Prion

Diseases
Dinusha Yagama De Silva
Group 11
Semester 7
 introduction

• Prion disease is a neurogenerative disease which is characterized by rapidly

progressive loss of groups of neurons.
• It is caused by aggregation & intercellular spread of misfolded prion
protein (PrPsc).
• These types of neurogenerative disease of accumulation of protein
aggregates are called proteinopathy.
• These disease can be due to mutations in the DNA/ proteins or
environmental or stochastic factors.
• Disease onset usually occurs between the ages of 35 and 55 or later.
 Prion diseases

• Creutzfeldt- Jakob disease (CJD) • Bovine Spongiform Encephalopathy

(BSE)
• Variant Creutzfeldt- Jakob disease
(vCJD) • Chronic wasting Disease (CWD)

• Gerstmann- Straussler- Schenker • Scrapie

Syndrome • Transmissible mink encephalopathy
• Fatal Familial Insomnia • Feline spongiform encephalopathy
• Kuru • Ungulate spongiform
encephalopathy
Normal prion protein
𝑪
(𝑷𝒓𝑷 )
• Protein mainly found in cell
membranes of neurons
• Made with 𝜶- helices
• Function: unknown
• But, suspected to be role in synapses
between neurons in uptake of Copper
into cell, antioxidant activity & prevent
neuronal dysfunction.
 Mechanism of
Prion Disease

• 𝜶- helix undergo
conformational change
into 𝜷- pleated sheet.
• Act as template for
chain reaction.
• Amyloid fibers 𝑃𝑟𝑃𝐶 𝑃𝑟𝑃 𝑆𝑐
Mechanism of Prion Disease
 𝑪 𝑺𝒄
𝑷𝒓𝑷 versus 𝑷𝒓𝑷

Property 𝑃𝑟𝑃𝐶 𝑃𝑟𝑃 𝑆𝑐

Solubility Soluble Non- soluble

Susceptibility to Susceptible Resistant

Proteinase K

Structure Monomer Aggregate/ multimeric

Infectivity Non- infectious Infectious

Pathogenesis

• 𝜶- helix containing isoforms of PrPc undergo conformational

change to 𝜷- pleated sheet isoform which accumulate in
neurons.
• These PrPsc aggregate and form cytoplasmic vacuoles in
neurons.
• This vacuolization in neurons results in neuronal loss/death.
• The exact mechanism of vacuolization in neurons is still
unknown.
• Microscopically, results in accumulation of PrPsc causes
vacuolization in gray mater, giving spongy appearance
histologically.
• Macroscopically results in brain atrophy.
Transmissible Spongiform
Encephalopathy (TSE)

• Varying sized cysts form due to

apoptosis of neurons.
• Gives the brain its spongy appearance.
• These vacuoles are membrane bound
and in advanced cases can fuse to form
cyst like large spaces called status
spongiosus.
Transmissible
Spongiform
Encephalopathy
(TSE)
• Cortical Ribboning
Transmission

• Mainly occur in 3 ways:

1. Sporadic
2. Genetic
3. Acquired
 Creutzfeldt- Jakob Disease (CJD)

• Most common spongiform encephalopathy in humans.

• Main types of CJD:
1. Familial CDJ (fCJD)
2. Variant CJD (vCJD)
3. Iatrogenic (iCJD)
4. Sporadic (sCJD)
• Cause spongiform encephalopathy of any part of cerebral
cortex, cerebellum and/or thalamus.
Familial Creutzfeldt- Jakob Disease
(fCJD)

• Mutation in PRNP gene at the 200th position.

• Rarest form of CJD .
• Regardless of the nature of inheritance, onset is in
adulthood.
• Results in rapidly progressive dementia, startle myoclonus.
 Variant Creutzfeldt- Jakob Disease
(vCJD)

• Consuming of infected cattle

• Ex) meat from a cow that had Bovine Spongiform
encephalopathy (“mad cow disease”).
• Can be transmitted to other humans through blood
transfusion (preclinical stage).
Iatrogenic Creutzfeldt- Jakob Disease (iCJD)

• Accidently spread by someone with

CJD via contaminated medical
equipment in medical procedures.
• Most commonly by contaminated
corneal transplant.
• This form is much rarer nowadays due
to improved hygiene techniques.
 Sporadic Creutzfeldt- Jakob Disease
(sCJD)

• Most common form of CJD (>85%).

• No clear cause.
• Some research suggest it could be due to spontaneous
point mutation in 129th position in PRNP gene.
• Starts as subtle changes in memory and behaviour.
 Kuru

• Prevalent in a tribe in New Guinea.

