Prion Disease Flashcards
Compare and contrast the clinical presentations of prion disorders with those of the more common neurodegenerative conditions Identify the key neuropathological features of prion diseases Evaluate the prion hypothesis Discuss the factors that led to the emergence of variant Creutzfeldt-Jakob disease
Define prion diseases
Transmissible diseases that do not involve any transfer of DNA or RNA - only the transmission of proteins
What is the red flag for a prion disease?
A rapidly progressive - over weeks - movement disorder
What is the most common prion disease?
Creutzfeldt-Jakob disease
What does prion stand for?
Proteinaceous infectious only
Name at least 3 prion diseases which affect humans
Creutzfedlt-Jakob disease, Gerstmann-Straussler-Sheinker syndrome, fatal familial insomnia, kuru
In which country is kuru endemic?
Papua New Guinea
Name at least 3 prion diseases found in non-human animals
Scrapie, bovine spongiform encephalopathy, feline spongiform encephalopathy, chronic wasting disease, transmissible mink encephalopathy
Which animal prion disease developed into human variant Creutzfedlt-Jakob disease?
Bovine spongiform encephalopathy
What is the UK incidence of prion diseases?
1-2 per million
What percentage of UK prion diseases are familial?
10-15%
How is variant Creutzfeldt-Jakob disease different to other prion diseases?
Younger age of onset
Describe the macroscopic pathology of prion disease
Global severe brain atrophy and enlargement of ventricles
Describe the microscopic pathology of prion disease
Neuronal loss, astrogliosis, accumulation of prion protein, vacuolisation of the cerebral cortex and cerebellar molecular layer
State some symptoms of sporadic Creutzfedlt-Jakob disease
Rapidly progressive dementia, EEG changes, motor disturbances, death within a year
Give the investigations used in Creutzfeldt-Jakob disease
CT, MRI, EEG, frontal lobe biopsy (last resort)
Why might a frontal lobe biopsy for Creutzfeldt-Jakob disease produce a false negative?
The distribution of pathology in CJD is unpredictable so can be missed
State at least four past causes of iatrogenic Creutzfeldt-Jakob disease
Human hormone therapy, dural transplant, neurosurgery, stereotactic EEG, corneal transplant
What is Gerstmann-Straussler-Scheinker syndrome?
An autosomal dominant prion disease causing a mild dementia
What is the prognosis with Gerstmann-Straussler-Scheinker syndrome?
Mean duration 4-5 years with mean age of death 50
What is fatal familial insomnia?
An autosomal dominant prion disease causing early sleep disturbances, neuropsychiatric symptoms, and a late dementia
Where is the PRNP gene located?
Chromosome 20
Where is PrP^C expressed?
The membranes of neurons and glia
Which codon acts as a prion disease risk factor?
Codon 129, with valine-valine or methionine-methionine homozygotes at greater risk than heterozygotes
How is variant Creutzfedlt-Jakob disease associated with codon 129?
All affected patients have been methionine-methionine homozygotes
How is PrP^P different to PrP^C in sporadic prion disease?
It undergoes alternative post-translational modification into an insoluble beta-pleated sheet form and starts a process of autocatalytic conversion
Why is tissue ore-treated with proteinase K to allow PrP^P detection?
PrP^P, unlike other proteins, is resistant to proteinase K degradation
Can PrP^C knockout mice get prion disease?
No
What appears to determine strain variation in prion disease?
Glycosylation of the prion protein (the number of attached polysaccharide chains)
As characterised by genotype and glycotype, what is the most common subtype of prion disease?
Methionine-methionine 1 (frequency 57%)
Describe the pattern of PrP^P deposition in the MM1 subtype of prion disease
PrP^P is deposited synaptically, with perivacuolar deposition around areas of spongiform change
State at least 3 functions PrP^C has been implicated in, as summarised by Wulf et al in 2017
Signal transduction, vesicle trafficking, anti-apoptosis, extracellular matrix interactions, heat-shock protein, chaperone protein, metal binding
State at least 2 potential mechanisms for local spread of proteinopathies
1) Cell death causing protein aggregate release, which is then taken up by viable cells
2) Exocytosis of protein aggregate, which is then taken up by viable cells
3) Synaptic release of the aggregate and spread along a neuronal network
Name the drug proposed for use as post-exposure prophylaxis against prion disease
Pentosan polysulphate
