia, and the United States (note: the Canadian, one of the Irish, Japanese and U.S. cases were reported in persons who visited or resided in the United Kingdom during a key exposure period of the U.K. population to the BSE agent). There has never been a case of vCJD that did not have a history of exposure within a country where this cattle disease, BSE, was occurring. It is believed that the persons who have developed vCJD became infected through their consumption of cattle products contaminated with the agent of BSE. There is no known treatment of vCJD and it is invariably fatal. Creutzfeldt-Jacob Disease (CJD), first pointed up in 1921 by Alfons Jacob (Jacob, 132-146), remains a mysterious disease. CJD, along with diseases as kuru, Gerstmann-Straussler-Scheinker syndrome (GSS) and Fatal Familial Insomnia (FFI), are "prional" diseases caused by large aggregations of protein in the brain. These proteins cause macroscopic vacuolation of brain tissue and as a result the diseases are known as "spongiform encephalopathies." Prional diseases distinctively do not appear to rely on nucleic acids for their transmission (Griffith, 1041-43). Diseases such as CJD in fact are the result of a polymerization reaction in with the disease isoform of a protein (designated PrPsc, for prion protein scrapie) causes a conversion of the normal host-encoded protein, PrPc (cellular), to the PrPsc isoform through an autocatalytic process (Prusiner, 1515-22 and Kocisko, 471-4). PrPsc protein does not appear to have its amino-acid sequence modified although its glycosylation pattern almost definitely differs from PrPc. Hence, the conversion is not a covalent alteration however rather a conformational change. Since there are phenotypically distinguishable strains of CJD, it is assumed that each strain converts the protein in a unique manner. Interest in Creutzfeldt-Jacob Disease recently has reached new levels due mainly to a remarkable outbreak of CJD in Britain, which has been related with an epizootic of another prion disease, bovine spongiform encephalopathy (BSE). The epizootic was first discovered in 1986: since then, there have been over 164 000 cases of BSE reported in the United Kingdom (Coursens, 197-198), affecting almost one-third of all cattle herds. BSE is strangely species-nonspecific for a prion disease, and has been shown to cause encephalopathies in many species, including cats and ungulates, sheep and goats (Bruce, 405-11). The disease has shown, unpredictably, to be transmitted by ingestion of BSE-infected brain homogenates. Since the beginning of 1985, 26 individuals in Britain between the ages of 19 and 45 have been diagnosed with CJD. Nevertheless, these 26 individuals show signs of features not normally related with CJD, such as florid plaques rather than synaptic deposits of protein, unusual behavioral changes and ataxia, and a long-drawn-out disease course. Most notably, these 26 individuals have a median age of 28, compared to a normal CJD-onset disease of roughly 60. Accordingly, this strain of CJD has been called 'new variant' CJD (nvCJD). The coincidence of this new epidemic of CJD merely ten years after the discovery of BSE has sounded public-health alarms all over the world, and led to much thought in both the popular media and scientific circles that the etiological agent of BSE may be responsible for nvCJD. Two years after the first case of nvCJD was described, scientific data are beginning to provide support for this hypothesis. There are three distinct types of usually defined Creutzfeldt-Jacob disease. The most common kind, with an incident rate of about one in 106, is sporadic and actually attributable to an unlucky mutation in the PRNP gene or happenstance development of the disease isoform. There is, also, a genetically transmitted CJD, which accounts for about fifteen percent of all cases (Windl, 259-264) and is caused by a coding mutation in PRNP. There have also been many cases of iatrogenic exposure, in which patients undergoing dura matter or corneal grafts, receiving human cadaveric pituitary-derived growth hormone or gonadotropin as treatment, or exposed to unclean instruments have acquired CJD (Weller, 1-4). The appearance of the new variant CJD in Britain has caused some to question whether this is in fact a new disease or rather a newly discovered, other than previously occurring disease. The evidence points towards the conclusion that nvCJD is in fact, an emergent disease, and not one that has been hidden. Despite the fact that there is always a possibility that this disease has been unobserved and in the past classified as one of the other three forms of CJD, there are several data that make the chance of such a misclassification remote. First, the neuropathologies associated with nvCJD are different from the regular form of the disease. Second, there have been no earlier reports of neuropathologies like that of nvCJD in the medical literature (Will, 921-925) and the similarities between the neuropathologies of the ten cases of nvCJD makes them almost indistinguishable, unlike the variations seen in traditional CJD. Finally, countries other than the UK with CJD surveillance have not reported an increase in the incidence of CJD among those aged below 45 years. All of these data point to a disease