Prion diseases are also called transmissible spongiform encephalopathies (TSEs) because of the sponge-like holes they leave in infected brains. The infectious agents in prion diseases are prions, or proteinaceous infectious particles, that can reproduce themselves. Prions have the ability to transform normal, benign protein molecules into infectious, deadly ones by altering their structure. These deadly proteins initiate a sequence of events in which many benign proteins are transformed into new deadly ones upon contact. Prions are distinct from all other infectious materials in that they do not contain any genetic material. There are multiple prion diseases, including bovine spongiform encephalopathy (BSE), or "mad cow disease." Some prion diseases are hereditary, and involve a mutation in the gene that encodes for the prion protein. Prion diseases are transmissible within a species and between compatible species.
Research on prion diseases was founded by Dr. Stanley Prusiner, a neurologist at the University of California San Francisco. He spent two decades working on the revolutionary topic of self-reproducing prions. At the time, many other scientists regarded their existence as a preposterous idea. Despite being shunned by the scientific community, Dr. Prusiner was able to prove that prions were truly infectious proteins that could cause brain disease in people and animals. The Nobel Prize for Medicine or Physiology was awarded to Dr. Prusiner in 1997 for discovering this new type of disease-causing agents that contain no DNA.
Prion diseases are transmissible between hosts of a single species and different, compatible species. The term "spongiform" in TSE comes from the spongy appearance of the damaged brain tissue. Some examples of infectious prion diseases include scrapie in sheep and goats, kuru in cannibalistic humans of Papua New Guinea, and BSE, or mad cow disease, which is transmitted to humans through infected beef products. Prion diseases can also be transmitted through injections of infected material from a compatible organism. Because of the ability of prions to cross many species barriers, all organisms that carry prion diseases are potential vectors for human infection.
Prion diseases can also be hereditary, as seen in some cases of Creutzfeldt-Jakob disease (CJD), fatal familial insomnia (FFI), and Gerstmann-Straussler-Scheinker disease (GSS). Hereditary prion diseases occur when the PRNP gene that encodes for the normal human PrPc protein, found on the surface of neurons, is mutated so that the prion PrPSc protein (Sc for scrapie) is formed. The PrPSc protein has a different conformational structure than the normal protein and is the infectious agent. PrPSc proteins can convert similar PrPc proteins upon contact into more infectious agents, thereby reproducing themselves. Prion diseases are inherited when at least one copy of the mutated PRNP gene is present. Nervous tissue from patients with hereditary prion diseases is also infectious.
A third category of prion disease is sporadic. CJD and FFI sometimes occur in people with no known history of the disease in their family and with no known exposure to infectious materials. The cause of disease in these cases is unknown. Patients with sporadic prion diseases may have a susceptibility polymorphism in their PRNP gene, and may have spontaneous mutations forming prion proteins.
Sporadic CJD, with no recognizable pattern of transmission, has an incidence of about one case per million people per year worldwide, making up 85% of total CJD cases, and 80% of all prion disease cases. In the United States, there are approximately 200 sporadic CJD cases per year. Approximately 15% of CJD cases are inherited and associated with a different prion type than that of sporadic CJD. Inherited CJD may show up in geographic clusters. A 60- to 100-fold increase in CJD is seen in Libya- or Slovakia-born Israelis due to a PRNP gene mutation rather than transmission or environmental factors. Other communities genetically at increased risk are found in some areas of Chile. CJD cases caused by accidental transmission routes such as surgical instruments and transplants are extremely rare and make up less than 1% of total cases. In the United States, the CJD cases are almost always in patients older than 30 years of age. In the United States, patients under 30 dying of CJD are less than one case per 100 million people per year, whereas in the United Kingdom, patients dying of a variant CJD (vCJD) in this age group make up over 50% of the CJD cases.
GSS is rarer than CJD, striking one person in every 10 million people. These figures are likely to be underestimated since prion diseases may be misdiagnosed as other neurological disorders. Kuru occurs in approximately 1% of the indigenous New Guinea population it is associated with. Kuru is found mostly in children older than five years and adult females under 40 years of age.
