Transmissible spongiform encephalopathy

Transmissible spongiform encephalopathies (TSEs), also known as prion diseases,^[1] are a group of progressive, incurable, and invariably fatal conditions that are associated with the degeneration of the nervous system in many animals, including humans, cattle, and sheep. Strong evidence now supports the once unorthodox hypothesis that prion diseases are transmitted by abnormally shaped protein molecules known as prions.^[2][3] Prions consist of a protein called the prion protein (PrP).^[2] Misshapen PrP (often referred to as PrP^Sc) conveys its abnormal structure to naive PrP molecules by a crystallization-like seeding process. Because the abnormal proteins stick to each other, and because PrP is continuously produced by cells, PrP^Sc accumulates in the brain, harming neurons and eventually causing clinical disease.^[2][4][3]

Prion diseases
Other names	Transmissible spongiform encephalopathy (TSE)
Micrograph showing spongiform degeneration (vacuoles that appear as holes in tissue sections) in the cerebral cortex of a patient who had died of Creutzfeldt–Jakob disease. H&E stain, scale bar = 30 microns (0.03 mm).
Specialty	Infectious diseases
Symptoms	Dementia, seizures, tremors, insomnia, psychosis, delirium, confusion
Usual onset	Months to decades
Types	Bovine spongiform encephalopathy, Fatal familial insomnia, Creutzfeldt-Jakob disease, kuru, Huntington's disease-like 1, scrapie, variably protease-sensitive prionopathy, chronic wasting disease, Gerstmann-Sträussler-Scheinker syndrome, feline spongiform encephalopathy, transmissible mink encephalopathy, exotic ungulate encephalopathy, camel spongiform encephalopathy, PrP systemic amyloidosis, Familial Alzheimer-like prion disease
Causes	Prion
Risk factors	Contact with infected fluids, ingestion of infected flesh, having one or two parents that have the disease (in case of fatal familial insomnia)
Diagnostic method	Currently there is no way to reliably detect prions except at post-mortem
Prevention	Varies
Treatment	Palliative care
Prognosis	Invariably fatal
Frequency	Rare

Prion diseases are marked by mental and physical deterioration that worsens over time.^[5][6] A defining pathologic characteristic of prion diseases is the appearance of small vacuoles in the various parts of the central nervous system that create a sponge-like appearance when brain tissue obtained at autopsy is examined under a microscope.^[2][3] Other changes in affected regions include the buildup of PrP^Sc, gliosis, and the loss of neurons.^[7]

In non-human mammals, the prion diseases include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle (popularly known as "mad cow disease") chronic wasting disease (CWD) in deer and elk, and others.^[8] prion diseases of humans include Creutzfeldt–Jakob disease, Gerstmann–Sträussler–Scheinker syndrome, fatal familial insomnia, kuru, and variably protease-sensitive prionopathy.^[6][9] Creutzfeldt-Jakob disease has been divided into four subtypes: sporadic (sCJD), hereditary/familial (fCJD), iatrogenic (iCJD) and variant (vCJD). These diseases form a spectrum of related conditions with overlapping signs and symptoms.

Prion diseases are unusual in that their aetiology may be genetic, infectious, or sporadic.^[2] Genetic (inherited) prion diseases result from rare mutations in PRNP, the gene that codes for PrP (see Genetics, below). Unlike conventional infectious diseases, which are spread by agents with a DNA or RNA genome (such as viruses or bacteria), prion diseases are transmitted by prions, the active material of which is solely abnormal PrP. Infection can occur when the organism is exposed to prions through ingestion of infected foodstuffs or via iatrogenic means (such as treatment with biologic material that had been inadvertently contaminated with prions).^[10] The variant form of Creutzfeldt–Jakob disease in humans is caused by exposure to BSE prions.^[11][12][13] Whereas the naturally occurring transmission of prion diseases among nonhuman species is relatively common, prion transmission to humans is very rare; rather, the majority of human prion diseases are sporadic (idiopathic) in nature^[14] (see Infectivity, below). Sporadic prion diseases occur in the absence of a mutation in PrP or a source of infection.

