These disorders are very rare. Although the exact prevalence of prion disease is unknown, studies suggest that this group of conditions affects about one person per million worldwide each year. Approximately 350 new cases are reported annually in the United States.

Between 10 and 15 percent of all cases of prion disease are caused by mutations in the PRNP gene. Because they can run in families, these forms of prion disease are classified as familial. Familial prion diseases, which have overlapping signs and symptoms, include familial Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), and fatal familial insomnia (FFI).

The PRNP gene provides instructions for making a protein called prion protein (PrP). Although the precise function of this protein is unknown, researchers have proposed roles in several important processes. These include the transport of copper into cells, protection of brain cells (neurons) from injury (neuroprotection), and communication between neurons. In familial forms of prion disease, PRNP gene mutations result in the production of an abnormally shaped protein, known as PrP^Sc, from one copy of the gene. In a process that is not fully understood, PrP^Sc can attach (bind) to the normal protein (PrP^C) and promote its transformation into PrP^Sc. The abnormal protein builds up in the brain, forming clumps that damage or destroy neurons. The loss of these cells creates microscopic sponge-like holes (vacuoles) in the brain, which leads to the signs and symptoms of prion disease.

The other 85 to 90 percent of cases of prion disease are classified as either sporadic or acquired. People with sporadic prion disease have no family history of the disease and no identified mutation in the PRNP gene. Sporadic disease occurs when PrP^C spontaneously, and for unknown reasons, is transformed into PrP^Sc. Sporadic forms of prion disease include sporadic Creutzfeldt-Jakob disease (sCJD), sporadic fatal insomnia (sFI), and variably protease-sensitive prionopathy (VPSPr).

Acquired prion disease results from exposure to PrP^Sc from an outside source. For example, variant Creutzfeldt-Jakob disease (vCJD) is a type of acquired prion disease in humans that results from eating beef products containing PrP^Sc from cattle with prion disease. In cows, this form of the disease is known as bovine spongiform encephalopathy (BSE) or, more commonly, "mad cow disease." Another example of an acquired human prion disease is kuru, which was identified in the South Fore population in Papua New Guinea. The disorder was transmitted when individuals ate affected human tissue during cannibalistic funeral rituals.

Rarely, prion disease can be transmitted by accidental exposure to PrP^Sc-contaminated tissues during a medical procedure. This type of prion disease, which accounts for 1 to 2 percent of all cases, is classified as iatrogenic.