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45 Cards in this Set

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Transmissible Spongiform Encephalopathies cause problems due to
failure to clear a protein (prion) leads to neuronal death
what is the major distinguishing key of prion diseases
transmissibility of a protein can lead to dz in other ppl
what structure of prion is damaging to a host? what is importance about this form?
B-sheet (aberrant form)

Aberrant forms are resistant to degradation, and are non-immunogenic to host
common pathogenesis of Creutzfeld-Jacob Disease (CJD)

another important way?
spontaneous conversion from alpha to beta prions

passed by person to person (reusing surgical tools, eating mad cow beef)
man hunts a deer and wants to take it home and eat it. If he is in CO, WV or a few other places what dz does he have to worry about?
Chronic wasting disease (CWD, deer and elk)
all ppl who had nvCJD had changes where
homozygous methionine at codon 129
Rapidly progressive dementia and myoclonus. Death within year of onset. Due to an infective protein
Creutzfeld-Jakob Disease
what 2 ways can you distinguish mad cow (nvCJD) from sporadic CJD?
ncCJD: “florid” plaque

other finding is “Pulvinar sign” in MRI
what are prion proteins?
small proteins, expressed primarily in neurons, and inserted into neuronal cell membranes
what chromosome are prion proteins encoded on?

What is the gene and how many copies of the gene are there?
1. Encoded on chromosome 20


2. CPRNP gene (single copy)
describe the pathogenesis of prion dz (i.e., the protein conformational change that occurs)
conversion of normal prion structure to abnormal:

alpha helix ---> beta sheet
list the 3 causes that can lead to the development of abnormal prion protein and thus disease
1. genetic (inherited or spontaneous mutation: point mutation, insertion, deletion)

2. incorrect post-translational modification

3. "spontaneous" conversion
describe:

1. normal degradation of a prion protein

2. what occurs with degradation of mutated prion protein

3. what occurs from an infection of a prion protein
1. Normal (PrP^sen) --> proteolysis --> degradation

2. Mutated (PrP^res) --> incomplete proteolysis --> amyloid

3. Infection: mutated + normal protein --> (2) mutated proteins --> amyloid
1. Creutzfield-Jacob Disease (CJD) can be caused by what 2 types of mutations?

2. CJD due to infection are associated with what 3 things?

3. CJD causes what type of neurologic disorder
1. Inherited or somatic mutation

2. Infection
a) Surgical instruments
b) Dura mater grafts
c) Human Growth hormone

3. Pre-senile dementia
New variant CJD (nvCJD) results via?
infection via prion-contaminated beef
1. Gerstmann-Straussler Scheinker Disease (GSS) is caused by what type of mutation?

2. What neurologic problems does it cause?
1. Inherited mutation

2. Progressive ataxia/dementia
1. Fatal Familial Insomnia (FFI) is caused by what type of mutation?

2. Which part of the brain are the abnormal proteins found?

3. What neurological problems does it cause?
1. Inherited mutation; rare somatic mutations, spontaneous conversions.

2. Thalamus

3. Intractable insomnia, dementia.

***Rare somatic mutations, spontaneous conversions
Kuru results due to what?
Ritualistic cannibalism

***(Fore’ people, New Guinea)
what is the pathogenesis of Scrapie (sheep)
sheep --> sheep infection via blood, placenta
Bovine spongiform encephalopathy (BSE) results from what?
Infection via sheep/cattle meat and bone meal
Transmissible mink encephalopathy (TME) is found in what type of animals

What is the pathogenesis of this disease?
1. Captive animals.

2. Infection via sheep/cattle meat
Chronic wasting disease (CWD, deer and elk) is spread to humans via what?

how is CWD initially spread to deer and elk?
1. Current mechanism of spread unknown

2. Initial infection via sheep (blood) contaminated grasses
CJD can result in slightly different diseases due to what?

Also describe what is different
1. Mutations (point, insertion, deletion) at **different locations** in the prion gene (250 codons, chromosome 20)

2. results in different:
a) Location
b) Onset
c) Symptomatology
d) Duration
flip to see the where the different prion diseases affect the brain
mutation for Sporadic CJD (85%) occurs at what codon?

what does this lead to?
1. Codon 129

(*normal*, Met/Val)
mutation for Familial CJD (5%) occurs at what codon(s)?

what does this lead to?
Codon 200 (178, 208, 210)

(Glu --> Lys)
mutation for GSS occurs at what codon(s)?

what does this lead to?
Codon 102 (105, 117, 145, 198)

(Pro --> Leu)
mutation for FFI occurs at what codon(s)?

what does this lead to?
Codon 178

(Asp --> Asn)
mutation for nvCJD (infection with bovine prion) occurs at what codon(s)?

what does this lead to?
Codon 129

***determine susceptibility...... in all cases, homozygous mehtionine
mutation for nvCJD protection (Japanese) occurs at what codon(s)?

what does this lead to?
Codon 219

(Glu --> Lys)
What is the age of onset for CJD? What is seen on microscopy? What is seen clinically? What is the worldwide frequency?
1. onset 60-65 yrs

2. microscopy: Progressive vaculoation, degenteration of brain

3. Rapidly progressive dementia and myoclonus (death within year of onset)

4. Occurs in low frequency worldwide (1/million, 15/million over age 60)

*** Familial, sporadic (85%) and acquired forms (brain biopsies, corneal transplants, pituitary growth hormone, dura mater grafts, ingestion of contaminated meat).
in England/UK how is nvCJD passed to human?
Passed to human by ingesting beef from cattle w/ bovine spongiform encephalopathy (damn Brits)
describe what is seen on post mortem histopath of nvCJD pts
"florid" plaque of nvCJD
what protein is detectable in the CSF in sporadic CJD?

what protein is found to be elevated in nvCJD
1. 14-3-3 protein (less/later on in nvCJD)

2. INC CSF tau protein
(nvCJD) - after a tonsillar biopsy is done what lab test preformed to look for the BSE prion?

What is seen on MRI
1.Western Blot assay (humans and animals)

***New blood test developed (2011), not yet available

2. "Pulvinar sign" on MRI
classic CJD vs. nvCJD:

median age of death
cCJD - 68 yo

nvCJD - 28 yo
classic CJD vs. nvCJD:

median duration of illness
cCJD: 4-5 months

nvCJD: 13-14 months
classic CJD vs. nvCJD:

signs and symptoms
cCJD - dementia; early neurologic signs

nvCJD -
a) prominent psychiatric/behavioral sym.
b) abnormal physical sensations
c) delayed neurologic signs
classic CJD vs. nvCJD:

periodic spharp waves on electroencephologram
cCJD: often present

nvCJD: absent
classic CJD vs. nvCJD:

agent in lymphoid tissue
cCJD: not readily defected

nvCJD: readily detected
classic CJD vs. nvCJD:

immunohistochemical analysis of brain tissue
cCJD: variable accumulation

nvCJD: marked accumulation of protease resistant prion protein
classic CJD vs. nvCJD:

florid plaques
cCJD: rare or absent

nvCJD: large number
classic CJD vs. nvCJD:

Pulvinar sign on MRI
cCJD: not reported

nvCJD: present >75% of cases
classic CJD vs. nvCJD:

INC glycoform ration on immunoblot analysis of protease-resistant prion protein
cCJD: not reported

nvCJD: marked accumulation of protease-resistant prion protein
classic CJD vs. nvCJD:

treatment
none currently

non-specific for pain, myoclonus, other symptoms