Creutzfeldt-Jakob disease (CJD) is a very rare and incurable degenerative neurological disorder (brain disease) that is ultimately fatal. Among the types of transmissible spongiform encephalopathy found in humans, it is the most common.
The prion that is believed to cause Creutzfeldt-Jakob exhibits at least two stable conformations. One, the native state, is water-soluble and present in healthy cells. As of 2007, its biological function is presumably in transmembrane transport or signaling. The other conformational state is very poorly water-soluble and readily forms protein aggregates.
People can also acquire CJD genetically through a mutation of the gene that codes for the prion protein (PRNP). This only occurs in 5-10% of all CJD cases.
The CJD prion is dangerous because it promotes refolding of native proteins into the diseased state. The number of misfolded protein molecules will increase exponentially, and the process leads to a large quantity of insoluble prions in affected cells. This mass of misfolded proteins disrupts cell function and causes cell death. Mutations in the gene for the prion protein can cause a misfolding of the dominantly alpha helical regions into beta pleated sheets. This change in conformation disables the ability of the protein to undergo digestion. Once the prion is transmitted, the defective proteins invade the brain and are produced in a self-sustaining feedback loop, causing exponential spread of the prion, leading to death within a few months, although a few patients have lived as long as two years.
Stanley B. Prusiner of University of California, San Francisco (UCSF) was awarded the Nobel Prize in physiology or medicine in 1997 for his discovery of prions. For more than a decade, Yale University neuropathologist Laura Manuelidis has been challenging this explanation for the disease. In January 2007 she and her colleagues published an article in the Proceedings of the National Academy of Science and reported that they have found a virus-like particle (but without finding nucleic acids so far) in less than 10% of the cells a scrapie-infected cell line and in a mouse cell line infected by a human CJD agent.
CDC monitors the occurrence of CJD in the United States through periodic reviews of national mortality data: According to the CDC:
These researchers noticed a genetic variation in some kuru patients that has been known to promote long incubation periods. They have also proposed that individuals who contracted CJD in the early 1990s represent a distinct genetic subpopulation, with unusually short incubation periods for BSE. This means that there may be many more vCJD patients who have longer incubation periods, which may surface many years later.
In 1997 a number of Kentuckians contracted the disease. It was discovered that all the victims had a penchant for squirrel brains. See: http://www.guardian.co.uk/uk/2008/aug/03/bse.medicalresearch for recent concerns.
The symptoms of CJD are caused by the progressive death of the brain's nerve cells, which is associated with the build-up of abnormal prion proteins. When brain tissue from a CJD patient is examined under a microscope, many tiny holes can be seen where whole areas of nerve cells have died. The word 'spongiform' in 'transmissible spongiform encephalopathies' refers to the 'spongy' appearance of the brain tissue.
Diffusion Weighted Imaging (DWI) images are the most sensitive. In about 24% of cases DWI shows only cortical hyperintensity; in 68%, cortical and subcortical abnormalities; and in 5%, only subcortical anomalies. The involvement of the thalamus can be found in sCJD, even is stronger and constant in vCJD.
Clinical testing for CJD has always been an issue. Diagnosis has mostly been based on clinical and physical examination of symptoms. In recent years, studies have shown that the tumour marker Neuron-specific enolase (NSE) is often elevated in CJD cases .
In one third of patients with sporadic CJD, deposits of "prion protein (scrapie)," PrPSc, can be found in the skeletal muscle and/or the spleen. Diagnosis of vCJD can be supported by biopsy of the tonsils, which harbour significant amounts of PrpSc; however, biopsy of brain tissue is the definitive diagnostic test.
|Characteristic||Classic CJD||Variant CJD|
|Median age at death||68 years||28 years|
|Median duration of illness||4-5 months||13-14 months|
|Clinical signs and symptoms||Dementia; early neurologic signs||Prominent psychiatric/behavioral symptoms; painful dysesthesias;
delayed neurologic signs
|Periodic sharp waves on electroencephalogram||Often present||Often absent|
|Signal hyperintensity in the caudate nucleus and putamen on diffusion-weighted and FLAIR MRI||Often present||Often absent|
|"Pulvinar sign" on MRI||Not reported||Present in >75% of cases|
|Immunohistochemical analysis of brain tissue||Variable accumulation.||Marked accumulation of protease-resistant prion protein|
|Presence of agent in lymphoid tissue||Not readily detected||Readily detected|
|Increased glycoform ratio on immunoblot analysis of
protease-resistant prion protein
|Not reported||Marked accumulation of protease-resistant prion protein|
|Presence of amyloid plaques in brain tissue||May be present||May be present|
Scientists have investigated using RNA interference to slow the progression of scrapie in mice. The RNA blocks production of the protein that the CJD process transforms into prions. This research is unlikely to lead to a human therapy for many years.
