Prion Disease Flashcards by Katerina Fernandez

What are prion diseases (2)

Protein-only infectious agent

Rare transmissible spongiform encephalopathies in humans + animals

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What is the neurological sequelae like in prion disease

Rapid neuro-degeneration

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What is the treatment for prion disease

Currently untreatable

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What gene is prion protein on

Chromosome 20

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What does prion protein gene code for

PrP is predominantly expressed in the CNS

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What is the normal PrP structure (2)

Alpha-helical configuration

Protease sensitive

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What is the abnormal PrPsc structure (2)

Beta-sheet configuration

Protease/radiation resistant

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How does prion protein propagate throughout the CNS

Seen of PrPsc acts as a template which promotes irreversible conversion of PrP to insoluble PrPsc (i.e. conformational change in PrP)

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What triggers PrP change to PrPsc

Unknown in sporadic cases

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How is prion disease classified in humans (3)

Sporadic (80%)
Acquired (<5%)
Genetic (15%)

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What is a sporadic prion disease in humans

Creutzfeldt-Jakob disease

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What are some acquired forms of prion disease (3)

Kuru
Variant CJD
Iatrogenic CJD (GH, blood, surgery)

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What is the cause of genetic prion disease

PRNP mutations (e.g. Gertsmann-Straussler-Sheinker syndrome, Familial Fatal Insomnia)

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What are the clinical features of sporadic CJD (5)

Rapid onset dementia, with: 
Myoclonus 
Cortical blindness
Akinetic mutism 
LMN signs

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What is the mean age of onset for sporadic CJD

65 years (range from 45-75 years)

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What is the incidence of sporadic CJD

1/million/year

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What is the prognosis for sporadic CJD

Death within 6 months

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What are some proposed causes of sporadic CJD (3)

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

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How is sporadic CJD diagnosed (7)

EEG 
MRI
CSF
Neurogenetics to rule out genetic cause 
Tonsillar biopsy is NOT useful 
Brain biopsy 
Autopsy

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What is seen on the EEG of a patient with sporadic CJD (2)

Periodic, triphasic complexes (non-specific)

2/3rds are abnormal only

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What is seen on the MRI of a patient with sporadic CJD (2)

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Basal ganglia - increased signal

Cortical/striatal signal change on DWI MRI

What is seen on the CSF of a patient with sporadic CJD

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14-3-3- protein, S100

What is seen histologically in sporadic CJD (2)

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Spongiform vacuolation

PrP amyloid plaques

What is the differential diagnosis for sporadic CJD (8)

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AD
Vascular dementia 
Mixed dementia (AD and vascular) 
CNS neoplasm (glioma, metastases)
Cerebral vasculitis
Paraneoplastic syndrome 
Familial CJD
vCJD

What is the age of presentation for vCJD

Younger than for sCJD (median age 26 years)

What is the median survival time for vCJD

14 months

What are the clinical signs of vCJD (9)

Psychiatric onset: dysphoria, anxiety, paranoia, hallucinations Neurological: ataxia, myoclonus, chorea, dementia

How is vCJD diagnosed (8)

MRI brain - positive pulvinar sign EEG - non-specific slow waves CSF - 14-3-3, S100 not useful Neurogenetics (almost 100% are MM at codon 129 so far) Tonsilar biopsy is 100% sensitive and specific (Brain biopsy) Autopsy PrPcs type 4t detectable in CNS + most lympho-retucular tissues

What is seen on MRI of vCJD

Positive pulvinar sign

What are the neurogenetics of vCJD

Almost 100% are MM at codon 129

What is the significance of tonisllar biopsy in vCJD (5)

100% sensitive and specific for vCJD Early clinical diagnosis Eliminates need for further investigation (e.g. brain biopsy to exclude other treatable causes) Important for therapeutic trials and early treatment may be positive during incubation period before clinical onset (sheep scrapie, mouse models)

What is the histological finding in vCJD

Florid plaques

How is iatrogenic CJD transferred (5)

Human cadaveric growth hormone Corneal transplants neurosurgical procedures e.g. dural gradts pre-1991 Blood transfusions, other blood products Other surgical procedures (appendicectomy and tonsillectomy in vCJD)

What are the clinical features of iatrogenic CJD (3)

Progressive ataxia initially Dementia and myoclonus later stages Speed of progression depends on route of inoculation (CNS inoculation fastest)

What are some important screening questions for prion disease for before surgery/donation (3)

Neurosurgical operations before 1991 Family history suggestive of prion disease Neurological problems suggesting prion disease

What is important to do if operating on someone who may have prion disease

Sterilisation + disposal of surgical instruments vital Theoretical concern regarding possibility of iatrogenic transmission of vCJD through transfusion, IVIg, surgical procedures etc... this could become a major public health issue.

What are the possible genetics of prion disease (3)

Codon 129 polymorphism Specific PRNP mutation Related to other neuro-genetic conditions (e.g. Huntington's, spinocerebellar ataxia)

What codon 129 mutations are associated with prion disease

Methionine-Methionine (MM) Not Methionine-Valine or Valine-Valine

What is the mode of inheritance for prion protein mutations

Autosomal dominant

What family history is relevant in familial prion disease (4)

Dementia MS Ataxia Psychiatric

What is seen on the EEG in familial prion disease

Non-specific

What is seen on the MRI in familial prion disease

Basal ganglia: sometimes high signal

What is the most important investigation in familial prion disease

Neurogenetics

What are the clinical features of Grestmann-Straussler-Scheinker syndrome (GSS) (6)

``` Slowly progressive ataxias Diminished reflexes Dementia Onset age 30-70 years Survival 2-10 years PRNP P102L, but several other mutations ```

What are the clinical features of fatal familial insomnia (FFI) (5)

``` Untratable insomnia Dysautonomia Ataxia (Thalamic degeneration) Mutation: PRNP D178N +/- pyramidal/extrapyramidal signs and late cognitive decline ```

What is Kuru

Prion disease from the Fore tribes of Papua New Guinea highlands. There was an epidemic in 1950/60s (women and children) Last endo-canibalistic feast in 1957 Longest incubation - up to 45 years NO MM's left Progressive cerebellar syndrome (death within 2 years) Dementai was late or absent

What is the treatment for CJD (4)

Symptomatic Delayed prion conversion Anti-prion antibody Depletion of neuronal cellular prion protein

What is involved in the symptomatic treatment of prion disease (2)

Clonazepam - myoclonus | valproate, levetiracetam, piracetam

What is involved in treating to delay prion conversion (3)

Quinacrine Pentosan (intra-ventricular adminstration) Tetracycline

What is anti-prion antibody

Treatment aimed at preventing peripheral prion replication and blocks progression to disease in infected mice, but does not penetrate into CNS

What is involved in treating for depletion of neuronal cellular prion proteins

Prevents onset of disease in mice and blocks neuronal cell loss + reverses early spongiosis

Prion Disease Flashcards

(51 cards)