Transmissible spongiform encephalopathy

"'Transmissible spongiform encephalopathies (TSEs, also known as prion diseases) are a group of progressive conditions that affect the brain and nervous system of animals. According to the most widespread hypothesis they are transmitted by prions, though some other data suggest an involvement of a "Spiroplasma" infection [cite journal|journal=J Med Microbiol.|year=2007|volume=56|issue=9|pages=1235–1242|title="Spiroplasma" spp. from transmissible spongiform encephalopathy brains or ticks induce spongiform encephalopathy in ruminants |author=Bastian FO, Sanders DE, Forbes WA, Hagius SD, Walker JV, Henk WG, Enright FM, Elzer PH|pmid=17761489|doi=10.1099/jmm.0.47159-0] . Mental and physical abilities deteriorate and myriad tiny holes appear in the cortex causing it to appear like a sponge (hence 'spongiform') when brain tissue obtained at autopsy is examined under a microscope. The disorders cause impairment of brain function, including memory changes, personality changes and problems with movement that worsen over time. Prion diseases of humans include classic Creutzfeldt-Jakob disease, new variant Creutzfeldt-Jakob disease (a human disorder related to mad cow disease), Gerstmann-Sträussler-Scheinker syndrome, fatal familial insomnia and kuru. These conditions form a spectrum of diseases with overlapping signs and symptoms.

Unlike other kinds of infectious disease which are spread by microbes, the infectious agent in TSEs is a specific protein called prion protein. Misshaped prion proteins carry the disease between individuals and cause deterioration of the brain. TSEs are unique diseases in that their aetiology may be genetic, sporadic or infectious via ingestion of infected foodstuffs and via iatrogenic means (e.g. blood transfusion). [cite journal | author=Brown P, Preece M, Brandel JP, Sato T, McShane L, Zerr I, Fletcher A, Will RG, Pocchiari M, Cashman NR, d'Aignaux JH, Cervenakova L, Fradkin J, Schonberger LB, Collins SJ | title=Iatrogenic Creutzfeldt-Jakob disease at the millennium | journal=Neurology | year=2000 | pages=1075–81 | volume=55 | issue=8 | pmid=11071481] Most TSEs are sporadic and occur in an animal with no prion protein mutation. Inherited TSE occurs in animals carrying a rare mutant prion allele, which expresses prion proteins that contort by themselves into the disease-causing conformation. Transmission occurs when healthy animals consume tainted tissues from others with the disease. In recent times a type of TSE called bovine spongiform encephalopathy (BSE) spread in cattle in an epidemic fashion. This occurred because cattle were fed the processed remains of other cattle, a practice now banned in many countries. The epidemic could have begun with just one cow with sporadic disease.

Prions cannot be transmitted through the air or through touching or most other forms of casual contact. However, they may be transmitted through contact with infected tissue, body fluids, or contaminated medical instruments. Normal sterilization procedures such as boiling or irradiating materials fail to render prions non-infective.

Classification

Features of TSE

The degenerative tissue damage caused by human prion diseases (CJD, GSS, and kuru) is characterised by four features: spongiform change, neuronal loss, astrocytosis and amyloid plaque formation. These features are shared with prion diseases in animals, and the recognition of these similarities prompted the first attempts to transmit a human prion disease (kuru) to a primate in 1966, followed by CJD in 1968 and GSS in 1981.These neuropathological features have formed the basis of the histological diagnosis of human prion diseases for many years, although it was recognized that these changes are enormously variable both from case to case and within the central nervous system in individual cases. [cite journal | author=Jeffrey M, Goodbrand IA, Goodsir CM | title=Pathology of the transmissible spongiform encephalopathies with special emphasis on ultrastructure | journal=Micron | year=1995 | pages=277–98 | volume=26 | issue=3 | pmid=7788281 | doi=10.1016/0968-4328(95)00004-N]

The clinical signs in humans vary, but commonly include personality changes, psychiatric problems such as depression, lack of coordination, and/or an unsteady gait (ataxia). Patients also may experience involuntary jerking movements called myoclonus, unusual sensations, insomnia, confusion, or memory problems. In the later stages of the disease, patients have severe mental impairment (dementia) and lose the ability to move or speak. [cite journal | author=Collinge J | title=Prion diseases of humans and animals: their causes and molecular basis | journal=Annu Rev Neurosci | year=2001 | pages=519–50 | volume=24 | pmid=11283320 | doi=10.1146/annurev.neuro.24.1.519]

Early neuropathological reports on human prion diseases suffered from a confusion of nomenclature, in which the significance of the diagnostic feature of spongiform change was occasionally overlooked. The subsequent demonstration that human prion diseases were transmissible reinforced the importance of spongiform change as a diagnostic feature, reflected in the use of the term "spongiform encephalopathy" for this group of disorders.

