Creutzfeldt-Jakob disease (CJD) is an extremely rare degenerative brain disorder (i.e., spongiform encephalopathy) characterized by sudden development of rapidly progressive neurological and neuromuscular symptoms. With symptom onset, affected individuals may develop confusion, depression, behavioral changes, impaired vision, and/or impaired coordination. As the disease progresses, there may be rapidly progressive deterioration of cognitive processes and memory (dementia), resulting in confusion and disorientation, impairment of memory control, personality disintegration, agitation, restlessness, and other symptoms and findings. Affected individuals also develop neuromuscular abnormalities such as muscle weakness and loss of muscle mass (wasting); irregular, rapid, shock-like muscle spasms (myoclonus); and/or relatively slow, involuntary, continual writhing movements (athetosis), particularly of the arms and legs. Later stages of the disease may include further loss of physical and intellectual functions, a state of unconsciousness (coma), and increased susceptibility to repeated infections of the respiratory tract (e.g., pneumonia). In many affected individuals, life-threatening complications may develop less than a year after the disorder becomes apparent.
In approximately 90 percent of cases, CJD appears to occur randomly for no apparent reason (sporadically). About 10 percent of affected individuals may have a hereditary predisposition for the disorder. Reports in the medical literature suggest that familial cases of CJD are consistent with an autosomal dominant mode of inheritance. In addition, in some extremely rare cases, CJD may take an infectious form. The disorder is thought to result from changes (mutations) in the gene that regulates the production of the human prion protein or direct contamination (transmission) with abnormal prion protein in infected brain tissue.
A variant form of CJD (V-CJD) has been reported in the United Kingdom that affects younger people (median age at onset: 28 years) than does classic CJD. In 1996, experts suggested the possibility that this variant might be associated with consumption of beef from cows with a related infectious brain disorder known as Bovine Spongiform Encephalopathy (BSE) or "Mad Cow Disease." BSE was first identified in the UK in 1986 and the number of reported cases grew rapidly, peaking in the winter of 1992-93 when almost 1,000 new cases were reported each week. Later, BSE also began to appear in some other European countries. Scientific research and debate continue concerning the potential link between BSE and V-CJD. In addition, coordinated national and international efforts are in place concerning the prevention, study, and surveillance of BSE and CJD. In early December 2000, European Union agriculture ministers agreed upon new measures to combat the spread of mad cow disease, including incinerating any cow over 30 months of age that had not tested negative for BSE. (BSE is thought to become detectable and infectious when cattle are approximately 30 months old.)
Creutzfeldt-Jakob disease (CJD), an extremely rare degenerative brain disorder (i.e., spongiform encephalopathy), is characterized by the sudden onset of rapidly progressive neurological and neuromuscular symptoms. Initially, these symptoms, which typically become apparent during the fifth or sixth decade of life, may include subtle signs of confusion, depression, forgetfulness, sleeping difficulties (insomnia), and/or behavioral changes. Affected individuals may also experience impaired vision, abnormal physical sensations, and/or difficulties with voluntary coordination.
Individuals with Creutzfeldt-Jakob disease may then experience rapidly progressive loss of intellectual abilities, demonstrating impaired memory and judgment and distinct personality changes (dementia). Neuromuscular abnormalities become more apparent at this stage of the disorder and may include muscle weakness and loss of muscle mass (wasting); muscular rigidity; tremors; repeated, involuntary, shock-like muscle spasms (myoclonus) and/or slow, continual, involuntary writhing movements, particularly of the arms and legs (athetosis); increasingly impaired coordination of voluntary movements; and/or difficulty with speech (dysarthria) due to impaired muscular control. Vision may also become increasingly impaired.
In individuals with CJD, neurological and neuromuscular impairment continues to progress, and later stages of the disorder may be characterized by loss of physical and intellectual functions, coma, and increased susceptibility to repeated infections of the respiratory tract (e.g., pneumonia). In many cases, life-threatening complications tend to develop less than a year after the disorder becomes apparent.
A variant form of Creutzfeldt-Jakob disease (V-CJD) has been reported in the medical literature. V-CJD appears to occur in younger individuals (i.e., before the age of approximately 40 years, with many cases occurring in adolescents) and tends to have a longer clinical course.
