a fully detailed PPT about prions are waiting for you to review.

1. Transmissible Spongiform
Encephalopathies
Mahmoud Abuharb, M.D, cardiothoracic
surgery department
Prion pree-on
约瑟夫

2. Introduction to Prions
• Pronounced “pree-on”
• Shortened term for:
Proteinaceous Infections Particle
• Causes TSE (Transmissible Spongiform
Disease) which attacks the central nervous
system (the brain).

3. The function of normal prions
PrPC
• protection against apoptotic and oxidative
stress.
• cellular uptake or binding of copper ions.
• transmembrane signalling.
• formation and maintenance of synapses.
• adhesion to the extracellular matrix.

4. Discovery
• Study started in 1967 by British scientist,
Tikvah Alper, at Hammersmith Hospital in
London.
• Discovered by American neurologist,
Stanley B. Prusiner, in 1982.

5. Differences From Bactera & Viruses
• Prions do not contain nucleic acid; they
don’t have DNA or RNA.
• They are extremely resistant to heat and
chemicals.
• Prions are very difficult to decompose
biologically; they survive in soil for many
years.

6. Where are prions?
• Proteins on the cell membrane of neurons of
the brain in mammals
• Normal prion protein is noted as PrPC
• Mutated prion protein is noted as PrPSC
• The secondary structure of the prion protein
seems to be affected.

7. Basic Structure
• Normal prions contain about
200-250 amino acids
twisted into three telephone
chord-like coils known as
helices, with tails of more
amino acids.
• The mutated, and infectious,
form is built from the same
amino acids but take a
different shape.
• 100 times smaller than the
smallest known virus.
Normal Mut
ated

8. PrPC
129
Sh1
H1
106-126
Sh2
H2
H3
Octa-repeat
GPI
N-terminus

9. Abnormal folding of a protein protein (and that
protein only) causes a prion disease
PrPC
to PrPSc

10. Basic Structure
Normal Mut

11. Differences between cellular and scrapie proteinsDifferences between cellular and scrapie proteins
PrPPrPCC
PrPPrPSCSC
Solubility
Soluble Non soluble
Structure
Alpha-helical Beta-sheeted
Multimerisation state
Monomeric Multimeric
Infectivity
Non infectious Infectious
Susceptibility to Proteinase K
Susceptible Resistant

13. Transmissible Spongiform
Encephalopathies (TSEs):
• A group of progressive Neurodegenerative
disorders that affect both humans and
animals.
• Long incubation periods
• Always fatal

14. TSEs Around the World
• Cases have been reported from the united
kingdom, Canada , Ireland , Italy , Japan ,
The Netherlands , Portugal , Saudi Arabia ,
and the United States .
• Genetic prion diseases have been reported
in china.

15. Route of Transmission
• Ingestion of diseased animals meat, organs
and different products (rendering).
• The remnants of the diseased animals,
urine, saliva and other body fluids might
linger in the soil by binding to clay and
other minerals and then accumulate in the
Environmet for decades.

16. • Iatrogenic infection;
-contaminated surgical instruments with the
Prion agent.
-receiving transplantation organs from
patients with Prion disease.

17. Who is susceptible?
• Generally, Everybody is susceptible,
because there are NO protective antibodies
produced against Prions in the infected
humans.

18. Pathology
• There are NO pathological process
OUTSIDE the CNS.
• NO inflammatory process.
• So in the CNS we can see:-
-Atrophy of cerebral cortex and cerebellum.
-Proliferation and hypertrophy of the
astrocytes and amyloid plaques.
-Mild spongious status of the grey matter.
-Diffuese neuronal degeneration and minimal
demyelination.

19. Pathogenesis of infection
1. Direct brain contact
2. Vascular inoculation
3. Oral (intestinal) inoculation

20. Human TSEs
• Kuru
• Creutzfeldt-Jakob Disease (CJD)
• Variant Creutzfeldt-Jakob Disease (vCJD)
• Gerstmann-Sträussler Scheinker Syndrome
(GSS)
• Fatal Familial Insomnia (FFI)

21. Kuru
• Is the first reported and well studied.
• Very long incubation period up to 50 years.
• Headache, arthralgia, cerebellar ataxia,
voluntary tremors, involuntary
movements(myoclonic jerks,
fasciculations), euphoria, dementia,
progressive wasting and malnutrition.
• Most patients die within 1 year of
symptoms onset.

