California
Association
for
Medical Laboratory Technology
Distance Learning Program
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Prion Diseases Course
Number: DL-983 © California Association
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Prion Diseases
Objectives
After completion of this course the participant will be able
to:
1. define Transmissible Spongiform Encephalopathies
2. discuss prions
3. describe animal TSE including Scrapie, Chronic Wasting Disease,
and Bovine Spongiform Encephalopathy
4. describe human TSE including Kuru, Gerstmann-Sträussler-Scheinker
Disease, Fatal Familial Insomnia, Alpers’ Disease, Creutzfeldt-Jakob Disease,
and variant Creutzfeldt-Jakob Disease
5. describe sterilization and disinfection practices
Introduction
The headlines in Britain shouted messages such as “Bring
Back the Beef,” and “Scientists baffled by mystery of new BSE cases.”
In 1985 an epidemic of Mad Cow Disease began devastation in the beef industry
in the United Kingdom that jolted the world. A disease among the cows was diagnosed
as being caused by a transmissible spongiform encephalopathy (TSE), also known
as a prion disease. TSEs are responsible for a number of animal and human conditions
that were first thought to be caused by a virus. Research has indicated that
the causative infectious agent does not contain a nucleic acid genome, therefore
cannot be a virus. Others speculate that the agent is a virino, which is a small
non-coding regulatory nucleic acid coated with a host-derived protective protein.
Still others believe the agent is a prion. In both humans and animals this agent
causes progressive brain damage and ultimately death.
Animal TSE can affect cows in the form of Bovine Spongiform Encephalopathy
(BSE), also known as “Mad Cow Disease.” BSE is most prevalent in
the United Kingdom and has caused the government to dispose of hundreds of thousands
of infected cattle, causing a crisis in the beef industry. In 1995 a few cases
of TSEs began appearing in young adults in England. These cases were a variant
of Creutzfeldt-Jakob Disease and were ascribed to eating infected meat from
BSE cattle. Other TSEs are found in animals as well as in humans. While these
diseases, in humans, are rare, they are always fatal.
Transmissible spongiform encephalopathies (TSE)
TSEs are also known as prion diseases. The prion (proteinaceous
infectious particle) is a normal protein that has a change in its three dimensional
configuration. As the prion attacks the brain it causes large vacuoles in the
cortex and cerebellum, resulting in the spongiform appearance. The normal protein
(PrPc) is a glycoprotein with secondary structures dominated by alpha helices,
easily soluble and easily digested by proteases. The abnormal, disease-producing
prion (PrPSc) is a glycoprotein with secondary structures dominated by beta
helices, insoluble in all but strong solvents, and resistant to digestion by
proteases. When PrPSc molecules come in contact with PrPc molecules, the PrPc
molecule is converted into the PrPSc molecule. As this process occurs, the molecules
form aggregates that might be the cause of the cell damage that results in vacuole
formation.
Prion disease may be acquired through one of three routes. First,
when the disease has no known apparent cause, it is called sporadic. Second,
the disease may be inherited through an autosomal dominant trait, and third,
the disease may be acquired through infected food, homografts, or medical equipment.
Prions appear to be resistant to enzymes, chemicals and heat that break down
other proteins. Normal disinfection procedures do not eliminate prions either.
In addition, they are extremely resistant to high doses of ionizing and ultra-violet
irradiation with some residual activity remaining in the environment. In 2000,
the World Health Organization developed recommendations on the safest and most
unambiguous method for ensuring that there is no risk of residual infectivity
on contaminated instruments. The recommendation is for incineration of all disposable
instruments, material and wastes, and is the preferred method for all instruments
exposed to highly infected tissues. For non-disposable instruments, pretreatment
by immersion in sodium hydroxide followed by heating in a gravity displacement
autoclave is required prior to routine sterilization. For surfaces and heat
sensitive instruments, flood with 2N sodium hydroxide for 1 hour and then rinse.
Dry goods can be immersed in sodium hydroxide followed by heating in a porous
load autoclave.
