Transcript Prion Diseases

Prion
Diseases
Garrett Preston Clark, D.O.
What Are Prions?
Small proteinaceous infectious
particles which resist inactivation by
procedures that modify nucleic acids
 Do not have a nucleic acid genome
 Also known as transmissible spongiform
encephalopathies (TSEs)
 Progressive neurodegenerative disorders
that affect both humans and animals

http://www-micro.msb.le.ac.uk/3035/Prions.html
What Are Prions?
A prion is a modified form of a normal
cellular protein known as PrPc.
 This protein is found predominantly on the
surface of neurons attached by a
glycoinositol phospholipid anchor.
 Thought to be involved in synaptic
function.
 Modified form of PrPc i.e. the prion, known
as PrPsc (for scrapie  Sheep).

http://www-micro.msb.le.ac.uk/3035/Prions.html
What Are Prions?
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Normal (PrPc) is sensitive to proteases.
PrPsc is resistant to proteases and
accumulates in cytoplasmic vesicles of diseased
individuals.
Theory indicates that when prion proteins are
introduced into a normal cell, PrPc converts to
PrPsc.
Exact process unknown
Could involve a chemical or conformational
modification.
http://www-micro.msb.le.ac.uk/3035/Prions.html
http://fig.cox.miami.edu/~cmallery/255/255prot/p
rion.jpg
What Are Prions?
Disease occurs when the normal protein
structure in the α-helix isoform (PrPc), is
changed to the abnormal β-pleated sheet
isoform. (PrPsc).
 In 1997, Dr. Stanley Prusiner was awarded
the Nobel Prize in Physiology and
Medicine for the discovery of Prions.

Robbins Patholiogic Basis of Disease, 6th
Edition
Prion Disease:
http://www-micro.msb.le.ac.uk/index.html
Prion Disease:
http://www-micro.msb.le.ac.uk/index.html
http://depts.washington.edu/~daglab/Images/Pri
on_Protein.jpg
Prion Disease
Long incubation periods
 Associated with neuronal loss, and a
failure to induce inflammatory response
 Able to induce abnormal folding of normal
cellular proteins in the brain
 Usually rapidly progressive and fatal.
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http://www.cdc.gov/ncidod/dvrd/prions/
Human Prion Diseases:
1.
2.
3.
4.
5.
Creutzfeldt-Jakob Disease (CJD)
Variant Creutzfeldt-Jakob Disease
(vCJD)
Gerstmann-Straussler-Scheinker
Syndrome
Fatal Familial Insomnia
Kuru
http://www.cdc.gov/ncidod/dvrd/prions/
Animal Prion Diseases:
1.
2.
3.
4.
5.
6.
Bovine Spongiform Encephalopathy
(BSE)
Chronic Wasting Disease (CWD)
Scrapie
Transmissible mink encephalopathy
Feline spongiform encephalopathy
Ungulate spongiform encephalopathy
http://www.cdc.gov/ncidod/dvrd/prions/
Characteristics:
Loss of motor control,
 Dementia
 Paralysis wasting
 Eventually death
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Post-mortem shows non-inflammatory
lesions, vacuoles, amyloid protein deposits
and astrogliosis (Hence, Spongiform)
http://www-micro.msb.le.ac.uk/3035/Prions.html
CreutzfeldtJakob Disease (CJD)
Showing Spongiform Change:
http://www.cdc.gov/ncidod/dvrd/cjd/index.htm
CreutzfeldtJakob Disease (CJD)
Showing Spongiform Change:
http://www.nlm.nih.gov
Infectivity:
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4.
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Humans may be infected by prions in 2
ways:
Infection may be aquired:
Diet
Surgery
Growth hormone injections
Corneal transplants
OR: Apparent inherited transmission where it
is an autosomal dominant trait.
http://www-micro.msb.le.ac.uk/index.html
Infectivity:
Prions may be ingested and absorbed
across the gut wall at Peyers patches.
 They may be absorbed through the
mucosal associated lymphoid tissue
(MALT) mechanism.
 Lymphoid cells phagocytise the prion.
 Travel to other lymphoid sites (nodes,
spleen, etc.) where the prion can replicate
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http://www-micro.msb.le.ac.uk/index.html
Infectivity:
Many of these sites are innervated.
 Eventually the prion gains access to a
nerve.
