Prion Diseases

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Prion Diseases

• Garrett Preston Clark, D.O.

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What Are Prions?

• Small proteinaceous infectious particles which
  resist inactivation by procedures that modify
  nucleic acids
• Do not have a nucleic acid genome
• Also known as transmissible spongiform
  encephalopathies (TSEs)
• Progressive neurodegenerative disorders that
  affect both humans and animals

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What Are Prions?

• A prion is a modified form of a normal cellular
  protein known as PrPc.
• This protein is found predominantly on the
  surface of neurons attached by a glycoinositol
  phospholipid anchor.
• Thought to be involved in synaptic function.
• Modified form of PrPc i.e. the prion, known as
  PrPsc (for scrapie ? Sheep).

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What Are Prions?

• Normal (PrPc) is sensitive to proteases.
• PrPsc is resistant to proteases and accumulates
  in cytoplasmic vesicles of diseased individuals.
• Theory indicates that when prion proteins are
  introduced into a normal cell, PrPc converts to
  PrPsc.
• Exact process unknown
• Could involve a chemical or conformational
  modification.

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What Are Prions?

• Disease occurs when the normal protein structure
  in the a-helix isoform (PrPc), is changed to the
  abnormal ß-pleated sheet isoform. (PrPsc).
• In 1997, Dr. Stanley Prusiner was awarded the
  Nobel Prize in Physiology and Medicine for the
  discovery of Prions.

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Prion Disease
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Prion Disease
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Prion Disease

• Long incubation periods
• Associated with neuronal loss, and a failure to
  induce inflammatory response
• Able to induce abnormal folding of normal
  cellular proteins in the brain
• Usually rapidly progressive and fatal.

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Human Prion Diseases

1. Creutzfeldt-Jakob Disease (CJD)
2. Variant Creutzfeldt-Jakob Disease (vCJD)
3. Gerstmann-Straussler-Scheinker Syndrome
4. Fatal Familial Insomnia
5. Kuru

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Animal Prion Diseases

• Bovine Spongiform Encephalopathy (BSE)
• Chronic Wasting Disease (CWD)
• Scrapie
• Transmissible mink encephalopathy
• Feline spongiform encephalopathy
• Ungulate spongiform encephalopathy

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Characteristics

• Loss of motor control,
• Dementia
• Paralysis wasting
• Eventually death
• Post-mortem shows non-inflammatory lesions,
  vacuoles, amyloid protein deposits and
  astrogliosis (Hence, Spongiform)

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CreutzfeldtJakob Disease (CJD) Showing Spongiform
Change
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CreutzfeldtJakob Disease (CJD) Showing Spongiform
Change
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Infectivity

• Humans may be infected by prions in 2 ways
• Infection may be aquired
• Diet
• Surgery
• Growth hormone injections
• Corneal transplants
• OR Apparent inherited transmission where it is
  an autosomal dominant trait.

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Infectivity

• Prions may be ingested and absorbed across the
  gut wall at Peyers patches.
• They may be absorbed through the mucosal
  associated lymphoid tissue (MALT) mechanism.
• Lymphoid cells phagocytise the prion.
• Travel to other lymphoid sites (nodes, spleen,
  etc.) where the prion can replicate

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Infectivity

• Many of these sites are innervated.
• Eventually the prion gains access to a nerve.
• Propagation up the axon to the spinal cord
• Eventually leads to brain infectivity.

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CreutzfeldtJakob Disease (CJD)

• Is a human prion disease
• Neurodegenerative disorder
• Is rapidly progressive and always fatal
• Infection leads to death usually within 1 year of
  onset of illness.

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CreutzfeldtJakob Disease (CJD)

• CJD is not related to BSE".
• Classic CJD is distinct from "variant CJD
• Variant CJD, is related to Bovine Spongiform
  Encephalopathy (BSE).

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CreutzfeldtJakob Disease (CJD)

• Classic CJD has been recognized since the early
  1920s.
• Sporadic disease occurs worldwide, including the
  United States
• Rate of approximately one case per 1 million
  population per year
• Risk increases with age and in persons over 50
  years of age.

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CreutzfeldtJakob Disease (CJD)

• Approximately 85 of cases of CJD occur as
  sporadic disease.
• 5-15 develop CJD because of inherited mutations
  of the prion protein gene.
• These inherited forms include Gerstmann-Straussler
  -Scheinker syndrome and fatal familial insomnia.

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CreutzfeldtJakob Disease (CJD)

• Median age at death is 68 years
• Median duration of illness 4-5 months
• Clinical signs and symptoms of dementia and early
  neurological signs
• Initial subtle changes in memory
• Behavior changes
• Rapidly progressive dementia
• And

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STARTLE MYOCLONUS !!!!
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Variant CJD (vCJD)

• First described in 1996 in the United Kingdom.
• Different clinical and pathologic characteristics
  from classic CJD
• Median age at death for vCJD patients is 28
  years.
• Median duration of illness for vCJD is 14 months,
  compared to 5 months for classic CJD.

