Transmissible spongiform encephalopathy

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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Transmissible spongiform encephalopathies are a group of progressive conditions that affect the brain and nervous system of humans and animals and are transmitted by prions. 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) (reviewed in Prusiner, 1991; Collinge, 2001).

These spontaneous disorders in humans are very rare affecting only about one person per million worldwide each year.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rinky Agnes Botleroo, M.B.B.S.

Prion diseases are a group of neurodegenerative disorders which include Kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker (GSS) syndrome, and fatal familial insomnia in men, natural scrapie in sheep and goats, transmissible mink encephalopathy in ranch-reared mink, chronic wasting disease of mule deer, Bovine Spongiform Encephalopathy or “Mad Cow disease“.Scarpie was fiirst described in 1732.Kuru is the first recognized prion disease in humans which was described in1957. Gajdusek, Gibbs and his colleagues demonstrated its transmissibility in 1965 .Later on, they also described the transmission of Creutzfeldt-Jakob disease (CJD) and Gerstmann-Sträussler-Scheinker. In 1982, Stanley B. Prusiner presented “prion hypothesis” which explains that a misfolded protein is responsible for the pathogenesis of prion diseases.

• Natural Scrapie^[1] is a infection that affects sheep and it is caused by an unknown infectious agent.
• It was first recognized in 1732.
• Kuru is the first prion disease in humans which was described in 1957.It is a fatal neurodegenerative disease that affected only people of a single language group in the remote mountainous interior of New Guinea.
• In 1959, veterinary pathologist W.J. Hadlow first described several similarities between Scrapie and Kuru.
• In 1959, I. Klatzo also recognized that Kuru’s histopathology was similar to that of Creutzfeldt-Jakob disease (CJD).
• Creutzfeldt-Jakob disease (CJD) is another neurodegenerative progressive disease of unknown etiology that A.M. Jakob had first described in 1921.^[2]It is fatal.
• Gajdusek, C.J. Gibbs, Jr., and M.P. Alpers used the existing knowledge of Scrapie and started trials to transmit Kuru by inoculating Kuru brain tissue into non-human primates, It took them several years but finally they became successful in 1965.
• Later Gajdusek and his colleagues went on to demonstrate that not only the more common sporadic form of Creutzfeldt-Jakob disease (CJD) but also familial Creutzfeldt-Jakob disease (CJD) and a generally similar familial brain disease (Gerstmann-Sträussler-Scheinker syndrome) were also transmissible, first to non-human primates and later to other animals.^[2]
• In 1982, ^[1]Stanley B. Prusiner presented “prion hypothesis”. Prusiner discovered that a misfolded form of a ubiquitous normal host protein usually but not all the time was detectable in tissues containing TSE agents.
• These misfolded proteins greatly helps in in understanding their pathogenesis and also in confirming the diagnosis.
• Prusiner also explained that the TSE agent was likely to be composed partially of an abnormal protein, for which he used the term “prion” protein.
• Expression of the prion protein by animals-while not essential for life-was later found to be compulsory to infect them with TSEs

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Rinky Agnes Botleroo, M.B.B.S.

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) (reviewed in Prusiner, 1991; Collinge, 2001).

• 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.
• 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 recognised that these changes are enormously variable both from case to case and within the central nervous system in individual cases..
• 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.
• 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 ([2], [3], [4], [5]). 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.

• 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.

Listed below are the prion diseases identified to date. Click the linked diseases to go to their respective topic sites. CDC does not currently offer information here on every prion disease listed.

• Creutzfeldt-Jakob Disease (CJD)
• Variant Creutzfeldt-Jakob Disease (vCJD)
• Gerstmann-Straussler-Scheinker Syndrome
• Fatal Familial Insomnia
• Kuru

• Bovine Spongiform Encephalopathy (BSE)
• Chronic Wasting Disease (CWD)
• Scrapie
• Transmissible mink encephalopathy
• Feline spongiform encephalopathy
• Ungulate spongiform encephalopathy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rinky Agnes Botleroo, M.B.B.S.

Prion diseases cause a progressive decline in brain function due to misfolding of proteins in the brain, called prion proteins (PrP) These are unique diseases,their aetiology may be genetic, sporadic or infectious via ingestion of infected foodstuffs and via iatrogenic means (e.g. blood transfusion/donated organs)

• 10 -15 percent of all the cases of prion disease are caused by mutations in the PRNP gene.
  • Familial prion diseases results from mutations in the PRNP gene.This specific form of prion diseases are known as familial prion diseases as they can run in families.
  • These include familial Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), and fatal familial insomnia (FFI).
  • The PRNP gene gives instructions to make a protein,called prion protein (PrP).
  • The exact function of this prion protein is unknown,it is thought that it has roles in several important processes.
  • These processes include the transport of copper into cells, protecting brain cells (neurons) from injury (neuroprotection), and maintaining communication between neurons.
  • In familial forms of prion disease, PRNP gene mutations result in the production of an abnormally shaped protein, known as PrPSc, from one copy of the gene.
  • PrPSc can bind to the normal protein (PrPC) and cause its transformation into PrPSc,this process is not fully understood.
  • This abnormal protein accumulates in the brain, forming clumps which damage or cause destruction of neurons. The loss of these cells creates microscopic sponge-like holes (vacuoles) in the brain, which causes signs and symptoms of prion disease.^[1]

• Rest of the 85-90 percent of cases of prion disease are either sporadic or acquired.^[1]
  • People with sporadic prion disease have no family history of the disease and no identified mutation in the PRNP gene.
    • Sporadic disease occurs when PrPC spontaneously, and for unknown reasons, is transformed into PrPSc.
    • Sporadic forms of prion disease include sporadic Creutzfeldt-Jakob disease (sCJD), sporadic fatal insomnia (sFI), and variably protease-sensitive prionopathy (VPSPr).
  • Acquired prion disease results from exposure to PrPSc from an outside source.
    • For example, variant Creutzfeldt-Jakob disease (vCJD) is a type of acquired prion disease in humans that results from eating beef products containing PrPSc from cattle with prion disease.
    • This form of the disease in cows is known as bovine spongiform encephalopathy (BSE) or, more commonly, “mad cow disease.”
    • Another example of an acquired human prion disease is Kuru, which was identified in population in Papua New Guinea. The disorder was transmitted when individuals ate affected human tissue during cannibalistic funeral rituals.

• Prion diseases can rarely be caused by accidental exposure to PrPSc-contaminated tissues during a medical procedure. These 1-2 percent of prion diseases are classified as iatrogenic.^[1]

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Transmissble Spongiform Encephalopathy should be differentiated from the diseases given below:

• Alzheimer’s disease
• Lewy Body Dementia
• Frontotemporal Dementia
• Vasculitis
• Hashi moto encephalopathy
• Electrolyte Imbalance
• Hepatic Encephalopathy
• HIV– related mental status change
• CNS malignancy
• Psychiatric conditions
• Paraneoplastic limbic encephalitis
• Lyme disease
• Syphilis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Rinky Agnes Botleroo, M.B.B.S.

Risk factors for prion disease include positive family history, personal history of psychosis, history of surgical procedures, grafts or implants, and history of ingestion of human growth hormones or contaminated meat.

Risk factors for Prion disease include the following:

• People who have a positive family history^[1]
• Consuming meat infected by “mad cow disease”
• People who recieve contaminated corneas /blood/any other tissue
• Using contaminated medical equipment.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]

The prevalence of major or mild neurocognitive disorder due to prion disease is unknown.^[1]

• Anecdotal
• Corneal transplantation
• Human growth factor injection^[1]

• Other major neurocognitive disorders^[1]