Human Prion Diseases

Prion diseases, also referred to as transmissible spongiform encephalopathies (TSE), occur in humans and animals, primarily affecting the central nervous system. They can be sporadic (spontaneous), familial (genetic/inherited) or acquired (transmitted by infection). The histologic hallmark of most of these diseases is the presence of microscopic vacuolization of the brain tissue, called spongiform degeneration (meaning that the tissue deteriorates, developing a spongy texture). However, the presence of an abnormal protein, called scrapie prion protein (PrPSc), prion, or abnormal prion protein, is required to definitively diagnose prion disease. PrPSc is believed to result from a change in the conformation (or shape) of a normal protein called cellular prion protein (PrPC), which is present in significant amounts in the brain, as well as in other tissues. PrPSc aggregates, mostly in the brain, become hard to break down, causing brain degeneration and neurologic disease. The abnormal prion protein can, under certain conditions, transmit the disease. Recently, the notion that the mechanisms that underlie prion disease are shared by other neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and Lou Gehrig’s disease, has gained ground. The average worldwide occurrence of prion diseases is approximately one case per million people per year. Currently, there is no cure for prion diseases.

Creutzfeldt-Jakob Disease (CJD) is the most common of the human prion diseases. There are three types of CJD: 1) sporadic, also called spontaneous, for which the cause is not known; 2) familial, also called genetic or inherited, which is due to a defect in the prion protein gene; 3) and acquired, which is transmitted by infection due to exposure to the infectious prion from contaminated meat, or from transplant of contaminated tissues or use of contaminated instruments during surgical procedures.

Classification of Human Prion Diseases

Form Phenotype (Clinical and Pathological Features)
Sporadic Sporadic Creutzfeldt-Jakob Disease (sCJD), Sporadic Familial Inssomnia (sFI)
Familial  Familial Creutzfeldt-Jakob Disease (fCJD), Fatal Familial Insomnia (FFI), Gerstmann-Sträussler-Scheinker
Acquired Iatrogenic Creutzfeldt-Jakob Disease (iCJD), variant Creutzfeldt-Jakob Disease (vCJD), Kuru

Sporadic Prion Diseases (sCJD)

Sporadic prion diseases are defined as those that neither harbor a genetic mutation in the prion protein gene, nor have a history of exposure to PrPSc. The events that trigger sporadic prion diseases are not known in detail but it is thought that PrPSc forms spontaneously because of the occurrence of some error of the metabolism in the brain cells. Sporadic prion diseases comprise three disease types based on their clinical, histopathological (or phenotypical) and PrPSc features: sporadic Creutzfeldt - Jakob disease (sCJD), sporadic fatal Insomnia (sFI) and the newly identified variably protease sensitive prionopathy (VPSPr). Sporadic CJD and VPSPr include five and three disease subtypes, respectively, based on the combination of normal variations of the PrPC gene (not mutations) and the biochemical features of PrPSc. The normal variations of the PrPC gene are related to the presence, at position 129 of the human PrPC gene, of a codon (the building block of genes) encoding either the amino acid (AA) methionine (M) or valine (V). This choice of one of two AA is called polymorphism. Since all individuals have essentially two “genes” called alleles, one from each parent, we all MM, MV, or VV at PrPC gene codon 129, and therefore, have M or V in the two PrPC copies encoded by the two PrP alleles.

This PrP polymorphism at codon 129 modifies the clinical presentation of the disease in each affected individual, i.e. when affected by a prion disease, individuals who are 129MM have a different disease than do affected individuals who are 129VV. Another disease modifier is shape or structure of the abnormal prion protein, which can be divided into two distinct types (1 and 2) based on Western blot examination. This combination of the PrPC genotype and PrPSc type harbored by the patient determines the distinct clinical and pathological manifestations in each affected individual (Table). Sporadic CJD is by far the common prion disease accounting for over 90% of all human prion diseases.

