Prion Diseases

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Prion Diseases

• Transmissible Spongiform Encephalopathies
• (TSE)

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Dr.Mohammad Jamil Al-Habbal

• MRCP (UK),FRCP (London),FRCP (Edin.)
• Consultant Internal Medicine
• King Fahad Specialist Hospital-Dammam

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DEFINITION

• 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.

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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

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In humans

• Creutzfeldt-Jakob disease (CJD) and its
  varieties 1iatrogenic Creutzfeldt-Jakob disease
  (iCJD),
• 2familial Creutzfeldt-Jakob disease (fCJD),
• 3sporadic Creutzfeldt-Jakob disease (sCJD)
• 4variant Creutzfeldt-Jakob disease (vCJD),
• Gerstmann-Sträussler-Scheinker syndrome (GSS)
• Fatal familial insomnia (fFI)
• Sporadic fatal insomnia (sFI)
• Kuru
• Alpers syndrome

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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.

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WHY PRION DISEASE?

• 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!

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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.

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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.

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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).

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Proposed mechanism of prion propagation
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PrPc and PrPsc
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Infection
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Infection
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Infection
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Infection
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Human Prion Diseases

• Creutzfeldt-Jakob Disease (CJD)
• Variant Creutzfeldt-Jakob Disease (vCJD)
• Gerstmann-Straussler-Scheinker Syndrome (GSS)
• Fatal Familial Insomnia (FFI)
• Kuru

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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
  (mean61.5yrs).
• Induced by somatic mutation or spontaneous
  conversion of PrPc into PrPsc. 

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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 manifestationssome patients may also
  show behavioral changes with agitation,
  depression, or confusion.
• Myoclonus most constant physical sign,present in
  gt 90 pts.
• Invariably fatal, with a median illness duration
  of 4 months death occurs within 12 months of
  illness onset in 8590 of pts.

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Diagnosis

• 1. EEG two cycles per second triphasic
  sharp-wave discharges.
• 2. CSF presence of 14-3-3 protein,
• 3. HistopathologyBiopsy 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 gtgt10 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 testsequencing the PRNP gene

Prion diseases damage the brain
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• This tissue slide shows sponge-like lesions in
  the brain tissue of a classic CJD patient. This
  lesion is typical of many prion diseases.

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CREUTZFELDT-JAKOB DISEASE 2.FAMILIAL

• It accounts for 515 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 .

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CREUTZFELDT-JAKOB DISEASE 3.IATROGENIC

• ? 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?

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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?

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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.

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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 132C 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.

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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.

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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).

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Clinical and Pathologic Characteristics Distinguishing Classic CJD from Variant CJD Clinical and Pathologic Characteristics Distinguishing Classic CJD from Variant CJD 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 gt75 of cases
Presence of "florid plaques" on neuropathology Rare or absent Present in large numbers
Immunohitochemical analysis of brain tissue Variable accumulation Marked accumulation of protease-resistance 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 protease-resistance prion protein
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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.

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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 gt3 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).

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GERSTMANN-STRAUSSLER-SCHEINKER SYNDROME (GSS)

• A familial disease with autosomal dominant
  inheritance,
• First described in1936 by Gerstmann, Straussler,
  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.

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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.

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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.

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Disappearance of kuru
Number of biannual cases of kuru in Papua New
Guinea.
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Animal Prion Diseases

• Scrapie
• Bovine Spongiform Encephalopathy (BSE)
• Chronic Wasting Disaese (CWD)
• Transmissible mink encephalopathy
• Feline spongiform encephalopathy
• Ungulate spongiform encephalopathy

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Spongiform Encephalopathies (in animals)
BSE in Cattle Scrapie in sheep
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Scrapie ??? ????? (???? ?????)

• 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.

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Bovine Spongiform Encephalopathy (BSE) or "Mad
Cow Disease??? ???? ?????

• 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.

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BSE epidemic in UK
Number of annual cases of BSE in cattle in UK
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BSE

• Although no. of cattles with BSE (UK) till 2003
  is gt180,000, 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.
• 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.

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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 132C 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.

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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.

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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 prion-contaminated MBM
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• THANK YOU

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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.