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LEARNING OBJECTIVES PRION DISEASES (TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES)
Prions (pronounced pree-ons, an acronym for proteinaceous infectious particles) are abnormal isoforms of a neuronal membrane glycoprotein, PrPC, which is highly expressed in the brain. The function of PrPC is unknown. There is some evidence that it is a signaling molecule. Abnormal prions (PrPSc) result from a change in the folding pattern of this protein, which makes it resistant to the action of proteases and causes it to precipitate as insoluble amyloid. This conversion results in neuronal degeneration and loss by an unknown mechanism.In familial prion diseases, the change in PrPC conformation is caused by mutations of the PrPC gene-PRNP (on chromosome 20) which alter its amino acid sequence. When extrinsic abnormal prions are introduced into the body, they interact with normal indigenous prions and, acting as templates, cause normal prions to change their conformation into abnormal. This conversion apparently takes place on a large scale. In sporadic prion diseases, misfolding of PrPCmay be caused by somatic mutations or by posttranslational modifications.
PATHOGENESIS OF PRION DISEASES
| Misfolding of the normal prion protein (PrPC) converts it to an insoluble, protease resistant isoform (PrPSc), which precipitates as amyloid. |
| Loss of function of PrPC or toxicity of PrPSccause neuronal degeneration and loss by some unknown mechanism. |
| In familial CJD, mutations of the Prion protein gene cause prions to misfold. |
| It is not clear what causes sporadic CJD. Polymorphisms of the prion protein gene at codon 129 increase susceptibility and influence the phenotype of sporadic CJD. |
| In iatrogenic and variant CJD, PrPSc introduced into the brain induce PrPC to misfold. Endogenous PrPScproduced in familial and sporadic CJD also has the same effect. |
The transmissibility of prion diseases has been proven by animal experiments. Natural transmission from animal to animal (especially in sheep) has been known for many years. In a few instances also, prion diseases have been accidentally transmitted from human to human by transplantation of tissues (dural grafts, cornea) or injection of pituitary extracts from patients with prion diseases. In 1996, transmission of bovine spongiform encephalopathy to humans was reported in the UK.
The human prion diseases are:
| Creutzfeldt-Jakob disease (sporadic, familial, iatrogenic, and variant
CJD)(see below).
Kuru. A now-extinct disease of New Guinea natives, transmitted by eating the brains of dead persons who had the disease. Gerstmann-Straussler syndrome. An autosomal dominant form of ataxia. Fatal familial insomnia. An autosomal dominant sleep disorder with pathological lesions in the thalamus. |
The most common animal prion diseases are:
Scrapie. An important disease of sheep that has been known for over 100 years. Sick animals rub against rocks or other hard surfaces, scraping their fleeces. The discovery of transmissibility and other important aspects of the biology of prion diseases was based on knowledge of scrapie. Bovine spongiform encephalopathy (BSE)-mad cow disease. Transmissible mink encephalopathy. Wasting disease of deer and elk. Prion diseases have also been reported in several other domesticated and wild animal species and can cross from one species to another. Experimental transmission to primates and guinea pigs has played an important role in elucidating their pathogenesis. |
PATHOLOGY OF PRION DISEASES
Pathology, in prion diseases, develops only in the brain. No other organ is affected. Early on, neurons develop intracytoplasmic vacuoles. As the disease progresses, vacuolization becomes more pronounced and the cortical neuropil develops a spongy appearance, hence the term spongiform encephalopathy. |
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| Spongiform encephalopathy | CJD: severe brain atrophy | Cerebellar degeneration |
Creutzfeldt-Jakob disease (CJD) is the most common prion disease of humans, but overall is a rare disease, affecting one in every million people. It affects middle aged or old persons and causes dementia, myoclonus, ataxia and other neurological abnormalities. This phenotype, also known as the Heidenhain variant, is seen in 70% of sporadic CJD. The other 30% have less typical features. The EEG shows perodic sharp wave complexes. CJD is inexorably progressive and fatal within months up to 1 to 2 years. A definitive diagnosis can only be made by microscopic examination of brain tissue showing the characteristic spongy change. Abnormal prions can be detected in brain tissue extracts by ELISA and in tissue sections by immunohistochemistry. A protein called 14-3-3 is elevated in the CSF of patients with CJD. Microtubule associated protein tau was also recently shown to be elevated in the CSF, including in the new variant (see below) and iatrogenic CJD cases in which 14-3-3 remains normal. Determination of tau can be done in routine hospital laboratories. Detection of these proteins provides much needed premortem diagnostic tests for CJD. Both, tau and 14-3-3, are also elevated in other neurological diseases (tau most notably in Alzheimer's disease) but these can be clinically distinguished from CJD. For this reason they are helpful only when the differential diagnosis has been narrowed down and more common neurological conditions such as Alzheimer's disease, stroke, HIV encephalitis, etc, have been excluded. Mutations of the PRNP gene and the codon 129 polymorphism can be detected by DNA analysis of blood and tissues.
