What are the five prion diseases found in humans?
- Fatal familial insomnia (FFI)
- Gerstmann-Staussler-Scheinker syndrome
- Variant Creutzfeldt-Jacob disease (vCJD)
- Creutzfeldt-Jacob disease (CJD)
What is Creutzfeldt-Jacob disease?
The most frequent of human prion diseases.
Causes of CJD:
- Sporadic (sCJD) → no known cause (85-95% of cases)
- Familial (fCJD), inherited genetic risk (7-10%)
- Iatrogenic (iCJD), exposure during medical procedures (<1%)
sCJD CANNOT be transmitted person-to-person by blood transfusion or meat contaminated with BSE. sCJD is NOT related to human “mad cow disease.”
What are the signs and symptoms of sCJD?
- Spongiform encephalopathy
- Death occurs w/in 1 year of symptom onset
- Rapidly progressive mental deterioration and myoclonus are the two cardinal clinical manifestations of sCJD
- May manifest as delirium and dementia
- Concentration, memory, and judgment difficulties are early signs
- Mood changes (apathy, depression) and sleep disturbances (hypersomnia, insomnia) are common
- Impaired speech and mumbling
- Loss of brain function resembles Alzheimer's disease, but is very rapid in progression
- Complete dementia usu. by the sixth month
- Provoked by startle
- Present in >90% of patients at some point during the illness
- May be absent at presentation, despite the presence of dementia
What evidence led to the protein-only hypothesis?
- No virus particles, bacteria, or fungi have been associated with prion diseases
- No nucleic acid is associated with infectivity; agent is resistant to UV radiation and nucleases
- No immune response to infection
With regard to prion diseases, what causes encephalopathy?
PrPc misfolding causes encephalopathy: protein misfolding → PrPc converted to PrPsc (Scrapie form) → prion disease
The mechanism of PrPsc pathogenesis is unknown: it can arise by mutation, from exogenous sources (meat, blood, etc.), or via experimental transmission between animals. Animals lacking PrPc, however, do not contract prion disease.
What are the normal functions of Prpc?
PrPc, the cellular form, is involved in:
- Maintaining the brain’s white matter
- Regulating innate immune cells
- Responses to oxidative stress
- Neuron formation
How many types of PrPsc have been classified?
4 types of human PrPsc have been identified, based on the ratio of PrP bands seen on Western blots after treatment with proteinase K.
Each PrPsc type is associated with different phenotypes of CJD.
How do prions self-replicate?
- Prions are infectious, but contain no genetic material
- After PrPc (native) → PrPsc (prion) conversion, the nucleus increases in size to become an amyloid fiber
- Fragmentation occurs, liberates new ends to allow for amplification, and allows the dissemination of infectious material
How is sCJD diagnosed?
Brain biopsy remains the gold standard and only definitive diagnostic test for all forms of CJD. sCJD is characterized by:
- Accumulation of PrPsc
- Neuronal loss w/o inflammation
- Spongiform change
A number of tests exist, however, to provide clinical support for the diagnosis:
- Detection of 14-3-3 protein in cerebral spinal fluid (CSF).
- Abnormal T2-weighted magnetic resonance imaging (MRI) signal.
- A characteristic electroencephalography (EEG) pattern of periodic synchronous bi-or triphasic sharp wave complexes (PSWCs).
What is the treatment and prognosis for patients with sCJD?
There is no effective treatment for sCJD.
Median disease duration is 5-6 months. Death usually occurs with 1 year of symptom onset.
What is the epidemiology of sCJD?
- More common among the older population: median age of death is 68 years. Most deaths occur among persons 60-79 years of age
- Slight majority (52.6%) of sCJD cases occur in females
- Vast majority (94.6%) of deaths are among whites
What is variant Creutzfeld-Jacob disease?
- vCJD is a type 4 prion
- Represents bovine-human transmission of BSE
- In cattle, BSE is transmitted via CNS, retina, the trigeminal and paraspinal ganglia, the distal ileum, and the bone marrow
- Muscle and milk DO NOT contain infectious BSE
What are the signs and symptoms of vCJD?
- vCJD can have a similar clinical presentation as sCJD
- Loss of brain function associated with vCJD progresses slower than sCJD, although still very rapidly in comparison to Alzheimer’s disease (AD)
Mean duration of illness is 14 months for vCJD (vs. 4-5 months for sCJD)
- Peripheral pathogenesis distinct from classical forms of CJD, with prominent involvement of lymphoreticular tissues
- vCJD is fatal
How is vCJD diagnosed?
Overall, vCJD diagnosis is similar to sCJD; however, differential diagnosis from sCJD includes:
- Type 4 PrPsc found in patients with vCJD
- Tropism from lymphoid organs (e.g., tonsils)
- Different abnormal MRI signal and EEG
Mean age at onset of vCJD is 29 years (range 11 to 74 years) compared with 65 years for sCJD
How can vCJD be differentiated from sCJD?
Type 4 PrPsc is unique to vCJD
- Can be transmitted person-to-person by blood transfusion or ingestion of food contaminated with BSE
Considerably younger age of onset (29 versus 65 years of age)
Less rapid progression of illness (14 versus 5 months)
- vCJD has a peripheral pathogenesis
- Differences in neuropathology
How did the UK bring their BSE epidemic under control?
- Ban on animal feed that contained animal ruminants (1988)
- Ban on specific bovine offal (SBO): brain, spinal cord, thymus, spleen, and intestine (1991)
- BSE epidemic peaked in 1992
What are TSE precautions for healthcare workers?
- Employ universal precautions when handling blood and CSF
- Highest risk from brain, spinal cord, and eye tissues
- Scrupulously avoid contact with post-mortem tissues (don’t get it into cuts or scratches on your skin)
- All precautions should be followed during autopsy and embalming
What are sterilization procedures for prions?
- Prions are highly resistant to disinfectants, heat, UV radiation, ionizing radiation, and formalin
- Keep instruments moist after use since sterilization is not as effective on dried tissue
- Flash sterilization or low temperature methods for sterilization should not be used
- Sterilization options all include autoclaving
How are prions related to Alzheimer’s disease?