Variant Creutzfeldt-Jakob disease appears to be initially characterized by depression, anxiety, withdrawal, and personality and behavioral changes. Delusions are sometimes reported. In some cases, individuals with the disorder may have abnormal sensations (dyesthesia) or pain in the face, arms, and legs. Within a few weeks or months, affected individuals experience the onset of progressive neuromuscular symptoms including an impaired ability to coordinate voluntary movement (cerebellar ataxia); severely diminished muscle tone (hypotonia); and slow, halting speech. In some cases, neuromuscular abnormalities may include irregular, rapid, involuntary jerky movements (chorea). As the disease advances, individuals with V-CJD demonstrate increasing memory impairment that progresses to dementia. During later stages of the disorder, affected individuals may experience repeated, involuntary, shock-like muscle spasms (myoclonus). In individuals with V-CJD, life-threatening complications tend to develop approximately two years after initial symptoms occur.
Scientists believe that a transmissible agent is responsible for causing Creutzfeldt-Jakob disease. Initially, this was thought to be a slow virus, since a period of many years may elapse between the initial exposure and the appearance of symptoms.
However, today it is believed that this agent is very different from viruses and other known infectious agents. Instead, the agent is called a prion, and it is thought to transform normal protein molecules into infectious ones.
Although the disease is caused by a transmissible agent, it is not considered to be contagious in the traditional sense. In approximately 90 percent of cases, Creutzfeldt-Jakob disease (CJD) appears to occur randomly for unknown reasons (sporadically). About 10 percent of affected individuals may exhibit a hereditary predisposition for the disorder. In some extremely rare cases, CJD may take an infectious form.
CJD is thought to result from direct contamination (transmission) with abnormal prion protein in infected brain tissue or from changes (mutations) in the gene* that regulates (encodes for) the production of the human prion protein. The term prion stands for proteinaceous infectious particles. Abnormal changes in the prion protein are thought to play some role in causing deterioration in certain areas of the brain, appearing as sponge-like holes and gaps (thus, the term spongiform encephalopathy). Such spongiform degeneration in turn results in the progressive neurological and neuromuscular symptoms associated with CJD.
The gene that regulates the production of the human prion protein, known as prion-related protein or PRNP, has been mapped to the short arm (p) of chromosome 20 (20p12-pter). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q”. Chromosomes are further subdivided into bands that are numbered.
Some researchers suggest that the normal cellular prion protein (PrPc) plays an essential role in preventing the degeneration and loss of brain cells. During one laboratory study, when researchers removed the normal prion protein from nerve cells (i.e., cultured neurons), the genetically altered neurons soon expired. However, when researchers restored normal PrPc to cells without the protein, affected neurons returned to health. Further research is necessary to determine the implications of such findings.
Many researchers suggest that CJD and other prion diseases result from abnormal changes in the shape of the prion protein. The modified form of PrPc that may cause disease is known as PrPsc (for scrapie prion protein). In other words, improper “folding” of the protein is thought to prevent it from being appropriately broken down by the body. As a result, abnormal prion proteins gradually accumulate, forming fixed deposits (plaques) in the brain and the associated, progressive neurological and neuromuscular impairment seen in those with such disorders. Laboratory studies conducted by an international research team suggest that a relatively small, specific portion of the prion protein (i.e., a specific prion peptide sequence) normally prevents the protein from folding improperly. Peptides are protein fragments consisting of one or more amino acids; in turn, amino acids are chemical compounds that are essentially the “building blocks” of proteins. The researchers demonstrated that adding the specific prion peptide to cells affected by scrapie, a form of spongiform encephalopathy that originates in sheep and goats, prevented the production of new, abnormal prion protein. In addition, the team established that normal prion proteins in a variety of animals may share the same “core region” or specific peptide sequence (i.e, prion peptide sequence 119 to 136). Such findings suggest that a specific part of the prion protein itself may be used to block its ability to fold incorrectly, potentially preventing progression to disease. However, much additional research is required before it may be determined whether such findings may have practical treatment implications in individuals with CJD or other forms of human prion disease. (For more information on other human prion diseases, please see the “Related Disorders” section of this report below.)
