Prion diseases are progressive, fatal, and untreatable degenerative disorders of the nervous system.
Prominent types of prion diseases affect nervous tissue and are known as transmissible spongiform encephalopathies. They include
Creutzfeldt-Jakob disease (CJD), the prototypic example (usually sporadic)
Variant CJD (vCJD; acquired by eating prion-contaminated beef)
Variably protease-sensitive prionopathy (VPSPr; sporadic)
Gerstmann-Sträussler-Scheinker disease (GSS; inherited)
Fatal insomnia (FI; includes a sporadic and an inherited form)
Kuru (acquired by ritual cannibalism)
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 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 transmissible. 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
Normal PrPC is water soluble and protease sensitive. A large percentage of PrPSc, however, 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. In acquired prion diseases, symptoms and signs develop months to years after the initial exposure to PrPSc.
Prion diseases should be considered in all patients with a rapid neurodegenerative condition.
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 to 2 cases per million people (1). How PrPSc first forms is unknown, though it is unlikely to be due to somatic mutations in the PrP gene (PRNP mutations) (2).
Familial prion diseases are caused by defects in the PrP gene (PRNP), which is contained in the short arm of chromosome 20 (3). The mutations causing prion diseases are almost all autosomal dominant; ie, they cause disease when they are inherited from only one parent. 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.
More than 50 mutations exist. Different gene defects cause different types of prion disease, which include
Diseases with mixed features of CJD and GSS
Diseases that are clinically distinct from other prion diseases, such as prion disease associated with diarrhea and autonomic neuropathy
Fatal familial insomnia (FFI)
To date, researchers have identified only 1 mutation that causes FFI, the familial form of fatal insomnia.
The PRNP mutations alter the amino acid sequence of PrPC, causing it to misfold and become PrPSc. Small abnormalities in specific codons (called polymorphisms, 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 (4).
Infectiously transmitted prion diseases are rare. They can be transmitted:
From person to person: Iatrogenically, via organ and tissue transplants, use of contaminated neurosurgical instruments, blood transfusion (rarely; vCJD only), or via cannibalism (kuru)
From animal to person: Via ingestion of contaminated beef (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, cats, goats, camels, and 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 most states in the United States, Canada, South Korea, Norway, Finland, and Sweden (3), 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 affected animals. Studies find that barriers between species may be weakened when CWD has been transmitted from animal to animal several times (as may happen in the wild or through secondary passage through production animals) or when CWD strains change, possibly making CWD more likely to be transmitted to humans (5, 6).
Transmission references
1. Maddox RA, Person MK, Blevins JE, et al. Prion disease incidence in the United States: 2003-2015. Neurology. 2020;94(2):e153-e157. doi:10.1212/WNL.0000000000008680
2. McDonough GA, Cheng Y, Morillo KS, et al. Neuropathologically directed profiling of PRNP somatic and germline variants in sporadic human prion disease. Acta Neuropathol. 2024;148(1):10. Published 2024 Jul 24. doi:10.1007/s00401-024-02774-2
3. Appleby BS, Shetty S, Elkasaby M. Genetic aspects of human prion diseases. Front Neurol. 2022;13:1003056. Published 2022 Oct 5. doi:10.3389/fneur.2022.1003056
4. Pocchiari M and Manson J: Human Prion Diseases. In Handbook of Clinical Neurology, edited by M Pocchiari, and J Manson. New York, Elsevier, 2018, vol 153, pp. 2–498.
5. 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. 286(9):7490–7495, 2011. doi: 10.1074/jbc.M110.198465
6. Osterholm MT, Anderson CJ, Zabel MD, Scheftel JM, Moore KA, Appleby BS. Chronic Wasting Disease in Cervids: Implications for Prion Transmission to Humans and Other Animal Species. mBio. 2019;10(4):e01091-19. Published 2019 Jul 23. doi:10.1128/mBio.01091-19
Treatment of Prion Diseases
Supportive care
There is no treatment for prion diseases. Treatment is supportive (1).
Patients should be encouraged to prepare advance directives (eg, preferred end-of-life care) soon after the disorder is diagnosed. Hospice care is recommended.
Genetic counseling may be recommended for family members of patients with a familial prion disease (2).
Treatment references
1. Appleby BS, Yobs DR. Symptomatic treatment, care, and support of CJD patients. Handb Clin Neurol. 2018;153:399-408. doi:10.1016/B978-0-444-63945-5.00021-0
2. Goldman JS, Vallabh SM. Genetic counseling for prion disease: Updates and best practices. Genet Med. 2022;24(10):1993-2003. doi:10.1016/j.gim.2022.06.003
Prevention of Prion Diseases
People should not consume animals that are known or suspected to be infected with prion disease.
Prions resist standard disinfection techniques and may be a risk to surgeons, pathologists, or technicians who handle contaminated tissues or instruments as well as to other patients in whom those prion-contaminated instruments will be used.
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 hour
Immersion in sodium hydroxide 1 N (normal) or 10% sodium hypochlorite solution for 1 hourImmersion in sodium hydroxide 1 N (normal) or 10% sodium hypochlorite solution for 1 hour
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