Prion disease Flashcards
what are prion diseases
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
normal prion protein
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
prion protein structure
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
prion replication
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
prion disease classification
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
presentation of sporadic CJD
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
epidemiology of sporadic CJD
mean age - 65yrs (range 45-75yrs)
incidence v rare - 1/million/yr
death 6mo
cause of sporadic prion disease
uncertain
?somatic PRNP mutation
?spontaneous conversion of PrPC to PrPsc
?environmental exposure to prions
diagnosis of sporadic CJD
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
normal adult EEG
ossilation of 9-10 Hz - alpha rhythm (posterior brain rhythm)
EEG of CJD
periodic burst of abnormal activity - periodic complexes
MRI scan of sporadic CJD
increased signal in basal ganglia
histopath of sporadic CJD
spongiform vacuolation
brain becomes a mush of bags of water
basal ganglia and cortex are predisposed - probably this that gives high signal on MRI
amyloid plaques in sporadic CJD
have the abnormal form of prion protein in
ddx of sporadic CJD
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
epidemiology of variant CJD (vCJD)
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
presentation of vCJD
Psychiatric onset:
* dysphoria, anxiety, paranoia, hallucinations
Then neurological:
* peripheral sensory symptoms and pain
* ataxia
* myoclonus
* chorea
* dementia
diagnosis of vCJD
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
MRI for vCJD
pulvinar sign
high signal in posterior thalamus
pulvinar sign in vCJD following blood transfusion
tonsillar biopsy in cCJD
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)
histology of vCJD
plaques
with abnormal prion protein
transmission of iatrogenic CJD
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
clinical features of iatrogenic CJD
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