22. Gertsmann-Strassler-Scheinker
syndrome (GSS)
• Very rare in humans,1-10 persons in 1
billion annually.
• Incubation period up to 5 years.
• Strike average 43-48 years old.
• Most cases are familial with autosomal
dominant.
• Dementia, difficulty walking, ataxia,
tremor, dysmetria, nystagmus.

23. Fatal familial insomnia (FFI)
• The first case was found in Italy.
• Incubation period up to 13 months.
• Strike average 35-61 years old.
• Loss of normal circadian rhythm activity,
hallucinations, delirium, confusion,
impairment of memory, decreased ADH and
increased cortisone secretions, abnormal
secretion of GH, Prolactin and melatonin.

24. Creutzfeldt-Jacob Disease (CJD)
• Sporadic, familial or iatrogenic.
• Sporadic form (sCJD) is the most common
human Prion disease, account for >85% of
cases and occur worlwide.
• Most patients die within 1 year.
• Strike average over 50 years old.
• The cause behind (sCJD) is still unknown.
• Muscular twitching, impaired vision and
over 90% of patients may go blind, memory
and judgement, insomnia, ataxia,
depression, in sever cases coma may occur.

25. Familial CJD
• About 10-15% of CJD patients
• Autosomal dominant inheritance
• Associated with prion protein gene
abnormalities
• Usually a family history of CJD is present

26. Iatrogenic CJD
• <1% of CJD patients
• Transmission through:
– Human Growth Hormone
– Dura Mater Graft
• Lyodura
– Cornea transplantation
– Use of neurosurgical instruments and EEG
depth electrodes

27. CJD Transmission
• Not contagious
• Not transmitted through casual contact or
airborne particles

28. CJD Transmission
• CJD does not appear to be transmissible
through blood
– Follow-up of recipients of blood from donors
subsequently diagnosed with CJD
– Investigation of CJD cases with history of
receipt of blood products

29. New variant CJD (vCJD)
• (vCJD) is Unlike the traditional forms of
(CJD),where it is strongly linked to
exposure probably to food.
• Occurs worldwide.
• Characterized by extreme rapid progression
from symptoms to disability and death.

30. Clinical comparsion between
(sCJD)and(vCJD)
• vCJD affecting younger agents average 29
years old while sCJD average 65 years old.
• Prolongation of illness vCJD median of 14
months while sCJD4.5 months.
• vCJD lack of periodic sharp waves on EEG
while sCJD is typical finding.
• vCJD there is extensive distribution of
plaques while sCJD lack of plaques.

31. All human TSEs share the
following
• A prolonged incubation period of several
years
• A progressive debilitating neurologic
syndrome that is invariably fatal
• Pathological changes that are confined to the
CNS and consist of the following 3 classic
features: spongiosis, gliosis, and neuronal
loss
• A transmissible agent that does not elicit any
specific immunologic response in the host
and is unusually resistant to conventional
inactivation procedures

33. Animal TSEs
• Scrapie_Sheep
• Bovine Spongiform Encephalopathy
(BSE)_Cattle
• Chronic Wasting Disease (CWD)_Deer

34. scrapie
• Is a progressive neurological disorder of
sheep.
• The name scrapie is derived from one of the
clinical signs of the condition, wherein
affected animals will compulsively scrape
off their fleeces against rocks, trees, or
fences.

36. Bovine Spongiform
Encephalopathy (BSE)
• First recognized among cattle in the United
Kingdom in 1986.
• is a progressive neurological disorder of
cattle.
• The nature of the transmissible agent is
not well understood.
• Know as ‘the mad cow disease’
• Incubation period 2.5 - 5 years

37. • abnormal gait, changes in behavior,
tremors and hyper-responsiveness to
certain stimuli, poor balance and
coordination, weight loss, decreased
milk production, lameness, ear
infections and teeth grinding due to pain
and eventually coma and death.