In March of 1996, the British government announced that consumption of beef from cows with an infectious brain disorder (Bovine Spongiform Encephalopathy) may have caused a variant form of Creutzfeldt-Jakob disease (V-CJD) in several young people in the United Kingdom. Cows with Bovine Spongiform Encephalopathy, also known as BSE or “Mad Cow disease,” experience rapidly progressive neurological and neuromuscular symptoms similar to those associated with CJD in humans. As with CJD, abnormal changes in prion proteins are also thought to play a role in the brain degeneration associated with BSE.
BSE was first recognized in the UK in 1986 and was linked to contaminated cow feed composed of sheep meat and bone meal. The sheep may have been infected with scrapie. In the late 1980s, Britain banned the use of such feeds in animals raised for human consumption.
By the summer of 2002, European experts had counted 97 people in Great Britain, three in France, and one in Ireland who had died or were dying from the new variant of CJD (V-CJD) since it was first identified in 1996. All of the cases identified in England had a particular genetic trait, which is not a mutation, that may have predisposed them to the condition. The genetic abnormality involves a variation of the prion protein. Approximately 40 percent of the British population has this genetic trait.
Creutzfeldt-Jakob disease (CJD) appears to affect males and females in equal numbers. It is an extremely rare human disorder that occurs worldwide with an incidence rate that has remained stable at approximately one case per million people annually. In individuals in which CJD is thought to take an infectious form (e.g., iatrogenic transmission), symptoms appear to occur approximately 10 years after initial infection (incubation period) although, in some cases, incubation periods have extended up to 30 years.
In individuals with the classical form of Creutzfeldt-Jakob disease (i.e. sporadic form), the disorder usually becomes apparent in the fifth or sixth decade of life (i.e., a median of approximately 60 years of age). In some (but not all) rare cases of classical CJD in which the disorder is thought to be inherited, the disorder may become apparent earlier in life (such as in the third or fourth decade). The clinical course of the disease tends to be rapidly progressive, with life-threatening complications occurring less than a year after the disorder becomes apparent.
Variant CJD appears to affect primarily individuals before the age of approximately 40 years, with many cases occurring in adolescents. V-CJD appears to have a more extended clinical course, with life-threatening complications typically occurring approximately two years after initial symptoms occur.
According to the medical literature, Creutzfeldt-Jakob disease (CJD) should be considered in adults who experience a sudden onset of rapidly progressive dementia and neuromuscular symptoms such as repeated, involuntary, shock-like muscle spasms (myoclonus). However, confirming a diagnosis may be difficult since other neurological disorders share similar symptoms; in addition, laboratory tests may not detect abnormalities associated with CJD. In rare cases, computer-assisted tomography (CAT) scanning may reveal deterioration in certain areas of the brain, findings that may be associated with a number of other neurological disorders. (During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of the brain's tissue structure.. In classical CJD, electroencephalography (EEG), which records the brain's electrical impulses, may reveal characteric, abnormal brain wave patterns that are often apparent during later stages of CJD. However, such EEG testing alone cannot provide a definitive diagnosis. In addition, in individuals with Variant Creutzfeldt-Jakob disease, such testing may not show the EEG patterns typically observed in the classical form of the disease.
In some cases, removal and microscopic study of a small sample of brain tissue (biopsy) may reveal the characteristic sponge-like holes and gaps and other abnormalities (vacuolization and widespread plaques [spongiform degeneration]) occurring in CJD. However, such study may result in a “false negative” in some cases if the brain tissue that has been biopsed is not directly affected. In classical CJD, extensive spongiform changes and plaque formation occur throughout the outer layer of the two hemispheres of the cerebrum (cerebral cortex). In V-CJD, spongiform changes are most prominent in the paired nerve cell clusters within the cerebrum that play a role in controlling movements (basal ganglia) and the structure deep within the brain that transmits sensory impulses to the cerebral cortex (thalamus). In addition, plaque formation may be apparent in the cerebrum and the portion of the brain that plays a role in maintaining balance and coordinating voluntary movements (cerebellum).
