Transmissible spongiform encephalopathy

Transmissible spongiform encephalopathies (TSEs), also known as prion diseases,<ref name="ninds">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> are a group of progressive, incurable, and fatal conditions that are associated with the prion hypothesis and affect the brain and nervous system of many animals, including humans, cattle, and sheep. According to the most widespread hypothesis, they are transmitted by prions, though some other data suggest an involvement of a Spiroplasma infection.<ref name="jmm.0.47159-0">Template:Cite journal</ref> Mental and physical abilities deteriorate and many tiny holes appear in the cortex causing it to appear like a sponge when brain tissue obtained at autopsy is examined under a microscope. The disorders cause impairment of brain function which may result in memory loss, personality changes, and abnormal or impaired movement which worsen over time.<ref>Template:Cite journal</ref>

TSEs of humans include Creutzfeldt–Jakob disease, Gerstmann–Sträussler–Scheinker syndrome, fatal familial insomnia, and kuru, as well as the recently discovered variably protease-sensitive prionopathy and familial spongiform encephalopathy. Creutzfeldt-Jakob disease itself has four main forms, the sporadic (sCJD), the hereditary/familial (fCJD), the iatrogenic (iCJD) and the variant form (vCJD). These conditions form a spectrum of diseases with overlapping signs and symptoms.

TSEs in non-human mammals include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle – popularly known as "mad cow disease" – and chronic wasting disease (CWD) in deer and elk. The variant form of Creutzfeldt–Jakob disease in humans is caused by exposure to bovine spongiform encephalopathy prions.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite journal</ref>

Unlike other kinds of infectious disease, which are spread by agents with a DNA or RNA genome (such as virus or bacteria), the infectious agent in TSEs is believed to be a prion, thus being composed solely of protein material. Misfolded 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).<ref>Template:Cite journal</ref> 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 the 1980s and 1990s, bovine spongiform encephalopathy 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. In turn, consumption (by humans) of bovine-derived foodstuff which contained prion-contaminated tissues resulted in an outbreak of the variant form of Creutzfeldt–Jakob disease in the 1990s and 2000s.<ref>Template:Cite journal</ref>

Prions cannot be transmitted through the air, 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. However, treatment with strong, almost undiluted bleach and/or sodium hydroxide, or heating to a minimum of 134 °C, does destroy prions.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Classification

Differences in shape between the different prion protein forms are poorly understood.

Known spongiform encephalopathies

ICTVdb Code	Disease name	Natural host	Prion name	PrP isoform	Ruminant
Non-human mammals
90.001.0.01.001.	Scrapie	Sheep and goats	Scrapie prion	PrPSc	Yes
90.001.0.01.002.	Transmissible mink encephalopathy (TME)	Mink	TME prion	PrPTME	No
90.001.0.01.003.	Chronic wasting disease (CWD)	Elk, white-tailed deer, mule deer and red deer	CWD prion	PrPCWD	Yes
90.001.0.01.004.	Bovine spongiform encephalopathy (BSE) commonly known as "mad cow disease"	Cattle	BSE prion	PrPBSE	Yes
90.001.0.01.005.	Feline spongiform encephalopathy (FSE)	Cats	FSE prion	PrPFSE	No
90.001.0.01.006.	Exotic ungulate encephalopathy (EUE)	Nyala and greater kudu	EUE prion	PrPEUE	Yes
	Camel spongiform encephalopathy (CSE)<ref>Template:Cite news</ref>	Camel		PrPCSE	Yes
Human diseases
90.001.0.01.007.	Kuru	Humans	Kuru prion	PrPKuru	No
90.001.0.01.008.	Creutzfeldt–Jakob disease (CJD)		CJD prion	PrPsCJD	No
	Variant Creutzfeldt–Jakob disease (vCJD, nvCJD)		vCJD prion<ref>Believed to be identical to the BSE prion.Template:By whom</ref>	PrPvCJD
90.001.0.01.009.	Gerstmann-Sträussler-Scheinker syndrome (GSS)		GSS prion	PrPGSS	No
90.001.0.01.010.	Fatal familial insomnia (FFI)		FFI prion	PrPFFI	No
	Familial spongiform encephalopathy<ref>Template:Cite journal</ref>

