Transcript Slide 1

‫(ربنا الذي اعطى ك َّل شئ خلقه ثم هدى)‬
‫سورة طه‪ :‬اآلية رقم ‪50‬‬
Prion Diseases
Transmissible Spongiform Encephalopathies
(TSE)
Dr.Mohammad Jamil Al-Habbal
MRCP (UK),FRCP (London),FRCP (Edin.)
Consultant Internal Medicine
King Fahad Specialist Hospital-Dammam
DEFINITION
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Family of progressive neurodegenerative disorders.
Affect both humans and animals.
Long incubation periods.
A unique feature of these diseases is that they can be inherited,
arise spontaneously or may be acquired through infection.
Characteristic neuropathologic feature of multifocal spongiform
changes in brain with astrogliosis & neuronal loss.
No inflammatory response.
The causative agent is an abnormal prion protein (PrPsc) which
induce abnormal folding of normal prion proteins (PrPc) in the
neurons.
Usually rapidly progressive and always fatal.
No effective therapy.
The following diseases are caused by prions
In animals:
– Scrapie in sheep
– Bovine spongiform encephalopathy (BSE) in cattle
(known as mad cow disease)
– Transmissible mink encephalopathy (TME) in mink
– Chronic wasting disease (CWD) in elk and mule deer
– Feline spongiform encephalopathy in cats
– Exotic ungulate encephalopathy (EUE) in nyala, oryx
and greater kudu
In humans :
– Creutzfeldt-Jakob disease (CJD) and its varieties:
1:iatrogenic Creutzfeldt-Jakob disease (iCJD),
2:familial Creutzfeldt-Jakob disease (fCJD),
3:sporadic Creutzfeldt-Jakob disease (sCJD)
4:variant Creutzfeldt-Jakob disease (vCJD),
– Gerstmann-Sträussler-Scheinker syndrome (GSS)
– Fatal familial insomnia (fFI)
– Sporadic fatal insomnia (sFI)
– Kuru
– Alpers syndrome
Humans might be infected by prions in 2 ways:
1: Acquired infection (diet and following
medical procedures such as surgery,
growth hormone injections, corneal
transplants) i.e. infectious agent
implicated.
2: Apparent hereditary mendelian
transmission where it is an autosomal and
dominant trait.
WHY PRION DISEASE?
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Transmissible (animals & humans)
Causative agent is a protein!
Iatrogenic – CJD
Fatal and no therapy.
Outbreak of BSE in UK during 1986 & its
human type (vCJD) in1996
• Caused by feeding cattles animal protein.
• Islamic Teaching!
What is the Prion ?
Professor Stanley Prusiner
discovered prions
• To date, the evidence indicates that the infectious agent in the TSEs
is a protein discovered by: Stanley Prusiner (in 1996) who:
1. Pioneered in the study of these proteins.
2. Awarded the Nobel Prize in 1997.
3. Named them prion proteins (designated PrP) or simply prions.
PrPc
• The normal protein.
• Called PrPc (for cellular).
• A transmembrane glycoprotein normally found at the
surface of certain cells (e.g., neural and hematopoietic
stem cells).
• Has its secondary structure dominated by alpha helices
(probably 3 of them).
• Easily soluble.
• Easily digested by proteases.
• Encoded by a gene designated (in humans) PRNP
located on chromosome 20.
PrPsc
• The abnormal, disease-producing protein (infectious).
• Called PrPsc (for scrapie).
• Has the same amino acid sequence and number as the
normal protein; that is, their primary structures are
identical but:
- its secondary structure is dominated by beta conformation
- Insoluble in all solvents.
- Highly resistant to digestion by proteases.
- When PrPsc comes in contact with PrPc, it converts the
PrPc into PrPsc (even in the test tube).
Proposed mechanism of prion propagation
PrPc and PrPsc
Infection
Infection
Infection
Infection
Human Prion Diseases
• Creutzfeldt-Jakob Disease (CJD)
• Variant Creutzfeldt-Jakob Disease (vCJD)
• Gerstmann-Straussler-Scheinker
Syndrome (GSS)
• Fatal Familial Insomnia (FFI)
• Kuru
CREUTZFELDT-JAKOB DISEASE (CJD)
1.SPORADIC
• Firstly reported by the German neurologists
Creutzfeldt and Jakob in 1920s .
• It accounts for »85% of all CJD cases.
• Estimated incidence of one case/1 million
population per year with equal sex ratio.
• A peak age of onset between 55 and 75 yrs
(mean:61.5yrs).
• Induced by somatic mutation or spontaneous
conversion of PrPc into PrPsc.
Clinical Features
• Dementia: rapidly progressive, visual abnormalities.
• Ataxia: cerebellar dysfunction, including muscle incoordination,gait
and speech abnormalities.
