Prion Disease Flashcards
What are prion diseases (2)
Protein-only infectious agent
Rare transmissible spongiform encephalopathies in humans + animals
What is the neurological sequelae like in prion disease
Rapid neuro-degeneration
What is the treatment for prion disease
Currently untreatable
What gene is prion protein on
Chromosome 20
What does prion protein gene code for
PrP is predominantly expressed in the CNS
What is the normal PrP structure (2)
Alpha-helical configuration
Protease sensitive
What is the abnormal PrPsc structure (2)
Beta-sheet configuration
Protease/radiation resistant
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)
What triggers PrP change to PrPsc
Unknown in sporadic cases
How is prion disease classified in humans (3)
Sporadic (80%)
Acquired (<5%)
Genetic (15%)
What is a sporadic prion disease in humans
Creutzfeldt-Jakob disease
What are some acquired forms of prion disease (3)
Kuru
Variant CJD
Iatrogenic CJD (GH, blood, surgery)
What is the cause of genetic prion disease
PRNP mutations (e.g. Gertsmann-Straussler-Sheinker syndrome, Familial Fatal Insomnia)
What are the clinical features of sporadic CJD (5)
Rapid onset dementia, with: Myoclonus Cortical blindness Akinetic mutism LMN signs
What is the mean age of onset for sporadic CJD
65 years (range from 45-75 years)
What is the incidence of sporadic CJD
1/million/year
What is the prognosis for sporadic CJD
Death within 6 months
What are some proposed causes of sporadic CJD (3)
Somatic PRNP mutation
Spontaneous conversion of PrPc to PrPsc
Environmental exposure to prions
How is sporadic CJD diagnosed (7)
EEG MRI CSF Neurogenetics to rule out genetic cause Tonsillar biopsy is NOT useful Brain biopsy Autopsy
What is seen on the EEG of a patient with sporadic CJD (2)
Periodic, triphasic complexes (non-specific)
2/3rds are abnormal only
What is seen on the MRI of a patient with sporadic CJD (2)
Basal ganglia - increased signal
Cortical/striatal signal change on DWI MRI
What is seen on the CSF of a patient with sporadic CJD
14-3-3- protein, S100
What is seen histologically in sporadic CJD (2)
Spongiform vacuolation
PrP amyloid plaques
What is the differential diagnosis for sporadic CJD (8)
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
