Prion diseases are a less common group of neurodegenerative disorders. There are several disorders distinguished by clinical presentation and pathoetiologic basis but marked by spongiform neurodegeneration and an unusual protein-based molecular pathogenesis. The particular agents responsible for the diseases are not nucleic acids, viruses, or living organisms but rather “proteinaceous infectious particles” or prion molecules, a concept developed and established through the groundbreaking research of Stanley Prusiner, who was awarded a Nobel Prize for this work. The prion protein is a specific, relatively small translational product of just over 200 amino acids length. This neuronal protein (prion protein [PrP]) is present in cells in its usual, “normal” cellular conformation (known as PrP^C) with a protein secondary structure consisting of about 45% alpha helical segments and very little beta sheet internal structure. However, in prion diseases, there is an abnormal “scrapies” or protease-resistant conformation (known as PrP^Sc or PrP^res), which is marked by 40%, beta-pleated sheet molecular architecture and has only about 30% alpha helical structure. In the prion diseases, there is an accumulation of the abnormally folded PrP^res protein causing nervous system dysfunction and destruction, through protein-protein interactions presumably within cells but ultimately spreading between cells. Specifically, misfolded copies of the protein cause conformation changes in normal PrP^C, converting it, in turn, to the abnormal form. There is an exponential increase in brain accumulation of abnormal prion protein, leading to rapidly escalating progressive nervous system destruction.

Prion diseases have a plural epidemiology: They may occur in both sporadic, nongenetic forms and genetic, familial forms, like many neurodegenerative disorders, but they may also occur as “acquired diseases,” through transmission by iatrogenic, surgical, or cannibalistic exposures of persons to nervous system tissue of affected individuals. Hence, they are also known as transmissible spongiform encephalopathies. The archetypical and most common of these uncommon disorders is Creutzfeldt-Jakob disease (CJD), named after two neurologists who described some cases of rapidly progressive dementia in the early part of the 20th century (which may not necessarily all have represented prion disorders). Although prion disease is sometimes easily recognizable, the differential diagnosis is often broad, particularly early in the course of the disease. The rapidity of symptom progression, together with the fact that different alternative diagnoses may have specific effective treatments, makes expeditious recognition and diagnosis particular important for this set of disorders.

Prion diseases can be classified by their clinical-epidemiologic bases. Prion diseases may occur as sporadic genetic or acquired forms (Table 68.1). The hallmark of sporadic CJD (sCJD) is generally a rapidly progressive dementia, typically with gait dysfunction, although there are other rarer clinical phenotypes such as sporadic fatal insomnia (sFI). There are three distinct clinical forms of genetic prion diseases: Familial CJD (fCJD) clinical presentation is like that of sCJD; Gerstmann-Sträussler-Scheinker (GSS) disease is typically marked more by ataxia; and familial fatal insomnia is marked by severe insomnia and autonomic changes. Acquired CJD, transmitted through exposure to prions, was first described in the disease Kuru, discovered in New Guinea during the mid-20th century. Transmitted by ritual cannibalism, this disease has fortunately since vanished. Other forms of acquired disease include iatrogenic CJD (iCJD) transmitted through medical products, grafts, or transplants and variant CJD transmitted via consumption of tissues of cows who had bovine prion disease.

CJD occurs across all human populations, with an incidence of about 1.5 cases per million individuals per year, or about 400 persons per year in the United States. It is an uncommon
dementia. Compared to the approximately 1.5 per thousand individuals per year (500,000 in the United States) who develop Alzheimer disease, CJD is a condition with a thousandfold less common incidence. However, because the survival after a diagnosis of CJD is typically less than 1 year, whereas that for Alzheimer disease may be 20 years, the prevalence of CJD among living persons is still rarer. Among the 6 million Americans with dementia, the large majority of whom have Alzheimer disease, only about a few hundred have CJD, or about 1 in 20,000. Conversely, because of the short survival time for CJD, a higher proportion, nearly 1 in 1,000 deaths of persons with dementia each year are due to CJD. As a proportion of the total number of deaths in the nation, CJD represents about 1 in 10,000 deaths, despite having an incidence of only about 1.5 in a million. There has been increased attention and interest in the prion disorders, but there is no evidence that sCJD has had increased incidence over the decades. There has been a mildly increasing secular trend in the annual death rate in the United States over the past 30 years from about 0.9 cases per million to about 1.5 cases per million population, but this is almost certainly due to increased ascertainment rather than increased disease incidence.

Prion protein is a normal cellular protein, which is most expressed in the nervous system, and localizes to the synaptic regions, although its function is unknown. Prion protein belongs to the larger family of genes known as cluster of differentiation (CD) genes, many of whose members are found in cells of the immune lineage and whose functions may include cell-cell interactions and signaling. Presence of prion protein in various other bodily tissues likely relates to expression in cells of lymphatic lineage. The relative paucity of prion protein in non-neural tissues likely explains the confinement of prion disease symptoms to the nervous system. It also explains the lack of any demonstrable transmission from person to person, other than through exposure to nervous system tissues (which have included brain, pituitary, dura, and cornea). It is likely that in individuals developing sCJD, chance explains a rare spontaneous conversion of PrP^C to PrP^res. However, once PrP^res is formed, there is an escalating production of more PrP^res through the process of protein-protein induced conformational change mentioned earlier. This process can be shown to occur in vitro, in culture, and in animal models.

A number of observations have established the protein-based nature of the disease process. Injection of PrP^res into experimental animals in their brains or even elsewhere (in sufficient quantities) results in prion degenerative brain disease. The transmissible agents are not destroyed by nuclease enzymes that inactivate DNA or RNA nor by ultraviolet or X-irradiation and because of its folded state, is resistant to proteases. However, prions are inactivated by destructive/denaturing agents such as concentrated formic acid, phenol, bleach, or sodium hydroxide (lye) as well as by extreme dry heat (600°C). Although injected PrP^res causes prion degeneration and death in normal mice, mice that are genetic knockouts for the prion gene do not have prion degeneration, regardless of the amount of PrP^res they are administered, because they have no PrP^C which can be converted.

Prion proteins are highly conserved, but interspecies differences do provide a barrier to transmissibility. Exposure to or consumption tissues from sheep with prion disease (scrapies) has never been associated with human prion disease. In addition, in experimental animal systems, it can be shown that there is a greater barrier to transmission if the prion agent is from a molecularly more distant species. However, it is clear that bovine prion protein is sufficiently similar to human prions, as to allow transmission of BSE to humans. The small but prolonged epidemic of vCJD resulted from a preceding epidemic of BSE in cattle. Evidence to date indicates that in some persons, consumption of bovine material, likely containing nervous system tissue, led to vCJD, through a process of transluminal gastrointestinal lymphatic-mediated transmission to the nervous system. In vCJD, but not sCJD or fCJD, abnormal prion protein can be shown to be present in lymphoid-containing extraneural tissues, including blood, tonsils, and appendix.