Although this group of diseases has been included for discussion in the chapter on viruses that affect the nervous system, it has been evident for some time that the cause of these diseases is neither a virus nor a viroid (nucleic acid alone, without a capsid structure). The transmissible, or “infectious” nature of prions was discovered by Gibbs and Gadjusek in the Fore tribes of New Guinea, who practiced ritual cannibalism and ate the brains of the deceased. The resulting disease, kuru, is described further on but the important point is that the aforementioned workers were able to transmit the disease to chimpanzees after a long latent period of years. Prusiner is credited with doggedly pursuing this problem, for which he was awarded the Nobel Prize. He (1993, 1994, 2001) has presented evidence that the transmissible pathogen is a proteinaceous infectious particle that is devoid of nucleic acid, resists the action of enzymes that destroy RNA and DNA, fails to produce an immune response, and electron microscopically does not have the structure of a virus. To distinguish this pathogen from viruses and viroids, Prusiner introduced the term “prion.”
The very same prion protein (PrP) is normally encoded by a gene on the short arm of chromosome 20 in humans. The discovery of mutations in the PrP genes of patients with familial Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker syndrome (described in the following text) attests to the fact that prion diseases may be both genetic and infectious. This is another way in which prions are unique among all pathogens. It is now possible to detect inherited types of prion diseases during life, using DNA extracted from leukocytes. How prions arise in sporadic forms of spongiform encephalopathy is not fully understood. The conversion of the normal cellular protein to the infectious form involves a conformational change in the protein structure as described in Prusiner’s review in 2001. Remarkably, as discussed below, the current theory holds that an abnormally folded prion protein can act as a template for the conversion of normal PrP to PrPsc (the latter denoting the scrapie prion; see Pathogenesis). A description of the human prion diseases is given here, the most important by far being Creutzfeldt-Jakob disease.
These terms refer to a distinctive cerebral disease in which a rapidly or subacutely progressive and profound dementia is associated with diffuse myoclonic jerks and a variety of other neurologic abnormalities, mainly visual or cerebellar. The major neuropathologic changes are found in the cerebral and cerebellar cortices, and the outstanding features are widespread neuronal loss and gliosis accompanied by a striking vacuolation or spongy state of the affected regions—hence the designation, more frequently used in the past, subacute spongiform encephalopathy (SSE). The widely used term Creutzfeldt-Jakob disease (CJD) may not be an entirely appropriate eponym as it is most unlikely that the patient described by Creutzfeldt and at least three of the five patients described by Jakob did not have the same disease that we now recognize as subacute spongiform encephalopathy. However, decades of use make it virtually impossible to displace.
One of the more interesting aspects of the development of the prion concept has been the hypothesis that many conditions, most in the category of degenerative neurologic disease and characterized by the accumulation of specific proteins such as amyloid, tau, synuclein, and ubiquitin may have a similar mechanism in sequential, contiguous conformational change in protein aggregation.
The disease appears in all parts of the world and in all seasons, with an annual incidence of 1 to 2 cases per million of population. The incidence is higher in Israelis of Libyan origin, in immigrants to France from North Africa, and perhaps in Slovakia. The incidence of spongiform encephalopathy is somewhat higher in urban than in rural areas, but a consistent temporal or spatial clustering of cases has not been observed, at least in the United States.