prion

Question 1

where is the prion gene found?

Answer 1

chromosome 20

Question 2

what does prion stand for?

Answer 2

protein-only infectious agent

Question 3

what happens when prion enters brain?

Answer 3

• When they enter the brain they can trigger a cascade where existing prion proteins become rapidly affected and develop the abnormal isoform of the prion protein
  
  • This leads to the development of spongiform vacuolisation of the brain
  • Results in rapid neurodegeneration

Question 4

what is thought to be the normal function of prion protein ?

Answer 4

poorly understood but it is thought to have some role in copper metabolism

• The normal protein does NOT cause any issues - it is only when we get the abnormal isoform that it causes neurodegeneration

Question 5

name the relevant codon in prion disease?

Answer 5

Codon 129

Question 6

What are the polymorphism found on prion codon? which causes disease?

Answer 6

THREE polymorphisms that we can find:
○ MM - this predisposes to prion disease
○ MV
○ VV

M = Methionine 
V = Valine

Question 7

what are the differences in structure between normal and abnormal prion proteins?

Answer 7

normal - PrP:
○ The normal protein has an alpha-helical structure
○ It is protease-sensitive and sensitive to radiation

abnormal PrPsc:
○ This has a beta-pleated sheet configuration and is RESISTANT to proteases and radiation so it is difficult to get rid of (e.g. surgical instruments contaminated with diseased prions are impossible to clean)

Question 8

explain the mechansim of prion replication?

Answer 8

○ Once you get a seed of the abnormal prion protein (PrPSc) it seems to act as a template which promotes conversion of PrP into insoluble PrPSc

○ This is what results in rapid neurodegeneration

○ The trigger for this process is unclear in sporadic cases

Question 9

what are teh types of prion disease?

Answer 9

Sporadic, Acquire, Genetic

• Sporadic
○ Creutzfeldt-Jakob Disease (80%)
§ Disease of older people
• Acquired (5%)
○ Kuru
○ Variant CJD
§ This results from the earlier BSE (bovine
spongiform encephalopathy) epidemic
§ Average age: 25-30 years
○ Iatrogenic CJD
§ Growth hormone (from cadavers)
§ Blood
§ Surgery
○ NOTE: these diseases may have very long
incubation times (10-40 years)
• Genetic (15%)
○ PRNP mutations
§ i.e. inherited mutation of the prion protein
gene
§ Examples:
□ Gerstmann-Straussler-Sheinker
syndrome GSSS
□ Familial Fatal Insomnia

Question 10

Rapid dementia with:
		○ Myoclonus
		○ Cortical blindness 
		○ Akinetic mutism
		○ LMN signs 
	• Mean age: 65 years (range 45-75 years)

is which condition?

Answer 10

sporadic cjd

Question 11

how to diagnose sporadic cjd? what do we see on ivx?

Answer 11

EEG - abnromal; Periodic, triphasic complexes

MRI - Increased signal in basal ganglia
Increased intensity on DWI MRI of the cortex and basal ganglia

CSF
Raised 14-3-3 protein and S100

Brain biopsy is the only way of confirming CJD but this is often done at autopsy

• spongiform vacuolisation on histology
• a certain amyloid plaque

Question 12

list some ddx for Sporadic CJD

Answer 12

Cerebral vasculitis
Paraneoplastic syndrome

	        ○ Alzheimer's disease 
		○ Vascular dementia
		○ Mixed dementia 
		○ Familial CJD 
		○ vCJD

Question 13

what are 14-3-3 protein, S100 ?

Answer 13

markers of rapid neurodegeneration

Question 14

when is tonsillar biopsy used?

Answer 14

○ Tonsillar biopsy may be used in vCJD but NOT in CJD

Question 15

the following is common in which cjd type?

○ Younger age of onset (median = 26 years) 
		○ Median survival time = 14 months 
		○ Psychiatric onset
			§ Dysphoria
			§ Anxiety 
			§ Paranoia 
			§ Hallucinations 
		○ Followed by neurological symptoms
			§ Peripheral sensory symptoms 
			§ Ataxia 
			§ Myoclonus 
			§ Chorea 
			§ Dementia

Answer 15

vCJD

caused by (bovine spongiform encephalopathy)

Question 16

what is seen on MRI with vCJD?

Answer 16

shows pulvinar sign (high intensity in the putamen)

Question 17

what are csf findings in vcjd?

Answer 17

14-3-3- and S100 are NOT useful this time

Question 18

what do the genetic look like in vcjd?

Answer 18

Almost 100% are MM at codon 129

Question 19

which test is 100% sensitive and specific for vCJD?

Answer 19

tonsilar biopsy

Question 20

in vcjd what would be found in the CNS and most lympho-reticular tissues ?

Answer 20

PrPSc type 4T

Question 21

causes of iatrogenic CJD?

Answer 21

○ Human cadaveric growth hormone
○ Corneal transplants
○ Neurosurgical procedures (e.g. corneal grafts)
○ Blood transfusions
○ Other surgical procedures (e.g. appendicectomy, tonsillectomy)

Question 22

the gene mutations causing iatrogenic CJD are of which type?

Answer 22

autosomal dominant

Question 23

the gene mutations causing familial prion disease are of which type?

Answer 23

autosomal dominant

Question 24

which is the most common mutation in Gerstmann-Straussler-Sheinker Syndrome?

Answer 24

PRNP P102L

Question 25

which is the most common mutation in Fatal Familial Insomnia?

Answer 25

PRNP D178N

Question 26

○ Untreatable insomnia
○ Dysautonomia (blood pressure and heart rate dysregulation)
○ Ataxia
○ Thalamic degeneration

are symptoms of?

Answer 26

Fatal Familial Insomnia

Question 27

○ Slowly progressive ataxia
○ Diminished reflexes
○ Dementia
○ Onset age 30-70 years

are symptoms of?

Answer 27

Gerstmann-Straussler-Sheinker Syndrome

Question 28

Kuru

name the what where and when?

Answer 28

from cannibalism
• Local practices promoting the ingestion of the brain tissue of village elders
• In the 1950s and 1960s there was an epidemic of Kuru in Papua New Guinea

progressive cerebellar syndrome with absent (or late) dementia

Question 29

rx for CJD?

Answer 29

• Symptomatic
		○ Clonazepam for the myoclonus 
		○ Others: valproate, levetiracetam
	• Delaying Prion Conversion
		○ Quinacrine
		○ Pentosan
		○ Tetracycline 
	• Anti-prion antibody

Question 30

florid plaques are seen in?

Answer 30

vCJD

Question 31

Is this statement true or false?

vCJD is more rapidly progressive than sporadic CJD

Answer 31

false