PRION disease Flashcards
What is prion disease?
Protein-only infectious agents
Rare transmissable spongiform encephalopathies in humans and animals resulting in rapid neuro-degeneration and death in months
currently untreateable
What is prion protein?
Normal protein present in the human body (involved in copper metabolism, but otherwise unknown function)
If isoforms are aquired: patholgoical prion protein can cause neurodegerneration
What are the genetic predispositions of prion disease?
Prion protein is present on codon 129 on chromosome 20
Several polymorphisms (esp. MM) associated with higher risk of developing prion disese
What pathological chagnes does the normal Prion Protein (PrP) undergo in prion disease?
PrPSc abnormally folds → Beta-sheet configuration + protease/radiation resistant (e.g. surgical instuments cannot be cleaned from it)
Seed of PrPSc acts as a template which promotes irreversible conversion of PrP to insoluble PrPSc
As soon as you get one abnormal isoform:you will develop prion diseaes in the future
What is sporadic Prion disease?
How common is it?
Spontaneous development of CJD (no causes currently known)
Makes up 80% of the prion disease in the world
But still very rare (1/million/year)
Known as Cretzfeld-Jakob Disease
What is acquired Priond disease?
When one abnormal misfolded PrPSc enters the circulation)
- Kuru (Cannibalism)
- variant CJD
- iatrogenic CJD (surgical instruments, blood, GH)
What are genetic prion disease?
Inherited mutation of the prion protein gene (15% of all prion disease)
Usually very rare
What is the usual presentaiton of sporadic CJD?
Rapid dementia with
* myoclonus (jerky, irregular tremor)
* cortical blindness
* akinetic mutism
* LMN signs
What is the usual age of onset of sporadic CJD?
Mean age 65 (45-75)
older people
What are ECG changes seen in sporadic CJD?
Serial EEG shows periodic triphasic changes (also seen in lithium toxicity + hepatic encephalopathy)
abnormal in 2/3 of cases
What are changes seen on MRI in sporadic CJD?
Normal/ highlighting basal ganglia
cortical/striatal signal change on DWI MRI
What are signs seen on CSF in sporadic prion disease?
14-3-3 protein +ve/ S100
(protein that is an indicator of neurodegeneration)
What are the genetics of the PrP codon in sporadic CJD?
Most cases 129 codon MM
What are histological changes seen in post-mortem in bran histology in sporadic CJD?
- Spongiform vacuolation
- PrP amyloid plaques
What are possible differentials for a patient with rapid dementia?
- Sporadic CJD (+other forms of prion diseases)
- Alzheimers, Vascular dementia, mixed dementia
- CNS neoplasm
- Cerebral vasculitis
- Paraneoplastic syndrome
What form of CJD can be diagnosed by tonsillar biopsy?
Variant CJD
(100% sens. + spec.)
What is the incubation period of CJD?
Usually years
(about 10 years time often)
What is the expected suvival time of sporadic vs. variant CJD?
Sporadic: usually <6 months
Variant: usually about 14 months
What is Variant CJD?
A form of Prion disease, due to ingesiton of bovine spongiform encephalopathy (BSE)
BSE is a transmissible prion disease occurring in cattle also known as “mad cow disease”
What is the epidemiology of variant CJD?
Younger age of onset – typically 30yrs (median 26)
What is the usual clinical presentation of variant CJD?
Psychiatric symptoms to start (anxiety, paranoia, hallucinations)
followed by the development of neurological symptoms (peripheral sensory symptomsataxia and myoclonus)
Later symptoms include chorea, ataxia, dementia
What EEG and MRI changes would you expect in a patient with variant CJD?
EEG: Non- specific slow waves
MRI: Posterior thalamus highlighted on MRI-T2 (pulvinar sign)
What are CSF changes in variant CJD?
Usually unremarkable (14-3-3 and S100 are negative)
What investigations would be done and how would you diagnose familial Prion disease?
Family History (usually Autosomal dominant, but unlikely to be labeled as Prion disease)
EEG + MRI non specific (MRI might show basal ganglia high signal)
Diagnosis: Neurogenetics for mutations
What is Ferstmann-Strausser-Scheinker syndrome?
Autosomal dominant form of prion disease,
Develops between 20-60yrs, mean
survival = 5yrs
with dysarthria progressing to cerebellar ataxia ending in dementia
What is Fatal Familial Insomnia?
Autosomal domiant inherited forms of Prion disease
Insomnia and paranoia progressing to hallucinations and weight loss. Then a mute period. Death 1-18/12 after start of symptoms
What is the genetic form of the PrP in familial prion disease and variant CJD?
All people with variant CJD are MM homozygous and most familial prion disease cases are MM homozygous at codon 129 of Prion protien
What are the characteristics of Kuru?
A form of variant CJD due to cannibalism in PNG
Progressive cerebellar syndrome (death within 2yrs) following 45yr incubation
Dementia is late or absent
Epidemic was in the 1950/60s
What are the treatment option of prion diseae?
No treatment available
- symptomatic management
- Delaying prion conversion very early but no real treamtment benefits
