Creutzfeldt-Jakob Disease

Creutzfeldt-Jakob disease (CJD) is a rare, degenerative, invariably fatal brain disorder. It is believed to be caused by an infectious protein, called a prion. It affects about one person in every one million people per year worldwide; in the United States there are about 200 cases per year.^[1] CJD usually appears in later life and runs a rapid course. Typically, onset of symptoms occurs around age 60, and about 90% of patients die within one year. In the early stages of disease, patients may have failing memory, behavioral changes, lack of coordination, and visual disturbances. As the illness progresses, mental deterioration becomes pronounced and involuntary movements, blindness, weakness of extremities, and coma may occur.

Light photomicrograph of brain tissue showing the presence of typical amyloid plaques found in a case of variant Creutzfeldt-Jakob disease (vCJD). Magnified 158X. Source: CDC.

Types

There are four types of CJD:

Sporadic CJD

The disease appears even though the person has no known risk factors for the disease. This is by far the most common type of CJD and accounts for at least 85% of cases.

Hereditary CJD

The person has a family history of the disease and/or tests positive for a genetic mutation associated with CJD. About 5%-10% of cases of CJD in the United States are hereditary.

Acquired CJD

The disease is transmitted by exposure to brain or nervous system tissue, usually through certain medical procedures. There is no evidence that CJD is contagious through casual contact with a patient who has CJD. Since CJD was first described in 1920, fewer than 1% of cases have been acquired CJD.

Variant CJD

A new type of CJD, called variant CJD (vCJD), was first described in 1996 and has been found in Great Britain and several other European countries. The initial symptoms of vCJD are different from those of classic CJD and the disorder typically occurs in younger patients. Research suggests that vCJD may have resulted from human consumption of beef from cattle with bovine spongiform encephalopathy (BSE). BSE is the cow form of CJD, which became epidemic in the UK in the 1980s and 1990s when brain and spinal cord tissue from infected cows was allowed to re-enter the cow food chain.

Other prion disorders

Cattle, such as the one pictured here, experience progressive degeneration of the nervous system if affected by BSE. Source: Wikimedia Commons

CJD belongs to a family of human and animal diseases known as the transmissible spongiform encephalopathies (TSEs). Spongiform refers to the characteristic appearance of infected brains, which become filled with holes until they resemble sponges under a microscope. CJD is the most common of the known human TSEs. Other human TSEs include kuru, fatal familial insomnia (FFI), and Gerstmann-Straussler-Scheinker disease (GSS). Kuru was identified in people of an isolated tribe in Papua New Guinea and has now almost disappeared. Kuru may have been spread through cannibalism. FFI and GSS are extremely rare hereditary diseases, found in just a few families around the world. Other TSEs are found in specific kinds of animals. These include bovine spongiform encephalopathy (BSE), which is found in cows and is often referred to as “mad cow” disease; scrapie, which affects sheep and goats; mink encephalopathy; and feline encephalopathy. Similar diseases have occurred in elk, deer, and exotic zoo animals.

Creutzfeldt-Jakob disease (CJD) is the most well-known of the human TSEs.

Symptoms

Symptoms of CJD vary, but they commonly include personality changes, psychiatric problems such as depression, lack of coordination, or an unsteady gait. Patients also may experience involuntary jerking movements called myoclonus, unusual sensations, insomnia, confusion, or memory problems. In the later stages of the disease, patients have severe mental impairment and lose the ability to move or speak.

Causes

Most scientists believe CJD, like other TSEs, are caused by an abnormal version of a protein called a prion (prion is short for proteinaceous infectious particle).^[2][3][4] Some scientists disagree with the prion hypothesis.^[5]

Prion proteins occur in both a normal form, which is a harmless protein found in the body's cells, and in an infectious form, which causes disease. The harmless and infectious forms of the prion protein are nearly identical, but the infectious form takes on a different folded shape from the normal protein.^[6]

Human TSEs can occur in three ways:

Sporadic TSEs

Sporadic TSEs may develop because some of a person's normal prions spontaneously change into the infectious form of the protein and then alter the prions in other cells in a chain reaction.

Inherited TSEs

Inherited cases arise from a change, or mutation, in the prion protein gene that causes the prions to be shaped in an abnormal way. This genetic change may be transmitted to an individual's offspring.

Transmission through infected individuals

This type of transmission is relatively rare. TSEs cannot be transmitted through the air or through touching or most other forms of casual contact. However, they may be transmitted through contact with infected tissue, body fluids, or contaminated medical instruments. Normal sterilization procedures such as boiling or irradiating materials do not prevent transmission of TSEs.

Diagnosis

There is currently no single diagnostic test for CJD. When a doctor suspects CJD, the first concern is to rule out treatable forms of dementia such as encephalitis (inflammation of the brain) or chronic meningitis. A neurological examination will be performed, and the doctor may seek consultation with other physicians. Standard diagnostic tests will include a spinal tap to rule out more common causes of dementia and an electroencephalogram (EEG) to record the brain’s electrical pattern, which can be particularly valuable because it shows a specific type of abnormality in CJD. Computerized tomography of the brain can help rule out the possibility that the symptoms result from other problems such as stroke or a brain tumor. Magnetic resonance imaging (MRI) brain scans also can reveal characteristic patterns of brain degeneration that can help diagnose CJD.