BSE has been transmitted to humans primarily in the United Kingdom, causing vCJD. An epidemic of mad cow disease began in the United Kingdom in 1985 when cattle feed was contaminated with brain tissue from scrapie-infected sheep. More than 170,000 cattle were infected before the disease was brought under control. Cattle feed containing sheep matter was banned in 1988. In 1989, slaughter techniques that allow nervous tissue to be included in beef intended for human consumption were banned. The mad cow disease epidemic of the United Kingdom reached its peak in 1992, but then declined quickly. More than one million cattle may have been infected with BSE in the United Kingdom. However, as of December 2003, only 143 cases of vCJD have been reported in the United Kingdom, out of 153 cases worldwide. The percentage of BSE cases in cattle reported outside of the United Kingdom is steadily increasing as surveillance increases and disease rates rise. The BSE epidemic in the United Kingdom may have peaked, and may now be in decline. How much of the population has vCJD in the incubation phase is yet to be determined.
To prevent the spread of BSE to the United States, severe restrictions were placed on the importation of ruminants and ruminant products from Europe. In 1997, the U.S. Department of Agriculture (USDA) also implemented a ban on the use of ruminant tissue in ruminant feed. In 2002, the CDC reported a case of vCJD in the United States in a 22-year-old patient who was born and grew up in the United Kingdom. Mad cow disease made its first appearance in cattle of the United States in December 2003, when the USDA announced a possible diagnosis in a cow from Washington State. This diagnosis was confirmed within the month at a laboratory in the United Kingdom. The cow was believed to be imported from Canada in the year 2001 and had been slaughtered for human consumption. The USDA recalled all beef slaughtered at the same slaughter plant on the same date as the infected cow.
Causes and symptoms
Ingested prions are absorbed through Peyer's patches of the small intestine, lumps of lymphoid tissue that readily allow the passage of gut antigens straight through them. Peyer's patches are a part of the mucosal-associated lymphoid tissue that presents microorganisms to the immune system and would normally facilitate a protective immune response. Prions do not activate any immune response. Prions passed through Peyer's patches travel to various sites in the lymph system, such as nodes and the spleen. Because many lymph sites are innervated, prions gain access to the nervous system, make their way to the spinal cord, and eventually the brain.
Prions are not killed by high doses of ultraviolet radiation as are bacteria and viruses. Prions are also resistant to high temperatures, strong degradative enzymes, and chemicals. Because of these properties, prions are resistant to many methods of sterilization and to protective, degradative enzymes in the human brain. The plaques formed in the brain by prion proteins are amyloid deposits similar to those seen in Alzheimer's disease . Most brain cells contain enzymes that degrade these aggregations. Prions are resistant to these enzymes. The plaques continue to grow and cause damage to the brain, usually along with the formation of large vacuoles that give the brain a spongiform appearance. Brain damage manifests itself in a loss of coordination, paralysis, dementia , and wasting, followed by death. Pneumonia also frequently occurs in patients with prion diseases. All prion diseases are inevitably fatal; there are no known cures.
Prion diseases can be inherited in an autosomal dominant matter. This means if one parent carries the mutation on their PRNP gene, each offspring has a 50% chance of inheriting the mutation. In this manner, patients with a prion disease have inherited at least one copy of a mutated PRNP gene on human chromosome 20. There are a variety of mutations in the gene that cause resultant mutated proteins to be expressed, with each type of mutation resulting in a different prion strain, and a different inherited prion disease. Strains show very different and reproducible patterns of brain degeneration. Extracts of autopsied brain tissue from infected patients have been used for research on prion diseases. It has been demonstrated that only animals whose PRNP gene is similar enough to humans can be infected with human prions. Similarly humans can only be infected by prions from animals whose PRNP gene ultimately encodes for a prion protein that is similar to humans. Prions transform their normal cellular counterparts into other prions only between prion-compatible species. Infectious prion diseases are transmitted through consumption of infected materials or through injection of ground-up infected tissues. Prion diseases are not contagious in the traditional sense. Individuals who live with patients with prion diseases are at no increased risk. While casual contact does not transmit the disease, brain tissue and cerebrospinal fluid from patients with prion diseases should be avoided.
