MI: Prion Disease

Question 1

What is the rapid plasma reagent test?

Answer 1

Screening test for active syphilis

Question 2

Name a CSF marker that supports the diagnosis of sCJD

Answer 2

14-3-3

Question 3

What is a characteristic finding of CJD on a diffusion-weight MRI?

Answer 3

High signal in the caudate/putamen or at least in cortical regions (temporal, parietal, occipital)

Question 4

What does ‘prion’ stand for?

Answer 4

Protein-only infectious agent

Question 5

What are prion diseases and what do they cause?

Answer 5

• Rare transmissible spongiform encephalopathies caused by prions
• They lead to spongiform vacuolisation of the brain and rapid neurodegeneration

Question 6

What is the prion protein gene and on which chromosome is it found?

Answer 6

PRNP gene, chromosome 20

Question 7

What is a possible physiological role of the normal prion protein?

Answer 7

It may have some role in copper metabolism

Question 8

Describe the structure of the normal prion protein.

Answer 8

Alpha-helix

Question 9

Describe the structure of an abnormal prion protein.

Answer 9

Beta-pleated sheet

Question 10

Why is the abnormal prion protein difficult to get rid of?

Answer 10

Resistant to proteases and radiation

Question 11

How does prion replication take place?

Answer 11

Seeding of an abnormal prion protein (PrPsc) seems to act as a template which promotes the conversion of PrPc to the insoluble PrPsc

Question 12

List some types of prion disease. Which type is most common?

Answer 12

Sporadic CJD (80%)

Acquired (<5%)

• Kuru
• Variant CJD (results from BSE epidemic)
• Iatrogenic CJD

Genetic (15%)

• PRNP mutations e.g. fatal familial insomnia, Gerstmann-Straussler-Sheinker syndrome

Question 13

Give some examples of inherited prion diseases. What are they caused by?

Answer 13

• Fatal familial insomnia
• Gerstmann-Straussler-Sheinker syndrome

Caused by PRNP gene mutations

Question 14

Describe the clinical features of sporadic CJD.

Answer 14

Rapid dementia with:

• Myoclonus
• Cerebellar dysfunction
• Cortical blindness
• Akinetic mutism
• LMN signs

NOTE: usually in older people (>65)

Question 15

What is the epidemiology and prognosis of sporadic CJD?

Answer 15

• Mean age of onset 65 years (range 45-75 years)
• Prognosis - death with 6 months

Question 16

What are some possible causes of sporadic CJD?

Answer 16

No known cause

• Somatic PRNP mutation
• Spontaneous conversion of PrPc into PrPsc
• Environmental exposure to prions

Question 17

How might sCJD be diagnosed?

Answer 17

• EEG - abnormal in 2/3
• MRI
• CSF
• Neurogenetics
• Brain biopsy
• Autopsy - must be done by experience pathologist

Question 18

Describe the EEG appearance in sporadic CJD.

Answer 18

Triphasic complexes

Question 19

Describe the MRI appearance of sporadic CJD.

Answer 19

Increased intensity on DWI MRI of the basal ganglia and cortex

Question 20

Which markers will be raised in the CSF of a patient with CJD?

Answer 20

14-3-3

S100

Question 21

What is the only way of confirming a diagnosis of CJD?

Answer 21

Brain biopsy (usually at autopsy)

Question 22

Describe the histological appearance of CJD.

Answer 22

Spongiform vacuolisation

NOTE: there are amyloid plaques but these are different from the plaques seen in Alzheimer’s disease

Question 23

List the differential diagnosis for CJD.

Answer 23

• Alzheimer’s disease
• Vascular dementia
• Mixed dementia (AD + vascular)
• CNS neoplasms
• Cerebral vasculitis
• Paraneoplastic syndromes
• Other CJD types (familial, variant)

Question 24

What is variant CJD?

Answer 24

CJD in younger people that has resulted from the BSE epidemic

Question 25

What animal disease is vCJD linked to?

Answer 25

Bovine spongiform encephalopathy (Mad cow disease)

Question 26

Describe the epidemiology and clinical features of vCJD

Answer 26

* Younger age of onset - median age 26 years * Median survival 14 months * **Psychiatric onset** - dysphoria, anxiety, delusions, hallucinations * Followed by neurological symptoms - peripheral sensory symptoms, ataxia, myoclonus, chorea, dementia

Question 27

What is a characteristic MRI feature of vCJD?

Answer 27

Pulvinar sign - bilateral hyperintensity in the posterior thalamus ##FOOTNOTE Hockey stick sign

Question 28

How is the use of CSF markers different in vCJD?

Answer 28

14-3-3 and S100 are NOT useful in vCJD diagnosis

Question 29

Which investigation is most useful for vCJD?

Answer 29

**Tonsillar biopsy** - Prions localise in lymphoid tissue - Type 4t - 100% sensitive and specific - May be positive during incubation period before symptom onset ## Footnote NOTE: this is not useful in sCJD

Question 30

Describe the role of neurogenetics in vCJD.

Answer 30

Almost 100% of patients are MM at codon 129 (in the PRNP gene)

Question 31

List some causes of iatrogenic CJD.

Answer 31

* Human cadaveric growth hormone * Corneal transplants * Neurosurgical procedures e.g. dural grafts (pre-1991) * Blood transfusions

Question 32

Outline the clinical features of iatrogenic CJD.

Answer 32

* Starts with progressive ataxia * Dementia and myoclonus occur at a later stage ## Footnote Speed of symptom progession in iatrogenic CJD depends on route of innoculation (CNS innoculation is fastest)

Question 33

What is the inheritance pattern of inherited prion disease?

Answer 33

Autosomal dominant

Question 34

Which specific polymorphism in the PRNP gene is significant in inheried prion disease

Answer 34

MM (methionine-methionine) polymorphism at codon 129 (may confer earlier onset)

Question 35

What are some alternative diagnoses for someone presenting with features suggestive of prion disease?

Answer 35

* Spinocerebellar ataxia * Huntington's disease

Question 36

What is crucial to ask in the history when assessing inherited prion diseases?

Answer 36

Family history

Question 37

Describe the clinical features of Gerstmann-Straussler-Sheinker syndrome.

Answer 37

* Slowly progressive ataxia * Diminished reflexes * Dementia Onset age 30-70 years with 2-10 year mean survival ## Footnote NOTE: **PRNP P102L** mutation is most common

Question 38

Describe the clinical features of fatal familial insomnia.

Answer 38

* Untreatable insomnia / paranoia * Progressing to hallucinations and weight loss * Then a mute period * Dysautonomia (BP and HR dysregulation) * Ataxia * Late cognitive decline * (Thalamic degeneration) * Death 1-18/12 after start of symptoms ## Footnote NOTE: **PRNP D178N** mutation is most common

Question 39

What is Kuru?

Answer 39

- Prion diorder from Papua New Guinea that was spread due to the tradition of endo-cannibalism - Characterised by progessive cerebellar syndrome with late or absent dementia - Death occured within 2 years

Question 40

Outline the principles of treament of CJD.

Answer 40

**Symptomatic** - Clonazepam for clonus - (Valproate, levetiracetam, priacetam) **Delaying prion conversion** - Quinacrine - Pentosan (intraventricular administration) - Tetracycline **Anti-prion antibody** - Blocks peripheral prion replication and progession to disease in mice but cannot access CNS **Depletion of neuronal cellular prion protein** - Prevents diease onset in mice and blocks neuronal cell loss and reverses early spongiosis

Question 41

Where should possible cases be reported to?

Answer 41

* National prion clinic (Queen Square, UCL) * NCJDSU in Edinburgh