38. Mad CowMad Cow

40. Chronic Wasting Disease (CWD)
• Is a progressive neurological disorder of the
deer.
• Clinical symptoms
– Weight loss
– Behavioral changes
– Excessive salivation
– Difficulty swallowing

42. Does animal TSEs transmissible
to humans ?
• BSE maybe? because of the strong related
evidence with vCJD.
• CWD maybe? because the genetic
susceptibility among cases with human
TSEs and exposure to deers.
• Scrapie NO , or at least by so far NO

43. Evidence for BSE-vCJD Link
• Epidemiological evidence
– Geographic clustering in the United Kingdom
– Absence of vCJD cases in BSE-free countries
• Laboratory evidence
– Experimental study using macaques
– Western blot analysis of infecting prions
– Experimental study using panels of inbred and
cross-bred mice

44. vCJD caused by BSE?vCJD caused by BSE?

45. Diagnosis
• Labs:-
-CSF; elevation of 14-3-3 protein is
diagnostic.
-EEG; the classic EEG pattern interupted by
generalized bilaterally synchronous
biphasic or triphasic periodic sharp wave
complexes.
-MRI scans.

46. -Neuropathology; spongiform change,
reactive gliosis, neuronal loss and absence of
inflammatory changes.
-Identification of ‘PrPSc
’ which is the ‘’gold
standard’’ and the definitive diagnosis,
Specimen obtained by biopsy or autopsy.

47. Figure 1. Histopathology showing spongiform degeneration and astrocytic gliosis (adapted from the Prion Group at the University of Duesseldorf )

48. MRIMRI
Proton density Weighted T2
EEG abnormalitiesEEG abnormalities
normal sCJD

50. Differential diagnosis
• Alzheimer disease
• Multiple sclerosis
*Key point*
Spongiform changes and PrPSc
positive.

51. Treatment
• Unfortunately no therapeutic or
prophylactic regimens.
• Only supportive care can be given.
• Antiviral such as acyclovir, interferon,
amphotericin B shown no effect.
• Some studies suggested that amantadine
and arabinoadenosine could improve or
stabilize disease status in some patients.

52. Vaccine?
• The development of a vaccine against the
infectious form of prions has proven to be
unsuccessful due to the lack of innate or
antigen-induced immune response against
the host-encoded protein.

53. Prognosis
Is very poor, ALL cases are FATAL.

54. Kuru

55. Prophylaxis
• Properly sterilizing medical equipment may
prevent the spread of the disease. If you
have or may have CJD, you should not
donate organs or tissue, including corneal
tissue.
• Health care workers especially the
neurosurgeons, pathologists and nurses
should keep their skin intact and follow the
safety procedure.

56. • For the individuals with history of inherited
prion disease, prenatal genetic consulting
should be performed.
• All countries should ban the use of
ruminant tissues in ruminant feed.

58. Stop cannibalism

60. Variant CJD

61. In September 1995, reporter Van Smith of Baltimore’s Weekly City Paper visited Valley Proteins Inc, a Baltimore rendering plant:
Smith observed these items listed: a horse, the grill grease and used
frying oil from Camden yards, a baby elephant who died in
Baltimore, Illinois, tons of waste meat and inedible animal parts from
the local supermarkets and slaughterhouses, carcasses from the zoo,
thousands of dogs, cats, raccoons, possums, deer, foxes, snakes, and
the rest of the local animal shelters waste and road kill that must be
disposed each month.
Animal Rendering
The practice of
processing
animal
byproducts into
commercial
material as
animal
feed.

62. What is the problem with prions?
*Very resistant agent:-
• resists dry heat ( > 200ºC)
• resists steam autoclaving (up to134ºC, 18
mins.)
• resists formaldehyde
• resists UV-radiation
• resists Gamma-radiation ( > 0.3 MGray)
• NO effective treatment.

63. For more on prion diseases:
• www.cjdsurveillance.com
– Information on National Prion Disease
Pathology Surveillance Center (NPDPSC)
– established by CDC and AANP
– NPDPSC provides free, state-of-the-art
diagnostic testing
• www.cdc.gov/ncidod/diseases/cjd/cjd/htm
– Links to various prion disease articles and sites

64. Thank you