Although research has shown that the infectious capacity of prions is encoded in the conformation of PrP^Sc,^[2][4] it is likely that auxilliary components contribute to their formation and/or infectivity. Purified PrP^C appears to be unable to convert to the infectious PrP^Sc form in a protein misfolding cyclic amplification (PMCA) assay unless other components are added, such as a polyanion (usually RNA) and lipids. 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.^[15] Considering that the cofactors can be produced by chemical synthesis instead of being sourced solely from infected cases (or any animal at all), it is fair to say that they do not form the infectious part of the prion. However, these catalysts (especially the polyanion) do have a tendency to be included in the prion aggregate, which makes seeding new aggregates easier in vitro.^[16][17]

Classification

Differences in shape between the different prion protein forms are incompletely understood, although new methods such as cryo-electron microscopy are beginning to address this problem.^[18]

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)[19]	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[20]	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[21]

Pathology

The degenerative tissue damage caused by prion disease in the nervous system is characterised by four features: spongiform change (the presence of many small vacuoles), the death of neurons, astrocytosis (abnormal increase in the number of astrocytes), and deposits of abnormal PrP (some of which have the characteristics of amyloid).^[22] These neuropathological features have formed the basis of the histological diagnosis of prion diseases for many years, although it has been recognized that these changes are highly variable both from case to case and within the central nervous system in individual cases.^[23][22] In humans, prion diseases with different genetic or infectious causes often have different patterns of pathology. For instance, amyloid plaques are rare in most prion diseases, but they are common in some diseases such as kuru and variant CJD. Owing to the rarity of amyloid per se in prion diseases, it is thought that non-amyloid forms of PrPSc are responsible for neurodegeneration.^[22] In rare instances of human prion disease, tauopathy resembling the neurofibrillary tangles in Alzheimer's disease is present, highlighting the many ways in which the pathology of prion diseases can vary.^[22] Despite this variation, all prion diseases have in common the buildup of abnormal PrP in the nervous system.

Signs and symptoms

The clinical signs of prion diseases in humans vary, but the classical signs of sporadic CJD include rapidly progressive dementia, behavioral abnormalities, disturbances of movement such as lack of coordination and/or an unsteady gait (ataxia), and involuntary jerking movements (myoclonus).^[24][25] Patients also may experience unusual sensations, insomnia, and confusion, and in the later stages of the disease they may lose the ability to move or speak.^[26] The clinical course of prion diseases usually is relatively rapid (the mean survival time for sporadic CJD is 6 months, although it can sometimes be a year or more),^[24] and all prion diseases are ultimately fatal. Studies of heritable and acquired (infectious) prion diseases have found that the relatively brief symptomatic phase is preceded by a long silent phase during which the pathology develops in the brain. For example, the incubation period for kuru following infection with prions can exceed 50 years.^[3] The highly variable nature of signs and symptoms in prion diseases makes them difficult to distinguish from other neurologic disorders based solely on their clinical traits.^[24]

Genetics

Only 10-15% of human prion disease cases are heritable; most of them occur sporadically, that is, in the absence of known genetic mutations or infection.^[27][24] However, discovery of the gene involved in heritable prion diseases was a critical event in linking abnormalities of the prion protein to genetic, infectious and idiopathic prion diseases.^[2] All familial forms of prion disease are caused by inherited mutations in the PRNP gene, which codes for PrP.^[27] Three general types of PRNP mutation can lead to disease: point mutations that change an amino acid in a specific part of PrP; a premature stop codon that results in shortened PrP molecules; or the insertion of extra octapeptide repeats that abnormally lengthen part of the protein.^[27] These mutations increase the likelihood that PrP will fold into the wrong shape (PrP^Sc) and amplify within the nervous system. Different mutations can cause prion diseases with different clinical and pathological characteristics.^[27]

