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prion diseases

Saturday 6 March 2004

Transmissible spongiform encephalopathies (TSEs) such as scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle or Creutzfeldt-Jacob disease (CJD) and Gerstmann- Straussler-Scheinker syndrome (GSS) in humans, are caused by an infectious agent designated prion.

Prion diseases have a broad spectrum of clinical manifestations, including dementia, ataxia, insomnia, paraplegia, paresthesias, and deviant behavior.

Neuropathological findings range from an absence of atrophy to widespread atrophy, from minimal to widespread neuronal loss, from sparse to widespread vacuolation or spongiform changes, from mild to severe reactive astrocytic gliosis, and from an absence of PrP amyloid plaques to an abundance of plaques. None of these findings except the presence of PrP amyloid plaques is unequivocally diagnostic of a prion disease.


- Creutzfeldt-Jacob disease (CJD) (MIM.123400)
- Gerstmann- Straussler-Scheinker syndrome (GSS) (MIM.137440)
- kuru
- familial atypical spongiform encephalopathy (FASE)
- familial fatal insomnia (MIM.600072)

Microscopical synopsis

- spongiform encephalopathy
- neuronal loss
- gliosis
- Proteinase resistant form of PrP: synaptic or extracellular amyloid deposits.

Creutzfeldt–Jakob disease

- Types

  • familial Creutzfeldt–Jakob disease
  • sporadic 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.

“Protein only” hypothesis

The “protein only” hypothesis states that the prion consists partly or entirely of a conformational isoform of the normal host protein PrPC and that the abnormal conformer, when introduced into the organism, causes the conversion of PrPC into a likeness of itself.

Since the proposal of the “protein only” hypothesis more than three decades ago, cloning of the PrP gene, studies on PrP knockout mice and on mice transgenic for mutant PrP genes allowed deep insights into prion biology.

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.

Susceptibility to prion diseases

Polymorphisms influence the susceptibility to sporadic, inherited, and infectious forms of prion disease. Dominant negative alleles in approximately 12 percent of the Japanese population encode for lysine at position 219 and interfere with the conversion of wild-type PrPC into PrPSc. Dominant negative inhibition of prion replication has also been found in sheep, with a substitution of the basic residue arginine at position 171.

PrP knockout mice

Reverse genetics on PrP knockout mice containing modified PrP transgenes was used to address a variety of problems: mapping PrP regions required for prion replication, studying PrP mutations affecting the species barrier, modeling familial forms of human prion disease, analysing the cell specificity of prion propagation and investigating the physiological role of PrP by structure-function studies.


- transmissible spongiform encephalopathies


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