Creutzfeldt-Jakob disease variant

Collinge J. Variant Creutzfeldt-Jakob disease. Lancet 354 317-323,1999. 

Partanen, J. (2003). Genetic susceptibility to variant Creutzfeldt-Jakob disease, Lancet, 361, 447. 

Like any other protein, the molecular structure of the prion is subject to conformational flexibility and to various thermal-induced fluctuations between varying conformational states. However, if these fluctuations permit the PrP conformation to be attained, then this abnormal conformer promotes the widespread conversion of PrP to PrP , leading to the precipitous deposition of the abnormal protein throughout the brain (mirrored by the rapid and relentlessly downhill clinical course). This pathological self-propagating shape conversion of a-helical PrP to P-sheet PrP may in principle be initiated by a seed PrP molecule in the neurotoxic conformation. This explains the transmissibility of prion diseases and accounts for how susceptible humans exposed to beef from an animal with mad cow disease develop variant Creutzfeldt-Jakob disease. 

Because they are derived from cattle, there is a concern that gelatins might be vehicles for the transmission of the prion agent responsible for bovine spongiform encephalopathy (BSE) in cattle and variant Creutzfeldt-Jakob disease (vGD) in humans. There is at present no evidence that these products have contributed to the transmission of BSE or vCJD. However, the incubation period may be up to several years, and due prudence is warranted when such products are used. 

In human populations, exposure to the BSE agent (probably in contaminated bovine-based food products) has been strongly linked to the 1996 appearance of a new transmissible spongiform encephalopathy of humans called variant Creutzfeldt-Jakob Disease (vCJD). 

Variant Creutzfeldt-Jakob Disease Vancomycin Resistant Staphylococcus Aureus (VRSA)... 

Cooper ID, Bird SM (2003) Predicting incidence of variant Creutzfeldt-Jakob disease from UK dietary exposur e to bovine spongiform encephalopatliy for tire 1940 to 1969 and post-1969 birtli cohorts, hit J Epidemiol 32 784—791. 

Yuli HM, Ritchie DL, Langeveld JP, van Zijderveld EG, Bruce ME, honside JW, Head MW (2006) Detection of type 1 prion protein in variant Creutzfeldt-Jakob disease. Am J Pathol 168 151-157. 

Head MW, Ritchie D, Smith N, McLoughlin V, Nailon W, Samad S, Masson S, Bishop M, McCardle L, Ironside JW (2004) Peripheral tissue involvement in sporadic, iatrogenic, and variant Creutzfeldt-Jakob disease An immunohistochemical, quantitative, and biochemical study. Am J Pathol 164 143-153. 

Hilton DA (2006) Pathogenesis and prevalence of variant Creutzfeldt-Jakob disease. J Pathol 208 134-141. 

Ironside JW (2006) Variant Creutzfeldt-Jakob disease Risk of transmission by blood transfusion and blood therapies. Haemophilia 12(Suppl 1) 8-15. 

Incidence of variant creutzfeldt-jakob disease in the UK. Lancet 2000, 356, 481 82. 

With respect to the risk of transmission of variant Creutzfeldt-Jakob disease by blood, some countries exclude from donation donors who lived in the UK for more than 6 months between 1980 and 1996 (13). 

As in several other countries, the Health Council of the Netherlands has prepared recommendations on the need for routine leukodepletion by filtration of blood. The presence of leukocytes in blood products has no beneficial effect for the recipient, except in special cases, such as patients undergoing organ transplantation (41). Apart from preventing the adverse effects associated with leukocyte transfusion, it has been postulated that the risk of transmission of new variant Creutzfeldt-Jakob disease can be prevented by using leukodepleted blood products. 

However, the emergence of variant Creutzfeldt-Jakob disease (vCJD) in the UK and France has raised concern about a new theoretical risk of infection in patients treated with blood and blood products (198). Animal experiments in which blood from sheep infected with bovine spongiform encephalopathy and natural scrapie-infected sheep into scrapie-free recipient animals have suggested disease transmission by the blood transfusion route in 2 of 24 sheep with bovine spongiform encephalopathy and in 4 of 21 sheep with scrapie (199). Many European countries have incorporated leukodepletion of all blood products, as leukocytes are believed to play a key role in the pathogenesis of variant Creutzfeldt-Jakob disease (198). In some countries, people who have lived in the UK for a period longer than 6 months between 1980 and 1996 are excluded from blood donation (13). Furthermore, it has been shown that various steps used in the manufacture of plasma-derived products also contribute to reduced infectivity by bovine spongiform encephalopathy (198). 