• Most patients develop pyramidal and extrapyramidal dysfunction with
abnormal reflexes, spasticity, tremors, and rigidity.
• Psychaitric manifestations:some patients may also show
behavioral changes with agitation, depression, or confusion.
• Myoclonus: most constant physical sign,present in > 90% pts.
• Invariably fatal, with a median illness duration of 4 months & death
occurs within 12 months of illness onset in 85–90% of pts.
Diagnosis
1. EEG: two cycles per second triphasic sharp-wave discharges.
2. CSF: presence of 14-3-3 protein,
3. Histopathology:Biopsy or Autopsy (confirmatory diagnosis): The typical
neuropathology consists of a microscopic picture of spongiform
changes, gliosis, and neuronal loss in the absence of inflammatory
reaction. Amyloid plaques demonstrated in >>10% of patients.
4. PrPsc :The presence of PrPsc in biopsy or autopsy of brain samples can
be demonstrated by immunodiagnostic tests, such as:
a) immunohistochemical staining.
b) Histoblot
c) Western blot techniques
d) Conformation-dependent immunoassay(CDI)
5. Genetic test:sequencing the PRNP gene
Prion diseases damage the brain
• This tissue slide shows sponge-like lesions in
the brain tissue of a classic CJD patient. This
lesion is typical of many prion diseases.
CREUTZFELDT-JAKOB DISEASE
2.FAMILIAL
• It accounts for 5–15% of CJD patients.
• Autosomal dominant inheritance pattern with a family
history of CJD.
• Most patients presented with personality changes
followed by progressive dementia and a Parkinsonian
syndrome.
• The mean age at onset was 44.8 years, and the mean
duration of illness was 4.2 years.
• spongiform changes, neuronal loss, and mild gliosis
were predominantly seen in frontal and temporal lobes .
CREUTZFELDT-JAKOB DISEASE
3.IATROGENIC
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The transmissible nature of CJD was first described in 1968, after
intracerebral inoculation of a brain biopsy tissue from a CJD patient
into a chimpanzee.
• Person-to-person transmission of the CJD agent was reported in:
1.Corneal transplant
2.Contaminated EEG depth electrodes
3.Neurosurgical instruments
4.Cadaveric pituitary-derived gonadotropin
5.Human growth hormone (hGH)
6.Dura mater grafts
7.Blood transfusion?
Bloodborne Transmission
• Experimental transmission of CJD to laboratory animals
intracerebrally inoculated with blood obtained from CJD
patients indicated the possible presence of the CJD
agent in human blood in low concentrations .
• Three studies have clearly confirmed the infectivity of
blood derived from experimentally infected guinea pigs
or mice after intracerebral inoculation of healthy animals
• Whether the results of these animal studies provide any
knowledge on blood-borne transmission of the CJD
agent in humans?
Bloodborne Transmission
• The FDA, on recommendation from its TSB
Advisory Committee and with support from
the CDC and the National Institutes of
Health,had recommended a blood donor
deferral policy to exclude donors who have
spent specific periods of time in UK and other
European countries.
DECONTAMINATION OF CJD PRIONS
• Prions are extremely resistant to common
inactivation procedures, and there is some
disagreement about the optimal conditions for
sterilization.
• Autoclaving at 132°C for 5 h or treatment with
2 N NaOH for several hours is recommended
for sterilization of prions.
• The term "sterilization" implies complete
destruction of prions; any residual infectivity
can be hazardous.
Creutzfeldt-Jakob Disease
4.Variant (vCJD)
-Variant CJD was first described in 1996 in UK.
-Has different clinical and pathologic characteristics
from other types of CJD.
-Till Feb 2006,159 cases of vCJD were diagnosed in
UK and 153 have died.
-? Begening of a growing epidemic,unclear.
Evidence for Relationship between BSE and vCJD
• Since 1996, evidence has been increasing for a
causal relationship between ongoing outbreaks
of BSE and vCJD.
• Strong scientific evidences: agent responsible
for BSE(in cattle) and vCJD (in humans), is the
same (PrPsc).
Clinical and Pathologic Characteristics
Distinguishing Classic CJD from Variant CJD
Characteristic
Classic CJD
Variant CJD
Median age at death
68 years
28 years
Median duration of illness
4-5 months
13-14 months
Clinical signs and symptoms
Dementia;
early
neurologic
signs
Prominent psychiatric/behavioral
symptoms; painful dyesthesiasis;
delayed neurologic signs
Periodic sharp waves on EEG
Often present
Often absent
Pulvinar sign on MRI
Not reported
Present in >75% of cases
Presence of "florid plaques" on
neuropathology
Rare or
absent
Present in large numbers
Immunohitochemical analysis of
brain tissue
Variable
accumulat
ion
Marked accumulation of proteaseresistance prion protein
Presence of agent in lymphoid tissue
Not readily
detected
Readily detected
Increased glycoform ratio on
immunoblot analysis of
protease-resistance prion
protein
Not reported
Marked accumulation of proteaseresistance prion protein
Histopathology of vCJD
(A) Section from frontal cortex stained by the
periodic acid-Schiff (PAS) method,showing a field
with aggregates of plaques surrounded by
spongiform degeneration
(B) Multiple plaques and amorphous deposits
are PrP- immunopositive. Scale bar, 50 µm.