The only way to confirm a diagnosis of CJD is by brain biopsy or autopsy. In a brain biopsy, a neurosurgeon removes a small piece of tissue from the patient’s brain so that it can be examined by a neuropathologist. This procedure may be dangerous for the patient, and the operation does not always obtain tissue from the affected part of the brain. Because a correct diagnosis of CJD does not help the patient, a brain biopsy is discouraged unless it is needed to rule out a treatable disorder. In an autopsy, the whole brain is examined after death. Both brain biopsy and autopsy pose a small, but definite, risk that the surgeon or others who handle the brain tissue may become accidentally infected by self-inoculation. Special surgical and disinfection procedures can minimize this risk. A fact sheet with guidance on these procedures is available from the National Institute of Neurological Disorders and Stroke (NINDS) and the World Health Organization.

Scientists are working to develop laboratory tests for CJD. One such test, developed at NINDS, is performed on a person’s cerebrospinal fluid and detects a protein marker that indicates neuronal degeneration. This can help diagnose CJD in people who already show the clinical symptoms of the disease. This test is much easier and safer than a brain biopsy. The false positive rate is about 5%–10%. Scientists are working to develop this test for use in commercial laboratories. They are also working to develop other tests for this disorder.

Treatment

CJD, like other TSEs, tend to progress rapidly and usually culminate in death over the course of a few months to a few years. There is currently no treatment that can halt progression of any of the TSEs. Treatment is aimed at alleviating symptoms and making the patient as comfortable as possible.

Clinical Trials

For a list of government-sponsored clinical trials on Creutzfeldt-Jakob Disease, visit ClinicalTrials.gov.

Research

The leading scientific theory at this time maintains that CJD is caused by a type of protein called a prion. The harmless and infectious forms of the prion protein are nearly identical, but the infectious form takes a different folded shape than the normal protein. Researchers are examining whether the transmissible agent is, in fact, a prion and trying to discover factors that influence prion infectivity and how the disorder damages the brain. Using rodent models of the disease and brain tissue from autopsies, they are also trying to identify factors that influence the susceptibility to the disease and govern when in life the disease appears.

Expected Outcome

About 90% of patients die within one year. In the early stages of disease, patients may have failing memory, behavioral changes, lack of coordination, and visual disturbances. As the illness progresses, mental deterioration becomes pronounced and involuntary movements, blindness, weakness of extremities, and coma may occur.

History

Creutzfeldt-Jakob disease is named for two researchers, Hans Gerhard Creutzfeldt and Alfons Maria Jakob, who described the symptoms years before prions were suspected as the cause.

The idea of an infectious protein, or prion has always been controversial. Other infectious agents that catalyze their own reproduction, like bacteria and viruses, have their genetic information, or blueprint for reproduction, in nucleic acids (DNA or RNA). If the prion theory is correct, in prions the information for reproduction is in the structure of the protein itself. The infectious prion causes normal cell proteins to misfold and become infectious prions.

Both the 1976 and 1997 Nobel Prizes for Medicine or Physiology were awarded for the discovery of prions. In 1976, Baruch S. Blumberg and D. Carleton Gajdusek were awarded "for their discoveries concerning new mechanisms for the origin and dissemination of infectious diseases."^[7] They studied kuru, a prion disease endemic in cannibals in Papua New Guinea. Gajdusek's career has been marred by a criminal conviction and admission that, in the course of his research trips in the South Pacific, Gajdusek brought children back to live with him in the United States and molested them.^[8][9]

In 1997, Stanley B. Prusiner was awarded the Nobel Prize "for his discovery of Prions - a new biological principle of infection."^[10]

References

1. ↑ National Institute of Neurological Disorders and Stroke. Creutzfeldt-Jakob Disease Fact Sheet
2. ↑ Lopez CD, Yost CS, Prusiner SB, Myers RM, Lingappa VR. Unusual topogenic sequence directs prion protein biogenesis. Science. 1990 Apr 13;248(4952):226-9. Abstract
3. ↑ Hsiao K, Baker HF, Crow TJ, et al. Linkage of a prion protein missense variant to Gerstmann-Sträussler syndrome. Nature. 1989 Mar 23;338(6213):342-5.
4. ↑ Owen F, Poulter M, Lofthouse R, et al. Insertion in prion protein gene in familial Creutzfeldt-Jakob disease. Lancet. 1989 Jan 7;1(8628):51-2.
5. ↑ Manuelidis L, Yu ZX, Barquero N, Mullins B. Cells infected with scrapie and Creutzfeldt-Jakob disease agents produce intracellular 25-nm virus-like particles. Proceedings of the National Academy of Science 104: 1975-1970. (2007).
6. ↑ Pan KM, Baldwin M, Nguyen J, et al. Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins. Proc Natl Acad Sci USA. 1993 Dec 1;90(23):10962-6. Full Text
7. ↑ Nobel Foundation Web site. The Nobel Prize in Physiology or Medicine 1976.
8. ↑ News in Brief. Nature 385, 762 (27 Feb 1997).
9. ↑ Molotsky I. Nobel Scientist Pleads Guilty to Abusing Boy. NY Times. February 19, 1997.
10. ↑ Nobel Foundation Web site. The Nobel Prize in Physiology or Medicine 1997

External Links

Creutzfeldt-Jakob Disease Foundation

Alzheimer's Association: This site includes information on CJD.

CJD Insight: Patient Support Site

National Organization for Rare Disorders

CJD Aware!: An information resource site for CJD.

[1]Alzheimer's Disease Education and Referral Center (ADEAR)]

National Hospice and Palliative Care Organization