Inherited prion diseases
GERSTMANN-STRAUSSLER-SCHEINKER DISEASE Caused by the GSS prion, this disease was first described in 1928. GSS is associated with variations in at least one PRNP gene sequence at positions 102 and 117. It is also highly associated with a polymorphism on both gene copies at position 129 on the human PRNP gene. GSS typically occurs between the ages of 35 and 55. It is characterized by progressive cerebellar ataxia and associated motor complications, following a time course of 2–10 years before death. Dementia with GSS is less common than with CJD, except in very late stages of disease following a long time course. GSS is almost always inherited, but has been known to occur sporadically as well.
CREUTZFELDT-JAKOB DISEASE Caused by the CJD prion, this disease is associated with variations in the PRNP gene at positions 178 and 200, along with an insertion of extra DNA in the familial form. CJD was first described in the 1920s as a progressive dementia, following a course of one year, ending in death. CJD presents with a variety of motor disturbances, including twitching. CJD typically occurs between the ages of 50 and 75. While CJD is an inherited disease, the majority of CJD occurs sporadically. Other CJD cases are due to accidental exposure to infected material.
FATALFAMILIAL INSOMNIA Caused by the FFI prion, FFI is a rare disorder first described in 1986. It is caused by inherited mutations in the PRNP gene at position 178 and a polymorphism at position 129. FFI typically occurs between the ages of 40 and 60, and is characterized by progressive sleep disturbance classified as untreatable insomnia, ataxia (motor dysfunction), and dysautonomia (sensory dysfunction). The disease course is 7–18 months, followed by death. Postmortem studies associate this prion disease with severe selective atrophy of the thalamus, a brain region controlling sleep and wakefulness. Sporadic FFI has been reported without the characteristic gene mutation.
ALPERS SYNDROME Alpers syndrome is the term used to describe prion diseases in infants.
Infectious prion diseases
SCRAPIE Caused by the scrapie prion, scrapie is the first prion disease ever studied. Scrapie was first described in sheep and goats more than 200 years ago. It is transmitted through feed contaminated with nervous tissue. It can also be transmitted through pasture infected with placental tissue from infected sheep. The term "scrapie" comes from the behavior of infected sheep that rub up against the fences of their pens to remain upright despite severe ataxia, a loss of muscular coordination due to brain damage. Autopsies of infected animals reveal spongiform encephalopathy. In 1943, scrapie was demonstrated as transmissible when a contaminated vaccine infected healthy sheep.
KURU Decades after scrapie was first discovered, a similar disorder was described in humans called kuru. Kuru was characterized in 1950 as a progressive cerebellar ataxia associated with a shivering tremor, with a disease course of three to nine months, followed by death. The word kuru comes from the Fore language and means 'tremor.' Caused by the kuru prion, kuru primarily occurred in the Fore highland people of southern New Guinea, whose cultural practice used to involve ritualistic ingestion of the brain tissue of recently deceased family members. The brain tissue was ground into a pale gray soup, heated, and consumed. Statistically, women of the Fore tribe were more likely than men to develop kuru, due to their greater involvement in the preparation of the brain tissue. Infection in the female population was probably via both ingestion and through minor skin abrasions. Clinically, kuru resembles CJD. Since this practice has stopped, the disease has ceased to occur.
BOVINE SPONGIFORM ENCEPHALOPATHY Humans consuming infected beef are susceptible to the BSE prion strain. Strain typing shows one major strain. BSE is especially insidious in that it is compatible with and transmissible to a wide variety of species. While food items containing blood or nervous tissue are potential vectors for human infection, milk and milk products from cows are not believed to pose any risk for transmitting the BSE prion to humans (see also vCJD).