The normal function(s) of PrP are incompletely understood, although it is likely that the protein participates in many biochemical processes.^[28] It is expressed throughout much of the body, and is especially abundant in the nervous system.^[29] When the PRNP gene is inactivated in animals such as mice, cattle and goats, the PrP-deficient animals are resistant to prion infection.^[29] Although the absence of a functional PRNP gene can result in changes in various tissues, the animals are viable and appear to be relatively normal, at least at young ages.^[29]

Infectivity

In 1959, William Hadlow recognized striking similarities between the kuru cases described by D. Carleton Gajdusek and scrapie, the transmissible disease of sheep and goats.^[30] The shared features of human and nonhuman prion diseases prompted Gajdusek to conduct a series of experiments in which he demonstrated that human spongiform encephalopathies (as prion diseases were then commonly known) are transmissible to nonhuman primates. His research group reported the transmissibility of kuru in 1966,^[31] Creutzfeldt-Jakob disease (CJD) in 1968,^[32] and Gerstmann–Sträussler–Scheinker syndrome (GSS) in 1981.^[33] These experiments showed that human spongiform encephalopathies, like those in nonhuman species, can be infectious; because the diseases have an unusually long incubation period following exposure to the infectious agent,^[25] the agent was sometimes referred to as a 'slow virus'.^[34][2] The infectious agent was not shown with reasonable certainty to be primarily a protein until the work of Stanley Prusiner gave rise to the prion concept in 1982.^[35][2]

Infectious prion diseases in humans are uncommon and decreasing in incidence. Iatrogenic versions have been recognized since the 1980's: Creutzfeldt–Jakob disease has been inadvertently transmitted to patients via injections of growth hormone harvested from human cadaveric pituitary glands, from cadaveric dural allografts, and (more rarely) from corneal transplants, transfusion of blood products, and exposure to contaminated instruments used for brain surgery.^[24] Prions can survive heating in the autoclave, a method used for the conventional sterilization of surgical instruments^[36]. For this reason, special precautions need to be taken to ensure the sterility of neurosurgical instruments.^[37]

Dietary consumption of affected animal parts can transmit prion disease, especially in nonhuman species in which infectious prion diseases are relatively common. In humans, infection via consumption is very rare, two well-known examples being kuru and variant Creutzfeldt-Jakob disease (vCJD).^[6] Kuru is a (now extinct) prion disease that reached epidemic proportions in the mid-20th century in the Fore people of Papua New Guinea. Until the practice was abandoned in the mid-20th century, the Fore people would consume their dead as a funerary ritual.^[38] With the cessation of ritual cannibalism, new cases of kuru slowly ceased to appear.^[24] A more well-known infectious human prion disease is vCJD, a zoonotic prion disease that is caused by the consumption of tissues from cows with bovine spongiform encephalopathy (BSE).^[25] Cows are thought to have acquired BSE by consuming food that contained meat products derived from animals with prion disease, possibly sheep with scrapie.^[24] Fortunately, vCJD has largely been eliminated by efforts to exclude tainted meat products from the food chain. Regulations in many 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.^[39]

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, bodily 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.^[40]

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.^[41]

Other hypotheses

The infectious protein hypothesis has become the prevailing explanation for the causation of prion diseases.^[24][2][34] However, in the years following the recognition of their infectivity, other hypotheses have been proposed. These include unorthodox forms of carbohydrates, lipids, nucleic acids, or unusual or cryptic infectious agents^[2] Regarding causation by nucleic acid-based infectious agents, a hypothesis championed by Laura Manuelidis invokes a cryptic viral agent,^[42] and another proposed by Frank O. Bastian holds that Spiroplasma infection, specifically Spiroplasma mirum, is a cause of transmissible spongiform encephalopathies.^[43] No alternative hypothesis has garnered sufficient support to challenge the prion paradigm.^[2][44][45]

