Creutzfeldt-Jakob disease

Creutzfeldt-Jakob disease (CJD) is a very rare and incurable degenerative neurological disorder (brain disease) that is ultimately fatal. It is the most common of the transmissible spongiform encephalopathies (TSEs).

Causes

Transmissible spongiform encephalopathy diseases (also known as prion diseases) are caused by a unique type of infectious agent called prions, an abnormally structured form of a protein found in the brain. Other prion diseases include Gerstmann-Sträussler-Scheinker syndrome (GSS), fatal familial insomnia (FFI) and kuru in humans, as well as bovine spongiform encephalopathy (BSE) and scrapie in animals.

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 get produced in a self-sustaining feedback loop, causing exponential spread of the prion, and the patient dies within a few months; a few patients live as long as two years.

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.
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.
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).
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.
In more than 85 percent of cases, the duration of CJD is less than 1 year (median: 4 months) after onset of symptoms.

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 a similar disease kuru in Papua New Guinea //www.forbes.com/forbeslife/health/feeds/hscout/2006/06/22/hscout533415.html. The reasoning behind the claim is that kuru, was transmitted through cannablism 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. //www.forbes.com/forbeslife/health/feeds/hscout/2006/06/22/hscout533415.html

Symptoms

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.

Diagnosis

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)," PrP^Sc, 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 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

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.

(Source:CDC)

Variant Creutzfeldt-Jakob Disease (vCJD)

A new variant of the disease (usually called just variant Creutzfeldt-Jakob Disease (vCJD) but sometimes new variant Creutzfeldt-Jakob Disease (nvCJD)) is distinguished from the classical type by its early onset (usually in the 20s) and a predominance of psychiatric and sensory symptoms. The prions in this form are thought to be transmitted by consuming the nervous tissue of bovines with so-called mad cow disease (Bovine Spongiform Encephalopathy), although there is no definite proof of this association as yet. It has been shown, however, that PRP^Sc particles accumulate in gastrointestinal lymphoid tissue (specifically, Peyer's patches) in animals after oral infection (Maignien et al 1999; Beekes and McBride, 2000; Shmakov and Ghosh, 2001; Ghosh 2002). Furthermore, in vitro studies have shown the uptake of these particles by human gastrointestinal tract cells (Morel et al, 2005). Further suggestive of an oral route of transmission in humans is the fact that over 95% of identified cases of vCJD are in Britain, which suffered a mad cow disease epidemic in the mid-80s. There are very few cases of vCJD. In Britain in 2005, 5 people died from vCJD. There are currently 5 people alive with vCJD in Britain.

Treatment

As of May 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 in January 2003. The drug, called pentosan polysulphate (PPS) and commonly used to treat cystitis, was infused into the patient's lateral ventricle within the brain. Simms has remained stable since the treatment. The drug may slow or halt the progress of the disease but does not improve the patient's health and is not widely available in the UK.^*

Transmission

The defective protein can be transmitted by human growth hormone 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. From 10 to 15 percent of CJD cases are inherited. (CDC)

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.

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 is 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 lived in high-risk areas of Europe from 1980 to the mid-1990s. Given the large number of U.S. military personnel 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, procluding 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 six months or more since 1980. In 2000, the same policy was applied to people who have resided in France for more than six months.

History

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 their initial studies were suffering from a different disorder.

Victims

Many Americans first learned about the disease when the famed choreographer George Balanchine died of it in 1983.

References

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
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

External links

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

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