Bloodborne Transmission
• A highly probable bloodborne, person-to-person
transmission of vCJD was reported in the UK in
a 69-year-old man who had vCJD onset in late
2002, 6.5 years after receipt of 5 units of packed
red blood cells. One of the red blood cell units
was obtained from a 24-year-old donor who
developed vCJD >3 years after donation.
• Both the donor and recipient died of
pathologically confirmed vCJD.
• The reports of bloodborne spread of vCJD in the
UK appear to justify the precautionary deferral
policy recommended by FDA (USA).
GERSTMANN-STR¨AUSSLER-SCHEINKER SYNDROME
(GSS)
• A familial disease with autosomal dominant inheritance,
• First described in1936 by Gerstmann, Str¨aussler, & Scheinker.
• It occurs at an estimated annual incidence of 5 cases/100 million
population.
• Neurologic signs and symptoms: cerebellar ataxia, gait
abnormalities, dementia, dysarthria, ocular dysmetria, and
hyporeflexia or areflexia in the lower extremities with infrequent
myoclonus and diagnostic EEG, and a neuropathologic feature of
numerous amyloid plaques.
• GSS is considered a variant of the familial form of CJD, but it is
primarily associated with mutations at codon 102 of the prion protein
gene.
FATAL FAMILIAL INSOMNIA
(FFI)
• A familial disease with autosomal dominant inheritance, have been
reported since 1939.
• Patients with severe dementia and bilateral symmetrical
degeneration of the thalamus
• Progressive insomnia and autonomic dysfunction, followed by
dysarthria, tremor, and myoclonus.
• Neuropathologic examination showed neuronal degeneration and
reactive astrocytosis confined to the anterior and dorsomedial nuclei
of the thalamus; no spongiform changes or inflammatory infiltrates
were noted.
• Rare sporadic cases of FFI were reported.
• FFI is primarily associated with a mutation at codon 178 of the prion
protein gene.
Kuru
• Kuru was once found among the Fore tribe in
Papua New Guinea in 1957.
• Ingesting brain tissue of dead relatives for
religious reasons was the route of transmission
whose rituals included eating the brain tissue of
their recently deceased members of the tribe.
• Since this practice (ritualistic cannibalism )
was halted, the disease has disappeared.
• Clinically, the disease resembles CJD.
Disappearance of kuru
Number of biannual cases of
kuru in Papua New
Guinea.
Animal Prion Diseases
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Scrapie
Bovine Spongiform Encephalopathy (BSE)
Chronic Wasting Disaese (CWD)
Transmissible mink encephalopathy
Feline spongiform encephalopathy
Ungulate spongiform encephalopathy
Spongiform Encephalopathies
(in animals)
• BSE in Cattle
• Scrapie in sheep
Scrapie:
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)‫داء الحكه (قعاص الغنم‬
This disease of sheep (and goats)
The first TSE to be studied.
Known for several hundreds yrs
Transmitted from animal to animal in feed
contaminated with nerve tissue.
• Loss of motor control,paralysis wasting and
death.
Bovine Spongiform Encephalopathy (BSE) or
"Mad Cow Disease” ‫مرض جنون البقر‬
• An epidemic of this disease began in UK in 1985
• Over 170,000 cattle were sickened by it.
• Transmission of scrapie agent (PrPsc) to cattles
by feeding the contaminated meat &bone meal.
• The use of such food (MBM) was banned in
1988 and after peaking in 1992, the epidemic
declined quickly.
BSE epidemic in UK
Number of annual cases of
BSE in cattle in UK
BSE
• Although no. of cattles with BSE (UK) till 2003 is >180,000, the total
estimated number is excess of 2 million.
• Between 1980-996 ,about 750,000 BSE-infected cattles have been
slaughtered and consumed by millions of U.K. residents.
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The disease can pass along the food chain and
the consumers may be infected by ingestion of
prion-contaminated beef.
• Milk from BSE Infected Cattle is Banned by the British government.
