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Creutzfeldt-Jakob Disease TREATMENTOFHEMOPHILIA APRIL 2009 • NO 49 CREUTZFELDT-JAKOB DISEASE James W. Ironside National Creutzfeldt-Jakob Disease Surveillance Unit School of Molecular and Clinical Medicine, University of Edinburgh Western General Hospital United Kingdom Published by the World Federation of Hemophilia (WFH), 2009 © World Federation of Hemophilia, 2009 The WFH encourages redistribution of its publications for educational purposes by not-for-profit hemo- philia organizations. In order to obtain permission to reprint, redistribute, or translate this publication, please contact the Communications Department at the address below. This publication is accessible from the World Federation of Hemophilia’s website at www.wfh.org. Additional copies are also available from the WFH at: World Federation of Hemophilia 1425 René Lévesque Boulevard West, Suite 1010 Montréal, Québec H3G 1T7 CANADA Tel. : (514) 875-7944 Fax : (514) 875-8916 E-mail: [email protected] Internet: www.wfh.org The Treatment of Hemophilia series is intended to provide general information on the treatment and man- agement of hemophilia. The World Federation of Hemophilia does not engage in the practice of medi- cine and under no circumstances recommends particular treatment for specific individuals. Dose sched- ules and other treatment regimes are continually revised and new side effects recognized. WFH makes no representation, express or implied, that drug doses or other treatment recommendations in this publi- cation are correct. For these reasons it is strongly recommended that individuals seek the advice of a medical adviser and/or consult printed instructions provided by the pharmaceutical company before administering any of the drugs referred to in this monograph. Statements and opinions expressed here do not necessarily represent the opinions, policies, or recom- mendations of the World Federation of Hemophilia, its Executive Committee, or its staff. Treatment of Hemophilia Monographs Series Editor Dr. Sam Schulman Address for correspondence Dr. James W. Ironside Professor of Clinical Neuropathology and Honorary Consultant Neuropathologist National Creutzfeldt-Jakob Disease Surveillance Unit Division of Pathology, School of Molecular and Clinical Medicine University of Edinburgh Western General Hospital EH4 2XU United Kingdom Tel: +44 131 537 1980 Fax : +44 131 343 1404 Email: [email protected] Table of Contents Introduction . 1 The Prion Hypothesis . 1 What causes prion diseases? . 1 Molecular biology of prions . 1 Prion Detection and Decontamination . 2 Detection . 2 Decontamination . 2 Human Prion Diseases . 2 Sporadic CJD . 2 Genetic prion diseases . 3 Infectious prion diseases . 4 VariantCJD .............................................................................4 Infectivity of Blood in Prion Diseases . 6 Experimental studies . 6 Transmission of vCJD by blood transfusion . 7 Potential for transmission of vCJD by plasma products . 8 Asymptomatic vCJD infection in a hemophilic patient in the U.K. 8 Future Prospects . 9 Conclusion . 9 Glossary....................................................................................9 Acknowledgements . 12 References . 12 Creutzfeldt-Jakob Disease James W. Ironside Introduction attempts, no one has yet found unequivocal evi- dence of a DNA component of the infectious agent Creutzfeldt-Jakob disease (CJD) is a member of a in TSEs. group of diseases known as transmissible spongi- form encephalopathies (TSEs) or prion diseases [1, In 1982, Stanley Prusiner first proposed his prion 2]. These are rare, fatal disorders that result in the hypothesis, which suggested that the transmissible progressive destruction of the nervous system. In agent responsible for TSEs was composed entirely animals, the best known examples are scrapie in of a protein (the “prion” protein) [3]. His theory was sheep and bovine spongiform encephalopathy (BSE, extremely controversial because it went against one also known as mad-cow disease) in cattle. Human of the fundamental laws of molecular biology: that prion diseases are a unique group of neurological all infectious agents had to be made up of DNA in disorders that includes CJD, Gerstmann-Sträussler- order to replicate. Scheinker syndrome, and fatal familial insomnia. A few years later, the gene that codes for the prion Human prion diseases present with progressive protein was discovered in both normal and infected neurological symptoms and result in death, usually cells. Prusiner concluded that the transmissible after a period of several months. There is no cure, agent was actually a misfolded version of the prion although widespread efforts at finding a form of protein, which is normally found on the outer sur- treatment or palliation for prion diseases are under- face