2-35 Prions

Question 1

What are the five prion diseases found in humans?

Answer 1

1. Kuru
2. Fatal familial insomnia (FFI)
3. Gerstmann-Staussler-Scheinker syndrome
4. Variant Creutzfeldt-Jacob disease (vCJD)
5. Creutzfeldt-Jacob disease (CJD)

Question 2

What is Creutzfeldt-Jacob disease?

Answer 2

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.”

Question 3

What are the signs and symptoms of sCJD?

Answer 3

• 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

Mental Deterioration:

• 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

Myoclonus:

• Provoked by startle
• Present in >90% of patients at some point during the illness
• May be absent at presentation, despite the presence of dementia

Question 4

What evidence led to the protein-only hypothesis?

Answer 4

• 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

Question 5

With regard to prion diseases, what causes encephalopathy?

Answer 5

PrP^c misfolding causes encephalopathy: protein misfolding → PrP^c converted to PrP^sc (Scrapie form) → prion disease

The mechanism of PrP^sc pathogenesis is unknown: it can arise by mutation, from exogenous sources (meat, blood, etc.), or via experimental transmission between animals. Animals lacking PrP^c, however, do not contract prion disease.

Question 6

What are the normal functions of Prp^c?

Answer 6

PrP^c, the cellular form, is involved in:

• Maintaining the brain’s white matter
• Regulating innate immune cells
• Responses to oxidative stress
• Neuron formation

Question 7

How many types of PrP^sc have been classified?

Answer 7

4 types of human PrP^sc have been identified, based on the ratio of PrP bands seen on Western blots after treatment with proteinase K.

Each PrP^sc type is associated with different phenotypes of CJD.

Question 8

How do prions self-replicate?

Answer 8

• Prions are infectious, but contain no genetic material
• After PrP^c (native) → PrP^sc (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

Question 9

How is sCJD diagnosed?

Answer 9

Brain biopsy remains the gold standard and only definitive diagnostic test for all forms of CJD. sCJD is characterized by:

• Accumulation of PrP^sc
• 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).

Question 10

What is the treatment and prognosis for patients with sCJD?

Answer 10

There is no effective treatment for sCJD.

Median disease duration is 5-6 months. Death usually occurs with 1 year of symptom onset.

Question 11

What is the epidemiology of sCJD?

Answer 11

• 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

Question 12

What is variant Creutzfeld-Jacob disease?

Answer 12

• 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

Question 13

What are the signs and symptoms of vCJD?

Answer 13

• 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

Question 14

How is vCJD diagnosed?

Answer 14

Overall, vCJD diagnosis is similar to sCJD; however, differential diagnosis from sCJD includes:

• Type 4 PrP^sc 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

Question 15

How can vCJD be differentiated from sCJD?

Answer 15

• 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

Question 16

How did the UK bring their BSE epidemic under control?

Answer 16

• 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

Question 17

What are TSE precautions for healthcare workers?

Answer 17

• 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

Question 18

What are sterilization procedures for prions?

Answer 18

• 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

Question 19

How are prions related to Alzheimer’s disease?

Answer 19

• AD is a form of progressive dementia, which usually begins after the age of 60 (1 in 10 people over 65 are affected by AD)
• Polymorphism in the Prnp gene is a risk factor for AD
• PrP^c binds to amyloid-β (Aβ) peptides → Aβ misfolds → amyloid plaques form → AD develops
• Mice injected with brain tissue from AD patients will develop disease, so is misfolded amyloid-β a “prion”? Is AD an infectious disease???