Prion Diseases (Transmissible Spongiform Encephalopathies)



  • Transmissible spongiform encephalopathies (TSEs) or prion diseases are a family of progressive neurodegenerative diseases of humans and animals that cause irreversible cumulative brain damage and are uniformly fatal.
    • Prions
      • The infectious agents that cause TSE
      • The term prion was coined to denote “a small proteinaceous infectious particle resistant to inactivation by most procedures that modify nucleic acids.”
    • Prion proteins (PRP)
      • Normal cellular glycoproteins (PRPC) encoded by the PRNP gene
      • Are found on neurons and white blood cells
  • The infectious particles that cause TSEs are protease-resistant conformers of PRPC (PRPRES or PRPSC for protease-resistant or scrapie-causing PRPs, respectively).
  • Human TSEs include Creutzfeldt-Jakob disease (CJD), the more recently identified variant CJD (vCJD), kuru, Gerstmann-Sträussler-Scheinker syndrome, and fatal familial insomnia syndrome.
  • Six TSEs in animals have been described: bovine spongiform encephalopathy (BSE, also known as mad cow disease), scrapie in sheep and goats, feline spongiform encephalopathy, transmissible mink encephalopathy, exotic ungulate encephalopathy, and chronic wasting disease of cervids.


  • CJD
    • CJD is the most prevalent form of TSE in humans and occurs as either a sporadic or a familial disease.
    • ~85% of cases are sporadic because there is no family history and no known source of transmission. Sporadic CJD occurs throughout the world at a rate 1/1,000,000 people.
    • Familial CJD (fCJD) cases are associated with a gene mutation in PRNP and account for ~10–15% of cases. fCJD shows an autosomal dominant inheritance, with >50 mutations in PRNP identified.
    • ~1% of CJD cases are iatrogenic, resulting from accidental transmission of the causative agent via contaminated surgical equipment, as a result of cornea or dura mater transplants, or administration of human-derived pituitary growth hormones.
    • No evidence confirms person-to-person transmission among family members via direct contact, droplet, or airborne spread.
    • Disease is characterized by progressive dementia, myoclonus, visual or cerebellar disturbance, pyramidal/extrapyramidal dysfunction, and/or akinetic mutism.
    • Classic sporadic CJD most often occurs between the ages of 50 and 70 years and affects both sexes equally; whites have about a 2-fold higher rate than blacks.
    • Death usually occurs within 1 year of onset of symptoms.
  • vCJD
    • New form of CJD, first reported in 1994; has unique clinical features
    • In contrast to CJD, affects younger patients including adolescents (average age, 29 years) and has a longer duration of illness with median of 14 months as opposed to 4.5 months with CJD
    • Strong epidemiologic evidence links vCJD to BSE:
      • BSE is a TSE that affects cattle; it was first reported in the United Kingdom. The most likely route of exposure is through bovine-based foods derived from BSE-infected cattle.
      • Highest incidence of vCJD is seen in the United Kingdom, the country with the largest potential exposure to BSE.
      • 3 cases of vCJD have been confirmed in the United States, although each were likely to have been contracted outside the United States.
  • Clinical features, found early in the illness, include the following:
    • Prominent psychiatric symptoms (e.g., depression, schizophrenia-like psychosis) and ataxia
    • Other neurologic signs (e.g., paresthesia/dysesthesia, chorea, dystonia, myoclonus, and akinetic mutism) develop as the disease progresses.
  • Recently, clinical criteria for the diagnosis of vCJD were validated in the United Kingdom by autopsy/biopsy-proven cases compared to noncases.
  • Fatal familial insomnia (FFI)
    • An autosomal dominant disorder, caused by mutation at codon 178 of PRNP, also identified in fCJD. If there are homozygous alleles at codon 129 encoding methionine in conjunction with the codon 178 mutation, FFI ensues. If codon 129 encodes valine in conjunction with the codon 178 mutation, then fCJD develops.
    • Clinical features include insomnia, dysautonomia, ataxia, myoclonus, and late dementia.
    • Pathology reveals minimal vacuolization and no plaques.
  • Gerstmann-Sträussler-Scheinker syndrome
    • A disorder with autosomal dominant inheritance
    • Clinical features include ataxia and dementia.
    • Pathology reveals amyloid plaques.


  • TSE arises when exogenous or endogenous PRPRES cause PRPC to misfold into the abnormal protease-resistant form associated with TSE.
  • Progressive accumulation of PRPRES in the CNS disrupts function, leading to vacuolization and cell death. There is no host-adaptive immune response beyond microglial cell activation involved in the pathologic process.
  • Neuropathologic findings include neuronal loss, atrophy, vacuolization or spongiform change, reactive astrogliosis, and cell death.
  • PRPRES also accumulate in the reticular endothelial system, mucosa-associated lymphoid tissues, and areas of chronic inflammation throughout the body.


  • Prions are infectious proteins lacking nucleic acids that are believed to cause TSE.
  • Infection arises when normal protease-sensitive host proteins, involved in neuronal function, undergo spontaneous misfolding to yield the abnormal protease-resistant form associated with infectivity.
  • Newly formed host PRPRES recruit neighboring cellular PRPC and convert it to the infectious conformer. The exact molecular and cellular mechanisms surrounding propagation of PRPRES remains unknown.
  • Although the presence of PRPC is necessary for the migration of PRPRES to the RES, the mechanism for migration to the CNS remains unknown.
  • Prions reproduce by recruiting neighboring normal cellular PRP and stimulating its conversion to the infectious form.
  • Whether PRPRES reproduce without any genetic material, thus bypassing the central dogma is still hotly debated.
  • Not all scientists believe the prion hypothesis, and some have argued that the causative agent is virus-like and possesses nucleic acids although none has ever been isolated from TSE pathologic specimens.

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