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Variant CJD (vCJD)

• Strong scientific evidence that the agent
  responsible for outbreak of prion disease in
  cows, BSE, is the same agent responsible for the
  outbreak of vCJD in humans
• Both disorders are fatal brain diseases with
  unusually long incubation periods measured in
  years.

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Variant CJD (vCJD)

• "Pulvinar sign" on MRI
• This is an abnormal signal in the posterior
  thalami on T2- and diffusion-weighted images and
  fluid-attenuated inversion recovery sequences on
  brain MRI.
• In the right clinical context, this signal is
  highly specific for vCJD but absent in CJD.

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Pulvinar Sign
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Pulvinar Sign
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BSE (bovine spongiform encephalopathy)

• Progressive neurological disorder of cattle
• Results from infection by a prion.
• Two cases of BSE identified in 1986
• Possibly originated as a result of feeding cattle
  meat-and-bone meal that contained
  scrapie-infected sheep products.
• Scrapie prion disease of sheep

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Also Known As
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BSE (bovine spongiform encephalopathy)

• BSE epidemic in the United Kingdom peaked in
  January 1993 at almost 1,000 new cases per week.
• Through the end of 2005 more than 184,000 cases
  of BSE had been confirmed in the United Kingdom
  alone in more than 35,000 herds.

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BSE (bovine spongiform encephalopathy)

• As of August 23, twelve cases of BSE have been
  identified in North America.
• Of these twelve cases, three were identified in
  the U.S. and nine in Canada.
• The first known case of BSE in the United States
  was identified in December 2003
• Preliminary trace-back suggested that the
  BSE-infected cow was imported into the United
  States from Canada in August 2001.

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BSE (bovine spongiform encephalopathy)
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KURU

• Nicknamed the laughing death
• Exotic disease confined pretty much to the Fore
  tribe of New Guinea
• Custom of eating the brains of dead relatives?
  promoted transmission of disease-causing prions
• Cannibalism ban significantly reduced the
  incidence of Kuru.

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KURU

• Kuru prion infects nerve cells, results in
• Craziness
• Dementia
• Loss of coordination
• Other neurological symptoms develop

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Fatal Familial Insomnia (FFI)

• First associated with a prion in 1992
• Is familial, as its name implies
• Causes sleep disturbance, motor and emotional
  problems, and eventually death
• Patients have a specific mutation in the prion
  gene

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Gerstmann-Straussler-Scheinker Syndrome (GSSS)

• Linked to two mutations in the prion gene in 1989
• PrPSC fragments accumulate in the brain in plaque
  structures.
• Similar plaques develop in Alzheimers disease,
  but they are composed of fragments of a different
  protein

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Scrapie

• Scrapie recognized in sheep and goats for more
  than 250 years.
• In 1982, it was first identified as a prion
  disease.

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Chronic Wasting Disease (CWD)

• Transmissible neurological disease of deer and
  elk
• Characterized by
• Loss of body condition
• Behavioral abnormalities
• Eventually death.
• Is classified as a transmissible spongiform
  encephalopathy (TSE) and is similar to mad cow
  disease in cattle and scrapie in sheep.

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TREATMENTS?

• All prion diseases are fatal no effective
  treatment !
• Tx currently symptomatic
• Medical Care
• Discontinue any medication that could impair
  memory or cause confusion.
• A number of potential therapeutic interventions
  are currently under development.

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Some Tx Possibilities

• Congo red and its analogs
• Anthracyclines
• Amphotericin B and its analogs
• Sulfated polyanions
• Tetrapyrroles
• All have limitations in terms of toxic effects
  and/or unfavorable pharmacokinetic properties.
• Amphotericin B failed to ameliorate CJD in a
  single patient.

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TREATMENTS

• Consultations
• Neurologist
• Infectious disease specialist

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QUESTIONS ! ! !

• 1) Pulvinar sign on brain MRI is indicative of
  which of the following prion diseases
• CJD
• vCJD
• Kuru
• BSE
• FFI

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QUESTIONS ! ! !

• 1) Pulvinar sign on brain MRI is indicative of
  which of the following prion diseases
• CJD
• vCJD
• Kuru
• BSE
• FFI

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QUESTIONS ! ! !

• 2) Which of the following disease states is most
  closely associated with startle myoclonus
• CJD
• vCJD
• Kuru
• BSE
• FFI

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QUESTIONS ! ! !

• 2) Which of the following disease states is most
  closely associated with startle myoclonus
• CJD
• vCJD
• Kuru
• BSE
• FFI

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QUESTIONS ! ! !

• 3) Which of the following prion diseases has the
  well known namesake of Mad Cow Disease
• CJD
• vCJD
• Kuru
• BSE
• FFI

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QUESTIONS ! ! !

• 3) Which of the following prion diseases has the
  well known namesake of Mad Cow Disease
• CJD
• vCJD
• Kuru
• BSE
• FFI