In addition, researchers have identified a specific protein that may lead to a diagnostic blood test for Creutzfeldt-Jakob disease. The protein, called S100, is normally found in certain brain cells (i.e., glial cells). The researchers found that, when comparing individuals with Creutzfeldt-Jakob disease and those with other disorders, people with CJD have abnormally increased levels of S100 in the fluid portion of the blood (serum). Although increased serum S100 levels may also be apparent in individuals with other neurological disorders (e.g., multiple sclerosis, brain damage due to an inadequate supply of oxygen [hypoxia], stroke), specialized imaging techniques and/or other diagnostic tests (e.g., lumbar puncture) may differentiate these disorders from CJD. According to the medical literature, it is possible that the serum S100 diagnostic test may become helpful in diagnosing CJD earlier in the course of the disease. Further studies are needed to determine the long-term safety, effectiveness, and reliability of serum S100 testing in diagnosing individuals with Creutzfeldt-Jakob disease.
The treatment of Creutzfeldt-Jakob disease is symptomatic and supportive. Affected individuals should be carefully monitored to help guard against infections.
Genetic counseling may be of benefit for families of affected individuals.
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Fauci AS, et al., eds. Harrison’s Principles of Internal Medicine. 14th ed. New York, NY: McGraw-Hill Companies, Inc.; 1998:2449-2451.
Adams RD, et al., eds. Principles of Neurology. 6th ed. New York, NY: McGraw-Hill Companies, Inc.; 1997:771-773.
Thoene JG, ed. Physicians’ Guide to Rare Diseases. Montvale, NJ: Dowden Publishing Company Inc; 1995:293-294.
Mandell GL, et al., eds. Mandell, Douglas and Bennett’s Principles and Practice of Infectious Diseases. 4th ed. New York, NY: Churchill Livingstone Inc; 1995:881-887.
Brown P, et al. Iatrogenic Creutzfeldt-Jakob disease at the millennium. Neurology. 2001;55:1075-81.
Majtenyi C, et al. A three-sister sibship of Gerstmann-Straussler-Scheinker disease with a CJD phenotype. Neurology. 2000;54:2133-2137.
Zeidler M, et al. Case 28-1999: Creutzfeldt-Jakob disease. N Engl J Med. 2000;342:292-293.
Supattapone S, et al. Elimination of prions by branched polyamines and implications for therapeutics. Proc Natl Acad Sci USA. 1999;96:14529-14534.
Chabry J, et al. Species-independent inhibition of abnormal prion protein (PRP) formation by a peptide containing a conserved PRP sequence. J Virol. 1999;73:6245-6250.
Kuwahara C, et al. Prions prevent neuronal cell-line death. Nature. 1999;400:225-226.
Otto M, et al. Diagnosis of Creutzfeldt-Jakob disease by measurement of S100 protein in serum: prospective case-control study. BMJ. 1998; 316:577-582.
Johnson RT, et al. Creutzfeldt-Jakob disease and related transmissible spongiform encephalopathies. N Engl J Med. 1998;339:1994-2004.
Hill AF, et al. The same prion strain causes VCJD and BSE. Nature. 1997;389:448-450.
Bruce ME, et al. Transmissions to mice indicate that “new variant” CJD is caused by the BSE agent. Nature. 1997;389:498-501.
Almond J, et al. Human BSE. Nature. 1997;398:437-438.
Rosenmann H, et al. Detection of 14-3-3 protein in the CSF of genetic Creutzfeldt-Jakob disease. Neurology. 1997;49:593-595.
Epstein LG, et al. Bovine spongiform encephalopathy and a new variant of Creutzfeldt-Jakob disease. Neurology. 1997;48:569-571.
Deslys JP, et al. New variant Creutzfeldt-Jakob disease in France. Lancet. 1997;349:30-31.
Hsich G, et al. The 14-3-3 brain protein in cerebrospinal fluid as a marker for transmissible spongiform encephalopathies. N Engl J Med. 1996; 335:924-930.
Collinge J, et al. Molecular analysis of prion strain variation and the aetiology of “new variant” CJD. Nature. 1996;383:685-690.
Will RG, et al. A new variant of Creutzfeldt-Jakob disease in the UK. Lancet. 1996;347:921-5.
Mastrianni JA, et al. Mutation of the prion protein gene at codon 208 in familial Creutzfeldt-Jakob disease. Neurology. 1996;47:1305-1312.
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McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Johns Hopkins University, Entry number 176640, last edit date 7/14/99; Entry number 123400, last edit date 6/4/99; Entry number 137440, last edit date 3/23/99; Entry number 600072, last edit date 1/5/00; Entry number 245300, last edit date 4/20/95.