Prions appear to be most infectious when in direct contact with affected tissues. For example, Creutzfeldt-Jakob disease has been transmitted to patients taking injections of growth hormone harvested from human pituitary glands, and from instruments used for brain surgery (Brown, 2000) (prions can survive the "autoclave" sterilization process used for most surgical instruments). It is also believed that dietary consumption of affected animals can cause prions to accumulate slowly, especially when cannibalism or similar practices allow the proteins to accumulate over more than one generation. An example is kuru, which reached epidemic proportions in the mid 20th century in the Fore people of Papua New Guinea, who used to consume their dead as a funerary ritual. [cite journal | author=Collins S, McLean CA, Masters CL | title=Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia, and kuru: a review of these less common human transmissible spongiform encephalopathies | journal=J Clin Neurosci | year=2001 | pages=387–97 | volume=8 | issue=5 | pmid=11535002 | doi=10.1054/jocn.2001.0919] Laws in developed countries now proscribe the use of rendered ruminant proteins in ruminant feed as a precaution against the spread of prion infection in cattle and other ruminants.

Note that not all encephalopathies are caused by prions, as in the cases of PML (caused by the JC virus), CADASIL (caused by abnormal NOTCH3 protein activity), and Krabbe disease (caused by a deficiency of the enzyme galactosylceramidase). PSL -- which is a spongiform encephalopathy -- is also probably not caused by a prion, although the adulterant which causes it among heroin smokers has not yet been identified. [cite web |url=http://www.hafci.org/infoline/enu/heroin.htm |title=hafci.org |accessdate=2007-12-02 |format= |work=] cite journal |author=Kriegstein AR, Shungu DC, Millar WS, "et al" |title=Leukoencephalopathy and raised brain lactate from heroin vapor inhalation ("chasing the dragon") |journal=Neurology |volume=53 |issue=8 |pages=1765–73 |year=1999 |pmid=10563626 |doi=] cite journal |author=Chang YJ, Tsai CH, Chen CJ |title=Leukoencephalopathy after inhalation of heroin vapor |journal=J. Formos. Med. Assoc. |volume=96 |issue=9 |pages=758–60 |year=1997 |pmid=9308333 |doi=] cite journal |author=Koussa S, Zabad R, Rizk T, Tamraz J, Nasnas R, Chemaly R |title= [Vacuolar leucoencephalopathy induced by heroin: 4 cases] |language=French |journal=Rev. Neurol. (Paris) |volume=158 |issue=2 |pages=177–82 |year=2002 |pmid=11965173 |doi=] This, combined with the highly variable nature of prion disease pathology, is why a prion disease cannot be diagnosed based solely on a patient's symptoms.

Genetics

Mutations in the PRNP gene cause prion disease. Familial forms of prion disease are caused by inherited mutations in the PRNP gene. Only a small percentage of all cases of prion disease run in families, however. Most cases of prion disease are sporadic, which means they occur in people without any known risk factors or gene mutations. Rarely, prion diseases also can be transmitted by exposure to prion-contaminated tissues or other biological materials obtained from individuals with prion disease.

The PRNP gene provides the instructions to make a protein called the prion protein (PrP). Normally, this protein may be involved in transporting copper into cells. It may also be involved in protecting brain cells and helping them communicate. 24 Point-Mutations in this gene cause cells to produce an abnormal form of the prion protein, known as PrP^Sc. This abnormal protein builds up in the brain and destroys nerve cells, resulting in the signs and symptoms of prion disease.

Familial forms of prion disease are inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases, an affected person inherits the altered gene from one affected parent.

In some people, familial forms of prion disease are caused by a new mutation in the PRNP gene. Although such people most likely do not have an affected parent, they can pass the genetic change to their children.

Competing hypotheses

Viral hypothesis

This hypothesis postulates that an infectious viral agent is the cause of the disease. Evidence for this hypothesis is as follows::*Incubation time is comparable to a lentivirus:*Strain variation of different isolates of PrPsc [PMID: 14522852] :*An increasing titre of PrPsc as the disease progresses suggests a replicating agent.

This hypothesis is largely discreditedFact|date=May 2008, as no infectious, non-human nucleic acid has ever been isolated from the disease. It is largely based on the fact that infectious agents have previously been viral in origin, preferring this as more plausible than the infectious protein hypothesis.