Ten to 15% of CJD cases are familial, autosomal dominant. Most familial cases are associated with a mutation at codon 200 of the PRNP gene resulting in a Glu to Lys substitution.There are several other less common mutations. These mutations presumably cause the PrP protein to misfold. Mutations of the PrP gene also cause the Gersmann-Straussler-Scheinker syndrome and fatal familial insomnia.
About 130 cases of variant CJD have been reported, most of them in the UK. These cases are suspected of having been caused by consumption of meat products contaminated by BSE. Variant CJD patients are young and have prominent psychiatric manifestations and ataxia. The brain shows spongiform encephalopathy and numerous amyloid plaques. Unlike classic CJD, prion protein can be detected in lymphoid tissues.
Over 250 cases of iatrogenic CJD have been caused by injection of growth hormone and gonadotrophin extracted from cadaveric pituitaries, contaminated dural grafts, corneal transplants, and contaminated surgical instruments.
The vast majority of CJD cases are sporadic and apparently spontaneous. The etiology of these cases is unknown. The story of the variant CJD from BSE has raised the specter of food contamination as a possible cause, but there is no evidence that sporadic CJD is caused by that mechanism. Somatic mutations of PrP can cause sporadic CJD but most sporadic cases show no such mutation. However, the PrP gene shows a polymorphism at codon 129 that can code for either Methionine or Valine. Most patients with sporadic and transmitted CJD are homozygotes for Methionine. In ddition to being a risk factor for developing CJD, this polymorphism affects the physicochemical properties of prions and influences the clinical phenotype and pathology of CJD.
The potential of accidental transmission of a fatal neurological disorder has scared pathologists and other health care workers connected with these diseases. This potential should not be underestimated. However, these fears are exaggerated. The disease is transmitted only by invasive methods such as inoculation or injection and not by casual contact such as occurs in the course of routine patient care. An autopsy can be safely done using standard precautions. Fixation of tissues in formalin does not eliminate transmissibility of CJD and other prion diseases. Additional chemical treatment with formic acid is needed.
Before prions were known, sporadic CJD and other prion diseases were thought to be "degenerative" diseases. When it was discovered that they can be transmitted, they were reclassified as infectious diseases. At one point, they were called slow virus diseases. However, they are obviously different from bacterial and viral infections. For one thing, prions contain no nucleic acid, and their chemistry and structure are not like those of bacteria or viruses. They damage neurons directly and do not elicit inflammatory and immune reactions. The familial forms of prion diseases can be regarded as inherited metabolic disorders, similar to Huntington's disease and familial Alzheimer's disease. Understanding the transmitted and sporadic forms is a challenge. An abnormal protein entering the body, crossing the blood-brain barrier, and causing its normal counterparts in neurons to change their folding pattern in a chain reaction that eventually destroys the brain sounds like science fiction. Prions have been compared to the Borg, an alien mechano-anthropoid species in Star Trek, which relentlessly assimilate other species with which they come in contact. Two Nobel prizes have been awarded for research in prion diseases. In 1976, Carleton Gajdusek received the prize for proving that they are transmissible, and in 1997 Stanley Prusiner was given the prize for the prion hypothesis.
