Prion Disease Flashcards
What are prion diseases?
Protein-only infectious agent
Rare transmissable spongiform encephalopathies in humans + animals
Rapid neuro-degeneration
Currently untreatable
What is the prion proton gene?
Encoded on chromosome 20.
Created prion protein which is predominantly expressed in the CNS.
What is the normal configuration of prion protein compared to PRPsc (scrapie isoform of the prion protein)?
Normal: Alpha-helical configuration, protease sensitive.
PRPsc: Beta-sheet configuration, protease/radiation resistant.
How does prion replication occur?
Seed of PrPSc acts as a template which promotes irreversible conversion of PrP to insoluble PrPSc ie. conformational change in PrP.
The trigger for this process remains unclear in sporadic cases.
What are classifications of prion disease?
Sporadic Creutzfeldt-Jakob Disease (80%)
Acquired (<5%):
- Kuru
- Variant CJD
- Iatrogenic CJD:
- GH
- Blood
- Surgery
Genetic (15%):
- PRNP mutations: e.g. Gerstmann-Straussler-Sheinker syndrome
- Familial Fatal Insomnia
What are the clinical features of sporadic CJD?
Rapid dementia with:
- Myoclonus
- Cortical blindness
- Akinetic mutism
- LMN signs
What is the epidemiology of sporadic CJD?
Mean age onset 65 yrs (range 45-75 yrs)
Incidence 1/million/year
Death within 6/12
What is the aetiology of sporadic CJD?
Cause uncertain:
- ?Somatic PRNP mutation
- ?Spontaneous conversion of PrPc to PrPsc
- ??Environmental exposure to prions
What are appropriate investigations for sporadic CJD?
EEG (electroencephalography):
- Periodic, triphasic complexes (non-specific)
- 2/3 abnormal
MRI:
- Basal ganglia – increased signal
- Cortical/striatal signal change on DWI MRI
CSF: 14-3-3 protein, S100
Neurogenetics to r/o genetic cause
Tonsillar biopsy NOT useful
Brain biopsy
Autopsy – by experienced pathologist
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What is this?
MRI scan - sporadic CJD
What is this?
Spongiform Vacuolation
What is this?
PrP Amyloid Plaques
What are differential diagnoses for sporadic CJD?
- Alzheimer’s disease
- Vascular dementia
- Mixed dementia (AD + vascular)
- CNS neoplasm eg. glioma, metastases
- Cerebral vasculitis
- Paraneoplastic syndrome
- Familial CJD
- vCJD
Which statement is NOT true of sporadic CJD?
A. Median survival time is <6 months
B. Tonsillar biopsy is diagnostic
C. EEG usually shows periodic complexes
D. Mean age of onset is 65 years old
E. CSF markers (S100, 14-3-3) of neuronal damage may be elevated
B. Tonsillar biopsy is diagnostic
What is the epidemiology of variant CJD/BSE?
Younger age of onset (median age 26 yrs)
Median survival time 14 months
What are clinical features of variant CJD/BSE?
Psychiatric onset:
- Dysphoria, anxiety, paranoia, hallucinations
Then neurological:
- Peripheral sensory symptoms
- Ataxia
- Myoclonus
- Chorea
- Dementia
What are appropriate investigations for vCJD?
MRI brain: Positive pulvinar sign
EEG: Non-specific slow waves
CSF: 14.3.3, S100 not useful
Neurogenetics (almost 100% are MM at codon 129 so far)
Tonsil biopsy 100% sensitive and specific.
(Brain biopsy)
Autopsy
PrPSc type 4t detectable in CNS + most lympo-reticular tissues
What is this?
MRI Pulvinar Sign
How are tonsillar biopsies used in vCJD?
100% sensitivity and specificity for vCJD.
Early clinical diagnosis
Eliminates need for further investigation (e.g. brain biopsy to exclude other treatable causes)
Important for therapeutic trials and early treatment
May be positive during incubation period before clinical onset (sheep scrapie, mouse models)
What is this?
vCJD Florid Plaques
Which statement is true of variant CJD?
A. The disease mainly affects elderly people
B. vCJD is more rapidly progressive than sporadic CJD
C. The initial symptoms are always neurological
D. Tonsillar biopsy is often diagnostic
E. EEG is usually abnormal
D. Tonsillar biopsy is often diagnostic
What are risk factors for iatrogenic CJD?
Human cadaveric growth hormone
Corneal transplants
Neurosurgical procedures eg. dural grafts, pre-1991
Blood transfusions, other blood products
Other surgical procedures - ?appendicectomy and tonsillectomy in vCJD
What are clinical features of iCJD?
Progressive ataxia initially
Dementia and myoclonus later stages
Speed of progression depends on route of inoculation (CNS inoculation fastest)
What are questions which should be asked to determine iCJD?
Neurosurgical operations before 1991?
Family history suggestive of prion disease
Neurological problems suggesting prion disease
What is a concern about surgery in iCJD patients?
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.
What are the three components of prion genetics?
Codon 129 polymorphism:
- Methionine – Methionine (MM)
- Methionine – Valine (MV)
- Valine – Valine (VV)
Specific PRNP mutations (~30 so far)
Consider other neuro-genetic conditions eg. Huntington’s, spinocerebellar ataxia
What is the mode of inheritence for prion protein mutations?
Mendelian
Autosomal dominant
What are clinical features of familial prion disease (GSS, FFI, CJD)?
F.H. crucial:
- Dementia
- “MS”
- Ataxia
- Psychiatric
What are appropriate investigations for familial prion disease?
EEG: Non-specific
MRI: Basal ganglia: Sometimes high signal
Neurogenetics crucial
If negative: SCA / Huntington’s
Autopsy
What is Gerstmann-Straussler-Scheinker syndrome (GSS)?
Inherited Prion Disease
- Slowly progressive ataxia
- Diminished reflexes
- Dementia
- Onset age 30-70 years
- Survival 2-10 years
- PRNP P102L, but several other mutations
What is Fatal Familial Insomnia (FFI)?
Inherited Prion Disease
- Untreatable insomnia
- Dysautonomia
- Ataxia (thalamic degeneration)
- PRNP D178N
- +/-pyramidal/extrapyramidal signs
- Late cognitive decline
What is the epidemiology of Kuru?
Foré tribes – Papua New Guinea highlands
Epidemic 1950’s/1960’s
- Women
- Children
Last endo-cannibalistic feast 1957
Longest incubation: Up to 45 years
No MM’s left
What are clinical features of Kuru?
Progressive cerebellar syndrome: Death within 2 years
Dementia late or absent
What is the management of CJD?
Symptomatic: Clonazepam – mycolonus (valproate, levetiracetam, piracetam)
Delaying prion conversion:
- Quinacrine
- Pentosan (intra-ventricular administration)
- 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.