focused in the UK with a new etiological agent. The evidence BSE may Cause nvCJD Owing to the limited number of cases of nvCJD and the rather recent initial outbreak of the disease, data are only now beginning to shed light on a possible direct link between nvCJD and BSE. Support for BSE as the etiological agent of nvCJD comes form three lines of evidence: first, the epidemiology of nvCJD; second, the relative transmissibility of BSE in other mammals; and third, molecular evidence, published recently. Together, these three lines of evidence provide a compelling case for a link between BSE and nvCJD. In 1994, initial speculation that BSE might be the causative agent of CJD was based solely on the correlation between seven surprising cases of CJD and the mad-cow disease outbreak in Britain. Without any hard evidence, the media in particular, tabloid newspapers implicated BSE as the etiological agent behind the new cases of CJD. The connection, although considered to some extent unfounded at the time has been proved better by other data that have become known in the ensuing two years. The first piece of the epidemiological jigsaw is that Britain is the only country in the world with a widespread BSE problem. Except one incident of nvCJD in France, Britain is also the only nation to have reported the new disease. It is unlikely that many CJD cases are not reported. The problem of BSE underreporting in other countries may be cause for some debate, as farmers try to avoid having their entire herd culled, but most human cases of CJD are pathologically determined. Since autopsies are performed at relatively high rates in Western countries, it is a fair assumption that most cases of CJD, at lest in the developed world, are reported. Second, and more convincing, there have been no reports of nvCJD in countries putatively free of BSE, such as the United States. If the disease's agent were found in both the US and the UK, the US should have had some sixty cases of nvCJD reported between 1994 and 1996. In fact, even on continental Europe, with a population slightly higher than the US and an extremely low rate of BSE infection, there has only been the one case of nvCJD in France. The lack of any case of nvCJD in a country without BSE provides a solid correlation between presence of BSE in cattle and nvCJD in humans, and is the most striking epidemiological evidence. Pathogenicity of BSE upon Ingestion A controlled study of the infectivity of BSE in humans could never be performed, and is practically impossible to find out retrospectively whether any of the victims actually consumed BSE-infected beef. Evidence does, on the other hand, show that BSE may be infective across the species boundary. These data are surprising as, based on the prion model of inheritance, the lack of high homology between different species' prional proteins theoretically ought to be an effective barrier against infection. Bruce and colleagues (405-11) have demonstrated that many species, including sheep, goats, and some ungulates can be infected with BSE through an oral route of transmission and maintain infectiousness in subsequent experiments that tested transmissibility to mice although the mice were subsequently vaccinated intracerebrally. Evidence presented by Collinge and colleagues (685-690) in a paper that supports the possibility that BSE causes nvCJD may argue exactly the opposite: that the BSE agent cannot be transmitted to humans. At the same time as BSE can be transmitted to wild-type FVB and C57BL mice easily, it has not been transmitted to mice, designated HuPrP+/+ Prn-p0/0, transgenic for the human prional protein. Although Dr. Collinge argues that this may be explained by the low frequency of BSE infection in humans or a long incubation period, the pathogenicity of BSE in these transgenic mice which lack a species barrier to human prional diseases such as kuru is undoubtedly lower than in nontransgenic mice. Finally, Ridley and colleagues, reporting on the inefficiency of BSE transmission to macaques (Ridley, 1996), claim that in spite of exposure to the BSE agent, more than 100 of their macaques have failed to develop a spongiform encephalopathy. These data are mainly erratic, since they are the result of observation and not a controlled experiment. However, given that the BSE agent has been found in the meal fed to these macaques, this may be evidence for a low rate of transmission in higher mammals. Regrettably, animal models such as this one, and those used by Collinge and Bruce (Collinge, 685-690 and Bruce, 405-11), make for very poor models of transmission to humans by the oral route due to physiological, immune, and prion-protein differences. Molecular Analysis Though the other results outlined above convinced many, including policy makers, that BSE could cause nvCJD, molecular evidence that the etiological agents of nvCJD and BSE are identical is necessary. This is ultimately very difficult to do, as the proteins that cause disease are host encoded and therefore the amino-acid sequences of the proteins will vary as usual between organisms. Crystallographic data would provide the most solid evidence of identical protein conformations among affected humans and cattle, but none has yet been produced. Strains of prional disease hypothesized to