PRION disease

Question 1

What is prion disease?

Answer 1

Protein-only infectious agents

Rare transmissable spongiform encephalopathies in humans and animals resulting in rapid neuro-degeneration and death in months

currently untreateable

Question 2

What is prion protein?

Answer 2

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

Question 3

What are the genetic predispositions of prion disease?

Answer 3

Prion protein is present on codon 129 on chromosome 20

Several polymorphisms (esp. MM) associated with higher risk of developing prion disese

Question 4

What pathological chagnes does the normal Prion Protein (PrP) undergo in prion disease?

Answer 4

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

Question 5

What is sporadic Prion disease?
How common is it?

Answer 5

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

Question 6

What is acquired Priond disease?

Answer 6

When one abnormal misfolded PrPSc enters the circulation)

• Kuru (Cannibalism)
• variant CJD
• iatrogenic CJD (surgical instruments, blood, GH)

Question 7

What are genetic prion disease?

Answer 7

Inherited mutation of the prion protein gene (15% of all prion disease)

Usually very rare

Question 8

What is the usual presentaiton of sporadic CJD?

Answer 8

Rapid dementia with
* myoclonus (jerky, irregular tremor)
* cortical blindness
* akinetic mutism
* LMN signs

Question 9

What is the usual age of onset of sporadic CJD?

Answer 9

Mean age 65 (45-75)
older people

Question 10

What are ECG changes seen in sporadic CJD?

Answer 10

Serial EEG shows periodic triphasic changes (also seen in lithium toxicity + hepatic encephalopathy)

abnormal in 2/3 of cases

Question 11

What are changes seen on MRI in sporadic CJD?

Answer 11

Normal/ highlighting basal ganglia
cortical/striatal signal change on DWI MRI

Question 12

What are signs seen on CSF in sporadic prion disease?

Answer 12

14-3-3 protein +ve/ S100

(protein that is an indicator of neurodegeneration)

Question 13

What are the genetics of the PrP codon in sporadic CJD?

Answer 13

Most cases 129 codon MM

Question 14

What are histological changes seen in post-mortem in bran histology in sporadic CJD?

Answer 14

1. Spongiform vacuolation
2. PrP amyloid plaques

Question 15

What are possible differentials for a patient with rapid dementia?

Answer 15

1. Sporadic CJD (+other forms of prion diseases)
2. Alzheimers, Vascular dementia, mixed dementia
3. CNS neoplasm
4. Cerebral vasculitis
5. Paraneoplastic syndrome

Question 16

What form of CJD can be diagnosed by tonsillar biopsy?

Answer 16

Variant CJD

(100% sens. + spec.)

Question 17

What is the incubation period of CJD?

Answer 17

Usually years
(about 10 years time often)

Question 18

What is the expected suvival time of sporadic vs. variant CJD?

Answer 18

Sporadic: usually <6 months
Variant: usually about 14 months

Question 19

What is Variant CJD?

Answer 19

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”

Question 20

What is the epidemiology of variant CJD?

Answer 20

Younger age of onset – typically 30yrs (median 26)

Question 21

What is the usual clinical presentation of variant CJD?

Answer 21

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

Question 22

What EEG and MRI changes would you expect in a patient with variant CJD?

Answer 22

EEG: Non- specific slow waves

MRI: Posterior thalamus highlighted on MRI-T2 (pulvinar sign)

Question 23

What are CSF changes in variant CJD?

Answer 23

Usually unremarkable (14-3-3 and S100 are negative)

Question 24

What investigations would be done and how would you diagnose familial Prion disease?

Answer 24

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

Question 25

What is Ferstmann-Strausser-Scheinker syndrome?

Answer 25

Autosomal dominant form of prion disease,

Develops between 20-60yrs, mean
survival = 5yrs
with dysarthria progressing to cerebellar ataxia ending in dementia

Question 26

What is Fatal Familial Insomnia?

Answer 26

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

Question 27

What is the genetic form of the PrP in familial prion disease and variant CJD?

Answer 27

All people with variant CJD are MM homozygous and most familial prion disease cases are MM homozygous at codon 129 of Prion protien

Question 28

What are the characteristics of Kuru?

Answer 28

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

Question 29

What are the treatment option of prion diseae?

Answer 29

No treatment available

1. symptomatic management
2. Delaying prion conversion very early but no real treamtment benefits