Prion Diseases (Transmissible Spongiform Encephalopathies)



  • Prion diseases or transmissible spongiform encephalopathies (TSEs) are a family of progressive neurodegenerative diseases of humans and animals that cause irreversible cumulative brain damage and are uniformly fatal.
  • Prions are the causative agent for prion disease and are misfolded forms of normally occurring prion protein (PRPc).
  • Human prion diseases include Creutzfeldt-Jakob disease (CJD), variant CJD (vCJD), kuru, Gerstmann-Sträussler-Scheinker syndrome, and fatal familial insomnia (FFI) 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 prion disease in humans and occurs as either a sporadic or a familial disease.
    • ~85% of cases are sporadic with 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 the gene (PRNP) for making PRPc 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
    • First reported in 1994; variant CJD has unique clinical features.
    • In contrast to CJD, vCJD affects younger patients (as young as 11 years of age with an average age of 29 years) and has a longer duration of illness with median of 14 months.
    • 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.
      • Three 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.
    • Clinical criteria for the diagnosis of vCJD have been validated in the United Kingdom by autopsy/biopsy-proven cases compared to noncases.
  • 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.


  • PRPc are metal-binding proteins normally found on neuronal cells and other cells throughout the body.
  • Infections arise when normal host PRPc undergoes spontaneous misfolding to yield the abnormal protease-resistant conformers (PRPRES or PRPSC for protease-resistant or scrapie-causing PRPs, respectively).
  • 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.
  • 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.


  • The majority of prion disease cases develop without explanation (sporadic CJD).
  • Genetic forms of prion disease variously arise from a number of missense, nonsense, insertion, or deletion mutations in the PRPc (PRNP) gene.
  • The etiologic agent for vCJD is BSE and can be transmitted to the CNS by oral, parenteral, or direct inoculation.
  • For vCJD, the mechanism of prion transmission to the CNS from oral and parenteral exposure remains uncertain.

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