be based on differences in conformation, and possibly glycosylation, of the host protein (Bessen and Marsh, 7859-68). This evidence is based on differences in migration patterns on an SDS-polyacrylamide gel of two types of mink spongiform encephalopathy, "hyper" (Hy) and "drowsy" (Dr), after limited treatment with proteinase K. It points to the conformation forced on PrPc by PrPsc as the cause of the difference in neuropathology associated with different forms of the disease. The disease progression for Hy as the name implies is rather rapid, and the Dr strain causes neuropathology more slowly. Recent experiments (Collinge, 685-690) at the molecular level give credence to the generally accepted BSE-nvCJD link, though the data are far from proof. This research gave rise to comparing the four different types of CJD (genetic, sporadic, iatrogenic, and "new variant") to each other in addition to BSE. This paper analyzed the prional proteins from 43 neuropathologically confirmed cases of CJD, including ten nvCJD cases. It was discovered that, among the traditionally seen cases of CJD, there were three distinct banding patterns on Western analysis after treatment with proteinase K. Types I and II were found to correspond to either the genetic, sporadic, or iatrogenic CJD. Type III was exclusively found in iatrogenic cases. These first three types of CJD differed only in the molecular weights of three fragments of the PrPsc, but had in effect identical band intensities. The type IV was seen solely in cases of nvCJD and showed a remarkably different banding pattern. Other evidence showed a unique glycosylation pattern to nvCJD, further showing that the disease's agent is different that those of the other three types of CJD. Interestingly, PrP from all ten cases of nvCJD was heterozygous for valine at residue 129, implying that there may be a genetic predisposition for contracting nvCJD. This evidence is confined by the fairly small sample size, particularly for some of the data on iatrogenic cases. Controls are missing for many experiments, particularly, for the study of the valine-methionine polymorphism at amino acid 129. Further evidence takes the form of comparison studies between the banding patterns, again on Western analysis, of nvCJD to the BSE from infected mice, macaques, cats and, certainly, cows. The glycoform signature of new variant CJD was statistically not different to the pattern seen in all of the other cases. This is in agreement with the idea that transmission of BSE to humans causes nvCJD. These data are absolutely biased. There is no basis for normalization of the results, and given the lack of transmission to transgenic mice, these data basically only serve to confirm the findings (Bruce, 405-11), that BSE can be transmitted to non-bovine species. Review Of the Evidence The epidemiological data only show a correlation, not causation. Studies in other animals may have no relation to what happens in humans. Finally, the molecular evidence is largely circumstantial in that the glycosylation patterns appear similar, however this does not involve for certain BSE as the causative agent for nvCJD. Overall, on the other hand, the data are more compelling. Despite the fact that all three lines of evidence are each not sufficient to prove that BSE causes nvCJD, all together there is no singe way to disprove the hypothesis, based on the evidence at hand. Remarkably, there are no studies that persuasively argue against the claim that BSE causes new variant CJD. This lack of any significant data to refute the BSE-CJD link is another critical element in support of the hypothesis. Notably, the data also make it almost completely impossible that pure chance is responsible for the development of nvCJD. Arguments that agents other than prions may be at work, for instance, are obviously doubtful since they do not essentially change any interpretation of the data. For case in point, if a nucleic acid based infectious agent, such as a virus or some smaller, unidentified DNA or RNA particle, caused the abnormal protein to form, it would not change the fact of the evidence. As an example, if a virus were responsible for the pathology associated with both BSE and nvCJD, it would not change the interpretation of any of the data above, though it might lead to new strategies for prevention. A recent article in Science (Lasmezas, 402-404), for example, claimed to show that the BSE agent could be transmitted without any noticeable PrPsc. This study was flawed for several reasons, including the lack of PrP0/0 mice, too-high detection threshold, and a lack of screening for microscopic vacuolation. In fact, the best support for the protein-only hypothesis comes from the incapability to start prional diseases in animals lacking the PrP gene. Moreover, protein polymerization is often a favored cascade thermodynamically that is kept in check by rather low body temperatures and rapid protein digestion. Policy Implications The European Union decided to ban British exports of beef, live bovine animals or embryos, any mammalian-derived meat and bone meal, and "any products liable to enter the human food chain" that were derived from cows. This action was made in response to publications at the time (Will, 921-925) that pointed visibly to a link