Signs and symptoms

The degenerative tissue damage caused by human prion diseases (CJD, GSS, and kuru) is characterised by four features: spongiform change (the presence of many small holes), the death of neurons, astrocytosis (abnormal increase in the number of astrocytes due to the destruction of nearby neurons), 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.<ref>Template:Cite journal</ref>

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.<ref name="Collinge Prion Diseases of Humans">Template:Cite journal</ref>

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, from cadaver dura allografts and from instruments used for brain surgery (Brown, 2000) (prions can survive the "autoclave" sterilization process used for most surgical instruments). 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.<ref>Template:Cite journal</ref> Laws in developed countries now ban the use of rendered ruminant proteins in ruminant feed as a precaution against the spread of prion infection in cattle and other ruminants.Template:Citation needed

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). Progressive Spongiform Leukoencephalopathy (PSL)—which is a spongiform encephalopathy—is also probably not caused by a prion, although the adulterant that causes it among heroin smokers has not yet been identified.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="pmid10563626">Template:Cite journal</ref><ref name="pmid9308333">Template:Cite journal</ref><ref name="pmid11965173">Template:Cite journal</ref> 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.

Cause

Genetics

Familial forms of prion disease are caused by inherited mutations in the PRNP gene. However, only a small percentage of prion disease cases are familial; most occur sporadically, without known genetic mutations or risk factors.<ref name="Mead Prion disease genetics">Template:Cite journal</ref> In rare instances, prion diseases can be transmitted through exposure to prion-contaminated tissues or biological materials from affected individuals.<ref name="Brown Iatrogenic Creutzfeldt-Jakob disease">Template:Cite journal</ref>

The PRNP gene encodes the prion protein (PrP), which under normal conditions may play a role in transporting copper into cells and protecting neurons.<ref name="Waggoner Brain Copper Content">Template:Cite journal</ref> Misfolding of the prion protein leads to the accumulation of pathogenic PrP^Sc, the hallmark of prion diseases, causing progressive neurodegeneration.<ref name="Prusiner Prions">Template:Cite journal</ref><ref name="Collinge Prion Diseases of Humans"/>

Epidemiological surveillance has identified cases of atypical bovine spongiform encephalopathy (BSE) and scrapie in livestock, as well as chronic wasting disease (CWD) in cervids, highlighting the zoonotic potential of prion diseases and their impact on animal and human health.<ref name="Belay Schonberger public health impact"/>

Protein-only hypothesis

Protein could be the infectious agent, inducing its own replication by causing conformational change of normal cellular PrP^C into PrP^Sc. Evidence for this hypothesis:

• Infectivity titre correlates with PrP^Sc levels. However, this is disputed.<ref>Template:Cite journal</ref>
• PrP^Sc is an isomer of PrP^C
• Denaturing PrP removes infectivity<ref>Template:Cite journal</ref>
• PrP-null mice cannot be infected<ref>Template:Cite journal</ref>
• PrP^C depletion in the neural system of mice with established neuroinvasive prion infection reverses early spongeosis and behavioural deficits, halts further disease progression and increases life-span<ref>Template:Cite journal</ref>

Multi-component hypothesis

Template:See also While not containing a nucleic acid genome, prions may be composed of more than just a protein. Purified PrP^C appears unable to convert to the infectious PrP^Sc form, unless other components are added, such as RNA and lipids.<ref name= "minimal prion">Template:Cite journal</ref> These other components, termed cofactors, may form part of the infectious prion, or they may serve as catalysts for the replication of a protein-only prion.