ACQUIRED CREUTZFELDT-JAKOB DISEASE While CJD is an inherited disease it can also be acquired through iatrogenic transmission, which is accidental exposure to CJD prion-contaminated material through a medical procedure using tainted human matter or surgical instruments. Recipients of corneal transplants and of grafts of dura mater (brain-associated connective tissue) have been infected with CJD. Because prions are resistant to many sterilization procedures and to degradation, surgical instruments used in brain surgery have infected new patients two years after being sterilized. More than 100 people have been infected with CJD through injections of human growth hormones prepared from pools of pituitary glands that included materials from humans with CJD. At present, growth hormones are prepared through recombinant DNA technology and surgical instruments used on potentially infected patients have new sterilization guidelines, so the transmission of CJD via these routes has ceased to occur. The National Center for Infectious Diseases has not found any iatrogenic CJD cases linked to contact with pathogens from surfaces like floors or countertops.
VARIANT CREUTZFELDT-JAKOB DISEASE (VCJD) Variant CJD appeared in 1996 during the mad cow disease epidemic in the United Kingdom. The specific strain found in these patients indicates that they have been infected with prions from contaminated beef, the BSE prion. However, victims of vCJD are homozygous for a polymorphism on the PRNP gene at position 129. Patients with
vCJD may develop the disease at an unusually early age with the current median age of 29 years at death. However, the incubation time period before the onset of symptoms may be as long as 40 years. The vCJD affects people between 15 and 60 years of age. The clinical symptoms associated with vCJD differ from those seen with CJD, including psychiatric or sensory symptoms early in the course of the disease, delayed onset of neurological abnormalities that follow a pattern identifiable as but different from CJD, and a duration of illness of at least six months, followed by death. As of January 2004, evidence indicates there has never been a case of vCJD transmitted through direct contact of one person to another.
MISCELLANEOUS INFECTIOUS PRION DISEASES Cats and mink are susceptible to species-specific forms of TSE. In many mid-western states of the United States, some elk and mule deer carry a form of TSE called chronic wasting disease (CWD). CWD prions may possibly be transmissible to humans consuming venison the same way as mad cow disease can be transmitted through contaminated beef.
There is currently no single diagnostic test for any prion disease. Physicians initially rule out other treatable forms of dementia such as classical encephalitis. Standard diagnostic tests include a spinal tap to exclude other diseases and an electroencephalogram (EEG) to record the patient's brain wave pattern. CT scans and magnetic resonance imaging (MRI) scans can rule out the possibility of stroke and reveal characteristic patterns of brain degeneration associated with various types of prion diseases.
Diagnosis classically relied on clinical symptoms, transmissibility, and postmortem neuropathology. With these diagnosis criteria, many cases of prion diseases may have been misdiagnosed as other neurodegenerative disorders. However, modern diagnosis is also dependent on detection of prion proteins, and identification of mutations in the PRNP gene. A genetic sequence analysis can be performed for a number of different mutations associated with familial CJD. The types of mutations present determine which symptoms will be most prominent. However, the presence of these mutations on the PRNP gene does not necessarily result in CJD. Most CJD patients contain a specific protein in their cerebrospinal fluid and an abnormal EEG brain wave pattern, diagnostic for CJD. However, confirmation requires neuropathological testing of brain tissue obtained through brain biopsy or autopsy. Brain biopsies are usually performed only when required to exclude another, treatable condition.
A diagnosis of prion disease is confirmed through examination of the brain tissue. Visible postmortem characteristics of the brain include noninflammatory lesions, vacuoles, amyloid protein deposits forming plaques that follow prion type-specific patterns, and measurable biochemical changes. While dramatic alterations in the brain's appearance are primarily the case, more subtle and noncharacteristic changes have also been reported. Some forms of prion disease with shorter durations only create plaques in a small percentage of patients.
Clinical signs of prion disease in sheep and cattle include cerebellar ataxia (loss of muscle coordination), polydipsia (excessive drinking), and an itching syndrome that, along with the lack of coordination, causes the animals to rub up against fences. However, animals are not diagnosed with prion disease until brain autopsy reveals neuropathology similar to that seen in humans.