 Propagation up the axon to the spinal cord
 Eventually leads to brain infectivity.
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http://www-micro.msb.le.ac.uk/index.html
CreutzfeldtJakob Disease (CJD):
Is a human prion disease
 Neurodegenerative disorder
 Is rapidly progressive and always fatal
 Infection leads to death usually within 1
year of onset of illness.
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http://www.cdc.gov/ncidod/dvrd/cjd/index.htm
CreutzfeldtJakob Disease (CJD):
CJD is not related to “BSE".
 Classic CJD is distinct from "variant CJD“
 Variant CJD, is related to Bovine
Spongiform Encephalopathy (BSE).
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http://www.cdc.gov/ncidod/dvrd/cjd/index.htm
CreutzfeldtJakob Disease (CJD):
Classic CJD has been recognized since
the early 1920s.
 Sporadic disease occurs worldwide,
including the United States
 Rate of approximately one case per 1
million population per year
 Risk increases with age and in persons
over 50 years of age.
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http://www.cdc.gov/ncidod/dvrd/cjd/index.htm
CreutzfeldtJakob Disease (CJD):
Approximately 85% of cases of CJD occur
as sporadic disease.
 5-15% develop CJD because of inherited
mutations of the prion protein gene.
 These inherited forms include GerstmannStraussler-Scheinker syndrome and fatal
familial insomnia.
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http://www.cdc.gov/ncidod/dvrd/cjd/index.htm
CreutzfeldtJakob Disease (CJD):
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Median age at death is 68 years
Median duration of illness 4-5 months
Clinical signs and symptoms of dementia
and early neurological signs
Initial subtle changes in memory
Behavior changes
Rapidly progressive dementia
And…
Robbins Pathologic Basis of Disease 6th Edition
STARTLE MYOCLONUS !!!!
http://www.keelynet.com/startle.jpg
Variant CJD (vCJD):
First described in 1996 in the United
Kingdom.
 Different clinical and pathologic
characteristics from classic CJD
 Median age at death for vCJD patients is
28 years.
 Median duration of illness for vCJD is 14
months, compared to 5 months for classic
CJD.
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http://www.cdc.gov/ncidod/dvrd/cjd/index.htm
Variant CJD (vCJD):
Strong scientific evidence that the agent
responsible for outbreak of prion disease
in cows, BSE, is the same agent
responsible for the outbreak of vCJD in
humans
 Both disorders are fatal brain diseases
with unusually long incubation periods
measured in years.
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http://www.cdc.gov/ncidod/dvrd/cjd/index.htm
Variant CJD (vCJD):
"Pulvinar sign" on MRI
 This is an abnormal signal in the posterior
thalami on T2- and diffusion-weighted
images and fluid-attenuated inversion
recovery sequences on brain MRI.
 In the right clinical context, this signal is
highly specific for vCJD but absent in CJD.
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http://www.cdc.gov/ncidod/dvrd/cjd/index.htm
Pulvinar Sign:
http://www.cjd.ed.ac.uk/vcjd.jpg
Pulvinar Sign:
http://www.emedicine.com/neuro/images/12641
264Pulvinar_sign-2.jpg
BSE (bovine spongiform
encephalopathy):
Progressive neurological disorder of cattle
 Results from infection by a prion.
 Two cases of BSE identified in 1986
 Possibly originated as a result of feeding
cattle meat-and-bone meal that contained
scrapie-infected sheep products.
 Scrapie = prion disease of sheep
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http://www.cdc.gov/ncidod/dvrd/bse/index.htm
Also Known As…
http://www.worth1000.com/entries/248000/2482
16QvXU_w.jpg
BSE (bovine spongiform
encephalopathy):
BSE epidemic in the United Kingdom
peaked in January 1993 at almost 1,000
new cases per week.
 Through the end of 2005 more than
184,000 cases of BSE had been
confirmed in the United Kingdom alone in
more than 35,000 herds.
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http://www.cdc.gov/ncidod/dvrd/bse/index.htm
BSE (bovine spongiform
encephalopathy):
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As of August 23, twelve cases of BSE have been
identified in North America.
Of these twelve cases, three were identified in
the U.S. and nine in Canada.