Protein-Only hypothesis

Protein could be the infectious agent, inducing its own replication by causing conformational change of normal cellular PrPC into PrPsc. Evidence for this theory::*infectivity titre correlates with PrPSc levels. However, this is disputed. [HIGH TITRES OF TSE INFECTIVITY ASSOCIATED WITH EXTREMELY LOW LEVELS OF PrPSc IN VIVO, Barron,JBC Papers in Press. Published on October 8, 2007 as Manuscript M704329200.] :*PrPSc is an isomer of PrPC:*Denaturing PrP removes infectivity Branched Polyamines Cure Prion-Infected Neuroblastoma Cells, Supattapone, Journal of Virology, April 2001, p. 3453-3461, Vol. 75, No. 7] :*Recombinant PrP is infectious [In vitro self-propagation of recombinant PrPSc-like conformation generated in the yeast cytoplasm, W . Yang , H . Yang , P . Tien, FEBS Letters , Volume 580 , Issue 17 , Pages 4231 - 4235] ;*PrP-null mice cannot be infected [Impairment of superoxide dismutase activation by N-terminally truncated prion protein (PrP) in PrP-deficient neuronal cell line, Sakudo, Biochemical and Biophysical Research CommunicationsVolume 308, Issue 3, 29 August 2003, Pages 660-667]

Epidemiology

These spontaneous disorders in humans are very rare affecting only about one person per million worldwide each year. However, transmissible TSEs can reach epidemic proportions as was seen in the UK BSE outbreak of the 80s and 90s. It is very hard to map the spread of the disease due to the difficulty of identifying individual strains of the prions. This means that if animals start to show the disease after an outbreak on a nearby farm then you cannot show that it is the same strain affecting both, suggesting transmission, or that the second outbreak came from a completely different source.

Possible cure or vaccine

Recent research from the University of Toronto and Caprion Pharmaceuticals have discovered one possible avenue which might lead to quicker diagnosis, a vaccine or possibly even treatment for prion diseases. The abnormally folded proteins which cause the disease have been found to expose a side chain of amino acids which the properly folded protein does not expose. Antibodies specifically coded to this side chain amino acid sequence have been found to stimulate an immune response to the abnormal prions and leave the normal proteins intact.cite web |url=http://www.sciencedaily.com/releases/2003/06/030602025719.htm |title=Researchers Discover Possible Diagnosis, Treatment, Vaccine For Mad Cow, Prion Diseases |accessdate=2007-12-02 |format= |work=]

Another idea involves using custom peptide sequences. Since some research suggests prions aggregate by forming beta barrel structures, work done "in vitro" has shown that peptides made up of beta barrel-incompatible amino acids can help break up accumulations of prion. Yet a third idea concerns genetic therapy, whereby the gene for encoding protease-resistant protein is considered to be an error in several species, and therefore something to be inhibited.

Notes

References

*"This entry incorporates public domain text originally from the National Institute of Neurological Disorders and Stroke, National Institutes of Health [http://www.ninds.nih.gov/health_and_medical/disorders/tse.htm] and the U.S. National Library of Medicine [http://ghr.nlm.nih.gov/condition=priondisease] "

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External links

* [http://www.ninds.nih.gov/health_and_medical/disorders/tse.htm "Transmissible Spongiform Encephalopathy"]
* [http://www.ninds.nih.gov/disorders/alzheimersdisease/alzheimersdisease.htm Neurodegenerative Disease.]
* [http://www.ninds.nih.gov/disorders/alpersdisease/alpersdisease.htm Neurodegenerative disease: Encephalopathy.]
* [http://www.cjd.ed.ac.uk/ UK CJD Surveillance Unit] Statistics for prion disease in the UK, information on TSEs, and a comprehensive list of other links.
* [http://www.cjdfoundation.org/ Creutzfeldt-Jakob Disease Foundation] Offers support and information concerning Creutzfeldt-Jakob Disease.
* [http://www.mad-cow-facts.com Mad Cow Disease] Info from the Center for Global Food Issues
* [http://thepathologicalprotein.com/ The Pathological Protein - Mad Cow, Chronic Wasting, and Other Deadly Prion Diseases] (2003, updated online 2005). Philip Yam, Scientific American magazine writer and News Editor.
* [http://ec.europa.eu/research/press/1998/pr2710en.html European Symposium]
* [http://www.ninds.nih.gov/news_and_events/proceedings/spastic_paraplegia.htm American Symposium]