Diagnosis

The variable presentation of prion diseases and their rapid progression following the appearance of signs and symptoms present a special challenge for diagnosis.^[46] Because the early signs of disease can mimic those in other brain disorders, the diagnosis of prion disease is often delayed.^[24] Upon clinical examination, sporadic CJD (the most frequent human prion disease) is suspected when the patient presents with rapidly progressing deterioration of cognition and movement. The diagnosis can be supported by the following tests: 1) Electroencephalogram (EEG) - in CJD, the pattern of brain waves changes over the course of the disease, one typical abnormality being periodic sharp and slow wave complexes in the electrical signal; 2) Cerebrospinal fluid (CSF) tests, in particular, measurement of the 14-3-3 protein, tau protein, and neurofilament light chain, all of which increase in prion diseases; 3) Magnetic resonance imaging (MRI) can detect characteristic changes in the structure of the brain; and 4) Real-time Quaking Induced Conversion (RT-QuIC) is used to detect the presence of abnormal PrP in the CSF.^[47][46][48] Although many of the changes detected by these tests can occur in other diseases, a combination of the tests can establish the presence of prion disease with high specificity and sensitivity. False positive diagnoses, though rare, are still possible; therefore, definitive diagnosis of prion diseases requires direct examination of brain tissue.^[46]

Treatment

There are currently no known ways to cure or prevent prion disease.^[49] Certain medications slow down the progression of the disease in mice, but these have not been found to be effective in trials with human patients.^[50] Ultimately, supportive care is the only option for easing the burden of disease in affected individuals.

Epidemiology

Prion diseases are unique in medicine in that they can be sporadic, genetic, or infectious in origin.^[24][2] There are a number of different prion diseases of humans and nonhuman species, each with its own characteristics (such as the primary host species, incidence, disease course, and pathology).^[22][51][8] In humans, the most common prion disease is sporadic CJD, which is estimated to occur worldwide in 1 to 2 persons per million per year.^[52] Of these, approximately 85% are sporadic, 10-15% are genetic, and less than 1% are infectious (acquired).^[24][52] The incidence of sCJD increases with age, and it is most likely to appear between the ages of 55 and 75.^[24] Although there may be subtle sex differences, males and females appear to be affected at a similar rate.^[53] Analyses in several countries suggest that the incidence of sCJD has risen in recent years.^[54][52][55] This increase may be due in part to improved detection of the disease, although the growing elderly population is also a possible factor.^[54][52][55] Much less common sporadic prion diseases include sporadic fatal insomnia (sFI), and variably protease sensitive prionopathy (VPSPr).^[56]

Genetic (heritable) human prion diseases are caused by changes in the PRNP gene that codes for PrP; together, they account for 10-15% of all human prion diseases.^[56] Three main categories of genetic prion disease are genetic Creutzfeldt-Jakob disease (gCJD), Gerstmann-Sträussler-Scheinker (GSS) syndrome, and fatal familial insomnia (FFI).^[56] Of these, the most frequently occurring type is gCJD, whereas FFI is extremely rare.^[24] In addition to the mutations in PRNP that cause disease, there are variations in the PRNP gene that can increase or decrease the likelihood of developing all three aetiological subtypes of prion disease (genetic, infectious and sporadic).^[56][24][57]

Infectious prion diseases in humans are very rare, historically accounting for less than 1% of cases; they include kuru, iatrogenic CJD (iCJD) and variant CJD (vCJD).^[14] Humans have been exposed to prions via contaminated foodstuffs, human cadaver-derived biologics (cadaveric hormones or cadaveric tissue grafts), or contaminated surgical instruments.^[56] From 1957 and 2004, more than 2700 cases of kuru among the Fore people of Papua New Guinea were documented.^[58] With the cessation of endocannibalism beginning in the 1950s, the number of cases rapidly declined, and today the disease is considered to be eradicated.^[57].