Two advisory committees of the US FDA, the Transmissible Spongiform Encephalopathies Advisory Committee and the Vaccines and Related Biologicals Product Advisory Committee, said at a joint meeting on 3 August 2000 that vaccines made from bovine-derived materials from countries with a known or uncertain risk of BSE carry only an infinitesimal risk of new variant Creutzfeldt-Jakob disease, and that no change in US immunization practice is indicated (Evans G, personal communication, 3 August 2000). 

BSE is not transmissible to humans. However, there appears to be a strong connection between BSE and a variation of Creutzfeldt-Jakob disease, known as variant Creutzfeldt-Jakob disease (vCJD), another disease grouped with other TSEs. Evidence to date indicates that there has never been a case of vCJD transmission from person to person, but rather it is thought to spread from the consumption of cattle products contaminated with BSE. BSE and vCJD share many characteristics, to the point of being nearly indistinguishable from each other. Clinical studies have shown that mice inoculated with BSE showed the same pattern of incubation time, clinical signs, and brain lesions as mice inoculated with tissues from patients with vCJD. This provides evidence that BSE and vCJD are of the same strain . Furthermore, these two diseases were not similar to other TSEs such as sporadic CJD and known scrapies strains. 

Since the outbreak of bovine spongiform encephalopathy (BSE) in the United Kingdom in 1986 and its subsequent link to the human neurological disorder variant Creutzfeldt-Jakob disease (vCJD),... 

Lucker, E., Horlacher, S., and Eigenbrodt, E. 2001. Brain in human nutrition and variant Creutzfeldt—Jakob disease risk (vCJD) Detection of brain in retail liver sausages using cholesterol and neuron specific enolase. Br. ]. Nutr. 86, S115-S119. 

In other acquired prion diseases, notably scrapie of sheep and variant Creutzfeldt-Jakob disease (vCJD) in humans, amino acids encoded at certain key positions in the endogenous host prion protein are strongly associated with susceptibility to prion infection [57-59]. Studies of CWD in elk, mule deer, white-tailed deer, and moose have found that similar correlations between PrP amino acid sequence and likelihood of CWD infection could exist in these species as well. 

Llewelyn CA, Hewitt PE, Knight RS, Amar K, Cousens S, Mackenzie J, Will RG (2004) Possible transmission of variant Creutzfeldt-Jakob disease by blood transfusion. Lancet 363 417 121... 

Wroe SJ, Pal S, Siddique D, Hyare H, Macfarlane R, Joiner S, Linehan JM, Brandner S, Wadsworth JD, Hewitt P, Collinge J (2006) Clinical presentation and pre-mortem diagnosis of variant Creutzfeldt-Jakob disease associated with blood transfusion a case report. Lancet 368 2061-2067... 

Mead S, Poulter M, Uphill J, Beck J, Whitfield J, Webb TE, Campbell T, Adamson G, Deriziotis P, Tabrizi SJ, Hummerich H, Verzilli C, Alpers MP, Whittaker JC, Collinge J (2009) Genetic risk factors for variant Creutzfeldt-Jakob disease a genome-wide association study. Lancet Neurol 8 57-66... 

Of particular interest are prion amplification assays that are capable of detecting prions in blood components such as plasma. However, blood typically has extremely low prion concentrations (i.e., 13 LD50 per mL [59]), and contains inhibitors of some of the most sensitive tests such as PMCA [19] and another assay [60]. Recently, we integrated antibody 15B3-based immunoprecipitation with QuIC reactions to increase sensitivity and isolate prions from inhibitors such as those in plasma samples [61]. Moreover, replacement of the rPrPc substrate after 24h in RT-QuIC reactions substantially improved the speed and sensitivity of the assay. Coupling of the immunoprecipitation and substrate replacement steps, which we call enhanced QuIC (eQuIC), dramatically enhanced detection of variant Creutzfeldt-Jakob disease (vCJD) brain tissue diluted into human plasma. 1014-fold dilutions, containing 2 ag/ml of proteinase K-resistant prion protein, were readily... 

P. Brown. Bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease. Br Med J 2001 322 841-844. 

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