‫(ربنا الذي اعطى ك َّل شئ خلقه ثم هدى)‬
‫سورة طه‪ :‬اآلية رقم ‪50‬‬
‫قال تعالى‪( :‬كلوا وأرعوا أنعامكم ‪ ,‬ان في ذلك آليات ألولي النهى)‬
‫طه‪54 :‬‬
‫و قال تعالى ‪ ( :‬وفاكهة وأبا‪,‬متاعا لكم والنعامكم)‬
‫عبس‪32,31:‬‬
‫وتفسير أبا ما تأكله البهائم من االعشاب وقيل التبن‪.‬‬
‫وقال تعالى ‪(:‬هو الذي انزل من السماء ما ًء لكم منه شراب ومنه شجر فيه تسيمون)‬
‫النحل‪10 :‬‬
‫وتفسير تسيمون اي ترعون بهائمكم من هذا الشجر‬
‫النهي عن تغيير فطرة المخلوقات التي خلقها هللا عليها‬
‫ ان هللا سبحانه وتعالى خلق االنسان والحيوان والطير واالشياء‬‫جميعا كل على هيئته التي خلقه عليها بما يتناسب مع وظيفته في‬
‫الحياة والطريقة التي يتعايش بها مع الطبيعة التي حوله لكي تقوم‬
‫حياته على الوجه الصحيح‪.‬‬
‫ فأذا ما تغيرت هذه الفطرة او الطريقة التي خلقه هللا عليها تغير‬‫نمط حياة هذا المخلوق والوظيفة التي خلق من اجلها وكان هذا‬
‫التغيير سببا في ضرره او ضرر االخرين من حوله خاصة‬
‫االنسان الذي كرمه هللا على جميع المخلوقات ‪.‬‬
‫النهي عن اكل لحوم الجاللة وشرب البانها وركوبها‬
‫ الجاللة ‪ :‬هي الحيوانات كاالبل والبقر والغنم والدجاج وغيرها التي تاكل‬‫العذرة او القاذورات‬
‫ فعن ابن عباس رضي هللا عنهما قال ‪:‬‬‫(نهى رسول هللا صلى هللا عليه وسلم عن شرب لبن الجاللة واكل لحومها )‬
‫رواه الخمسة وصححه الترمذي‪.‬‬
‫وفي رواية ابو داوود (نهى عن ركوب الجاللة )‬
‫ وعن عمرو بن شعيب عن ابيه عن جده رضي هللا عنهم قال‪:‬‬‫(نهى رسول هللا صلى هللا عليه وسلم عن لحوم الحمر االهلية ‪ .‬وعن الجاللة ‪:‬‬
‫عن ركوبها واكل لحومها ) رواه احمد والنسائي وابو داوود‬
‫المصدر‪ :‬سيد سابق (فقه السنة ‪:‬ج‪ 1‬ص‪)26‬‬
DECONTAMINATION OF CJD PRIONS
• Prions are extremely resistant to common
inactivation procedures, and there is some
disagreement about the optimal conditions for
sterilization.
• Autoclaving at 132°C for 5 h or treatment with
2 N NaOH for several hours is recommended
for sterilization of prions.
• The term "sterilization" implies complete
destruction of prions; any residual infectivity
can be hazardous.
PREVENTION AND THERAPEUTICS
• There is no known effective therapy for
preventing or treating CJD.
• The finding that phenothiazines and acridines
inhibit PrPSc formation in cultured cells led to
clinical studies of quinacrine in CJD patients.
• Although quinacrine seems to slow the rate of
decline in some CJD patients, no cure of the
disease has been observed.
Prion Diseases: summary
Creutzfeldt-Jakob Disease
CJD
humans
variant Creutzfeldt-Jakob Disease
vCJD
humans; acquired from cattle
with BSE
Bovine Spongiform Encephalopathy
BSE
Infection with prion
contaminated MBM
Kuru
infectious; in humans who
practiced cannibalism in Papua
New Guinea
Gerstmann-Sträussler-Scheinker disease
GSS
inherited disease of humans
Fatal Familial Insomnia
FFI
inherited disease of humans
Scrapie
infectious disease of sheep and
goats
other animal TSEs (cats, mink, elk, mule
deer )
Infection with prioncontaminated MBM
THANK YOU
Could Prions Be In Milk And Dairy?
• Animal studies do suggest that meat (from animal muscle
alone) can transmit prion-related diseases since muscle
is interlaced with lymph and nervous tissue--known to be
infected with BSE.
• Possibility that milk may also carry disease-inducing
prions cannot be excluded.
• British BSE expert has pointed out that at least one
human case suggests passage of prions in milk.
• Japanese woman dying of CJD was found to have the
infectious agent in her colostrum.
• The risk from milk does appear to be much smaller than
from eating beef or cattle organ tissues.
• Milk from BSE Infected Cattle is Banned by the British
government as it is under suspesion.