Viral hypothesis

This hypothesis postulates that a yet undiscovered infectious viral agent is the cause of the disease. The strongest evidence for viral replication in TSE infected brains is that long double stranded RNA is detected in 22L scrapie infected mouse brains <ref>Template:Cite report</ref> Other evidence for this hypothesis is as follows:

• Brain particle titers purified of PrP retain infectivity.<ref name="Botsios Manuelidis CJD and Scrapie">Template:Cite journal</ref>
• Brain titers exposed to nucleases reduced infectivity by >=99%.<ref name="Botsios Manuelidis CJD and Scrapie"/>
• Incubation time is comparable to a lentivirus.
• Strain variation of different isolates of PrP^sc.<ref>Template:Cite journal</ref>

Diagnosis

There continues to be a very practical problem with diagnosis of prion diseases, including BSE and CJD. They have an incubation period of months to decades during which there are no symptoms, even though the pathway of converting the normal brain PrP protein into the toxic, disease-related PrP^Sc form has started. At present, there is virtually no way to detect PrP^Sc reliably except by examining the brain using neuropathological and immunohistochemical methods after death. Accumulation of the abnormally folded PrP^Sc form of the PrP protein is a characteristic of the disease, but it is present at very low levels in easily accessible body fluids like blood or urine. Researchers have tried to develop methods to measure PrP^Sc, but there are still no fully accepted methods for use in materials such as blood.Template:Citation needed

In 2010, a team from New York described detection of PrP^Sc even when initially present at only one part in a hundred billion (10⁻¹¹) in brain tissue. The method combines amplification with a novel technology called Surround Optical Fiber Immunoassay (SOFIA) and some specific antibodies against PrP^Sc. After amplifying and then concentrating any PrP^Sc, the samples are labelled with a fluorescent dye using an antibody for specificity and then finally loaded into a micro-capillary tube. This tube is placed in a specially constructed apparatus so that it is totally surrounded by optical fibres to capture all light emitted once the dye is excited using a laser. The technique allowed detection of PrP^Sc after many fewer cycles of conversion than others have achieved, substantially reducing the possibility of artefacts, as well as speeding up the assay. The researchers also tested their method on blood samples from apparently healthy sheep that went on to develop scrapie. The animals' brains were analysed once any symptoms became apparent. The researchers could therefore compare results from brain tissue and blood taken once the animals exhibited symptoms of the diseases, with blood obtained earlier in the animals' lives, and from uninfected animals. The results showed very clearly that PrP^Sc could be detected in the blood of animals long before the symptoms appeared.<ref>Template:Cite journal</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Treatment

There are currently no known ways to cure or prevent prion disease.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Certain medications slow down the progression of the disease in mice, but are not effective in trials with human patients.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> But ultimately, supportive care is currently the only option for infected individuals.

Epidemiology

Transmissible spongiform encephalopathies (TSE) are very rare but can reach epidemic proportions.Template:Clarify 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 at one farm begin to show the disease after an outbreak on a nearby farm, it is very difficult to determine whether it is the same strain affecting both herds—suggesting transmission—or if the second outbreak came from a completely different source.Template:Citation needed

Classic Creutzfeldt-Jakob disease (CJD) was discovered in 1920. It occurs sporadically over the world but is very rare. It affects about one person per million each year. Typically, the cause is unknown for these cases. It has been found to be passed on genetically in some cases. 250 patients contracted the disease through iatrogenic transmission (from use of contaminated surgical equipment).<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> This was before equipment sterilization was required in 1976, and there have been no other iatrogenic cases since then. In order to prevent the spread of infection, the World Health Organization created a guide to tell health care workers what to do when CJD appears and how to dispose of contaminated equipment.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The Centers for Disease Control and Prevention (CDC) have been keeping surveillance on CJD cases, particularly by looking at death certificate information.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Chronic wasting disease (CWD) is a prion disease found in North America in deer and elk. The first case was identified as a fatal wasting syndrome in the 1960s. It was then recognized as a transmissible spongiform encephalopathy in 1978. Surveillance studies showed that CWD was endemic among free-ranging deer and elk in northeastern Colorado, southeastern Wyoming and western Nebraska. It was also discovered that CWD may have been present in a proportion of free-ranging animals decades before the initial recognition. In the United States, the discovery of CWD raised concerns about the transmission of this prion disease to humans. It was suspected that many cases of CJD were transmitted by CWD, however the evidence was minimal.<ref name="Belay Schonberger public health impact">Template:Cite journal</ref>