All TSEs, human and animal, have long incubation times and do
not induce an inflammatory response. They are not known to spread from human
to human, but transmission can occur through exposure to infectious materials
during invasive medical procedures. Exposure to human cadaveric-derived pituitary
hormones, dural and cornea homografts, and contaminated neurosurgical instruments
has been documented to cause infection. Formalin and glutaraldehyde-fixed TSE
tissue retains infectivity for long periods, if not indefinitely, consequently
the same precautions should be used with this type of tissue as with fresh material.
Prion Diseases
Animal:
Scrapie
Chronic Wasting Disease
Bovine Spongiform Encephalitis
Feline spongiform encephalitis
Transmissible mink encephalitis
Human:
Kuru
Gerstmann-Sträussler-Scheinker Disease (GSS)
Fatal Familial Insomnia (FFI)
Alpers’ Disease
Creutzfeldt-Jakob Disease (CJD)
Variant Creutzfeldt-Jakob Disease (vCJD)
Animal Diseases
Scrapie
More than 250 years ago Scrapie was recognized as a disease in
sheep and goats in Western Europe. In 1947, the first case was identified in
the United States in a flock of British origin. Since then more than 1,000 flocks
in the U.S. have been diagnosed with Scrapie. As with the other prion-caused
diseases, Scrapie is a fatal, degenerative disease affecting the central nervous
system. In the U.S. it has been reported in the Suffolk breed of sheep, along
with over a dozen other breeds and some crossbreeds. As of October 2003, 2,350
cases in sheep and 127 cases in goats have been diagnosed.
Transmission is mainly from the ewe to her offspring through contact
with the placenta and placental fluids. The incubation period is two to five
years with the sheep living one to six months after symptoms appear. There is
no evidence that Scrapie is transmittable to humans. Early signs of Scrapie
include slight changes in behavior or temperament, followed by scratching or
rubbing against fixed objects. This rubbing phenomenon is how the disease was
named Scrapie. Other symptoms include loss of coordination, weight loss, hopping
like a rabbit and swaying of the rear end. Diagnosis is made based on the animal’s
physical symptoms, the animal’s history and finally by exam of brain tissue.
A diagnostic test is undergoing evaluation by USDA’s Animal and Plant
Health Inspection Service for the detection of Scrapie in live animals.
Increased concern over this disease has caused packers and producers
to have difficulty in disposing of sheep offal and dead sheep, causing increases
in disposal costs. In addition, other countries are hesitant to purchase sheep
products from the U.S. Control programs are focusing on developing a diagnostic
test, investigating transmissibility, and providing effective cleanup strategies
that are economic for packers and producers.
Chronic Wasting Disease (CWD)
North American deer and elk are the target of this TSE. It was
first discovered in Colorado in the mule deer population and manifested itself
as a “wasting” syndrome, resulting in severe weight loss and consequent
death. CWD has spread outside the endemic zone of Colorado and Wyoming, including
small areas in New York, West Virginia, and Wisconsin. The present range includes
eleven states and two Canadian provinces and is expected to grow. The disease
has also been diagnosed in farmed elk herds in South Dakota, Nebraska, Oklahoma,
Montana, Kansas, and Colorado. These herds have undergone quarantine and no
further disease has been identified. CWD has infected Rocky Mountain elk, mule
deer, white-tailed deer, and moose. There is no evidence that this disease has
been passed to other ruminant animals, such as cattle, sheep, and goats. CWD
occurs mostly in adult animals. Symptoms include not only weight loss over time,
but also decreased interaction with other animals, listlessness, and repetitive
walking in a set pattern. Nervousness many also be exhibited in elk. A decreased
appetite for hay and increased drinking have been observed.
Transmission of the disease is thought to be from animal to animal
but may occur through birth. There is also evidence that it can be spread through
exposure to prions in the environment. Currently researchers are in the process
of developing a live-animal diagnostic test. As in other spongiform diseases,
brain lesions occur and current diagnosis is made after the animal has died.
