Diagnosis of prion diseases

Definition

Prion diseases diseases are rare and fatal degenerative brain disorders caused by an abnormal version of a protein in the brain. This protein aggregates and forms visible “holes” that show a spongy appearance seen through a microscope; hence, the name “spongiform encephalopathies.” Approximately 10 to 15 percent of prion diseases are genetically transmissible, whereas the remainder occur from unknown risk factors or are acquired through infection with prions.

The word “prion” was termed in 1982 by neurologist and biochemist Stanley B. Prusiner, who won the Nobel Prize in Physiology or Medicine in 1997. The term is derived from the words “protein” and “infectious.”

Types

Prion diseases occur in both human and nonhuman animals. The most common human diseases are Creutzfeldt-Jakob disease (CJD), kuru, fatal familial insomnia, and Gerstmann-Sträussler-Scheinker syndrome. Animal prion diseases include bovine spongiform encephalopathy (mad cow disease), scrapie, chronic wasting disease, and transmissible mink encephalopathy. Human prion diseases are classified into three categories: sporadic, genetic, and acquired.

CJD, the most common of the human prion diseases, usually occurs spontaneously and most often in persons age fifty years and older. Other human prion diseases are genetic in nature and can be inherited. Acquired prion diseases include the variant form of CJD, which is caused by eating beef infected with a prion disease. Kuru is a human prion disease that was spread by ritualistic cannibalism among New Guineans until the 1950’s.

Symptoms

Symptoms of the various prion diseases vary, but generally include personality changes, psychiatric problems such as depression, lack of coordination, and an unsteady gait. Other symptoms include jerking or spontaneous movements called myoclonus, unusual sensations, insomnia, confusion, and memory problems. As disease progresses, patients may exhibit mental impairment and loss of speech or movements.

Postmortem Diagnosis

Because prion diseases tend to progress rapidly and may cause death within a few months of severe symptoms, many diagnoses may not be determined until postmortem examination. This exam is called a conformation-dependent immunoassay (CDI). CDI tests identify prions in human brain tissue by using highly specific antibodies that bind to all disease-causing prions in the brain. Immunohistochemistry testing measures the prion proteins that are resistant to an enzyme called protease. Protease-resistant prions are abnormal, usually infectious, and will cause a disease state. The presence of these prions in the brain leads to a diagnosis of a prion disease.

Genetic Testing

Another approach to diagnosing a subset of prion diseases is genetic testing. Only one gene is known to be associated with prion diseases. The gene, PRNP, encodes for a protein called prion protein, which is active in the brain and other tissues of the body. The exact function of PRNP is not known, but it is thought to be involved in the transport of charged copper ions into cells. This protein may also be involved in cell signaling, cell protection, and the formation of synapses, in which cell to cell communication occurs.

More than thirty mutations of the PRNP gene have been identified in people with prion diseases (mutations in this gene cause disease). Genetic tests have been established to identify the mutations known for prion diseases by sequence analysis of the entire coding region and by targeted mutation analysis. These test methods, however, will not detect all disease-causing mutations, so the absence of a PRNP mutation does not rule out the diagnosis of a prion disease.

Clinical Features and Neuropathologic Findings

Prion disease should be considered when symptoms include dementia, neurologic signs, psychiatric problems, lack of coordination of movements, weakness, or seizures. The next step is to identify neuropathologic characteristics of prion diseases. Such findings include spongiform degeneration and astrogliosis (an increase of the number of astrocytes as nearby neurons die), distributed diffusely throughout the cortex and deep nuclei of the brain. Amyloid plaques may also be present, in which antiprion protein antibodies will bind.

Brain Imaging

Brain imaging through electroencephalogram (EEG) and examination of cerebrospinal fluid (CSF) may help support the diagnosis, but these alone are not enough to diagnose a prion disorder. These methods are often used to diagnose other disorders of the central nervous system and may not be reliable with genetic forms of prion diseases. However, EEG findings that show sharp periodic wave complexes, in which bursts of waves are seen every one-half to two seconds, may suggest a prion diagnosis. Prion diseases also show a characteristic magnetic resonance imaging (MRI) pattern, with diffusion weighted MRI, of mild to moderate generalized atrophy and hyperintensity of the basal ganglia. Patients with prion diseases often show a 10 percent increase in CSF protein concentration, which may be the result of the release of normal neuronal protein (14-3-3 protein) into the CSF as neurons die; however, this phenomenon is not specific to prion diseases.

Impact

Human prion diseases are rare. The worldwide incidence of genetic mutations and sporadic forms of disease is approximately one case per million humans. In the United States, there are approximately three hundred new human cases of prion diseases per year. About 10 percent of cases involve a genetic mutation.

The future for prion-disease diagnosis includes devising tools that will permit widespread screening for carriers of the infectious agent that causes the disease. This attempt at presymptomatic testing would signal who should receive treatment and, thus, would help prevent prions from spreading within the brain or from reaching the central nervous system that triggers disease.

Bibliography

"About Prion Disease." Centers for Disease Control and Prevention, 22 Apr. 2024, www.cdc.gov/prions/about/index.html. Accessed 2 Feb. 2025.

Brown, David R., ed. Neurodegeneration and Prion Disease. New York: Springer, 2005.

Gregori, Luisa. "A Diagnostic Blood Test for Prion Diseases." Blood, vol. 144, no. 18, 31 Oct. 2024, pp. 1853-1854, doi.org/10.1182/blood.2024026431. Accessed 2 Feb. 2025.

Herbst, A., et al. “Prion Disease Diagnosis by Proteomic Profiling.” Journal of Proteome Research 8 (2009): 1030-1036.

Prusiner, Stanley B. “The Prion Diseases.” Scientific American 272, no. 1 (January 1995): 48-57.

‗‗‗‗‗‗‗, ed. Prion Biology and Diseases. 2d ed. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory Press, 2004.

Safar, J. R., et al. “Diagnosis of Human Prion Disease.” Proceedings of the National Academy of Science 102 (2005): 3501-3506.