Primary-care physicians may notice symptoms of a neurological disorder in a patient and refer them to a neurologist, specialists in brain disorders. They would act as the treatment team for patients with prion diseases.
Oversight of the BSE Action Plan in the United States is done by the Department of Health and Human Services (DHHS). Under this plan, surveillance for human disease is the responsibility of the Centers for Disease Control and Prevention (CDC). Protection against this disease is the responsibility of the Food and Drug Administration (FDA). Research is primarily the responsibility of the National Institutes of Health (NIH).
There is no known effective treatment to arrest or cure prion diseases. Treatment focuses on alleviating the patient's symptoms, increasing their comfort, and palliative care. Treatment may include medications to control pain and motor disorders, catheters to collect urine, intravenous fluids to maintain hydration, and frequently repositioning the patient to avoid bedsores.
Possible future treatments developed may include chemicals that bind to and stabilize PrPc, agents destabilizing the PrPsc protein, or agents that interfere with the intereaction between PrPc and PrPsc.
Recovery and rehabilitation
There is no recovery or rehabilitation for prion diseases.
As of January 2004, no clinical trials on prion diseases have taken place. In September 2001, the government announced an agenda of the design and implementation of clinical trials on CJD. The trials were originally planned after a vCJD patient received an unproven treatment in California and seemed to be improving. The treatment was with the anti-malaria drug quinacrine, which blocks the formation of prion plaques in mouse cell culture but has undetermined effects in humans with prion diseases. Sadly, the patient died in December 2001. While planned clinical trials will focus on quinacrine, as of January 2004 they are still being designed. Other patients have taken this treatment outside of clinical trials and the results suggest possible limited benefit along with damaging side effects. Another unproven treatment is pentosan polysulphate, which also has dangerous side effects. The first patient to receive this treatment showed some improvement in the condition. As of October 2003, four other patients have been granted permission for its use.
Prions bring about slow degeneration of the central nervous system , inevitably leading to death. A very long time period passes between a patient's infection and the initial appearance of clinical symptoms, an incubation process that may take up to 40 years in humans. However, once the symptoms appear, the patient generally dies within a few months with rapid, progressive symptoms. At this time, prion diseases are fatal diseases.
Highly effective public health control procedures have been implemented in Europe to prevent potential BSE-infected tissue from entering the human food chain. The current risk of becoming infected with vCJD from eating beef and beef products in the United Kingdom is very small, at a rate of one case per 10 billion servings. Other countries have equal or lesser rates of risk. To reduce the risk of being infected with vCJD from food while traveling to geographical areas associated with risk, travelers who do not wish to avoid eating beef entirely may reduce their risk by selecting beef products in solid pieces, as opposed to ground beef tissue.
As of January 2004, there is no evidence that blood or blood products have transmitted TSEs to humans. However, to reduce the theoretical risk of transmission from blood products to humans, those individuals who have lived cumulatively for five or more years in Europe since the year 1980 to the present have been deferred by the FDA from donating blood or blood products. Individuals living specifically in the United Kingdom for three months or more from 1980 to 1996 are also deferred. Variant CJD (vCJD) is more likely to be transmitted through blood than classical CJD.
The CDC has established a National Prion Disease Pathology Surveillance Center (NPDPSC) that provides free, high-tech diagnostic services to physicians in the United States. Relatives of CJD patients who wish to assist research have their physician send brain tissue, blood, cerebrospinal fluid, and urine samples to the center.
Prion research has been done in yeast, a convenient organism easily used in scientific study. Yeast can be infected with prions, begin forming their own prion proteins, and pass the infection on to further generations of yeast. It has been noted that yeast can be "cured" of their prion disease by increasing the activity of chaperone proteins, which help maintain the normal conformational structure of the PrPc protein and keep it from being converted to prion conformation.
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National Prion Disease Pathology Surveillance Center. Case Western Reserve University 2085 Adelbert Road, Room 418, Cleveland, OH 44106. (216) 368-0587; Fax: (216) 368-4090. [email protected] <http://www.cjdsurv.com>.
Maria Basile, PhD