Both amphotericin B and doxorubicin have been investigated as potentially effective against CJD, but as yet there is no strong evidence that either drug is effective. Further study has been taken with other medical drugs, but none are effective.
Dr. Michael Geschwind, Dr. Bruce Miller and Dr. Stanley Prusiner from University of California, San Francisco are currently running a treatment trial for sporadic CJD using quinacrine, a medicine originally created for malaria. Pilot studies showed quinacrine permanently cleared abnormal prion proteins from cell cultures, but results have not yet been published on the clinical study.
The disease has also been shown to result from usage of HGH drawn from the pituitary glands of cadavers who died from Creutzfeldt-Jakob Disease, though the known incidence of this cause is (as of April 2004) quite small. The risk of infection through cadaveric HGH usage in the US only ceased when the medication was withdrawn in 1985.
It is thought that humans can contract the disease by consuming material from animals infected with the bovine form of the disease. The only suspected cases to arise thus far have been vCJD, although there are fears — based on animal studies — that consuming beef or beef products containing prion particles can also cause the development of classic CJD. When BSE material infects humans the resulting disease is known as (new) variant CJD Disease(nvCJD)
Cannibalism has also been implicated as a transmission mechanism for abnormal prions, causing the disease known as kuru, found primarily among women and children of the Fore tribe in Papua New Guinea. While the men of the tribe ate the body of the deceased and were not affected, the women and children ate the brain and contracted the disease from infected brain tissue.
Prions, the infectious agent of CJD, may not be inactivated by means of routine surgical instrument sterilization procedures. The World Health Organization and the US Centers for Disease Control and Prevention recommend that heat and chemical decontamination be used in combination to process instruments that come in contact with high-infectivity tissues. No cases of iatrogenic transmission of CJD have been reported subsequent to the adoption of current sterilization procedures, or since 1976. Copper-hydrogen peroxide has been suggested as an alternative to the current recommendation of sodium hydroxide or sodium hypochlorite. Thermal depolymerization also destroys prions in infected organic and inorganic matter, since the process dissolves protein at the molecular level.
On May 28, 2002, the United States Food and Drug Administration instituted a policy that excludes from donation anyone who spent at least 6 months in certain Western European countries, (or 3 months in the United Kingdom), from 1980 to 1996. Given the large number of U.S. military personnel and their dependents residing in Europe, it was expected that over 7% of donors would be deferred due to the policy. Later changes to this policy have relaxed the restriction to a cumulative total of 5 years or more of civilian travel in Western European countries (6 months or more if military). The 3-month restriction on travel to the UK, however, has not been changed.
The American Red Cross' policy is as follows: Since January 1, 1980-December 31, 1996 spending a total time of 3 months or more in Channel Islands, England, Falkland Islands, Isle of Man, Gibraltar, Northern Ireland, Scotland, and Wales would preclude you from donating. Since January 1, 1980 to present, spending a total time of 5 years or more in the above countries and countries in Europe. (For complete listing, please go to Redcross.org)
A similar policy applies to potential donors to the Australian Red Cross' Blood Service, precluding people who have spent a cumulative time of six months or more in the United Kingdom between 1980 and 1996.
In New Zealand anyone who lived in the UK, France or the Republic of Ireland for a total of six months or more between 1980 and 1996 is permanently deferred from donating blood in New Zealand
As of 1999, Health Canada announced a policy to defer individuals from donating blood if they have lived within the United Kingdom for one month or more from Jan. 1, 1980 to Dec. 31, 1996. In 2000, the same policy was applied to people who have resided in France, for at least three months from Jan. 1980 to Dec. 1996. Canada will not accept blood from a person who has spent more than 6 months in a Western European country since January 1, 1980.
The disease was also featured in an episode of the X-Files, Our Town, in which a group of cannibals eat the whole body (brain and all) of their fellow humans in order to stay young forever. They contract the disease from one of their victims, and it passes through the whole town, killing them.
During the fourth season of the TV series House, in episode four (Guardian Angels (House)), House's job applicants suspect the patient of having contracted CJD after doing cosmetic work on a cadaver with similar symptoms at a funeral parlour. To test the diagnosis the team dig up the grave and carry out a brain biopsy, which is negative.
The lead character in the BBC TV series "Bodies", Rob Lake (Max Beesley) begins to exhibit symptoms consistent with vCJD during the series finale. The episode closes with the character sitting down with a consultant colleague who specialises in neurology to hear his test results - but these are not revealed to the viewer.
A character in an episode of the TV series Bones is discovered to have CJD and is also a cannibal due to insanity; the characters make a point that they may never know which came first, he could have contracted the disease because of his cannibalism, or he could be a cannibal because the CJD has caused him to lose his mind; Since he worked with corpses, it is conceivable that he could have accidentally gotten infected blood or bone dust in his mouth, causing temporarily mild insanity which lead him to cannibalism, thus causing the CJD.
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