Prevention of CWD is by elimination of infected animals and limiting the distribution
of the disease to the endemic area for free-range animals and surveillance of
farm-raised animals. Hunters should contact state wildlife officials to avoid
endemic areas. Precautions to be taken when field-dressing these animals include
using gloves, boning-out the meat from the animal, and minimizing handling of
the brain and spinal cord.
Bovine Spongiform Encephalopathy (BSE) or Mad Cow Disease
In 1985, an epidemic began in England; before it was under control
over 200,000 cattle were stricken with BSE in Britain and Europe, crippling
the British livestock industry. “Mad Cow Disease” is aptly named
due to the behavior exhibited by the cattle when they are infected. The origin
of the disease appears to be cattle feed that contained Scrapie infected sheep
brain tissue that had been treated in a new way that did not destroy the infectiousness
of the Scrapie prions. Yes, the sheep Scrapie had crossed over into the cattle
population. In addition, waste cattle (presumably contaminated) were also ground
up for feed. In 1988, such food was banned, but it took until 1993 for the epidemic
to decline, due to the incubation period of three to eight years.
The epidemic in cattle peaked in January, 1993 at 1,000 new cases
per week. British agricultural officials took a series of actions to eradicate
BSE, making BSE a notifiable disease, prohibiting the inclusion of ruminant-derived
proteins in ruminant feed, and preemptively destroying over four and a half
million asymptomatic cattle over 30 months of age. As a result of these actions
the epidemic markedly subsided and now few animals are diagnosed with the disease.
BSE had not been shown to exist in the United States. This was due to the banning
of use of ruminant feed in 1997. However, in 2003 a cow infected with BSE was
found in Washington State. This cow was traced back to an import from Canada.
Since that time, two cases that appear to be endemic have been identified in
Texas and Alabama.
Human Diseases
Kuru
Kuru is a prion disease that was discovered in the early 1900s
in the people of New Guinea. The disease manifests itself as a neurodegenerative
disorder starting with unsteadiness, deterioration of speech, and tremor. It
then moves on to cause more severe tremors, shock-like muscle jerks, and uncontrolled
bursts of laughter. In the final stage, all the symptoms become severe, and
difficulty in swallowing and inability to feed oneself lead to starvation. The
incubation period for Kuru was determined to be from 2 years to 23 years from
exposure. The disease reached epidemic proportions in the 1960s after five decades
of neurological disease and death, mostly in the female population. So, how
did this group of natives acquire this devastating disease? In this part of
New Guinea there was a ritual of mortuary cannibalism. The females would remove
organs of the dead, which were then used as food sources, especially for children
and the elderly. Fortunately for these natives of New Guinea, this practice
has been eliminated from the culture. With the elimination of this practice,
the disease has disappeared in New Guinea.
Gerstmann-Sträussler-Scheinker Disease (GSS)
GSS Disease is an inherited neurodegenerative disorder caused by an accumulation
of a mutated prion protein amyloid. It is inherited as an autosomal dominant
disease, which means that both sexes are affected and there are no carriers
of the mutant gene. GSS slowly progresses with symptoms beginning between the
ages of 30 and 70. Patients experience lack of muscle coordination and have
difficulty walking. As the disease progresses, symptoms include slurring of
speech, involuntary movements of the eyes, rigid muscle tone and eventually
dementia, which is less common than in Creutzfeldt-Jakob Disease (CJD). In some
cases the disease progresses rapidly and consequently cannot be distinguished
from CJD. In GSS, spongiform changes in the brain tissue may or may not occur.
Patients with GSS can live from 2 to 10 years with treatment aimed at alleviating
symptoms. Currently there is no cure for this rare inherited disease. Current
research is focused on the prion that causes the disease, attempting to characterize
it, clarify the disease mechanism, and then developing ways to prevent, treat,
and cure GSS disease.
