Prion Disease

Aka: Prion Disease, Transmissible Spongiform Encephalopathy, Prion Protein Disease, Prion, Prion Protein, Proteinaceous Infectious Particles, PrP Protein, Mad Cow Disease, Scrapie, Bovine Spongiform Encephalopathy, Fatal Familial Insomnia, Gerstmann-Straussler-Scheinker Disease, Kuru

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II. Epidemiology

  1. Worldwide: 1 to 1.5 cases per 1 Million per year
  2. U.S.: 1 to 1.2 cases per 1 Million per year (400/year)

III. Definitions

  1. Prion Protein (PrP Protein, Proteinaceous Infectious Particles)
    1. Prion related-Proteins (PrP) are normal components of the cell
      1. This normal Protein, denoted cellular (PrPc) is suspected to play a role in cellular signaling
      2. Cellular PrP is encoded by the PRNP gene on Chromosome 20 in humans
    2. Neurodegenerative disorders may occur when these normal PrP are converted to misfolded abnormal prions
      1. Disease-associated Prion Proteins are denoted PrPsc (for Scrapie)
      2. PrPsc, even in small amounts, may trigger normal cellular PrP to undergo misfolding
      3. Prions are small infectious Protein particles that are resistant to standard forms of inactivation
  2. Prion Disease (Transmissible Spongiform Encephalopathy or TSE)
    1. Genetic, infectious and sporadic neuro-degenerative disorders (e.g. Dementia, Ataxia) associated with Prion Proteins
    2. These diseases are triggered by misfolded Proteins and their metabolic products that deposit in neural tissue

IV. Causes: Humans

  1. Sporadic (>80% of U.S. cases, all Sporadic CJD)
    1. See Creutzfeldt-Jakob Disease (focus on Sporadic CJD)
    2. Sporadic Creutzfeldt-Jakob Disease (sCJD)
  2. Genetic (mutations in prion-related Protein gene or PRNP, 10-15% of U.S. cases)
    1. Familial Creutzfeldt-Jakob Disease (fCJD)
    2. Gerstmann-Straussler-Scheinker Syndrome
      1. Slowly progressive Ataxia or Parkinsonism-like motor disorder with late onset Ataxia
      2. At least 12 mutations have been identified
      3. Onset at median age 50-60 years, but very young age onset may occur (typical range age 20 to 70)
      4. Testing including MRI, EEG and CSF biomarkers are typically non-diagnostic
    3. Fatal Familial Insomnia
      1. Very rare PRNP mutation D178N (cis codon 129M)
      2. Progressive Insomnia over months, autonomic instability (Tachycardia, Hyperhidrosis, fever)
      3. Dementia and motor deficits occur later in course
      4. Typical onset in late 40s and mean survival 18 months
  3. Acquired (rare, <1% of U.S. CJD cases)
    1. New Variant Creutzfeldt-Jakob Disease (vCJD)
      1. Transmission of Mad Cow Disease (BSE) to humans
    2. Iatrogenic Creutzfeldt-Jakob Disease (iCJD)
      1. Contaminated neurosurgery instruments
      2. Dura grafts
      3. Corneal grafts
      4. Cadaver-based pituitary Hormone administration
    3. Kuru (limited to Papua New Guinea, Fore tribe cannibals)
      1. https://en.wikipedia.org/wiki/Kuru_(disease)
      2. Ritualistic cannibalism on death of an infected person lead to epidemic kuru in the tribe
      3. No further Kuru cases occurred after cessation of the Ritualistic cannibalism practice

V. Causes: Animals

  1. Cow CJD (Bovine Spongiform Encephalopathy, BSE, Mad Cow Disease)
    1. Transmitted to cows by eating contaminated feed
      1. Cattle had been fed sheep offal, and MBM (meat and bone meal, post-butchering residuals)
      2. MBM was thought to be contaminated with infected sheep brain
      3. Specified Risk Materials (SRM, lymph, neural tissue, spinal cord) must now be excluded from meat products
    2. Transmission from animals to humans
      1. New Variant CJD (vCJD) is thought to be a transmission of Bovine Spongiform Encephalopathy
      2. Peak in UK BSE cases (1988-2005) followed by tens of thousands of UK vCJD cases (1994-2009)
      3. Since 2012, vCJD cases have been rare
      4. https://en.wikipedia.org/wiki/United_Kingdom_BSE_outbreak
  2. Sheep CJD (Scrapie)
    1. Only transmitted to humans if passed via cattle eating contaminated feed (see above)
  3. Chronic Wasting Disease (CWD, deer and elk)
    1. Possible transmission to humans from exposure to neurologic tissue (butchering) or contaminated meat ingestion

VI. Pathophysiology

  1. Transmitted via Prion Protein infectious agents
    1. Prions are the only infectious agent to contain no Nucleic Acids
  2. Prions cause other Proteins to precipitate
    1. Misfolded Prion Proteins and their metabolic products deposit as Plaques in the brain
    2. Results in Spongiform encephalopathy
  3. Prions are very difficult to control
    1. Resistant to disinfectants and sterilization
    2. Environmental decay is very slow
      1. Persists in environment despite removing animals
  4. Transmission
    1. At least 80% of CJD cases are sporadic
    2. Humans may acquire CJD via surgical procedures, transfusions, and contaminated meats (esp. neuro tissue exposure)
      1. Prions travel via lymph
      2. Spreads to brain via Lymphocytes
      3. Disease may have a long latent period after exposure (from 2 to 40 years)
      4. However, once the onset of clinical disease, progression is typically rapid, and uniformly fatal
    3. Animals may spread some Prion Diseases to one another via Saliva (e.g. Scrapie)
      1. Maddison (2010) J Infect Dis 201(11):1672-6 +PMID:20402590 [PubMed]
      2. However this does not appear to be a factor in transmission of Creutzfeldt-Jakob Disease between humans
  5. Prion Diseases share several characteristics
    1. Long Incubation Periods (months to years)
    2. Severity progresses invariably to death over the course of months
    3. Host immune response is absent
    4. Neurodegenerative findings are without signs of inflammation
    5. Microscopic spongiform changes
      1. Small vacuoles within neural tissue
      2. Neuronal loss
      3. Amyloid Plaques that accumulate Prion Protein (PrP)

VII. References

  1. Gladwin, Trattler and Mahan (2014) Clinical Microbiology, Medmaster, Fl, p. 382-6
  2. Belay (2001) Arch Neurol 58:1673-8 [PubMed]
  3. Brown (2000) Neurology 55(8):1075-81 [PubMed]
  4. Drisko (2002) J Am Coll Nutr 21(1):22-5 [PubMed]
  5. Geschwind (2015) Continuum 21(6): 1612-38 +PMID:26633779 [PubMed]

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