• Cannibalism of infected flesh as a sign of
respect to their dead relatives.
• Death of 3000 out of 11,000.
• Famously known for its “uncontrollable
laughter”.
• Kuru | Debunking A Rare Prion Disease –
YouTube
(https://www.youtube.com/watch?v=iKfcvnIuL3
Q)
 Fatal familial insomnia

• It is progressively worsening insomnia — an inability to sleep.

• It worsens to the point that it severely impacts daily
functioning, eventually causing coma and then death.
• Mutation in PRNP gene at 178th position (autosomal
dominant mutation).
• Large buildup in thalamus.
 Symptoms of CJD’s

• 1/3 presented with fatigue, sleep disturbances/problems,

reduced appetite.
• 1/3 have neurological problems such as memory loss,
behavioural changes & confusion.
• 1/3 have focal signs like cerebellar ataxia, aphasia, visual
disturbances & early unilateral motor weakness (and later
bilateral motor weakness).
 Symptoms of CJD’s

• Ataxia
• Poor memory
• Behavioural & personality changes
• Muscle weakness
• Myoclonus
• Dementia
• Insomnia
• Exaggerated startle response
• Hallucinations
 Diagnosis

• Lumbar puncture to analyze CSF and rule out infections.

• High level of 14-3-3 protein associate with acute neuronal injury.
• MRI
• Pulvinar sign: Bilateral FLAIR hyperintensities involving the pulvinar
thalamic nuclei.
• Hockey stick sign: Hyperintense signal involving the pulvinar and
dorsomedial thalamic nuclei bilaterally.
• Definitive diagnosis is with a brain biopsy (post-mortem/autopsy).
 Diagnosis – MRI

Normal Pulvinar sign Hockey stick sign

 Prevention

• No known treatment yet hence prevention is

the best solution.
• Properly cleaning and sterilizing medical
equipment.
• Screening for CJD for organ, tissue, or blood
transfusions.
• Newer regulations that govern the handling
and feeding of cows.
 Management

• Supportive care to patients and their

relatives/family.
• Antidepressants and/or psychological
assistance to help with anxiety and depression.
• Painkillers to relieve pain.
Clinical case

• 77-year-old female with a history of deterioration in her

memory, unsteady gait and jerking right arm.
• History of an NSTEMI, hypertension, aortic regurgitation and
diverticular disease.
• Initial memory test by the GP was normal and with a history of
ongoing family stress a diagnosis of depression was made.
• Complaints of double vision occurred, and an urgent
referral was made to neurology and CT of the brain.
 Clinical case

• CT brain with contrast did not show any abnormality.

• Reviewed again by the GP and at this stage her gait was so poor
that she was “bum shuffling”.
• Refused MRI due to concerns of claustrophobia and she was
admitted to a ward to see the Parkinson’s disease specialist.
• Neurological assessment by the consultant identified bilateral
tremor in upper limbs, full eye movements, reflexes
exaggerated bilaterally in lower limbs, myoclonic jerking of
lower limbs, dysphasia and dysphagia.
Clinical case

• Subtle gyriform area of cortical

restricted diffusion involving
the left temporal parietal
occipital lobe with
corresponding subtle T2 and
FLAIR hyperintensity.
• The report suggested that this
was more likely of
inflammatory etiology such as
encephalitis.
 Clinical case

• Suggested LP and urgent neurological opinion.

• Presentation, MRI and CSF findings concluded a diagnosis of probable
sCJD (>95% probability).
• The team advised the patient she had days to weeks to live and for
palliative care.
• Three days later the patient was unable to swallow her saliva and was
commenced on a syringe driver, being nursed on her side to aid
drainage of saliva and requiring suction for comfort.
• The following day the patient passed away. The time from onset of
symptoms to death was 66 days.
References

• Google images

• US National Library of Medicine (NCBI), National Institutes of Health (NIH)

• Diagnosing Variant Creutzfeldt-Jakob Disease with the Pulvinar Sign: MR Imaging Findings in 86 Neuropathologically Confirmed Cases |
American Journal of Neuroradiology (ajnr.org)

• Pulvinar sign (CNS) | Radiology Reference Article | Radiopaedia.org

• https://www.cdc.gov/prions/index.html

• Creutzfeldt-Jakob disease: a case study (gmjournal.co.uk)

• Creutzfeldt-Jakob disease - NHS (www.nhs.uk)

• The longest survivor of Creutzfeldt–Jakob disease with V180I mutation - Ryoo - 2021 - Alzheimer's & Dementia - Wiley Online Library

• Creutzfeldt-Jakob Disease | Symptoms, Causes & Treatment | Your Dementia Therapist

• https://my.clevelandclinic.org/health/diseases/15718-amyloidosis-al-amyloid-light-chain

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4626585/

• Fatal Familial Insomnia: What It Is, Symptoms, and Treatment Options (webmd.com)

• Prion Diseases | Johns Hopkins Medicine

Thank you