Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

PATHOLOGY > Prion disease > Flashcards

Prion disease Flashcards

1
Q

what are prion diseases

A

protein only infectious agents - have DNA inside
rare transmissible spongiform encephalopathies in humans and animals
* enter brain -> trigger cascade where existing prion proteins become rapidly affected
* get abnormal isoform of protein
* -> spongioform vacuolation of brain
caused rapid neurodegeneration
untreatable

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

normal prion protein

A

all have a normal prion gene - located on chr 20
prion protein involved in copper metabolism and binding - but otehr functions unknown
when get abnormal isoform -> neurodegeneration.

on codon 129 - polymorphisms MM MV and VV.
MM predisopose to prion disease

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

prion protein structure

A

L
* healthy prion
* has alpha-helical configuration
* sensitive to proteases and radiation

R
* PrPsc (scrapie ie the sheep form of prion disease)
* beta-sheet configuration
* protease resistant
* radiation resistant
* almost impossible to get rid of - get reuse surgical instrument even after autoclave etc

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

prion replication

A

seed of PrPsc acts as template -> promotes irrevsible conversion of PrP to insoluble PrP
ie conformational change in PrP

trigger remains unclear in sporadic process - possibly somatic mutation, or healthy protein converted to abnormal form - unknown
genetic - inherit abnormal form - might predispose to abnormal isoform later in life
different prion diseases have different triggers

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

prion disease classification

A

sporadic - Creutzfeldt-Jakob disease (80%) - worldwide cause for rapidly progressive for dementia

acquired (<5%)
* kuru
* variant CJD - from the mad cow epidemic, infected food entering human food chain. disease of young people
* iatrogenic CJD: Growth hormone, Blood, Surgery

route of innoculation alters length of innoculation time, all have long time

genetic (15%)
* inherited PRNP mutations eg. Gerstmann-Straussler-Sheinker syndrome (progressive ataxia) Familial Fatal Insomnia

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

presentation of sporadic CJD

A

rapid dementia associated with:
* myoclonus - vary in size, sometimes triggered by external stimuli

  • cortical blindness (problem with the occipital cortex - cant process vision)
  • akinetic mutism - inability to speak, then bedbound with ataxia and weakness
  • LMN signs - anterior horn cells - signs consistent with lower motor neuron disease
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

epidemiology of sporadic CJD

A

mean age - 65yrs (range 45-75yrs)
incidence v rare - 1/million/yr
death 6mo

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

cause of sporadic prion disease

A

uncertain
?somatic PRNP mutation
?spontaneous conversion of PrPC to PrPsc
?environmental exposure to prions

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

diagnosis of sporadic CJD

A

EEG - periodic, triphasic complexes (non-specific), 2/3 of EEG with CJD is abnormal
MRI
* increased signal in basal ganglia
* increased signal on diffusion weighted images in cortex in basal ganglia

CSF 14-3-3 protein, or S100 are markers of rapid neurodegeneration - raised

neurogenetics to rule out genetic cause

tonsillar biopsy not useful

brain biopsy - have to dispose of all equiptment

autopsy

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

normal adult EEG

A

ossilation of 9-10 Hz - alpha rhythm (posterior brain rhythm)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

EEG of CJD

A

periodic burst of abnormal activity - periodic complexes

ddx - hepatic encephalopathy, lithium toxicity
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

MRI scan of sporadic CJD

A

increased signal in basal ganglia

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

histopath of sporadic CJD

A

spongiform vacuolation
brain becomes a mush of bags of water

basal ganglia and cortex are predisposed - probably this that gives high signal on MRI

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

amyloid plaques in sporadic CJD

A

have the abnormal form of prion protein in

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

ddx of sporadic CJD

A

Alzheimer’s disease - can be rapid
Vascular dementia - cerebralla vasculitis (infarction)
Mixed dementia (AD + vascular)
CNS neoplasm eg. glioma, metastases
Cerebral vasculitis
Paraneoplastic syndrome - hard to dx, normal MRI can get paraneoplastic cerebral degeneration or limbic encephalitis
Familial CJD
vCJD

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

epidemiology of variant CJD (vCJD)

A

Peak was in 2000
young people - median age 26yrs
median survival 14mo
longer duration than sporadic CJD
Linked to BSE – linked to ingestion of infected bovine material
Notifyable disorder

