CHAPTER 95 PRION DISEASES

Although the human forms of prion disease, including Creutzfeldt-Jakob disease (CJD), are rare, this group of fatal disorders of the central nervous system has become the subject of extensive scientific and public interest. Prion diseases affect both humans and animals (Table 95-1); are caused by infectious agents, which may consist only of a host-encoded protein; and share properties that pose a major challenge to animal and public health (Table 95-2). The critical difference between prion diseases and other neurodegenerative conditions is that they are transmissible experimentally and, sometimes, naturally. The hypothesis that bovine spongiform encephalopathy (BSE) has been transmitted from cattle to the human population as variant CJD (vCJD)¹ and the possibility of secondary transmission through blood transfusion^2,³ have increased the level of interest in and concern about these diseases.

Human	Animal
Sporadic	Infectious
Sporadic CJD	Scrapie in sheep and goats
Genetic	Transmissible mink encephalopathy
Genetic CJD	BSE
Gerstmann-Sträussler-Scheinker disease	Spongiform encephalopathy ^* in the domestic cat, captive zoo species, including kudu, cheetah, tiger Chronic wasting disease of cervids
Fatal familial insomnia
Infectious
Kuru
Iatrogenic CJD
Variant CJD^*

BSE, bovine spongiform encephalopathy; CJD, Creutzfeldt-Jakob disease.

ETIOLOGY AND PATHOGENESIS

In all prion diseases, a post-translationally modified form of a normal membrane-associated protein, prion protein (PrP), is deposited in the brain and some other tissues. This is accompanied by neuropathological changes, including spongiform change, astrocytic gliosis, and neuronal loss, although, in addition, the abnormal form of prion protein (PrP^Sc) may be deposited in aggregates as amyloid plaques. The function of the normal host PrP has not been established.

According to the prion hypothesis, PrP^Sc is the infectious agent and acts as a template for its own replication without additional informational material such as DNA or RNA.⁴ Evidence of the synthetic production of infectious PrP provides strong support to this hypothesis,⁵ although whether this theory adequately explains the existence of multiple strains of infectious agent remains controversial. After exposure to infection, there is a prolonged incubation period, extending to years or even decades in natural disease, during which there is no evidence of clinical disease, despite the accumulation of PrP^Sc and infection in peripheral tissues, mainly in the lymphoreticular system. There is no host immune response and no available serological test to identify the presence of infection; this implies that infected animals may enter the human food chain and infected humans may potentially act as blood donors.

Prion diseases are unique in that they occur in sporadic, genetic, and infectious forms.⁴ According to the prion theory, this is explained by spontaneous conversion of the normal protein to the abnormal form in sporadic disease, by instability in protein structure in cases associated with mutations of the prion protein gene (PRNP), and by transmission of self-replicating PrP^Sc in infectious forms. The absence of detectable PrP^Sc in some types of experimental prion disease has led to the hypothesis that it is intermediate forms of PrP, rather than the end-stage protein (PrP^Sc or PrP^27–30), identified in postmortem brain samples, that are infectious. Whatever the structure of infectious PrP, these agents are remarkably resistant to normal sterilizing techniques,⁶ which adds to the concerns about onward transmission of infection.

HUMAN PRION DISEASES

Epidemiology

Sporadic Creutzfeldt-Jakob Disease

This rare disease occurs worldwide with mortality rates of 1 to 2 cases per million population per year in systematic surveys.⁷ The cause of sporadic CJD (sCJD) is unknown, and there is no good evidence of clustering of cases to indicate an environmental source of infection and no consistent risk factors identified in case-control studies.⁸ sCJD occurs predominantly in the older age groups, with a mean age at death of about 66 years, but younger patients can be affected, and a handful of teenagers with sCJD have been described.

Genetic Human Prion Diseases

Genetic Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease, and fatal familial insomnia are all associated with, and perhaps caused by, mutations in PRNP, with variations in clinical and pathological phenotypes that are related to the specific mutation.⁹ Genetic human prion diseases have been found in most countries, but the frequency of these cases varies; some countries such as Slovakia, Israel, and Italy have high localized incidences.¹⁰ Overall, in genetic cases, age at death is approximately 10 years younger than that in sCJD.

Iatrogenic Creutzfeldt-Jakob Disease

This form of CJD is caused by the transmission of infection from person to person in the course of medical or surgical treatment.¹¹ Numerically, the most frequent means of transmission have been through human dura mater grafts (168 cases worldwide) and human pituitary growth hormone (180 cases), although, in rare cases, other vectors have been implicated, including neurosurgical instruments, corneal grafts, and human pituitary gonadotrophin. Incubation periods range from 1.5 to more than 30 years and vary according to the route of inoculation.