Prion Disease

Question 1

Definition

Answer 1

Protein-only infectious agent
Rare transmissable spongiform encephalopathies in humans and animals resulting in rapid neurodegeneration
Currently untreatble

Question 2

Protein structure in prion disease

Answer 2

Prion protein gene on Chr 20, predominantly expressed in CNS
Normal protein structure PrP
Abdnormal Prp(SC) abnormally folds -> beta sheet configuration + protease?radiation resistant. Seed of PrP(SC) acts as a template which promotes irreversible conversion to insoluble PrP(SC)

Question 3

Genetics of prion disease

Answer 3

Codon 129 polymorphism and specific PRNP mutations

Question 4

Differentials of prion disease

Answer 4

Other neurogenetic conditions

Huntington’s, Spinocerebellar ataxia

Question 5

CJD Treatment

Answer 5

Symptomatic: Conazepam - mycolonus: (Valproate, Levetiracetam, Piracetam)
Delaying prion conversion: Quinacrine, Pentosan, Tetracycline

Question 6

EEG: Serial EEG shows triphasic changes
MRI: Normal/highlighting basal ganglia
CSF: 14-3-3 Protein +ve
PNRP: No mutations
Genetics: Most cases 129 codon MM
Western Blot: Types 1-3
Post Mortem: Spongiform vacuolation, PrP amyloid plaques

Answer 6

Sporadic CJD

Question 7

EEG: Non-specific slow waves
MRI: Posterior thalamus highlighted T2 (Pulvinar sign)
CSF: 14-3-3 can be normal
PNRP: No mutations
Genetics: All cases 129 codon MM
Western Blot: Type 4T from tonsillar biopsy (100% sens+spec)
Post Mortem: PrPsc 4T detectable in CNS + lymphoreticular tissue, Florid plaques

Answer 7

Variant CJD

Question 8

PNRP: No mutations
Genetics: Most 129 codon Homozygous (MM or VV)
Western Blot: Types 1-3

Answer 8

Iatrogenic CJD

Question 9

EEG: Non-specific
MRI: Sometimes high signal in basal ganglia
PNRP: Mutations present and diagnostic
Genetics: 129 codon homozygosity may confer earlier onset

Answer 9

Inherited Prion Disease

Question 10

Somatic PRNP mutation or Spontaneous conversion of PrPc to PRPsc and subsequent seeding
Rapid, progressive dementia with myoclonus, cortical blindness, akinetic mutism and LMN signs
Mean onset is 45-75 years
Mean survival time 6 months from symptoms

Answer 10

Sporadic CJD (80%)

Question 11

Exposure to bovine spongiform encephalopathy (BSE)
YOunger age of onset (30)
Mean survival 14 months
Psychiatric symptoms to start (anxiety, paranoia, hallucinations)
Development of neuro symptoms (peripheral sensory, ataxia, myoclonus)
Later - chorea,a taxia, dementia

Answer 11

Acquired Variant CJD

Question 12

Innoculation with human prions most commonly from surgery
Progressive ataxia initially
Dementia and myoclonus later stages
Speed of progression depends on route of inoculation
CNS inoculation fastest

Answer 12

Acquired Iatrogenic

Question 13

Exposure to human prions from cannibalistic feasts
Progressive cerebellar syndrome (death within 2 years) following 45 year incubation
Dementia is late or absent
Epidemic was 50s/60s

Answer 13

Acquired Kuru

Question 14

Autosomal dominant
Develops between 20-60 years, mean survival - 5 years
Dysarthria -> cerebellar ataxia -> dementia

Answer 14

Familial Gerstmann-Straussler-Schneiker Syndrome

Question 15

Autosomal dominant (50 families)
Insomnia and paranoia -> hallucinations -> weight loss
Mute period
Death 1-18 months after start

Answer 15

Fatal Familial insomnia