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Last updated:
June 14, 2021
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NORD gratefully acknowledges Caroline Stanclift, MS, NORD Editorial Intern from the Stanford University MS Program in Human Genetics and Genetic Counseling and Jennefer Kohler, MS, CGC, Clinical Instructor (Affiliated), Dept of Pediatrics, Division of Medical Genetics, Stanford University, for assistance in the preparation of this report.
Summary
Creutzfeldt-Jakob disease (CJD) is an extremely rare, degenerative brain disorder. It affects about one in every million people per year worldwide. People with CJD typically develop symptoms later in life and may show changes in behavior, memory troubles, lack of coordination and vision problems. As the disease progresses, there may be rapidly progressive deterioration of mental functioning, memory (dementia) and muscle control. CJD is a fatal disease. In most affected individuals, life-threatening complications develop less than a year after they start showing symptoms.
There are three major subtypes of CJD. In 85-90 percent of patients, CJD randomly appears even though the person has no known risk factors such as family history or environmental exposure (sporadic CJD). In about 10-15 percent of patients, there may be a family history of CJD (genetic CJD). In less than 1 percent of patients, the disease can be caused by exposure to infected brain or nervous system tissue through medical treatment (iatrogenic) or ingestion (orally) (acquired CJD). A subset of acquired CJD called variant CJD (vCJD) or, commonly, “mad cow disease” first appeared in the United Kingdom and is caused by eating beef infected with bovine spongiform encephalopathy (BSE). This vCJD occurs in younger people (median age of onset is 28 years).
All types of CJD are due to the presence of a disease-causing protein called a prion. Disease-causing prions can disrupt the structure of the brain and lead to degeneration. Currently, there are no treatments that can cure or stop the progression of CJD. Treatment is supportive and aimed at making the person as comfortable as possible.
Introduction
Creutzfeldt-Jakob disease (CJD) was named by two German doctors named Hans Creutzfeldt and Alfons Jakob who studied the disease in the 1920s. Over time, scientists noted the similarities of human CJD to animal diseases (called bovine spongiform encephalopathy or “mad cow disease” in cows and scrapie in sheep) and learned that human and animal forms are caused by a similar mechanism; an abnormal, infectious protein called a prion. The term prion, derived from proteinaceous infectious particle, was coined by Stanley Prusiner. In humans, there are three subtypes of CJD based on how the abnormal prion protein occurred: sporadic (sCJD), genetic (gCJD) and acquired (aCJD).
All types of Creutzfeldt-Jakob disease (CJD) are extremely rare degenerative brain disorders (i.e., spongiform encephalopathies), characterized by the sudden onset of cognitive impairments and neuromuscular symptoms. Specific signs and symptoms of each type are outlined below.
Sporadic CJD and genetic CJD
In sporadic CJD (sCJD) and genetic CJD (gCJD), symptoms typically arise between ages 40-60 years. Initially, these symptoms may look like 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 movement coordination.
Individuals 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 sCJD and gCJD, 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 patients, life-threatening complications tend to develop less than a year after the disorder becomes apparent.
Acquired CJD
Acquired CJD (aCJD) and a specific variant form of Creutzfeldt-Jakob disease (vCJD) occur very rarely (<1 percent of all CJD; less than 500 cases ever known). Symptoms are similar to other forms of CJD, however, there are three key differences. First, acquired forms of CJD typically occur in young adults (i.e., teens and 20s) rather than in the 40s-50s as in sCJD and gCJD. Second, patients tend to have a slightly longer clinical course. Third, acquired forms usually begin with more significant psychiatric symptoms. Delusions are also sometimes reported. Some people with the disorder may have abnormal sensations (dysesthesia) or pain in the face, arms, and legs. Within a few weeks or months, individuals with aCJD or vCJD 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 patients, neuromuscular abnormalities may include irregular, rapid, involuntary jerky movements (chorea). As the disease advances, individuals with aCJD or vCJD 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 aCJD or vCJD, life-threatening complications tend to develop approximately 13 to 14 months after initial symptoms occur.
All types of CJD are caused by the presence of abnormal prion proteins in the brain. 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 deterioration in turn results in the progressive neurological and neuromuscular symptoms associated with CJD.
How the abnormal prion protein arises is distinct in the different subtypes of CJD.
Sporadic CJD
sCJD accounts for 85% of CJD and is thought to result from random (sporadic) changes in prion protein structure. 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, researchers removed the normal prion protein from nerve cells (i.e., cultured neurons) and the cells did not survive. However, when researchers restored normal PrPc to cells without the protein, affected neurons returned to health. This suggests the normal prion protein is important for the health of neurons. Further research is necessary to determine the implications of such findings and the specific role of PRPc.
