What is Creutzfeldt-Jakob disease (CJD)?

Causes and Symptoms

Spongiform encephalopathies are inherited or transmissible neurological diseases that are associated with abnormalities in proteinaceous molecules called prions, which can aggregate, leading to spongelike lesions in the brain and causing disruptions in brain function. Prions are found in all species from yeast to humans, but their normal role is not known. Their evolutionary persistence in so many species implies an important purpose, although knockout mice lacking prions do not appear to be deleteriously affected.

Inherited spongiform encephalopathies are primarily attributed to mutations in the prion gene, producing abnormal prions that adopt an unusual conformation and clump together over time to cause the brain pathology and neurological symptoms characteristic of this type of disease. The diseases can be transmitted to a susceptible animal by inserting a fragment or extract from diseased tissue into the brain or blood or, much less efficiently, by oral ingestion. The infectious agent seems to be the abnormal prion itself, which apparently recruits normal prions in the brain to adopt the abnormal conformation, leading to their aggregation and the disruption of brain function. This is an unorthodox etiology, in that the infectious agent appears to be devoid of nucleic acid (RNA or DNA); its mode of action is not fully understood, nor is this etiology universally accepted.

Creutzfeldt-Jakob disease (CJD), known since the 1920s, is the major spongiform encephalopathy in humans, although it occurs in only one per million persons worldwide. It has different forms, namely sporadic, inherited, infectious, and, recently, new variant.

The sporadic form has no known basis, accounts for 85 percent of the cases, and usually affects individuals aged fifty-five to seventy years of age. The pathologic findings are limited to the central nervous system, although the transmissible agent can be detected in many organs. Researchers noted in 2002 that psychiatric and neurological symptoms are often present within four months of the disease’s onset. Common symptoms include withdrawal, anxiety, irritability, insomnia, and a loss of interest. Within a few weeks or months, a relentlessly progressive dementia becomes evident, and myoclonus is often present at some point. Deterioration is usually rapid, with 90 percent of victims dying within one year. CJD patients do not have fevers, and their blood and cerebrospinal fluid are normal.

The inherited or familial form has been noted in some one hundred extended families, accounting for 15 percent of the cases of CJD. At least seven different point mutations and one insertion mutation in the prion gene have been identified. Some prion mutations result in slightly different symptoms and are classified as different diseases. Other mutations may lead to the sporadic, infectious, or new variant forms.

The infectious form is rare and generally has been associated with medical procedures, such as organ transplants, inadvertent infection from contaminated surgical instruments, or treatment with products derived from human brains. Because the infectious agent is highly resistant to denaturation, thorough decontamination of surgical instruments has proven essential in minimizing transmission. A number of cases occurred in individuals receiving growth hormone extracts derived from human pituitary glands, a practice discontinued in the United States in 1985. The infectious form also appears to be the basis for kuru, a disease previously endemic among the Fore people of the eastern highlands of Papua New Guinea. Typically, it was characterized by cerebellar dysfunction, dementia, and progression to death within two years. Evidence indicates that the kuru agent was transmitted through the ritual handling and consumption of affected tissues, especially brains, from deceased relatives. With discontinuation of these cultural practices, kuru has virtually disappeared.

A new variant CJD (nvCJD) was first reported in Britain in 1996. It differed from sporadic CJD in affecting younger persons (aged sixteen to thirty-nine) and in its behavioral symptoms, pathology, and longer course. This variant followed the British epidemic of bovine spongiform encephalopathy
(BSE), known as mad-cow disease. Contaminated beef consumption was suspected as the source of nvCJD, which has subsequently been shown to have a molecular signature similar, if not identical, to that for BSE. Furthermore, nvCJD has been observed only in countries with BSE.

BSE first appeared in Britain in 1986 and has subsequently been diagnosed in twelve other countries. It occurs in adult cattle between two and eight years of age and is fatal. In the course of the disease, the animals lose coordination and show extreme sensitivity to sound, light, and touch. While it may be transmitted from mother to calf, the major cause of the BSE epidemic in Britain is attributed to feed containing contaminated ruminant-derived protein. Following a ban on incorporating such protein into cattle feed, the incidence has decreased. Since the beginning of the epidemic, a total of 200,000 cattle have been diagnosed with the disease; fewer than 1,000 new cases are currently reported per year. In the United States, a surveillance program is in effect, importation of beef from affected countries is prohibited, and incorporating ruminant-derived protein into cattle feed has been banned. Nevertheless, an infected cow was discovered in 2003 on a farm in Washington State. It had been imported from Canada.

When the British BSE outbreak occurred, concern arose for its human health implications, despite the fact that scrapie, the comparable condition in sheep, was long known not to be a risk to human consumers. A surveillance unit was established in 1990, and ten cases of the new variant form of CJD were reported in 1996. In 2000, twenty-eight cases were recorded in Britain. The numbers began to slow soon afterward, but fears of another epidemic remained.

Treatment and Therapy

Research on experimental animals has been crucial to understanding the unusual etiology of these diseases. Brain tissue from patients dying of kuru was inoculated into the brains of chimpanzees that, after a prolonged incubation period, developed a similar disease. CJD, BSE, and scrapie have been similarly transmitted to a wide variety of laboratory animals. Mouse models have been particularly useful. Knockout mice lacking their normal prion gene are not susceptible to transmissible disease, indicating the importance of endogenous brain prions in the etiology. Transgenic mice, whose own prions have been replaced with those from other species or with specific mutations, exhibit different susceptibilities to various infectious particles.

Because none of the spongiform encephalopathies stimulates a specific immune response, diagnosis of these diseases in living persons or animals is difficult. Postmortem identification of brain lesions is necessary to verify the diagnosis. The use of antibodies to prions is permitting rapid confirmation of the diagnosis from specimens obtained by brain biopsy or postmortem examination. As of 2013, no effective treatment was available for these diseases, which are uniformly fatal. Treatment focuses on alleviating pain and other symptoms. Although these diseases can be transmitted to health care workers and others having contact with CJD patients, the risk is no higher than for the general population. Isolation of patients is not suggested, but reasonable care should be exercised. No organs, tissues, or tissue products from these patients or others with an ill-defined neurologic disease should be used for transplantation, replacement therapy, or pharmaceutical manufacturing.

Perspective and Prospects

Clinically, Creutzfeldt-Jakob disease can be mistaken for other disorders that cause dementia in the elderly, especially Alzheimer’s disease. CJD, however, usually has a shorter clinical course and includes myoclonus. While nvCJD has a longer clinical course, it generally affects younger persons.

Continued monitoring of CJD and especially nvCJD in the United Kingdom is warranted. In addition, surveillance of the food supply in the United States and other countries should persist to prevent meat from BSE cattle from reaching consumers. Above all, further research into the etiology of these pathologies is needed. Research into prion biology and disease epidemiology, including studies of nvCJD clusters, must be pursued until the progression of these diseases is fully understood. Early detection and effective treatment await this understanding.

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