Of the approximately 500 cases of known iatrogenic CJD, most have been recipients of cadaveric pituitary hormones (200 cases, the most in France) or cadaveric dura mater grafts (200 cases, the most in Japan).^[57] The rest of the iCJD cases have been very uncommon; these have involved corneal transplants (2-10 cases), intracranial exposure to contaminated EEG electrodes (2 cases), exposure to contaminated surgical instruments (4 cases), or transfusion of blood (3 cases).^[37][57]

The variant form of CJD resulted from exposure of humans to prion-infected bovine meat.^[59][57] As of 2021, a total of 232 cases of vCJD had been reported worldwide.^[57] Of these, most were in the United Kingdom (178 cases) and France (28 cases), with the remaining 26 cases appearing in various other countries.^[57] All but one of these vCJD cases had a specific polymorphism (MM) at codon 129 of the PRNP gene, underscoring the importance of this gene locus as a modifier of susceptibility to prion disease.^[57] Removal of cattle with prion disease from the food chain has brought the vCJD crisis to an end, although there is still some concern that people with certain polymorphisms of PRNP may yet develop disease after a longer incubation period.^[56] In general, an improved understanding of prions and their transmissibility has greatly reduced the risk of infectious human prion diseases.^[60][61]

In nonhuman species, the epidemiology of prion diseases differs from that in humans in that most cases are infectious in origin.^[8][59] Scrapie can be transmitted among sheep and goats in captivity, and chronic wasting disease is unusual in that it is spreading both in captive and wild cervid populations, especially in North America.^[62]. Chronic wasting disease (CWD) was first identified in captive cervids in Colorado (USA) in 1967, and it has since expanded to include many areas of North America and in other countries.^[62] CWD is highly infectious, and is transmissible directly via direct contact between animals or by contact with prion-contaminated materials.^[62] Infected animals can shed prions into the environment in saliva, feces and urine, and the prions can remain infectious for years thereafter.^[62]

Other nonhuman prion diseases mostly have resulted from feeding animals prion-contaminated food; these include BSE, transmissible mink encephalopathy, exotic ungulate spongiform encephalopathy and feline spongiform encephalopathy.^[8] In the 1980s and 1990s, bovine spongiform encephalopathy (BSE, or "mad cow disease") spread in cattle at an epidemic rate, mostly in the UK.^[59] How the first cases of BSE arose in cattle is not known, but the epidemic was driven by feeding cattle meat and bone meal that contained the remains of infected animals.^[59] The epidemic peaked at 37,000 confirmed cases in cattle in 1992, and as a result of a ban on feeding cattle meat and bone meal, the numbers declined to single digits after 2011.^[59] Human consumption of meat from BSE-infected cattle caused an outbreak of variant CJD (see above). In the case of some newly emerging (or newly discovered) nonhuman prion diseases, such as CWD in Scandinavia and a prion disease of camels, the origins are sometimes unknown.^[59] While the transmission of prion disease from nonhumans to humans appears to be uncommon, the potential for zoonotic infection was highlighted by the BSE epidemic, and this possibility remains a concern among public health specialists.^[41][59]

History

In the 5th century BCE, Hippocrates described a disease like TSE in cattle and sheep, which he believed also occurred in humans.^[63] Publius Flavius Vegetius Renatus records cases of a disease with similar characteristics in the 4th and 5th centuries AD.^{[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.^[64] 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.^[65] 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.^[66] 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.^[67] Not until 1988 was the neuropathology of spongiform encephalopathy properly described in cows.^[68] 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.^[69] Although the infectious disease model of TSE has been questioned in favour of a prion transplantation model that explains why cannibalism favours transmission,^[63] the search for a viral agent was, as of 2007, being continued in some laboratories.^[70][71]

See also

• Proteinopathy
• Variably protease-sensitive prionopathy