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Guest Writer:
INTRODUCTION
The transmissible spongiform encephalopathies (TSEs)
are a group of invariably fatal neurodegenerative diseases found in
a wide range of mammals. The disease is found naturally in many ruminants
(scrapie, bovine spongiform encephalopathy-BSE), deer (chronic wasting
disease) and mink (transmissible mink encephalopathy), as well as
humans (see later). The disease can also be experimentally transmitted
to rodents, pigs and primates (6). TSEs are characterised by long
incubation times (in humans can be greater than 30 years), and an
infected individual will usually show some signs of progressive ataxia,
dysarthia, dysphagia, nystagmus, myoclonus and/or dementia. The time
from onset of symptoms to death is highly variable (in humans it ranges
from a few months to 10 years) (6).
THE
INFECTIOUS AGENT The two forms of the protein have some different properties(2): PrPC is anchored to the cell membrane by a glyco-phospho-inositol (GPI) anchor, whilst PrPSC accumulates in endosomes; PrPSC accumulates in diseased individuals in plaque deposits in the brain, and is partially resistant to proteolytic digestion with proteinase K; and PrPSC is highly resistant to most sterilising procedures, and is not inactivated by treatment with many sterilising agents such as UV light (3), nor by autoclaving (4). However, the two proteins seem to have the same post-translational modifications, and cannot be distinguished with monoclonal antibodies (5). In addition, there are no in vitro assays which can be used to determine PrPSCbiological activity. Much of the research in this area has therefore been concentrated on the primary sequence of the PrP gene, as well as the use of transgenic animals carrying different alleles of the gene. THE
PrP GENE
HUMAN
DISEASE Iatrogenic cases are extremely rare. They occur when contaminated material is transplanted (eg cornea or dura mater transplants), or instruments used in neuro-invasive procedures are contaminated (eg depth electrodes). most of the cases are due to batches of contaminated growth hormone prepared from human cadavers (10,11). Sporadic CJD has an incidence rate of c 1/million people/year, world wide. No correlation between sporadic CJD and populations that may be considered high risk (eg abattoir workers, shepherds) has been observed. It is currently believed that sporadic CJD arises through the spontaneous conversion of PrPCto PrPSC in an individual (2,6). Inherited CJD is caused by pathogenic polymorphisms in the human PrP gene. Such genetic lesions tend to be dominant although of variable penetrance, although it is possible given the long incubation times of the disease that asymptomatic people with a particular genetic lesion are dying of old age prior to onset of disease. A large number of different polymorphisms have been described for different lineages(12, 15). These include point mutations, such as p102l1 (13), as well as extra or fewer octa peptide repeats in the G-P rich region (12). GSS is an inherited disease similar to inherited CJD. Indeed, the former can be considered a sub-class of the latter. In addition to pathogenic mutations, humans also have a neutral polymorphism, M129V This mutation has been shown to have an effect on both sporadic and inherited CJD. People who are M/M homozygous AND have the P102L mutation suffer from FFI, whereas those who have M/V or V/V and the P102L mutation suffer from typical CJD (14). FFI is characterised by progressive insomnia and torpor, with quite different symptoms to typical CJD. Also, it has been shown that people who are homozygous (M/M or V/V) are more likely susceptible to sporadic CJD than people who are heterozygous at this allele (15). THE
BSE OUTBREAK References
This
article has been reproduced with the kind permission of its
author, Dr. Michael Poidinger when working at the Department
of Microbiology, University of
Queensland.
This
work may not be reprinted without the prior knowledge and consent
of its author.
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