Motor neuron disease

Definition

Creutzfeldt-Jakob disease (CJD) is a transmissible, rapidly progressing, fatal neurodegenerative disorder related to "mad cow disease."

Description

Before 1995, Creutzfeldt-Jakob disease was little-known outside of the medical profession; even within it, most doctors did not know much about it, and hardly any had ever seen a case. But with the discovery of a "new variant" form, the possibility that those with it became infected simply by eating beef, and the radical theory that the infectious agent is a rogue protein, CJD has become one of the most talked-about diseases in the world, and has taken on a significance far beyond the small number of deaths it currently causes each year.

First described in the 1920s, CJD is a neurodegenerative disease causing a rapidly progressing dementia which ends in death, usually within eight months of the onset of symptoms. It is also a very rare disease, affecting only about one in every million members of the population worldwide. In the United States, CJD is thought to affect about 250 people each year. CJD affects adults of all ages, but is rare in young adults and most common between ages 50 and 75.

Spongiform encephalopathies

The most obvious pathologic feature of CJD is the formation of numerous fluid-filled spaces in the brain (vacuoles), giving it a sponge-like appearance. CJD is one of several human "spongiform encephalopathies," diseases that produce this characteristic change in brain tissue. Others are kuru; Gerstmann-Straussler- Scheinker disease, predominantly characterized by cerebellar ataxia; and fatal familial insomnia, associated with progressive insomina, autonomic system disfunction, and weakness caused by motor system disfunction.

Kuru was prevalent among the Fore people in Papua New Guinea, spread from infected individuals after their deaths through the practice of ritual cannibalism, in which the relatives of the dead person honored him by consuming his organs, including the brain. Discovery of the infectious nature of kuru won the Nobel Prize for Carleton Gadjusek in 1976 and also alerted the medical world to the possibility of slow-acting infectious agents. The incubation period for kuru was between 4-30 years or more. While kuru has virtually disappeared following the cessation of the cannibalistic practices, several new cases continue to arise each year.

Cases of CJD have been grouped into three types: familial, iatrogenic, and sporadic.

• Familial CJD, representing 5-15% of cases, is inherited in an autosomal dominant manner, meaning that either parent may pass along the disease to a child, who may then develop CJD later in life.
• Iatrogenic CJD occurs when a person is infected during a medical procedure, such as organ donation, blood transfusion, or brain surgery. The rise in organ donation has increased this route of transmission; grafts of infected corneas and dura mater (the tissue covering the brain) have been shown to have transmitted CJD. Another source is hormones concentrated from the pituitary glands of cadavers, some of whom carried CJD, for use in people with growth hormone deficiencies. Iatrogenic infection represents a small fraction of all cases. The incubation period between exposure to the infectious agent is very long and is estimated to be from less than 10 to more than 30 years.
• Sporadic CJD represents at least 85% of all cases. Sporadic cases have no identifiable source of infection. Death usually follows first symptoms within eight months.

Animal forms and "mad cow disease"

Six forms of spongiform encephalopathies are known to occur in other mammals: scrapie in sheep, recognized for more than 200 years; chronic wasting disease in elk and mule deer in Wyoming and Colorado; transmissible mink encephalopathy; exotic ungulate encephalopathy in some types of zoo animals; feline spongiform encephalopathy in domestic cats; and bovine spongiform encephalopathy (BSE) in cows.

BSE was first recognized in Britain in 1986. Besides the spongiform changes in the brain, BSE causes dementia-like behavioral changes--hence the name "mad cow disease." BSE is thought to be an altered form of scrapie, transmitted to cows when they were fed sheep offal (slaughterhouse waste) as part of their feed.

The use of slaughterhouse offal in animal feed has been common in many countries and has been practiced for at least 50 years. The trigger for the BSE epidemic in Britain seems to have come in the early 1980s, when the use of organic solvents for preparation of offal was halted there. It seems likely that these solvents had been destroying the scrapie agent, thereby preventing infection, and that the change in preparation procedure opened the way for the agent to "jump species" and cause BSE in cows which consumed scrapie-infected meal. The slaughter of infected (but not yet visibly sick) cows at the end of their useful farm lives, and the use of their carcasses for feed, spread the infection rapidly and widely. For at least a year after BSE was first recognized in British herds, infected bovine remains continued to be incorporated into feed, spreading the disease still further. (It is thought that most cows with BSE became infected as a result of eating meal containing offal from other cows, not sheep.) Although milk from infected cows has never been shown to pass the infectious agent, passage from infected mother to calf has occurred through unknown means.

Beginning in 1988, the British government took steps to stop the spread of BSE, banning the use of bovine offal in feed and other products and ordering the slaughter of infected cows. By then, the slow-acting agent had become epidemic in British herds. In 1992, it was diagnosed in over 25,000 animals (1% of the British herd). By mid-1997, the cumulative number of BSE cases in the United Kingdom had risen to more than 170,000. The feeding ban did stem the tide of the epidemic; however, the number of new cases each week fell from a peak of 1,000 in 1993 to less than 300 two years later.