In the 1980s and 1990s, bovine spongiform encephalopathy (BSE or "mad cow disease") spread in cattle at an epidemic rate. The total estimated number of cattle infected was approximately 750,000 between 1980 and 1996 as a result of being fed the processed remains of other cattle. Subsequent human consumption of these infected cattle caused an outbreak of the human form CJD. There was a dramatic decline in BSE when feeding bans were put in place. On May 20, 2003, the first case of BSE was confirmed in North America, suspected to originate from imported BSE-infected cow meat. In the United States, the USDA created safeguards to minimize the risk of BSE exposure to humans.<ref name="Belay Schonberger public health impact"/>

Variant Creutzfeldt-Jakob disease (vCJD) was discovered in 1996 in England. There is strong evidence to suggest that vCJD was caused by the same prion as bovine spongiform encephalopathy.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> "Since 1996 and as of August 2013, a total of 229 cases of variant CJD cases have been identified from 11 countries: 177 from the United Kingdom, 27 from France, 4 from Ireland, 4 from the United States, 5 from Spain, 3 in the Netherlands, 2 each from Portugal, Italy and Canada, and 1 each from Japan, Taiwan and Saudi Arabia."<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

History

In the 5th century BCE, Hippocrates described a disease like TSE in cattle and sheep, which he believed also occurred in humans.<ref name="McAlister Sacred disease of our times">Template:Cite journal</ref> Publius Flavius Vegetius Renatus records cases of a disease with similar characteristics in the 4th and 5th centuries AD.Template:Citation needed In 1755, an outbreak of scrapie was discussed in the British House of Commons and may have been present in Britain for some time before that.<ref>Template:Cite journal</ref> Although there were unsupported claims in 1759 that the disease was contagious, in general it was thought to be due to inbreeding and countermeasures appeared to be successful. Early-20th-century experiments failed to show transmission of scrapie between animals, until extraordinary measures were taken such as the intra-ocular injection of infected nervous tissue. No direct link between scrapie and human disease was suspected then or has been found since. TSE was first described in humans by Alfons Maria Jakob in 1921.<ref>Template:Cite journal</ref> Daniel Carleton Gajdusek's discovery that Kuru was transmitted by cannibalism accompanied by the finding of scrapie-like lesions in the brains of Kuru victims strongly suggested an infectious basis to TSE.<ref>Template:Cite journal</ref> A paradigm shift to a non-nucleic infectious entity was required when the results were validated with an explanation of how a prion protein might transmit spongiform encephalopathy.<ref>Template:Cite journal</ref> Not until 1988 was the neuropathology of spongiform encephalopathy properly described in cows.<ref>Template:Cite journal</ref> The alarming amplification of BSE in the British cattle herd heightened fear of transmission to humans and reinforced the belief in the infectious nature of TSE. This was confirmed with the identification of a Kuru-like disease, called new variant Creutzfeldt–Jakob disease, in humans exposed to BSE.<ref name="Will Ironside Zeidler A new variant">Template:Cite journal</ref> Although the infectious disease model of TSE has been questioned in favour of a prion transplantation model that explains why cannibalism favours transmission,<ref name="McAlister Sacred disease of our times"/> the search for a viral agent was, as of 2007, being continued in some laboratories.<ref name="Manuelidis2007">Template:Cite journal</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

See also

• Proteinopathy
• Variably protease-sensitive prionopathy

References

• This entry incorporates public domain text originally from the National Institute of Neurological Disorders and Stroke, National Institutes of Health [1] Template:Webarchive and the U.S. National Library of Medicine [2]

External links

• Template:Cite journal