Prion disease Flashcards
What is a prion?
An infectious agent consisting only of protein, which can fold in multiple, structurally distinct ways, at least one of which is transmissible to other prion proteins, leading to disease that is similar to viral infection.
Which diseases are thought to be caused by prions?
The rare Transmissible Spongiform Encephalopathies (TES)
Which system is affected by all known prion diseases in mammals?
The nervous system: all affect the structure of the brain or other neural tissue, resulting in rapid neuro-degeneration. All are currently untreatable and universally fatal.
What is PrP?
Prion protein - the protein that prions are made of, which may occur in both infectious and non-infectious forms. Healthy form found throughout the body, even in healthy people and animals.PrP found in infectious material has a different structure and is resistant to proteases
What is PrP^C?
PrPC is a normal protein found on the membranes of cells. The C refers to ‘cellular’ PrP. Predominantly expressed in CNS
Which chromosome has the gene for PrPC?
20
What is PrP^SC?
The infectious isoform of PrP. Sc refers to ‘scrapie’, the prototypic prion disease, occurring in sheep.
Able to convert normal PrPC proteins into the infectious isoform by changing their conformation, or shape; this, in turn, alters the way the proteins interconnect. PrPSc always causes prion disease. PrPSc has a higher proportion of β-sheet structure in place of the normal α-helix structure.
Protease/radiation resistant.
Seed of PrPSc acts as template which promotes irreversible conversion of PrP to insoluble PrPSc
Is there currently a cure for prion disease?
Nope
Which 2 genetic mutations are associated with prion disease?
Codon 129 polymorphism
Specific PRNP mutations
Give 2 neuro-genetic differential conditions to consider
Huntington’s
Spinocerebellar ataxia
What treatment may be given for the symptomatic relief of myoclonus in CJD?
Clonazepam
Sodium valporate
Levetiracetam
Piracetam
What is myoclonus?
Irregular short duration jerk like episodes involving the somatic (skeletal) musculature
In CJD which treatments are used to delay prion “conversion”?
Quinacrine
Pentosan
Tetracycline
What are the 3 broad types of prion disease and what percentage does each make up?
Sporadic CJD (sCJD) - 80% Acquired CJD -
Which 3 prion diseases belong to the “acquired CJD” category?
vCJD (variant)
Iatrogenic
Kuru
List 4 inherited prion diseases/types of disease
Familial CJD
Gerstmann-Straussler-Scheinker syndrome (GSS)
Fatal familial insomnia (FFI)
Various atypical dementias
What are the EEG changes in sCJD?
Serial EEG shows periodic triphasic changes
What are the EEG changes in vCJD?
Non-specific slow waves
What are the MRI changes in sCJD?
Normal/highlighting basal ganglia
What are the MRI changes in vCJD?
Posterior thalamus highlighted on MRI-T” (pulvinar sign)
What are the MRI changes in inherited prion disease?
Sometimes high signal in basal ganglia
Which two types of prion disease give a high basal ganglia signal on MRI?
sCJD and inherited prion diseases
Which protein may show an elevated CSF level in prion disease?
14-3-3 protein
Which type of prion disease is most associated with an elevated 14-3-3 protein?
sCJD
Is CSF 14-3-3 a good diagnostic test for CJD?
No, it’s not sensitive or specific
Only half of patients diagnosed with CJD have an elevated 14-3-3 protein. About 1/3 of patients who do have an elevated 14-3-3 protein are found to have a different neurological disease, not CJD
What does CJD stand for?
Creutzfeldt-Jakob disease
In which type of CJD are diagnostic mutations present on PNRP (prion-protein gene) analysis?
Inherited prion diseases
(PNRP mutations not usually seen in sporadic or acquired CJD, but certain polymorphisms are associated with increased susceptibility)
Which PNRP (prion-protein gene) polymorphism is a recognised genetic marker for increased CJD susceptibility in Caucasions?
Codon 129 - homozygosity (MM or VV) associated with increased risk
In which type of CJD are all cases homozygous MM at codon 129?
vCJD
in sCJD and iatrogenic cases, most are homozygous
Which type of homozygosity is most commonly associated with CJD susceptibility, MM or VV?
MM
But VV also has higher susceptibility than heterozygous state.
In sCJD and iatrogenic CJD, which types of PrP^SC are detected by Western blot?
Types 1-3
In vCJD, which type of PrP^Sc protein is detected by Western Blot and from where is the sample taken?
Type 4t
From tonsillar biopsy
(100% sensitivity and specificity)
Give 2 post-mortem findings in sCJD
Spongiform vacuolation
PrP amyloid plaques
Give 2 post-mortem findings in vCJD
PrP^Sc detectable in CNS and lymphoreticular tissue
Florid plaques
Describe the aetiology of sCJD
Somatic (ie not inherited) PRNP mutation
OR
Spontaneous conversion of PrP^c to Prp^Sc and subsequent seeding
Describe the aetiology of vCJD
Exposure to bovine spongiform encephalopathy (BSE, “mad cow disease”)
Describe the aetiology of iatrogenic CJD
Innoculation with human prions - commonly during surgery
Describe the aetiology of kuru
Exposure to human prions through cannibalism
Papua New Guinea
What is the inheritance type (ie dominant/recessive etc) of the inherited prion diseases Gerstmann-Straussler-Scheinker syndrome and fatal familial insomnia?
Autosomal dominant
How many families in the world have fatal familial insomnia (FFI)?
40-50, with ~100 affected individuals
List 5 clinical features of sCJD
Rapid, progressive dementia Myoclonus Cortical blindness Akinetic mutism Lower motor neuron signs
What is the mean age of onset of sCJD?
45-75 years
What is the mean survival time of sCJD?
6-12 months of symptom onset
How does the age of onset differ in vCJD (compared to sCJD)?
Younger - typically around 30 years
What is the mean survival time of vCJD?
~14 months
Which symptoms develop first in vCJD?
Psychiatric: anxiety, paranoia, hallucinations
In vCJD, which group of symptoms follow the psychiatric symptoms?
Neurological: peripheral sensory symptoms, ataxia, myoclonus
List 3 late stage symptoms of vCJD
Chorea
Ataxia
Dementia
What determines the speed of progression of iatrogenic CJD?
Route of inoculation - fastest if introduced directly into CNS
What is the first symptom of iatrogenic CJD?
Progressive ataxia
Give 2 later stage symptoms of iatrogenic CJD
Dementia
Myoclonus
How long is the incubation period of kuru?
~45 years
How does kuru present and what is the survival time from presentation?
Progressive cerebellar syndrome 3 stages: ambulant, sedentary, terminal "Laughing sickness" - pathologic bursts of laughter Late/absent dementia Death within 2 years
When was the kuru epidemic in PNG?
1950s/60s
When does Gerstmann-Straussler-Scheinker (GSS) present and what is the mean survival from this point?
Develops between 20-60 years
~5 year survival
What are the 2 stages of GSS?
Dysarthria
Cerebellar ataxia
Dementia
(Gradual progression)
How does fatal familial insomnia (FFI) initially present?
Insomnia and paranoia
How do the symptoms of FFI progress?
Hallucinations and weight loss, followed by a final mute period
What is the mean survival time of FFI?
1-18 months after start of symptoms