between the then still-mysterious cases of CJD and BSE. Later, the European Union forged a scathing critique of British policies on the prevention of BSE in an inquiry into the BSE outbreak (European Parliament, 1996). The British banned specified offal from the food chain in response to the BSE epidemic, which had developed, but failed to ensure that the ban on the feeding of meat and bone meal to ruminants was effective. The British, for instance, did not have any legal penalties for the storage or administration of such feed. There was no surveillance mechanism for herds in which BSE had been detected until 1994. Finally, the British did not effectively monitor or maintain the ban on beef products (European Parliament, 1996). However, the UK now has strict rules for the control of BSE, with all cattle in a diseased herd culled or at a minimum prevented from market. The policy failures of the past have been replaced with strict pan-European guidelines on the production and distribution of beef and bovine products. If BSE is the etiological agent for nvCJD, and assuming a ninety percent effective ban on bovine offal, the CJD epidemic is likely to continue for a number of years. Mathematical models of the epidemic (Coursens, 197-198) foresee that, if the mean incubation is short for CJD, the number of cases will be around 100. If the mean incubation time is longer, say 25 years, with a low deviation from the mean, the UK could be in for a disastrous epidemic of some 80 000 individuals sooner or later contracting new variant CJD. North America has, for the moment, been safe of such a prospect, however conditions are ripe in the US, particularly, for a repeat of the British experience with BSE and CJD. The US Department of Agriculture (USDA) presently places few effective restrictions on the use of animal scraps in feed for ruminants (Kluger, 1997) -- the same mechanism that is speculated to have caused to the British BSE outbreak. As BSE can occur unexpectedly, pure good fortune is all that has kept US herds from becoming infected with BSE. In contrast, given that BSE is known to have a relatively long incubation time of four years, detection of BSE in one cattle herd would almost surely show a widespread problem. The simple solution for the US is to adopt European-like restriction on the use of offal. The cost of a BSE epidemic in terms of human life and lost revenue due to cattle culling would surely outweigh the some $100 million it would take to institute such new regulations on the US cattle industry. Conclusions The recent occurrence of a new variant of Creutzfeldt-Jacob disease is most likely related to the epizootic of Bovine Spongiform Encephalopathy that swept British cattle herds beginning in the mid-1980s. The evidence in support of this conclusion comes from epidemiological, animal, and molecular evidence, which together show that the etiological agent of BSE is identical at the molecular level to that of nvCJD and also that the prion can be acquired, at however low of a rate, by an oral route of transmission, across species boundaries. Despite the fact that exposure to BSE is highly unlikely in Britain anymore, there is a considerable chance that past exposure to BSE will cause the epidemic of nvCJD to continue, at least until the turn of the century. Works Cited Bessen, R.A. and Marsh, R.F. "Distinct PrP properties suggest the basis for strain variation in transmissible mink encephalopathy." 1994: 7859-68, Journal of Virology. Bruce, M. et al., "Transmission of bovine spongiform encephalopathy and scrapie to mice: strain variation and the species barrier." 1994: 405-11, Philosophical Transactions of the Royal Society of London. Collinge, J. et al. "Molecular analysis of prion strain variation and the aetiology of 'new variant' CJD", 1996:685-690, Nature. Coursens et al., "Predicting the CJD epidemic in humans"1997: 197-198, Nature. European Parliament Temporary Committee on Inquiry into BSE Draft Report Part (B): Results of the Investigation of the Temporary Committee of Inquiry into BSE. 19 December 1996. Fields, B. and Chesboro, B. "Chapter 90. Transmissible Spongiform Encephalopathies: A Brief Introduction" from Fields Virology 3d ed., 1996. Griffith, J., "Self Replication and Scrapie" 1967: 1041-43, Nature. Jacob, A., "A remarkable disease of the Central Nervous System with unusual anatomical features"1921: 132-146, Duetche Z. Nervenheilkd. (In German) Kluger, J., "Could Mad Cow Disease Happen Here?" 1997, Time. Kocisko, D. et al., "Cell-free formation of protease-resistant prion protein" 1994: 471-4, Nature. Lasmezas, C. et al., "Transmission of the BSE agent to Mice in the Absence of Abnormal Prion Protein"1997: 402-404, Science. Prusiner, S., "Molecular Biology of Prion Diseases"1991: 1515-22, Science. Ridley, R. et al., "Failure to transmit bovine spongiform encephalopathy to marmosets with ruminant-derived meal"1996, The Lancet. (letter) Weller, R. O. et al., Psychological Medicine, 1989:1-4. Will, R. et al., "A new variant of Creutzfeldt-Jacob disease in the UK" 1996: 921-925, The Lancet. Windl, O. et al., "Genetic basis of Creutzfeldt-Jakob disease in the United Kingdom: a systematic analysis of predisposing mutations and allelic variation in the PRNP gene" 1996: 259-264, Human Genetics. Read More