17
Q

presentation of vCJD

A

Psychiatric onset:
* dysphoria, anxiety, paranoia, hallucinations

Then neurological:
* peripheral sensory symptoms and pain
* ataxia
* myoclonus
* chorea
* dementia

18
Q

diagnosis of vCJD

A

MRI brain - positive pulvinar sign

EEG – non-specific slow waves, not useful for dx

CSF – 14.3.3, S100 not useful

Neurogenetics (almost 100% are MM at codon 129 so far)- increased sensitivity for vCJD

Tonsil biopsy 100% sensitive and specific

(Brain biopsy) - dont need because tonsil biopsy works

Autopsy

PrPSc type 4t detectable in CNS + most lympo-reticular tissues

19
Q

MRI for vCJD

A

pulvinar sign
high signal in posterior thalamus

20
Q

pulvinar sign in vCJD following blood transfusion

A
21
Q

tonsillar biopsy in cCJD

A

100% sensitivity and specificity -> Early clinical diagnosis, Eliminates need for further Ix
Important for therapeutic trials and early treatment
May be positive during incubation period before clinical onset - havent found it on tonsils or appendix that remove - suggest not likely to be an epidemic
(sheep scrapie, mouse models)

22
Q

histology of vCJD

A

plaques
with abnormal prion protein

23
Q

transmission of iatrogenic CJD

A

innoculated intobody
human cadaveric growth hormone
corneal transplants
neurosurgical procedure eg gural grafts
blood transfusions, other blood products - dont have a blood test to look for prion disease, so cant sceen blood for it.
other surgical procedures

24
Q

clinical features of iatrogenic CJD

A

Progressive ataxia initially

Dementia and myoclonus later stages

Speed of progression depends on route of inoculation (CNS inoculation fastest) - blood transfusion will take longer, than brain biopsy

25
Q

how do we prevent transmission of iatrogenic CJD

A

Ask:
* Neurosurgical operations before 1991?
* Family history suggestive of prion disease
* Neurological problems suggesting prion disease

Sterilisation + disposal of surgical instruments vital

Theoretical concern regarding possibility of iatrogenic transmission of vCJD through transfusion, IVIg, surgical procedures etc.. This could become a major public health issue

26
Q

prion genetics

A

codon 129 polymorphism
* methionine-methionine (MM)
* methionine-valine (MV)
* Valine-valine (VV)

MM confurs most susceptability to prion disease

Specific PRNP mutations - inherited mutations of the same gene

all autosomal dominant

27
Q

FH when suspicious of prion disease

A

if had these - could have actually had CJD:
* dementia
* MS
* ataxia
* psychiartric hx

28
Q

dx of familial prion disease

A

EEG - non-specific - not useful
MRI - basal ganglia - sometimes high signal (like sporadic CJD)
neurogenetics crucial
if -ve: Spinocerebellar ataxia/huntingtons
Autopsy

29
Q

summarise Gerstmann-Straussler-Scheinker syndrome (GSS)

A

inherited prion disease

Slowly progressive ataxia
Diminished reflexes
Dementia
Onset age 30-70 years
Survival 2-10 years
PRNP P102L, but several other mutations

30
Q

summarise fatal familial insomnia (FFI)

A

inherited prion disease

Untreatable insomnia
Dysautonomia - huge blood pressure dysregulation, bradycardia
Ataxia
dysarthric
(thalamic degeneration)
PRNP D178N
+/-pyramidal/extrapyramidal signs
late cognitive decline
Medori R, et al. NEJM 1992

31
Q

summarise Kuru

A

ingestion of neural tissue
Foré tribes – papua New Guinea highlands
ate the elders brains
Epidemic 1950’s / 1960’s - women and children
Last endo-cannibalistic feast 1957
Longest incubation: up to 45 years
No MM’s left
Progressive cerebellar syndrome: - death within 2 years
Dementia late or absent

32
Q

CJD treatment

A

Symptomatic: clonazepam – mycolonus
(valproate, levetiracetam, piracetam)

Delaying prion conversion
* quinacrine - doesnt work
* pentosan (intra-ventricular administration) - caused intraventricular haemorrhage
* tetracycline

Anti-prion antibody (prevents peripheral prion replication and blocks progression to disease in infected mice but does not get into CNS)

Depletion of neuronal cellular prion protein (prevents onset of disease in mice and blocks neuronal cell loss + reverses early spongiosis)

PATHOLOGY (94 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions