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83 Prion diseases
Transmissible spongiform encephalopathies or prion diseases are chronic neurologic disorders characterized by long incubation periods, progressive noninflammatory disease of brain and spinal cord, a failure of a specific immune response, and a uniformly fatal course. They are transmissible within their natural species and to a limited extent across species barriers. The pathology is characterized by neuronal loss, gliosis, and vacuoles in cytoplasm of neural cells giving the spongiform appearance on microscopic examination. Infectivity copurifies with an isoform of a normal surface glycoprotein expressed primarily in the central nervous system. The function of the normal prion protein is unclear; but the misfolded protein – the prion – induces post-translational conversion of normal prion protein with a helical structure into the infectious isoform rich in β-pleated sheets. This abnormal protease-resistant protein accumulates in brain, leading to disease. To date nucleic acid has not been detected in the transmissible protein fraction.
Prion diseases are recognized in animals (scrapie of sheep, bovine spongiform encephalopathy, and chronic wasting disease of deer and elk) and humans (kuru, Creutzfeldt–Jakob disease [CJD], and the variant of CJD related to bovine spongiform encephalopathy). The human forms of disease can be divided into three groups: (1) sporadic CJD, which represents 85% to 90% of cases, (2) familial CJD due to mutations in the gene coding for prion protein, making up 10% of cases, and (3) transmitted CJD due to iatrogenic transmission, cannibalism in the case of kuru, and, recently, transmission of bovine spongiform encephalopathy to humans.
Epidemiology
Sporadic CJD occurs worldwide at a rate of about 1 per million population per year. Rates are equal in men and woman. The mean age of onset is about 65 years with few cases below 55 or over 80 years of age. No geographic or temporal clustering is evident; conjugal exposure does not increase risk; and no occupations such as meat preparation, medical work, or farming appear related to disease. The assumption is that the great majority of cases of CJD result either from random misfolds of the prion protein which then causes a cascade of misfolding or from an unidentified environmental exposure.
Familial cases of CJD have been related to over 25 point mutations, insertions, and deletions in the gene coding for the prion protein. They show a pattern of autosomal dominant inheritance. In addition, polymorphisms in the gene, particularly a methioine/valine polymorphism at codon 129, influence susceptibility to sporadic and transmitted CJD and determine the phenotype of some hereditary forms.
Transmitted diseases include kuru, which was transmitted through ritual endocannibalism among the Fore tribal group of Central New Guinea, and variant CJD transmitted from bovine spongiform encephalopathy to young people predominantly in the United Kingdom. In addition, iatrogenic CJD has occurred with contaminated operating room tools, by injection of human growth hormone derived from cadaveric pituitaries, and from the use of human dura as grafts in neurosurgery. Although human growth hormone was replaced by safe recombinant growth hormone in 1985 and most neurosurgeons have abandoned the use of human dural grafts, exposure history must still be sought since incubation periods of up to 50 years have been observed for kuru and may be anticipated in iatrogenic transmission.
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