Prions cause Creutzfeldt–Jakob disease in humans throughout the world. The incidence of sporadic Creutzfeldt–Jakob disease is approximately 1 case per 1 million population, but among persons between the ages of 60 and 74 years, the incidence is nearly 5 per 1 million. Cases in patients as young as 17 years and as old as 83 have been recorded.
Creutzfeldt–Jakob disease is relentlessly progressive and usually causes death within a year after its onset. Each geographic cluster of cases of prion disease was initially thought to be a manifestation of viral communicability, but each was later shown to be due to a PRNP gene mutation except for new variant Creutzfeldt–Jakob disease.
Types
sporadic Creutzfeldt–Jakob disease
- variant Creutzfeldt–Jakob disease (vCJD)
familial Creutzfeldt–Jakob disease
The sporadic form of Creutzfeldt–Jakob disease, which is typically manifested as dementia and myoclonus, accounts for approximately 85 percent of all cases of prion disease in humans, whereas infectious and inherited prion diseases account for the rest.
Familial Creutzfeldt–Jakob disease, Gerstmann–Sträussler–Scheinker disease, and fatal familial insomnia are all dominantly inherited prion diseases caused by mutations in the prion protein gene (PRNP).
Experiments that showed transmission of these diseases by filtrates of brain from familial cases were wrongly attributed to a virus. There is no Creutzfeldt–Jakob disease virus, and familial prion diseases are caused by mutations in PRNP.
Neuropathological Features
There are often no recognizable gross abnormalities in the brains of patients with Creutzfeldt–Jakob disease. Patients who survive for several years have variable degrees of cerebral atrophy. The microscopical features of Creutzfeldt–Jakob disease are spongiform degeneration and astrogliosis.
Sporadic Creutzfeldt–Jakob disease is characterized by vacuolation of the neuropil in the gray matter; by exuberant reactive astrocytic gliosis, the extent of which is proportional to the degree of nerve-cell loss; and in rare cases by the formation of prion protein (PrP) amyloid plaques.
The neuropathological features of familial Creutzfeldt–Jakob disease are similar. Gerstmann–Sträussler–Scheinker disease due to a substitution at codon 102 (P102L), as well as other inherited forms of Gerstmann–Sträussler–Scheinker disease, is characterized by numerous deposits of PrP amyloid throughout the central nervous system.
New variant Creutzfeldt–Jakob disease is distinguished by the abundance of PrP amyloid plaques, which are often surrounded by a halo of intense vacuolation.
Amyloid plaques occur in approximately 10 percent of cases of Creutzfeldt–Jakob disease. These plaques are positive for antibodies against PrPSc on immunohistochemical staining.
The amyloid plaques in patients with Gerstmann–Sträussler–Scheinker disease consist of a dense core of amyloid surrounded by smaller globules of amyloid.
A characteristic feature of new variant Creutzfeldt–Jakob disease is the presence of "florid plaques" composed of a core of PrPSc amyloid surrounded by vacuoles.
Non-infectious prion diseases
Sporadic prion diseases might be initiated by a somatic mutation and in this respect might develop in a manner similar to prion diseases caused by germ-line mutations. In this situation, the mutant PrPSc must be capable of recruiting wild-type PrPC, a process that may occur with some mutations but is unlikely with others.
Alternatively, the activation barrier separating wild-type PrPC from PrPSc may be crossed on rare occasions in the context of a large population of people.
Twenty mutations in the human PRNP gene have been found to segregate with inherited prion diseases. Missense mutations and expansions in the octapeptide-repeat region of the gene cause familial prion diseases.
Infectious prion diseases
Although infectious prion diseases constitute less than 1 percent of all cases of prion disease, the circumstances surrounding the transmission of these infectious illnesses are often dramatic.
Ritualistic cannibalism has resulted in the transmission of kuru among the Fore people of New Guinea, industrial cannibalism has been responsible for bovine spongiform encephalopathy (BSE), or "mad cow disease," in Europe, and an increasing number of patients have contracted new variant Creutzfeldt–Jakob disease from prion-tainted beef products.
New variant Creutzfeldt–Jakob disease
The restricted geographic and temporal distribution of cases of new variant Creutzfeldt–Jakob disease raises the possibility that BSE prions have been transmitted to humans.
Although over 100 cases of new variant Creutzfeldt–Jakob disease have been recorded, no dietary habits distinguish patients with this disease from apparently healthy persons.
Moreover, it is unclear why teenagers and young adults seem to be particularly susceptible to the disease. These cases may mark the start of an epidemic of prion disease in Great Britain like those of BSE and kuru, or the number of cases of new variant Creutzfeldt–Jakob disease may remain small, as with iatrogenic Creutzfeldt–Jakob disease caused by cadaveric human growth hormone.
The most compelling evidence that new variant Creutzfeldt–Jakob disease is caused by BSE prions comes from studies of mice expressing the bovine PrP transgene.
The incubation times, neuropathological features, and patterns of PrPSc deposition in these transgenic mice are the same whether the inoculate originated from the brains of cattle with BSE or from humans with new variant Creutzfeldt–Jakob disease.
The origin of BSE is still obscure, although epidemiologic studies indicate that BSE probably arose from a single point source in the southwest of England in the 1970s. It probably originated from a rare case of prion disease in either sheep or cattle. Once established, the disease was spread in cattle by ingestion of prion-contaminated meat and bone meal.
Accidental transmission of Creutzfeldt–Jakob
The accidental transmission of Creutzfeldt–Jakob disease to humans appears to have occurred with corneal transplantation and use of contaminated electroencephalographic electrodes.
The same improperly decontaminated electrodes that had caused Creutzfeldt–Jakob disease in two young patients with intractable epilepsy were found to cause Creutzfeldt–Jakob disease in a chimpanzee 18 months after their implantation in the animal.
More than 70 cases of Creutzfeldt–Jakob disease associated with the implantation of dura mater grafts have been recorded. One case occurred after the repair of a perforated eardrum with a pericardial graft. Prion-contaminated human growth hormone preparations derived from human pituitary tissue have caused fatal cerebellar disorders with dementia in more than 120 patients ranging in age from 10 to 41 years. Four cases of Creutzfeldt–Jakob disease have occurred in women who received human pituitary gonadotropin.
References
Ingrosso L, Vetrugno V, Cardone F, Pocchiari M. Molecular diagnostics of transmissible spongiform encephalopathies. Trends Mol Med. 2002 Jun;8(6):273-80. PMID: 12067613