Fatal Familial Insomnia (FFI)
FFI is a rare autosomal dominant hereditary disease caused by
a prion that results in amyloid plaques that affect the thalamus, causing severe
selective atrophy. The thalamus is a center in the brain that is responsible
for regulation of sleep. As a result of the degradation of the thalamus, there
is an interruption of the body’s circadian rhythms. Consequently, patients
with FFI lose sleep, can have hallucinations, and eventually go into coma, with
death in about 18 months. The age of onset ranges from 30 to 60. The four stages
of FFI are:
o Progressive insomnia, panic attacks, and bizarre phobias developing over a
four-month period characterize the first stage.
o The second stage lasts about five months with symptoms including hallucinations,
panic, agitation, and sweating.
o In stage three, total insomnia is paired with weight loss and lasts about
three months.
o The final stage, which lasts six months, includes dementia, total insomnia,
loss of hearing and sudden death.
New techniques such as DNA sequencing or molecular hybridization should be developed
to make an early diagnosis, as the disease does not begin progression until
after child-bearing years. Currently there is no cure for this disease, but
gene therapy could be promising to prevent FFI. In this case, the correct gene
could be inserted to cause the correct protein to be developed, consequently
allowing for the thalamus to function normally, thus preventing insomnia and
subsequent deterioration.
Alpers’ Disease
Unfortunately, Alpers’ Disease affects infants and children.
It is an autosomal recessive disorder that can be seen in siblings and is known
also as Christensen’s disease or Christensen-Krabbe disease. Alfons Jakob
first recognized it in the early 1900s and his students, Souza, Freedom, and
Alpers further described cases. It is manifested by convulsions, developmental
delay, mental retardation, and dementia. Only thirteen cases have been identified
since 1931, but others may have been missed due to chronic liver dysfunction
being present, which may mask diagnosis of Alpers’ Disease. Liver failure
is usually the ultimate cause of death within the first two years of life. Final
diagnosis is at autopsy when spongiform plaques are identified in the gray matter
of the brain. There is no current treatment for the disease, only for the symptoms,
such as anti-convulsants for the seizures.
Creutzfeldt-Jakob Disease (CJD)
CJD is also referred to as subacute spongiform encephalopathy
due to the formation of microscopic vacuoles or holes in the neurons that appear
“sponge-like.” The disease is named for Drs. Hans Creutzfeldt and
Alfons Jakob who documented the first cases in the 1920s. This disease affects
both men and women in the 50 to 75 year age range, with one case per million
per year. Cases in persons under 30 years of age are extremely rare, with fewer
than 5 cases per billion. A person can acquire CJD in one of three ways. Firstly,
the disease can appear sporadically, without any apparent cause. Secondly, it
can be inherited as an autosomal dominant pattern. This type of transmission
occurs in about 10-15 % of the cases. Thirdly, an infectious agent can transmit
the disease. Iatrogenic transmission is an unintended consequence of a medical
procedure using instruments tainted by contaminated human growth hormone (about
100 cases), by corneal grafts from asymptomatic infected individuals, or by
infected neural material. In 1976, more stringent sterilization procedures were
put into place. Additionally, recombinant DNA technology is now used for producing
human growth hormone. Because of these advances, no further documented cases
of CJD have occurred from iatrogenic transmission. There are no known instances
of transfusion-related CJD.
Symptoms begin with insomnia, depression, confusion and problems
with memory, coordination, and sight. As the disease progresses, patients experience
progressive dementia and involuntary jerking movements. In the final stages
of the disease, patients lose all mental and physical functions, lapse into
coma and die, usually from pneumonia due to the unconscious state. CJD patients
will succumb within one year of diagnosis. There are no known effective treatments
for CJD, so treatment focuses on easing symptoms.
CJD is difficult to diagnose, so the first step is to rule out
other diseases that might have similar symptoms. It may be mistaken for Alzheimer’s
disease, Pick’s disease, Huntington’s disease, cerebral hematomas
and vascular irregularities. An EEG can detect a characteristic abnormal brain
pattern associated with the later stages of the disease, but cannot confirm
a CJD diagnosis. A new test to detect a specific protein (14-3-3) in cerebrospinal
fluid (CSF) has been developed, but again this does not give a definitive diagnosis.