The first known case of BSE in the United States
was identified in December 2003
Preliminary trace-back suggested that the BSEinfected cow was imported into the United States
from Canada in August 2001.
http://www.cdc.gov/ncidod/dvrd/bse/index.htm
BSE (bovine spongiform
encephalopathy):
http://www.cdc.gov/ncidod/dvrd/bse/index.htm
KURU:
Nicknamed the “laughing death”
 Exotic disease confined pretty much to the
Fore tribe of New Guinea
 Custom of eating the brains of dead
relatives promoted transmission of
disease-causing prions
 Cannibalism ban significantly reduced the
incidence of Kuru.
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http://science.education.nih.gov/home2.nsf/Educ
ational+Resources/Resource+Formats/Online+
Resources/+High+School/D07612181A4E785B
KURU:
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Kuru prion infects nerve cells, results in:
Craziness
 Dementia
 Loss of coordination
 Other neurological symptoms develop
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http://science.education.nih.gov/home2.nsf/Educ
ational+Resources/Resource+Formats/Online+
Resources/+High+School/D07612181A4E785B
Fatal Familial Insomnia (FFI)
First associated with a prion in 1992
 Is familial, as its name implies
 Causes sleep disturbance, motor and
emotional problems, and eventually death
 Patients have a specific mutation in the
prion gene
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http://science.education.nih.gov/home2.nsf/Educ
ational+Resources/Resource+Formats/Online+
Resources/+High+School/D07612181A4E785B
Gerstmann-Straussler-Scheinker
Syndrome (GSSS):
Linked to two mutations in the prion gene
in 1989
 PrPSC fragments accumulate in the brain
in plaque structures.
 Similar plaques develop in Alzheimer’s
disease, but they are composed of
fragments of a different protein
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http://science.education.nih.gov/home2.nsf/Educ
ational+Resources/Resource+Formats/Online+
Resources/+High+School/D07612181A4E785B
Scrapie:
Scrapie recognized in sheep and goats
for more than 250 years.
 In 1982, it was first identified as a prion
disease.
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http://science.education.nih.gov/home2.nsf/Educ
ational+Resources/Resource+Formats/Online+
Resources/+High+School/D07612181A4E785B
Chronic Wasting Disease (CWD):
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Transmissible neurological disease of deer and
elk
Characterized by:
Loss of body condition
Behavioral abnormalities
Eventually death.
Is classified as a transmissible spongiform
encephalopathy (TSE) and is similar to mad
cow disease in cattle and scrapie in sheep.
http://www.cwdinfo.org/index.php/fuseaction/about.main
http://www.worth1000.com/entries/248000/2482
16QvXU_w.jpg
TREATMENTS?
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All prion diseases are fatal no
effective treatment !
Tx currently symptomatic
Medical Care:
Discontinue any medication that could
impair memory or cause confusion.
A number of potential therapeutic
interventions are currently under
development.
http://www.emedicine.com/neuro/topic662.htm
Some Tx Possibilities:
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Congo red and its analogs
Anthracyclines
Amphotericin B and its analogs
Sulfated polyanions
Tetrapyrroles
All have limitations in terms of toxic effects
and/or unfavorable pharmacokinetic properties.
Amphotericin B failed to ameliorate CJD in a
single patient.
http://www.emedicine.com/neuro/topic662.htm#t
argetMED
TREATMENTS:
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Consultations:
Neurologist
Infectious disease specialist
QUESTIONS ! ! !
1) Pulvinar sign on brain MRI is indicative of
which of the following prion diseases:
A. CJD
B. vCJD
C. Kuru
D. BSE
E. FFI
QUESTIONS ! ! !
1) Pulvinar sign on brain MRI is indicative of
which of the following prion diseases:
A. CJD
B. vCJD
C. Kuru
D. BSE
E. FFI
QUESTIONS ! ! !
2) Which of the following disease states is
most closely associated with startle
myoclonus:
A. CJD
B. vCJD
C. Kuru
D. BSE
E. FFI
QUESTIONS ! ! !
2) Which of the following disease states is
most closely associated with startle
myoclonus:
A. CJD
B. vCJD
C. Kuru
D. BSE
E. FFI
QUESTIONS ! ! !
3) Which of the following prion diseases has
the well known namesake of Mad Cow
Disease:
A. CJD
B. vCJD
C. Kuru
D. BSE
E. FFI
QUESTIONS ! ! !
3) Which of the following prion diseases has
the well known namesake of Mad Cow
Disease:
A. CJD
B. vCJD
C. Kuru
D. BSE
E. FFI