In this article, the author reviews the group of diseases known as prion diseases, also referred to as the subacute spongiform encephalopathies. These diseases have a subacute to chronic clinical course with a similar neuropathology. All the diseases are transmissible and induced by an abnormal misfolded form of the prion protein that is extremely resistant to physical and chemical inactivation. The unusual nature of the transmissible agent and the emergence of variant Creutzfeldt-Jakob disease (as a result of ingestion of contaminated beef) have had a significant impact on public health in addition to science and medicine. New diagnostic tests, such as protein misfolding cyclic amplification and real time quaking-induced conversion, and new ideas about treatment of the subacute spongiform encephalopathies are discussed.
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• The transmissible subacute spongiform encephalopathies, or prion diseases, have a similar noninflammatory spongiform pathology and are caused by a similar transmissible agent -- an abnormal (“scrapie-like”) protease-resistant conformation of the prion protein (PrP), which is designated PrPSc.
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• Sporadic human prion diseases include Creutzfeldt-Jakob disease and fatal sporadic insomnia. Prion diseases acquired by infection include kuru (a subacute cerebellar disease found in the Highlands of New Guinea that was spread by ritual endocannibalism), variant Creutzfeldt-Jakob disease, and iatrogenic Creutzfeldt-Jakob disease. Familial human prion diseases, which are 10% of the overall cases, include familial Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome, and fatal familial insomnia.
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• Creutzfeldt-Jakob disease is a subacute fatal disease with a clinical triad of dementia, myoclonus, and EEG abnormalities that is usually associated with other neurologic abnormalities, along with neuropathological evidence of neuronal loss, spongiform changes, and astrocytosis. A new test that makes use of protein misfolding cyclic amplification, real-time quaking-induced conversion (RT-QulC), has high sensitivity and specificity and is helpful in making the diagnosis.
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• Prion diseases are transmissible after a prolonged incubation period by inoculating the infected CNS into nonhuman primates and other species via multiple routes of inoculation; however, transmission is most efficient with an intracerebral inoculation into a species identical to the source of the infected CNS tissue.
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• Some investigators consider Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and multiple system atrophy to be prion-like diseases in which a particular misfolded protein converts a normal form of the protein to the misfolded one that aggregates and allows it to propagate and spread throughout the CNS.
Historical note and terminology
In March of 1957, D Carleton Gajdusek entered the kuru region in New Guinea where Vin Zigas was stationed as a medical officer (40). This led to the first clinical and neuropathological descriptions of kuru (24; 38). In 1959, Hadlow, a veterinarian neuropathologist, noted the similarity between kuru and scrapie, a transmissible disease of sheep that had an extremely prolonged incubation period (30). This prompted attempts to transmit kuru into nonhuman primates following intracerebral inoculation of affected CNS tissue and to the eventual successful transmission of this disease (23).
Kuru and a number of other human (eg, Creutzfeldt-Jakob disease) and animal (eg, scrapie, bovine spongiform encephalopathy, and chronic wasting disease) diseases are grouped together as prion diseases or transmissible subacute spongiform encephalopathies because of their similar clinical and pathologic features as well as their transmissibility by an unconventional agent (23; 65; 67). This review focuses on kuru and fatal familial insomnia, with some discussion of Creutzfeldt-Jakob disease. The transmission of these diseases is of special interest because of the noninflammatory nature of the clinical-pathologic syndrome, the long incubation period ("slow" virus infection), and the unusual nature of the transmissible agent, the prion. The prion agent consists of prion protein (PrP) that is misfolded and protease-resistant, PrPSc. The importance of these diseases was demonstrated by the receipt of the Nobel Prize in 1976 and 1997 by Gajdusek and Prusiner respectively.
Fatal familial insomnia was first described in 1986 (43). In 1992 fatal familial insomnia patients were demonstrated to carry a mutation in the PrP gene, PRNP, as is the case with individuals with other forms of familial prion diseases; for this reason, fatal familial insomnia was proposed to be a prion disease (56). The transmission of fatal familial insomnia to experimental animals has confirmed its inclusion in this group of diseases (77). A noninherited disease, called fatal sporadic insomnia, with a similar clinical and pathological phenotype to fatal familial insomnia has also been described (52; 01). The prion diseases became more visible because of an epidemic of bovine spongiform encephalopathy (“mad cow” disease), found primarily in the United Kingdom, and the subsequent emergence of variant Creutzfeldt-Jakob disease. Variant Creutzfeldt-Jakob disease is thought to result from oral transmission of the bovine spongiform encephalopathy agent to humans. In addition, the recognition of chronic wasting disease as a prion disease of deer and elk in the United States has focused attention on prion diseases.