The export of British feed and beef to member countries was banned by the European Union, but cases of BSE had developed in Europe by then as well; however, by mid-1997, only about 1,000 cases had been identified. In 1989, the United States banned import of British beef and began monitoring U.S. herds in 1990. To date, no BSE has been detected in the United States, and only one case has been reported in North America in a cow imported to Canada from Britain.

New-variant CJD: the jump to humans

From the beginning of the BSE epidemic, scientists and others in Britain feared that BSE might jump species again to infect humans who had consumed infected beef. In 1995, this fear seemed to be realized with the first cases of a new variant of Creutzfeldt-Jacob disease, termed nvCJD. Its victims, 23 in all as of early 1998, are much younger than the 60-65 average for CJD, and the time from symptom onset to death has averaged 12 months instead of eight. EEG abnormalities characteristic of CJD are not typically seen in nvCJD.

Evidence is growing stronger that nvCJD is in fact caused by BSE.

• All but one of the cases so far have occurred in Britain, the location of the BSE epidemic
• BSE injected into monkeys produces a disease very similar to nvCJD
• BSE and nvCJD produce the same brain lesions after the same incubation period when injected into laboratory mice
• Brain proteins isolated from nvCJD victims, but not from the other forms of CJD, share similar molecular characteristics with brain proteins of animals that died from BSE.

While definitive proof is still lacking as of early 1998, many researchers now treat the BSE-nvCJD connection as solidly established.

Assuming that BSE is the source, the question that has loomed from the beginning has been is how many people will eventually be affected. Epidemiological models of infectious disease produce estimates ranging from less than one hundred to tens of thousands, depending on the assumptions used by the modelers. The incubation period of nvCJD in humans is not known, nor are the genetic and environmental risk factors which influence susceptibility, nor the quantity of infectious agent needed to cause the disease. It is estimated that between one and two million infected cattle have been eaten by humans, most in the earliest stages of the epidemic. Estimates cannot be based on the very few cases which have developed so far. These cases could represent the very few people with the right combination of exposure and susceptibility to a relatively fast-developing infection, or they could be the first few victims of a slower-acting, more highly infectious agent.

Causes & symptoms

Causes

It is clear that Creutzfeldt-Jakob disease is caused by an infectious agent, but it is not yet clear what type of agent that is. Originally assumed to be a virus, evidence is accumulating that, instead, CJD is caused by a protein called a "prion," (PREE-on, for "proteinaceous infectious particle") transmitted from victim-to-victim. The other spongiform encephalopathies are also hypothesized to be due to prion infection.

If this hypothesis is proved true, it would represent one of the most radical new ideas in biology since the discovery of DNA. All infectious diseases, in fact all life, uses nucleic acids--DNA or RNA--to code the instructions needed for reproduction. Inactivation of the nucleic acids destroys the capacity to reproduce. However, when these same measures are applied to infected tissue from spongiform encephalopathy victims, infectivity is not destroyed. Furthermore, purification of infected tissue to concentrate the infectious fraction yields protein, not nucleic acid. While it remains possible that some highly stable nucleic acid remains hidden within the purified protein, this is seeming less and less likely as further experiments are done. The "prion hypothesis," as it is called, is now widely accepted, at least provisionally, by most researchers in the field. The most vocal proponent of the hypothesis, Stanley Prusiner, was awarded the Nobel Prize in 1997 for his work in the prion diseases.

A prion is an altered form of a normal brain protein. The normal protein has a helical shape along part of its length. In the prion form, a sheet structure replaces the helix. According to the hypothesis, when the normal form interacts with the prion form, its helical part is converted to a sheet, thus creating a new prion capable of transforming other normal forms. In this way, the disease process resembles crystallization more than typical viral infection, in which the virus commands the host's cellular machinery to reproduce more of the virus. Buildup of the sheet form causes accumulation of abnormal protein clumps and degeneration of brain cells, causing dementia and ultimately death.

The brain protein affected by the prion, called PrP, is part of the membrane of brain cells, but its exact function is unknown. It is composed of about 250 subunits, called amino acids, coded for by a gene on chromosome 20. Slight genetic differences, called polymorphisms, give rise to two slightly different normal protein forms: subunit 129 is a "methionine" in one form, but is "valine" in the other. A person may have all of one, all of the other, or a mixture of the two, depending on their genetic inheritance. Both forms have the normal helical structure, and function normally. However, susceptibility to prion conversion is influenced by subunit 129: a person with a mixture of forms is more resistant to conversion, and a person with all valine appears to be somewhat more susceptible than one with all methionine. Exposure to the infectious agent is, of course, still required for disease development. Prion diseases are not contagious in the usual sense, and transmission from an infected person to another person requires direct inoculation of infectious material.

Familial CJD, on the other hand, does not require exposure but develops through the inheritance of other, more disruptive mutations in the gene for the normal PrP protein. Researchers believe these mutations increase the likelihood that the protein will spontaneously "flip" to the sheet form; once created, these can then convert other normal-form molecules. The other two inherited human prion diseases, Gerstmann-Straussler-Scheinker disease and fatal familial insomnia, involve different mutations in the same gene.