of cells. Prion diseases seem to result from a way. build-up of this abnormally folded protein in the cells of the central nervous system. Recently, an outbreak of a new form of CJD in humans (known as variant CJD) was linked to the Molecular biology of prions consumption of BSE-infected meat. In the U.K. a In humans, the prion protein gene (PRNP) is located handful of cases were later found to have resulted on the short arm of chromosome 20. It codes for a from blood transfusions from infected donors. The 253-amino acid precursor protein [2, 4] that is nor- bleeding disorders community has therefore been mally cut, glycosylated, and anchored to the exter- concerned with the potential of transmission of nal cell membrane. The normal cellular form of the vCJD through contaminated blood products. prion protein (PrPC) is produced in many tissues, Though no such clinical cases have been identified including skeletal muscle, follicular dendritic cells, so far, continued vigilance is required. platelets, and endothelial cells, but it is found at its highest levels in neurons (nerve cells) within the central nervous system [2]. The Prion Hypothesis PrPC has a short half-life, dissolves in water, and is What causes prion diseases? easily broken down by proteolytic enzymes [5]. The The nature of the transmissible agent responsible for precise function of PrPC is unknown, but a number TSEs has been the subject of intense debate for of possibilities have been proposed, including roles many decades. Early studies on the agent that caus- in the transmission of nerve signals and protection es scrapie indicated that it was small in size and against oxidative stress. In prion diseases, an abnor- remarkably resistant to most conventional forms of mal form of PrP (designated PrPSc) accumulates in decontamination (including fixation in formalde- the central nervous system. This abnormal protein hyde, exposure to high temperatures, and surpris- has an identical amino acid sequence to PrPc, but it ingly, to degradation by enzymes that destroy has a different three-dimensional shape that makes nucleic acids, the building blocks of DNA). Nucleic it relatively resistant to degradation by proteolytic acids are found in all living organisms and are nec- enzymes [2] and insoluble in water. PrPSc is closely essary for survival and reproduction. Despite many associated with infectivity in prion diseases and 2 Creutzfeldt-Jakob Disease appears to be the major (if not the sole) component Figure 1 of the transmissible agent. Exactly where and how the misfolding of the prion protein occurs in prion diseases is not fully under- stood. It is clear, however, that the normal PrPC must be present for prion diseases to develop. Genetically modified mice in which the prion gene was removed are resistant to prion infection [6]. Prion Detection and Decontamination Detection Western blot analysis of protease-resistant prion protein The only way to confirm a clinical diagnosis of Sc prion disease in humans is to conduct a neuropatho- (PrP ) in two cases of sporadic CJD (with MM and VV PRNP codon 129 genotypes) and one case of variant logical examination of the brain, usually at autopsy. CJD. The size of the non-glycosylated (bottom) band is Brain biopsy is not widely performed because it either 21kDa (termed type 1) or 19kDa (termed type 2). often leads to a worsening of symptoms. On exami- Diglycosylated PrPSc (**) predominates in the variant CJD nation of the diseased brain, several characteristic and the pattern is termed type 2B to distinguish it from changes are visible in the grey matter of the cere- type 2 cases in which the monoglycosylated form brum and cerebellum, including a loss of nerve cells (*) predominates (type 2A). (neurons) that leaves several tiny holes in the brain, making it look like a sponge (hence the term autoclaving, sodium hydroxide in molar concentra- “spongiform” encephalopathy). An increase in tions, and concentrated formic acid [9]. None of astrocytes and, in some cases, amyloid plaques, can these methods, however, is guaranteed to remove all also be detected [1]. prion infectivity, particularly from tissues such as the brain that are highly infectious. Furthermore, these The detection of PrPSc in the brain is an important methods can not be used to decontaminate blood or diagnostic aid. However, most currently available plasma products as they would render the products anti-PrP antibodies recognize both the normal and ineffective and/or unsafe. The need to develop a abnormal forms of the prion protein. Therefore, any screening test for human prion diseases is a high pri- normal PrPc in the brain sample must first be ority in attempts to reduce the chances for person-to- degraded by proteolysis, leaving only PrPSc as a person spread of
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