Creutzfeldt-Jakob Disease

CREUTZFELDT-JAKOB DISEASE

Creutzfeldt-Jakob disease is one of the transmissible spongiform encephalopathies, a family of diseases affecting humans and animals (see Table 1). They are transmissible, in that susceptible animals inoculated with diseased tissue will develop a similar disease; spongiform, in that, under a microscope, small spaces (vacuoles) in brain tissue are invisible, giving the appearance of a sponge; and encephalopathies, in that they affect the brain.

The disease was first reported by Hans Creutzfeldt in 1920 and Alfons Jakob in 1921. A related, exclusively familial disease, Gerstmann-Sträussler-Scheinker syndrome, was reported in 1928. Creutzfeldt-Jakob disease is a dementia characterized by a rapid progression and a multitude of varying cognitive and motor deficits.

The first advance in understanding the diseases occurred with the recognition that kuru, a disease afflicting only the Fore people of New Guinea, caused similar changes in brain tissue. Kuru is a rapidly progressive dementia (over months) characterized by cerebellar degeneration, causing clumsiness and difficulty walking (ataxia), tremor, and slurred speech. It has been linked to the Fore's practice of eating the brains of deceased relatives. Dr. D. C. Gadjusek, of the National Institutes of Health, hypothesized that ingestion of brain tissue caused the disease, and demonstrated in 1966 that inoculation of brain tissue from kuru patients into chimpanzees' brains caused the disease. Shortly afterward transmissibility was also demonstrated for Creutzfeldt-Jakob disease and Gerstmann-Str;äussler-Scheinker syndrome. Gadjusek and a colleague, Baruch S. Blumberg, were awarded the 1976 Nobel Prize in Medicine for this work.

Prions

The demonstration of transmissibility produced a search for the infectious agent. Initially researchers believed that a virus must be involved, but by the early 1980s the prion hypothesis had been proposed. "Prion" is a term coined by Dr. Stanley Prusiner in 1982 to indicate that the agent is both a protein and infectious. Prusiner, a University of California neurologist, received the 1997 Nobel Prize in medicine for his work on this new class of infectious agent.

The prion protein is a normal constituent of the human body, and although the exact function is unknown, it is involved in neuron development and prevention of neuronal cell death. The abnormal form of the protein has an insoluble conformation; that is, the protein folds in such a way that it can not easily interact with other body molecules. Since the abnormal form is resistant to degradation by normal body enzymes, it is termed protease-resistant prion protein. The abnormal protein can both accumulate into plaques and induce normal prion protein, in a chain reaction, to transform into the abnormal conformation. The prion protein is concentrated in nervous tissue but can also be found in other tissues, particularly white blood cells and the lymphatic system.

The prion hypothesis explains many of the characteristics of the Transmissible Spongiform Encephalopathies: how a familial disease could be infectious (the inheritance is due to a mutation in the prion gene, but the resultant abnormal protein can induce the conformational chain reaction in people without the mutation); why the agent is so resistant to disinfection (most viruses or bacteria are more susceptible to heat or detergents than insoluble proteins are); and how a disease can be infectious without the involvement of any DNA. The best evidence for the prion hypothesis comes from work on self-propagating prions of yeast.

Clinical features

Creutzfeldt-Jakob disease occurs worldwide, with an incidence rate of one per million, most commonly between the ages of fifty and seventy. There are familial forms of the disease, due to mutations in the prion protein gene, best studied in populations in Slovakia and among Libyan Jews. The disease can be iatrogenic, caused by exposure to infectious tissue, such as corneal transplants, dura mater grafts, contaminated surgical instruments, and medications made from human brain tissue, most notably human growth hormone. The time between exposure and onset of the disease can be many years. Most cases, however, are sporadic, or random. There has never been a known case of person-to-person infection. Although it can theoretically be transmitted by blood transfusion, no such case has been identified. There was much interest in the 1970s and 1980s in dietary risk factors, particularly ingestion of animal brains, but this has not been supported by more recent studies. Preliminary data reported in September of 2000 suggest that variant Creutzfeldt-Jakob disease can be passed on through blood transfusions and from a mother to her fetus.

