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Overview of Prion Diseases

(Transmissible Spongiform Encephalopathies)

By Pierluigi Gambetti, MD, Professor and Director, National Prion Disease Pathology Surveillance Center, Institute of Pathology, Division of Neuropathology, Case Western Reserve University

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Prion diseases are progressive, fatal, and untreatable degenerative brain disorders.

Prominent types include

A recently identified type is prion disease associated with diarrhea and autonomic neuropathy, which is inherited.

Prion diseases result from misfolding of a normal cell-surface brain protein called cellular prion protein (PrPC), whose exact function is unknown. Misfolded prion proteins are called prions or scrapie PrP (PrPSc—from the name of the prototypic prion disease of sheep).

Prions (PrPSc) are pathogenic and often infectious. They produce prion disease by

  • Self-replicating: PrPSc induces conformational transformation of PrPC, creating duplicate PrPSc, which, in a chain reaction, induces further transformation of PrPC into PrPSc. This transformation process spreads PrPSc to various regions of the brain.

  • Causing neuronal cell death

  • Being transmissible

Normal PrPC is water soluble and protease sensitive, but a large percentage of PrPSc is water insoluble and markedly resistant to protease degradation (similar to beta-amyloid in Alzheimer disease, which PrPSc resembles), resulting in slow but inexorable cellular accumulation and neuronal cell death. Accompanying pathologic changes include gliosis and characteristic histologic vacuolar (spongiform) changes, resulting in dementia and other neurologic deficits. Symptoms and signs develop months to years after the initial exposure to PrPSc.

Prion diseases should be considered in all patients with dementia, especially if it progresses rapidly.

Transmission of prion diseases

Prion diseases originate

  • Sporadically (apparently starting spontaneously, without a known cause)

  • Via genetic inheritance (familial)

  • Via infectious transmission

Sporadic prion diseases are the most common, with a worldwide annual incidence of about 1/1 million people. How PrPSc first forms is unknown.

Familial prion diseases are caused by defects in the PrP gene, which is contained in the short arm of chromosome 20. The genetic mutations causing prion diseases are autosomal dominant; ie, they cause disease when they are inherited from only one parent. Also, penetrance is variable; ie, depending on the type of mutation, a variable percentage of carriers of the mutation have clinical signs of the disease during their lifetime. Some gene defects cause familial CJD, some cause GSS, and others cause diseases with mixed features of CJD and GSS. To date, researchers have identified only one mutation that causes fatal familial insomnia (FFI), the familial form of fatal insomnia. The PrP gene mutations alter the amino acid sequence of PrPC, causing it to misfold and become PrPSc. Small abnormalities in specific codons (nucleotide sequences that are the building blocks of genes), which on their own do not cause disease, may determine the predominant symptoms and rate of disease progression in familial and other prion diseases (1).

Infectiously transmitted prion diseases are rare. They can be transmitted

  • From person to person: Iatrogenically, via organ and tissue transplants, use of contaminated surgical instruments, or, rarely, blood transfusion (as in vCJD); or via cannibalism (as in kuru)

  • From animal to person: Via ingestion of contaminated beef (as in vCJD)

Prion diseases are not known to be contagious through casual person-to-person contact.

Prion diseases occur in many mammals (eg, mink, elk, deer, domestic sheep and cattle) and can be transmitted between species via the food chain. However, transmission from animals to humans has been observed only in vCJD, after people consumed beef from cattle with bovine spongiform encephalopathy (BSE, or mad cow disease).

In several western US states, Canada, and now South Korea and Norway (2), there is concern that chronic wasting disease (CWD), the prion disease of elk and deer, may be transmissible to people who hunt, butcher, or eat the affected animals. Although transmission of CWD from animals to humans is unlikely, recent data indicate that the barriers between species may be weakened when CWD has been transmitted from animal to animal several times (as may happen in the wild [3]).

Transmission references

  • 1. Gambetti P, Kong Q, Zou W, et al: Sporadic and familial CJD: Classification and characterisation. Br Med Bull 66 (1):213–239, 2003. doi: https://doi.org/10.1093/bmb/66.1.213.

  • 2. Benestad SL, Mitchell G, Simmons M, et al: First case of chronic wasting disease in Europe in a Norwegian free-ranging reindeer. Vet Res 47 (1):88. 2016. doi: 10.1186/s13567-016-0375-4.

  • 3. Barria MA, Telling GC, Gambetti P, et al: Generation of a new form of human PrPSc in vitro by interspecies transmission from cervid prions. J Biol Chem 4;286 (9):7490–7495, 2011. doi: 10.1074/jbc.M110.198465.

Treatment of Prion Diseases

  • Supportive care

There is no treatment for prion diseases. Treatment is supportive.

Patients should be encouraged to prepare advance directives (eg, preferred end-of-life care) soon after the disorder is diagnosed.

Genetic counseling may be recommended for family members of patients with a familial prion disease.

Prevention of Prion Diseases

Prions resist standard disinfection techniques and may be a risk to other patients and to surgeons, pathologists, or technicians who handle contaminated tissues or instruments.

Transmission can be prevented by taking precautions when handling infected tissues and by using appropriate techniques to clean contaminated instruments. Using one of the following procedures is recommended:

  • Steam autoclaving at 132° C for 1 h

  • Immersion in sodium hydroxide 1 N (normal) or 10% sodium hypochlorite solution for 1 h