The modified or “misfolded” form of PrPc that causes disease is known as PrPsc (for scrapie prion protein). PrPsc can cause normal PrPc to change shape into the disease-causing form. The misfolded shape of PrPsc is thought to prevent it from being appropriately broken down by the body. As a result, more and more normal PrPc change into PrPsc, which gradually accumulate, forming fixed deposits (plaques) in the brain.
Genetic CJD
gCJD results from changes (mutations) in the PRNP gene which regulates (encodes for) the production of the human prion protein. Genetic forms of CJD are rare (10-15 percent of cases) and follow an autosomal dominant inheritance pattern. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. In the case of gCJD, the non-working gene is PNRP.
(aCJD)
Acquired forms of CJD account for 1 percent of all CJD (less than 500 cases ever reported in the world). Direct contamination (transmission) with PrPsc causes the acquired form. This transmission has been reported to occur through medical treatments (iatrogenic), most notably, growth hormone and dura mater grafts made from PrPsc infected human tissue, or from consumption of PrPsc -contaminated meat.
In March of 1996, the British government announced that consumption of beef from cows with the infectious brain disorder bovine spongiform encephalopathy (BSE) caused a variant form of Creutzfeldt-Jakob disease (vCJD) in several young people in the United Kingdom. Cows with 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, the sheep form of prion disease. In the late 1980s, Britain banned the use of such feeds in animals raised for human consumption.
CJD affects males and females in equal numbers. It is rare, arising in approximately one to two individuals per million people each year.
In individuals with aCJD, symptoms appear to occur approximately 10 years after initial infection (incubation period) although, in some patients, incubation periods have extended up to 30 years. No direct cases of surgically acquired CJD have been identified since 2005.
Since it was first identified in 1996, a total of 231 cases of vCJD have been reported worldwide. The majority (178/231) of the cases were in the United Kingdom. The annual number of confirmed cases of vCJD has declined globally in the past 15 years.
Genetic forms of the disease can be diagnosed through clinical symptoms, family history and genetic testing for variants in the PRNP gene. Genetic counseling is recommended for individuals with suspected genetic CJD.
Confirming or ruling out a diagnosis of sCJD in a living patient can be difficult. In 2018, the Centers for Disease Control and Prevention (CDC) updated the diagnostic criteria for sCJD stating a definite diagnosis of CJD can only be determined through positive brain tissue testing. This would include standard neuropathological techniques (i.e., histology and immunohistochemistry); and/or western blot confirmed protease-resistant PrP. This testing is usually performed at the time of autopsy.
Along with clinical symptoms, there are tests which can be useful to determine a probable diagnosis of CJD in a living patient. The first is called real-time quaking-induced conversion (RT-QuIC). This method looks for abnormal prion protein through formation of prion aggregates in fluid from the spinal cord. The second is brain imaging with magnetic resonance imaging (MRI), which allows specialist to look for distinct patterns of neurodegeneration. Using results from RT-QuIC, MRI, and clinical symptoms, specialists can determine if an individual meets the criteria for a probable CJD diagnosis. Other possible tests that could be considered include electroencephalogram (EEG), which records the brains electrical impulses.
Treatment
The treatment of Creutzfeldt-Jakob disease is symptomatic and supportive.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website:https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Uttley L, et al. Creutzfeldt-Jakob disease: a systematic review of global incidence, prevalence, infectivity, and incubation. Lancet Infect Dis. 2020 Jan;20(1):e2-e10.
Vallabh SM, et al. Prion protein quantification in human cerebrospinal fluid as a tool for prion disease drug development. Proc Natl Acad Sci USA, 2019. 116(16), 7793–7798.
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.
INTERNET
Sitammagari KK, Masood W. Creutzfeldt Jakob Disease. StatPearls. Last Update: March 6, 2021. https://www.ncbi.nlm.nih.gov/books/NBK507860/ Accessed May 18, 2021.
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Johns Hopkins University, Entry number 123400. 10/24/2014. https://www.omim.org/entry/123400 Accessed May 18, 2021.
Creutzfeldt-Jakob disease. Mayo Clinic. Jan. 05, 2021. https://www.mayoclinic.com/health/creutzfeldt-jakob-disease/DS00531 Accessed May 18, 2021.
Creutzfeldt Jakob Disease. Centers for Disease Control and Prevention. https://www.cdc.gov/prions/cjd/index.html Accessed May 18, 2021.
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