CJD can definitively be diagnosed by performing a brain biopsy or autopsy. However,
a brain biopsy can be a dangerous procedure, can result in a false-negative
result if the wrong area of the brain is chosen, and is quite costly. In addition,
there is a risk to healthcare workers if strict sterilization and infection
control precautions are not taken. When available, disposable equipment should
be used in suspected cases of CJD and then incinerated. If equipment is to be
reused, steam sterilization or cleaning with 1 N sodium hydroxide (followed
by steam sterilization) can be utilized. If this cannot be accomplished, the
equipment must be disposed of by incineration. Contaminated skin surfaces are
to be washed with 1 N sodium hydroxide or 10% bleach followed by rinsing with
copious amounts of water. Splashes to the eyes may be treated using copious
amounts of water or saline. Contaminated dry waste or sharps waste should be
autoclaved for 4.5 hours prior to incineration.
Variant Creutzfeldt-Jakob Disease (vCJD)
In 1996, a disturbing fact emerged that showed a causal relationship
between BSE and a new disease called variant Creutzfeldt-Jakob Disease (now
referred to simply as vCJD). Young adults were dying after exhibiting clinical
symptoms of CJD, including dementia and muscle jerks. Cases were predominately
coming from Britain, but several cases were documented from patients outside
of Britain. These patients were found to have lived in the British Isles for
at least five years during the epidemic (1980-1995). As of June, 2007 there
have been 161 deaths in Britain from definite or probable vCJD with four probable
cases still alive. Thirty-nine other cases have occurred outside Britain, primarily
in France and other European countries that imported meat from Britain. Of the
three documented cases in the U.S, two had lived in Britain and one had lived
in Saudi Arabia.
The incubation period for vCJD is still unknown. Documented patient
incubation times have been six or more years. The current risk of acquiring
vCJD from eating beef cannot be determined for travelers to Britain. However,
the risk decreases by avoiding beef or beef products or selecting beef or beef
products that are solid muscle pieces (versus calf brains or burgers or sausages).
Public health preventive measures have been put into place including enhancement
of BSE surveillance, culling of sick animals, and using the “over thirty
months scheme.” This excludes animals over 30 months of age from both
the human and animal food chain.
In 2002, there was a case of person-to-person, blood-borne transmission
of vCJD. This occurred in a 69 year-old man who had received, six years previously,
several units of blood. One of those units came from a 24 year-old donor who
developed vCJD three years after donation. Taking into consideration all other
factors, the conclusion was made that the recipient indeed did contract vCJD
from this donor. Due to the fact that vCJD can be easily detected in lymphoid
tissues and the existence of a possible blood phase had led researchers to believe
that blood-borne transmission of vCJD was possible.
To date there have been four cases of probable transmission of
vCJD by blood transfusion in Britain. The donors developed CJD 17 months to
40 months after donation. The recipients developed vCJD six to eight years after
receiving blood.
There is a donor deferral program in place in the U.S. Permanent
deferrals are for anyone who has been diagnosed with CJD or vCJD or are relatives
of anyone who has been diagnosed. An indefinite deferral is in place for anyone
who has spent more than three months in the United Kingdom from 1980 to 1996,
or anyone who has spent more than five years in Europe from 1980 to present.
Indefinite deferrals also apply to anyone who received a blood transfusion in
the United Kingdom from 1980 to present.