The large majority of CJD cases are sporadic, meaning they have no known route of infection or genetic link. Causes of sporadic CJD are likely to be diverse and may include spontaneous genetic mutation, spontaneous protein changes, or unrecognized exposure to infectious agents. It is highly likely that future research will identify more risk factors associated with sporadic CJD.

Symptoms

About one in four people with CJD begin their illness with weakness, changes in sleep patterns, weight loss, or loss of appetite or sexual drive. A person with CJD may first complain of visual disturbances, including double vision, blurry vision, or partial loss of vision. Some visual symptoms are secondary to cortical blindness related to death of nerve cells in the occipital lobe of the brain responsible for vision. This form of visual loss is unusual in that patients may be unaware that they are unable to see. These symptoms may appear weeks to months before the onset of dementia.

The most characteristic symptom of CJD is rapidly progressing dementia, or loss of mental function. Dementia is marked by:

• Memory losses
• Impaired abstraction and planning
• Language and comprehension disturbances
• Poor judgment
• Disorientation
• Decreased attention and increased restlessness
• Personality changes and psychosis
• Hallucinations.

Muscle spasms and jerking movements, called myoclonus, are also a prominent symptom of CJD. Balance and coordination disturbance (ataxia), is common in CJD, and is more pronounced in nvCJD. Stiffness, difficulty moving, and other features representing Parkinson's disease are seen and can progress to akinetic mutism, or a state of being unable to speak or move.

Diagnosis

CJD is diagnosed by a clinical neurological exam and electroencephalography (EEG), which shows characteristic spikes called triphasic sharp waves. Magnetic resonance imaging (MRI) or computed tomography scans (CT) should be done to exclude other forms of dementia, and in CJD typically shows atrophy or loss of brain tissue. Lumbar puncture, or spinal tap, may be done to rule out other causes of dementia (as cell count, chemical analysis, and other routine tests are normal in CJD) and to identify elevated levels of marker proteins known as 14-3-3. Another marker, neuron-specific enolase, may also be increased in CJD. CJD is conclusively diagnosed after death by brain autopsy.

Treatment

There is no cure for CJD, and no treatment which slows the progression of the disease. Drug therapy and nursing care are aimed at minimizing psychiatric symptoms and increasing patient comfort. However, the rapid progression of CJD frustrates most attempts at treatment, since ever-worsening cognitive deficits and more prominent behavioral symptoms develop so quickly. Despite the generally grim prognosis, a few CJD patients progress more slowly and live longer than the average; for these patients, treatment will be more satisfactory.

Prognosis

Creutzfeldt-Jakob disease is invariably fatal, with death following symptom onset by an average of eight months. About 5% of patients live longer than two years. Death from nvCJD has averaged approximately 12 months after onset.

Prevention

There is no known way to prevent sporadic CJD, by far the most common type. Not everyone who inherits the gene mutation for familial CJD will develop the disease, but at present, there is no known way to predict who will and who won't succumb. The incidence of iatrogenic CJD has fallen with recognition of its sources, the development of better screening techniques for infected tissue, and the use of sterilization techniques for surgical instruments, which inactivate prion proteins.

Strategies for prevention of nvCJD are a controversial matter, as they involve a significant sector of the agricultural industry and a central feature of the diet in many countries. The infectious potential of contaminated meat is unknown, because the ability to detect prions within meat is limited. Surveillance of North American herds strongly suggests there is no BSE here, and strict regulations on imports of European livestock make future outbreaks highly unlikely. Therefore, avoidance of all meat originating in North America, simply on grounds of BSE risk is a personal choice unsupported by current data. The ban on the export of British beef continues in countries of the European Union, although some herds in these countries have developed low levels of infection as well.

Key Terms

Autosomal dominant inheritance

A pattern of inheritance in which a trait will be expressed if the gene is inherited from either parent.

Encephalopathy

Brain disorder characterized by memory impairment and other symptoms.

Iatrogenic

Caused by a medical procedure.

Nucleic acids

The cellular molecules DNA and RNA which act as coded instructions for the production of proteins and which are copied for transmission of inherited traits.

Further Reading

For Your Information

Books

• Rampton, S., and J.C. Stauber. Mad Cow U.S.A.: Could the Nightmare Happen Here? Common Courage Press, 1997.
• Ratzan, S.C., ed. Mad Cow Crisis : Health and the Public Good. New York University Press, 1998.

  Periodicals

• Haywood, A.M. "Transmissible Spongiform Encephalopathies." New England Journal of Medicine 337(December 18, 1997): 1821-1828.
• Prusiner, S.B. "Prion Disease and the BSE Crisis." Science 278(October 10, 1997): 245-251.
• Prusiner, S.B."The Prion Diseases." Scientific American 272(January 1995): 48-57.

  Organizations

• Creutzfeldt-Jakob Disease Foundation. P.O. Box 611625, North Miami, FL 33261-1625. http://members.aol.com/crjakob/contact.html.
• The UK Creutzfeldt-Jakob Disease Surveillance Unit. http://www.cjd.ed.ac.uk/index.htm.

Gale Encyclopedia of Medicine. Gale Research, 1999.