Familial Prion Diseases (fCJD)

Familial prion diseases manifest as one of three distinct clinicopathological entities i.e. Familial Creutzfeldt-Jakob Disease (fCJD), Fatal Familial Insomnia (FFI) and Gerstmann-Sträussler-Scheinker disease (GSS). Familial prion diseases are defined by the presence of a mutation in the PrPC gene. As with the sporadic prion diseases, the genetic polymorphism at codon 129 of the PrP gene (MM, MV or VV) also modifies the characteristics of the familial prion disease because of the presence of a mutation, the PrP gene encodes for a prion protein with greater tendency to convert to PrPSc. Familial prion diseases account for approximately 10% of all human prion diseases.

Acquired Prion Diseases

Acquired prion diseases are caused by exposure to exogenous PrPSc through food ingestion or medical and surgical procedures. Kuru, which is now virtually extinct, is the progenitor of this disease group. Kuru affected a tribe of New Guinea that practices ritual cannibalism. The epidemic was probably started by the consumption of an individual or individuals affected by prion disease. The Variant CJD (vCJD) epidemic was caused in the UK by the consumption of prion-contaminated meat from cattle affected by the prion disease called bovine spongiform encephalopathy or BSE. Variant CJD was first reported in the UK in 1996. A total of 229 cases has been reported worldwide, of which 177 have been observed in the UK, 27 in France and fewer case in other countries. 4 cases have been reported in the US, all of which appear to be exposed to prion disease in foreign countries. However, in the US, the possibility that chronic wasting disease, the prion disease of elk and deer, be transmitted to humans needs to be carefully monitored. The CJD associated with administration of prion contaminated hormones, the use of prion contaminated tissue implants or surgical instruments is commonly identified as iatrogenic CJD (iCJD).

About Human Prion Diseases - Animal Prion Diseases Relevant to Humans

Bovine Spongiform Encephalopathy (BSE)

BSE is a prion disease of cattle. Since 1986, when BSE was recognized, over 180,000 cattle in the UK have developed the disease, and approximately one to three million are likely to have been infected with the BSE agent, most of which were slaughtered for human consumption before developing signs of the disease. The origin of the first case of BSE is unknown, but the epidemic was caused by the recycling of processed waste parts of cattle, some of which were infected with the BSE agent and given to other cattle in feed. Control measures have resulted in the consistent decline of the epidemic in the UK since 1992. Infected cattle and feed exported from the UK have resulted in smaller epidemics in other European countries, where control measures were applied later.

Compelling evidence indicates that BSE can be transmitted to humans through the consumption of prion contaminated meat. BSE-infected individuals eventually develop vCJD with an incubation time believed to be on average 10 years. As of November 2004, three cases of BSE have been reported in North America. One had been imported to Canada from the UK, one was grown in Canada, and one discovered in the USA but of Canadian origin. There has been only one case of vCJD reported in the USA, but the patient most likely acquired the disease in the United Kingdom. If current control measures intended to protect public and animal health are well enforced, the cattle epidemic should be largely under control and any remaining risk to humans through beef consumption should be very small. (For more details see Smith et al.British Medical Bulletin, 66: 185. 2003.)

Chronic Wasting Disease (CWD) 

CWD is a prion disease of elk and deer, both free range and in captivity. CWD is endemic in areas of Colorado, Wyoming, and Nebraska, but new foci of this disease have been detected in Nebraska, South Dakota, New Mexico, Wisconsin, Mississippi Kansas, Oklahoma, Minnesota, Montana, and Canada. Since there are an estimated 22 million elk and deer in the USA and a large number of hunters who consume elk and deer meat, there is the possibility that CWD can be transmitted from elk and deer to humans. As of November 2004, the NPDPSC has examined 26 hunters with a suspected prion disease. However, all of them appeared to have either typical sporadic or familial forms of the disease. The NPDPSC coordinates with the Centers for Disease Control and state health departments to monitor cases from CWD-endemic areas. Furthermore, it is doing experimental research on CWD transmissibility using animal models. (For details see Sigurdson et al.British Medical Bulletin. 66: 199. 2003 and Belay et al.Emerging Infectious Diseases. 10(6): 977. 2004.)