Laboratory Testing
The National Prion Disease Pathology Surveillance Center was established
in 1997 to acquire tissue samples and clinical information from as many cases
of human prion disease as possible. There are specific diagnostic activities
available within the center. In CSF, they can search for the presence of 14-3-3
protein, a marker of Creutzfeldt-Jakob disease. In DNA extracted from blood,
brain, or other tissues, they can search for the presence of a mutation of the
prion protein gene and determine the polymorphism at codon 129. This polymorphism
is an indicator of host susceptibility and the phenotypical disease expression
of familial, iatrogenic or sporadic CJD. Unfixed brain tissue from biopsy or
autopsy can be searched for the presence of the abnormal disease producing prion
(PrPSc). In fixed brain tissue they can exclude, confirm, and characterize the
prion disease by microscopic examination. Only frozen brain tissue examination
can confirm or exclude the diagnosis of prion disease.
Conclusion
Transmissible spongiform encephalopathies (TSE) are prevalent in both human
and animal populations. Surveillance, along with advances in detection, and
prevention are needed to eliminate these prion caused diseases. Research into
how prions are formed and transmitted may be the key to unlocking the mystery.
There is no current treatment for prion diseases. Once there is more information
about how prions work, treatment modalities may be discovered.
References
1. Akroush, Ann M., Fatal Familial Insomnia. 1996-1997. Available at: http://www-personal.umd.umich.edu/~jcthomas/JCTHOMAS/1997%20Case%20Studies/AAkroush.html.
Accessed January 7, 2008.
2. CDC. Prion Diseases. Available at: http://www.cdc.gov/ncidod/dvrd/prions/index.htm.
Accessed January 7, 2008. Has links to the following: CJD, vCJD, BSE, and
CWD.
3. Kuru: the Dynamics of a Prion Disease. Available at: http://www.as.ua.edu/ant/bindon/ant570/Papers/McGarth/McGarth.htm.
Accessed January 7, 2008.
4. National Institute of Neurological Disorders and Stroke, Alpers’
Disease Information Page, February 14, 2007. Available at: http://www.ninds.nih.gov/disorders/alpersdisease/alpersdisease.htm.
Accessed January 7, 2008.
5. National Institute of Neurological Disorders and Stroke, Gerstmann-Starussler-Scheinker
Disease Information Page, February 14, 2007. Available at: http://www.ninds.nih.gov/disorders/gss/gss.htm.
Accessed January 7, 2008.
6. USDA, APHIS, Veterinary Services, National Animal Health Programs. Scrapie.
Available at: http://www.aphis.usda.gov/lpa/pubs/fsheet_faq_notice/fs_ahscrapie.html.
Accessed January 7, 2008.
- Kuru disappeared from the native population in New Guinea because
a. immunization against the disease was developed
b. cow meat for consumption was banned
c. mortuary practices were discontinued
d. the affected tribe died out - The causative agent of transmissible spongiform encephalitis is
a. a proteinaceous infectious particle
b. an abnormally folded nucleic acid
c. a virino
d. an amino acid substitution - Which of the following are human prion diseases?
a. Scrapie, Kuru, BSE
b. Kuru, GSS, FFI
c. BSE, GSS, Kuru
d. Scrapie, FFI, GSS - The main characteristic of vCJD is:
a. vCJD attacks young adults
b. vCJD attacks natives of New Guinea
c. vCJD is inherited
d. vCJD has not been identified in the US - The best method of dealing with instruments contaminated by prions is
a. submerging in 1N sodium hydroxide
b. autoclaving
c. incinerating
d. baking - Which prion disease is not inherited?
a. Alpers’
b. GSS
c. FFI
d. BSE - Chronic wasting disease is
a. found in elk in California
b. causes loss of weight in cattle
c. was first identified in deer in Colorado
d. is restricted to Wyoming and Colorado - Which of the following prion diseases is associated with BSE?
a. FFI
b. vCJD
d. CJD
d. GSS - Which prion disease affects sheep?
a. Scrapie
b. Chronic Wasting Disease
c. Variant Creutzfeldt-Jakob disease
d. Bovine spongiform encephalitis - The National Prion Disease Pathology Surveillance Center can test for
a. prions in blood
b. polymorphism in codon 129 for susceptibility to FFI
c. PrPc in brain tissue to identify vCJD
d. 14-3-3 protein in CSF, a marker for CJD