The diagnostic criteria for Creutzfeldt-Jakob disease are presented in Table 2, and are self-explanatory. Often patients with Creutzfeldt-Jakob disease, particularly those with myoclonus, have a typical pattern of sharp waves on their electroencephalograph. Elevated levels of the 14-3-3 protein, a neuronal protein of unknown function, have been found in the cerebrospinal fluid of patients with Creutzfeldt-Jakob disease, and occasionally other cerebral diseases. If Creutzfeldt-Jakob disease is suspected, testing for this protein can help confirm the diagnosis.

Creutzfeldt-Jakob disease progresses rapidly, with a median duration from onset to death of four and a half months. There is no effective treatment for any of the Transmissible Spongiform Encephalopathies. Treatment is limited to comfort care and, if appropriate, genetic counseling. The search for possible therapies involves agents that may stimulate the body to break down the abnormal prion protein, that may disrupt the conformational chain reaction, or that may prevent spread of the prion to the nervous system in an exposed individual.

The epidemic of Bovine Spongiform Encephalopathy in the United Kingdom in the 1980s produced fears that this disease might enter the food chain, and affect humans and other species. This fear has proven true, although the eventual magnitude is as yet unknown. New diseases with prions identical to that causing bovine spongiform encephalopathy have been found in humans, cats, and zoo animals, most likely from prion-contaminated food. This new human disease, variant Creutzfeldt-Jakob disease, differs in that it typically affects people in their twenties and thirties; psychiatric symptoms are prominent; and the pathological appearance is different, with many prion protein-containing plaques found throughout the cortex. Only people with a prion protein gene coding for the amino acid methionine at codon 129 on both gene copies (homozygous for methionine) are susceptible to the disease. People homozygous for valine, or heterozygous for both valine and methionine, are not known to be susceptible to the new variant. Cases have occurred only in Great Britain and France. It is difficult to know if an epidemic will occur, but the incidence increased by 33 percent between 1994 and 2000. Some of this increase may reflect new diagnostic methods.

Not all scientists support the prion hypothesis. They hypothesize that a cofactor, probably a virus, is also present. The works by Manuelidis and Balter cited in the bibliography present these alternative views.

Chris MacKnight

See also Dementia.

BIBLIOGRAPHY

Balter, M. "Prions: A Lone Killer or a Vital Accomplice." Science 286 (22 October 1999): 660–662.

Caughey, B. "Transmissible Spongiform Encephalopathies, Amyloidoses and Yeast Proteins: Common Threads?" Nature Medicine 6 (2000): 751–754.

Collinge, J. "Variant Creutzfeldt-Jakob Disease." Lancet 354 (24 July 1999): 317–323.

MacKnight, C. "Clinical Implications of Bovine Spongiform Encephalopathy." Clinical Infectious Diseases 32 (2001): 1726–1731.

Manuelidis, L. "Dementias, Neurodegeneration, and Viral Mechanisms of Disease from the Perspective of Human Transmissible Encephalopathies." Annals of the New York Academy of Sciences 724 (1994): 259–281.

Prusiner, S. B., ed. Prion Biology and Diseases. Cold Spring Harbor Monograph Series, no. 38. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory, 1999.

Soto, C.; Kascsak, R. J.; Saborio, G. P.; Aucou Turier, P.; Wisniewski, T.; Prelli, F.; Kascsak, R.; Mendez, E.; Harris, D. A.; Ironside, J.; Tagliavini, F.; Carp, R. I.; and Frangione, B. "Reversion of Prion Protein Conformational Changes by Synthetic B-sheet Breaker Peptides." Lancet 355 (January 15, 2000): 192–197.

Supattapone, S.; Nguyen, H.-O. B.; Cohen, F. E.; Prusiner, S. B.; and Scott, M. R. "Elimination of Prions by Branched Polyamines and Implications for Therapeutics." Proceedings of the National Academy of Sciences 96 (1999): 14529–14534.

Wilson, K.; Code, C.; and Rickettsm. N. "Risk of Acquiring Creutzfeldt-Jakob Disease from Blood Transfusions: Systematic Review of Case-Control Studies." British Medical Journal 321 (1 July 2000): 17–19.

World Health Organization. "Transmissible Spongiform Encephalopathies." World Wide Web document. www.who.int