Prion Disease

Question 1

Define prion diseases

Answer 1

Transmissible diseases that do not involve any transfer of DNA or RNA - only the transmission of proteins

Question 2

What is the red flag for a prion disease?

Answer 2

A rapidly progressive - over weeks - movement disorder

Question 3

What is the most common prion disease?

Answer 3

Creutzfeldt-Jakob disease

Question 4

What does prion stand for?

Answer 4

Proteinaceous infectious only

Question 5

Name at least 3 prion diseases which affect humans

Answer 5

Creutzfedlt-Jakob disease, Gerstmann-Straussler-Sheinker syndrome, fatal familial insomnia, kuru

Question 6

In which country is kuru endemic?

Answer 6

Papua New Guinea

Question 7

Name at least 3 prion diseases found in non-human animals

Answer 7

Scrapie, bovine spongiform encephalopathy, feline spongiform encephalopathy, chronic wasting disease, transmissible mink encephalopathy

Question 8

Which animal prion disease developed into human variant Creutzfedlt-Jakob disease?

Answer 8

Bovine spongiform encephalopathy

Question 9

What is the UK incidence of prion diseases?

Answer 9

1-2 per million

Question 10

What percentage of UK prion diseases are familial?

Answer 10

10-15%

Question 11

How is variant Creutzfeldt-Jakob disease different to other prion diseases?

Answer 11

Younger age of onset

Question 12

Describe the macroscopic pathology of prion disease

Answer 12

Global severe brain atrophy and enlargement of ventricles

Question 13

Describe the microscopic pathology of prion disease

Answer 13

Neuronal loss, astrogliosis, accumulation of prion protein, vacuolisation of the cerebral cortex and cerebellar molecular layer

Question 14

State some symptoms of sporadic Creutzfedlt-Jakob disease

Answer 14

Rapidly progressive dementia, EEG changes, motor disturbances, death within a year

Question 15

Give the investigations used in Creutzfeldt-Jakob disease

Answer 15

CT, MRI, EEG, frontal lobe biopsy (last resort)

Question 16

Why might a frontal lobe biopsy for Creutzfeldt-Jakob disease produce a false negative?

Answer 16

The distribution of pathology in CJD is unpredictable so can be missed

Question 17

State at least four past causes of iatrogenic Creutzfeldt-Jakob disease

Answer 17

Human hormone therapy, dural transplant, neurosurgery, stereotactic EEG, corneal transplant

Question 18

What is Gerstmann-Straussler-Scheinker syndrome?

Answer 18

An autosomal dominant prion disease causing a mild dementia

Question 19

What is the prognosis with Gerstmann-Straussler-Scheinker syndrome?

Answer 19

Mean duration 4-5 years with mean age of death 50

Question 20

What is fatal familial insomnia?

Answer 20

An autosomal dominant prion disease causing early sleep disturbances, neuropsychiatric symptoms, and a late dementia

Question 21

Where is the PRNP gene located?

Answer 21

Chromosome 20

Question 22

Where is PrP^C expressed?

Answer 22

The membranes of neurons and glia

Question 23

Which codon acts as a prion disease risk factor?

Answer 23

Codon 129, with valine-valine or methionine-methionine homozygotes at greater risk than heterozygotes

Question 24

How is variant Creutzfedlt-Jakob disease associated with codon 129?

Answer 24

All affected patients have been methionine-methionine homozygotes

Question 25

How is PrP^P different to PrP^C in sporadic prion disease?

Answer 25

It undergoes alternative post-translational modification into an insoluble beta-pleated sheet form and starts a process of autocatalytic conversion

Question 26

Why is tissue ore-treated with proteinase K to allow PrP^P detection?

Answer 26

PrP^P, unlike other proteins, is resistant to proteinase K degradation

Question 27

Can PrP^C knockout mice get prion disease?

Answer 27

No

Question 28

What appears to determine strain variation in prion disease?

Answer 28

Glycosylation of the prion protein (the number of attached polysaccharide chains)

Question 29

As characterised by genotype and glycotype, what is the most common subtype of prion disease?

Answer 29

Methionine-methionine 1 (frequency 57%)

Question 30

Describe the pattern of PrP^P deposition in the MM1 subtype of prion disease

Answer 30

PrP^P is deposited synaptically, with perivacuolar deposition around areas of spongiform change

Question 31

State at least 3 functions PrP^C has been implicated in, as summarised by Wulf et al in 2017

Answer 31

Signal transduction, vesicle trafficking, anti-apoptosis, extracellular matrix interactions, heat-shock protein, chaperone protein, metal binding

Question 32

State at least 2 potential mechanisms for local spread of proteinopathies

Answer 32

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

Question 33

Name the drug proposed for use as post-exposure prophylaxis against prion disease

Answer 33

Pentosan polysulphate