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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, it is the most common.
Transmissible spongiform encephalopathy diseases are caused by a unique type of infectious agent called a prion, an abnormally structured form of a protein found in the brain; the diseases are thus sometimes called prion diseases. Other prion diseases include Gerstmann-Sträussler-Scheinker syndrome (GSS), fatal familial insomnia (FFI) and kuru in humans, as well as bovine spongiform encephalopathy (BSE) commonly known as mad cow disease, chronic wasting disease (CWD), and scrapie in sheep.
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 2006, its biological function is unknown. The other conformational state is very poorly water-soluble and readily forms protein aggregates.
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. 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, death within a few months, although a few patients have been known to live as long as two years.
Stanley B. Prusiner was awarded the Nobel Prize in physiology or medicine in 1997 for his discovery of prions. Yale University neuropathologist Laura Manuelidis has challenged this explanation for the disease. In January 2007 she and her colleagues published an article in the Proceedings of the National Academy of Science asserting that they have found a virus responsible for the diseases.
Incidence and prevalence
Although CJD is the most common human prion disease, it is still rare and only occurs in about one out of every one million people. It usually affects people aged 45–75, most commonly appearing in people between the ages of 60–65. The exception to this is the more recently-recognised 'variant' CJD (vCJD), which occurs in younger people. CDC monitors the occurrence of CJD in the United States through periodic reviews of national mortality data: According to the CDC:
- CJD occurs worldwide at a rate of about 1 case per million population per year.[How to reference and link to summary or text]
- On the basis of mortality surveillance from 1979 to 1994, the annual incidence of CJD remained stable at approximately 1 case per million persons in the United States.[How to reference and link to summary or text]
- In the United States, CJD deaths among persons younger than 30 years of age are extremely rare (fewer than 5 deaths per billion per year).[How to reference and link to summary or text]
- The disease is found most frequently in patients 55–65 years of age, but cases can occur in persons older than 90 years and younger than 55 years of age.[How to reference and link to summary or text]
- In more than 85 percent of cases, the duration of CJD is less than 1 year (median: 4 months) after onset of symptoms.[How to reference and link to summary or text]
New Concerns on Incidence and Prevalence
In The Lancet (June 2006), a University College London team has suggested that it may take more than 50 years for vCJD to develop, from their studies of kuru, a similar disease in Papua New Guinea.1 The reasoning behind the claim is that kuru was transmitted through cannibalism in Papua New Guinea when relatives would eat their dead relative's brains as a sign of mourning. In the 1950's, the practice was banned, thereby preventing any further possible transmission. In the late 20th century, however, kuru has reached epidemic proportions in certain Papua New Guinean communities, therefore suggesting that vCJD may also have a similar incubation period of 30 to 50 years.
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 1990's 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.
The first symptom of CJD is rapidly progressive dementia, leading to memory loss, personality changes and hallucinations. This is accompanied by physical problems such as speech impairment, jerky movements (myoclonus), balance and coordination dysfunction (ataxia), changes in gait, rigid posture, and seizures. The duration of the disease varies greatly, but sporadic (non-inherited) CJD can be fatal within months or even weeks (Johnson, 1998). In most patients, these symptoms are followed by involuntary movements and the appearance of a typical diagnostic electroencephalogram tracing.
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.
The diagnosis of CJD is suspected when there are typical clinical symptoms and signs such as rapidly progressing dementia with myoclonus. Further investigation can then be performed to support the diagnosis including
- Electroencephalography - often has characteristic triphasic spikes
- Cerebrospinal fluid analysis for 14-3-3 protein
- MRI of the brain - often shows high signal intensity in the caudate nucleus and putamen bilaterally on T2-weighted images
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.
- Clinical and Pathologic Characteristics
|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|
Source: Adapted from Belay E., Schonberger L. Variant Creutzfeldt-Jakob Disease and Bovine Spongiform Encephalopathy. Clin Lab Med 2002;22:849-62.
- An abnormal signal in the posterior thalami on T2- and diffusion-weighted images and fluid-attenuated inversion recovery sequences on brain magnetic resonance imaging (MRI); in the appropriate clinical context, this signal is highly specific for vCJD.
As of December 2006, there is no cure for CJD, a fatal disease, and the search for viable treatments continues. An experimental treatment was given to a Northern Irish teenager, Jonathan Simms, beginning in January 2003. The medication, called pentosan polysulphate (PPS) and used to treat interstitial cystitis, is infused into the patient's lateral ventricle within the brain. PPS does not seem to stop the disease from progressing. Both brain function and tissue continue to be lost. However, the treatment may have contributed to the longer than expected survival of the seven patients that were studied.
Scientists have investigated using special RNA 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.
The defective protein can be transmitted by human growth hormone (hGH) products, corneal grafts, dural grafts or electrode implants (acquired or iatrogenic form: iCJD); it can be inherited (hereditary or familial form: fCJD); or it may appear for the first time in the patient (sporadic form: sCJD). In the hereditary form, a mutation occurs in the gene for PrP, PRNP. 10 to 15 percent of CJD cases are inherited. (CDC) The issue of transmission is a vexing one for hospitals: prion proteins adhere to re-usable instruments and are not destroyed by conventional methods of decontamination (e.g., autoclaving), and contaminated instruments have simply to be discarded. Copper-hydrogen peroxide has been suggested as a potential method of decontamination, but this work is at a very preliminary stage.
Humans can contract the disease by consuming material from animals infected with the bovine form of the disease. The only 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 developement of classic CJD.
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 U.S. only ceased when the medication was withdrawn in 1985.
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.
Blood donor restrictions
In 2004 a new report published in the Lancet medical journal showed that vCJD can be transmitted by blood transfusions (Peden 2004). The finding alarmed healthcare officials because a large epidemic of the disease might arise in the near future. There is no test to determine if a blood donor is infected and in the latent phase of vCJD. In reaction to this report, the British government banned anyone who had received a blood transfusion since January 1980 from donating blood.
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 percent of donors would be deferred due to the policy.
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.
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 at least 6 months in a Western European country since January 1, 1980. 
The disease was first described by two German neurologists, Hans Gerhard Creutzfeldt and Alfons Maria Jakob. Some of the clinical findings described in their first papers do not match current criteria for Creutzfeldt-Jakob disease, and it is considered highly likely that at least two of the patients in initial studies were suffering from a different disorder.
- includeonly>"Pathogenic Virus Found in Mad Cow Cells", Yale, February 2 2007. Retrieved on 2007-02-02.
- Teenager with vCJD 'stable. BBC News. URL accessed on 2007-01-01.
- Bone, Ian Intraventricular Pentosan Polysulphate in Human Prion Diseases: A study of Experience in the United Kingdom. Medical Research Council. URL accessed on 2007-01-01.
- Revamp of brain 'could slow CJD'. BBC News. URL accessed on 2007-01-01.
- McDonnell G, Burke P. (2003). The challenge of prion decontamination. Clin Infect Dis 36: 1152–4.
- Solassol J, Pastore M, Crozet C, et al. (2006). A novel copper-hydrogen peroxide formulation for prion decontamination. J Infect Dis 194: 865–869.
- Beekes M, McBride PA (2000). Early accumulation of pathological PrP in the enteric nervous system and gut-associated lymphoid tissue of hamsters orally infected with scrapie. Neurosci Lett 278:181-184 PMID 10653023
- Brown, Paul; Will, Robert G.; Bradley, Raymond; Asher, David M.; and Detwiler, Linda (2001) Bovine Spongiform Encephalopathy and Variant Creutzfeldt-Jakob Disease: Background, Evolution, and Current Concerns. Emerging Infections Diseases 7, No. 1, January–February 2001, 6-16 
- Johnson RT, Gibbs CJ (1998). Creutzfeldt-Jakob disease and related transmissible spongiform encephalopathies. N. Engl. J. Med. 339 (27), 1994-2004 PMID 9869672
- Morel E, et al (2005). Bovine prion is endocytosed by human enterocytes via the 37 kDa/67 kDa laminin receptor. Am J Pathol. 167(4):1033-42 PMID 16192638
- Peden AH, et al (2004). Preclinical vCJD after blood transfusion in a PRNP codon 129 heterozygous patient. Lancet 364, 527-29 PMID 15302196
- Todd NV, Morrow J, Doh-ura K, Dealler S, O'Hare S, Farling P, Duddy M, Rainov NG, (2005) Cerebroventricular infusion of pentosan polysulphate in human variant Creutzfeldt-Jakob disease, Journal of Infectious Diseases, 50(5):394-6. PMID 15907546
- Maignien T, Lasmezas CI, Beringue V, Dormont D, Deslys JP (1999). Pathogenesis of the oral route of infection of mice with scrapie and bovine spongiform encephalopathy agents. J Gen Virol 80:3035-3042 PMID 10580067
- Shmakov AN, Ghosh S (2001). Prion proteins and the gut: une liaison dangereuse? Gut 48:443-447 PMID 11247881
- Ghosh S (2002). Intestinal entry of prions. Z Gastroenterol 40:37-39. PMID 11803499
- Collinge J, Whitfield J, McKintosh E, Beck J, Mead S, Thomas DJ, Alpers MP (2006). Kuru in the 21st century—an acquired human prion disease with very long incubation periods. The Lancet 367(9528):2068-2074
Research and news
- National Creutzfeldt-Jakob Disease Surveillance Unit, UK CJD surveillance unit at Western General Hospital in Edinburgh, Scotland
- "Mad Cow" Blood Donor Restrictions - Blood Centers of the Pacific
- Forecast information on vCJD and HIV/AIDS in the UK
- The National Prion Disease Pathology Surveillance Center at Case Western Reserve University in Cleveland, Ohio.
- Database tracking CJD victims in the geographical areas in which they lived, as well as other relevant information. Plus latest news.
- BBC report
- Human 'Mad Cow' Could Cause Eventual Epidemic - Forbes Magazine
- Filter removes mad cow proteins from blood - NewScientist.com, 22 Dec 2006
Support and other
- ICTVdb database ICTVdB Virus Code: 90.001.0.01. Prion accession number: 90_PRI01. CJD prion - HuPrPSc
- The CJD Foundation offers support, information and guidance to those dealing with CJD.
- CJD Alliance CJD Alliance, United Kingdom
- CJD Insight is a resource for those dealing with familial CJD.
- The CJD Support Network UK support and information for all forms of CJD.
- CJD Voice is an online forum for those with loved ones diagnosed with CJD.
- "Official Mad Cow Disease Home Page"
- UCSF Memory and Aging Center -- Provides clinical care for people with CJD as well as clinical trials
- Endocrine and Metabolic Diseases Information Service
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