Transmissible spongiform encephalopathies are diseases caused by prions. Prions differ from viruses in that they are infectious proteins that do not contain a nucleoid. Recognized spongiform encephalopathies include Creutzfeldt-Jakob Disease (CJD), Kuru, fatal familial insomnia (FFI), and Gerstmann-Straussler syndrome (GSS). Common characteristics of these diseases include dementia, ataxia, and myoclonus. Unfortunately, these diseases are associated with long incubation periods (20+ years) and once symptoms occur, rapidly progress to death.

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Image: Magnified 100X, and stained with H&E (hematoxylin and eosin) staining technique, this light photomicrograph of brain tissue reveals the presence of prominent spongiotic changes in the cortex, and loss of neurons in a case of variant Creutzfeldt-Jakob disease (vCJD). by Sherif Zaki, Wun-Ju ShiehAuto. License: Public Domain


Epidemiology and Etiology

Epidemiology

Overall, spongiform encephalopathies are extremely rare.

  • Known human diseases:
    • Creutzfeldt-Jakob Disease (CJD)
    • Kuru
    • Fatal familial insomnia (FFI)
    • Gerstmann-Straussler syndrome (GSS)
      • Incidence: 1 in 100 millions new cases/year

The most common spongiform encephalopathy is Creutzfeldt-Jakob disease.

    • Several variations exist: sporadic (sCJD), genetic (gCJD), iatrogenic (iCJD), and variant (vCJD)
      • Sporadic: mean age of onset is 62 years old
      • Variant and iatrogenic: younger age of onset (not clearly defined)
      • Genetic: clusters exist in North Africa, Israel, and Italy
    • 90% of cases are sporadic Creutzfeldt-Jakob disease (sCJD)
      • Incidence: 1 per 1,000,000 cases/year

Etiology

  • High-risk factors:
    • Cannibalism (Kuru)
    • Family history of gCJD, GSS, or FFI
TSE

“TSEs are caused by misfolding of prions. Pathogenic prion, PrPsc, is a conformation isoform of a normal host protein, PrPc” Image by Lecturio

Prions are usually located at the outer surfaces of neurons. When the PrPsc (abnormal protein) is acquired in the organism, it will approach the mucosal surface of the intestine and cause normal prion proteins to convert into pathogenic form. Image by Lecturio.

Video Gallery

Transmissible Spongiform Encephalopathy (TSEs) of Humans by Vincent Racaniello, PhD

Pathophysiology

Prion diseases occur when a normal, ⍺-helical protein known as PrPc is converted into an abnormal, β-pleated protein known as PrPsc. 

  • Can be thought of as a “protein-misfolding” disease
  • Abnormal PrPsc is resistant to protease degradation which facilitates conversion of PrPc into abnormal PrPsc. This constant conversion slowly replaces normal proteins.
  • PrPsc accumulates in lymphoreticular and secretory organs
    • Spreads to the CNS → astrocytosis → loss of neurons → vacuolation of the brain 
    • This process causes the classic symptoms of spongiform encephalopathy:
      • Cerebellar ataxia
      • Dementia
      • Death
Mad cow disease or bovine spongiform encephalopathy BSE

Image: “Section of brain from a cow infected with bovine spongiform encephalopathy. The brown staining indicates the presence of the agent causing the disease.” By CSIRO. License: CC BY 3.0

Transmission
Three primary ways of developing spongiform encephalopathies:

  1. Acquired or infectious:  acquire PrPsc from direct contact
    • Exposure to CNS-infected tissues, such as in a corneal transplant (iCJD)
    • Administration of cadaveric human pituitary hormones (iCJD)
    • Ingestion of food contaminated by BSE-infected (“mad cow”) animal products (vCJD)
    • Cannibalism of CNS-infected tissues (Kuru)
  2. Genetics:
    • Mutation from parental PrPc into abnormal PrPsc (gCJD, FFI, GSS)
  3. Spontaneous: 
    • Sudden misfolding of PrPc into abnormal PrPsc (sCJD)

Origins of prion diseases. Image by Lecturio.

Video Gallery

Pathogenesis – TSEs by Vincent Racaniello, PhD
Prion Protein – TSEs by Vincent Racaniello, PhD

Clinical Presentation and Diagnostics

Unfortunately, transmissible spongiform encephalopathies are associated with extremely long incubation time (20–50 years) and once symptoms appear, the disease rapidly progresses to death.

 

Symptoms Diagnosis
Creutzfeldt-Jakob disease Rapidly progressive dementia

  • Over weeks to months

Startle myoclonus

AtaxiaDeath within 1 year of symptom onset.

Head CT/MRI: normal appearance

CSF: ↑ in 14-3-3 protein

EEG: periodic sharp wave complexes

Post-mortem brain biopsy: intracytoplasmic vacuoles in the spongiform cortex, accumulation of PrPsc on histopathology, neuronal loss

Kuru First stage: tremors (shivering), ataxia, postural instability

Second stage: loss of ambulation, myoclonus

Late-stage: dementia

Death within 1 year of symptom onset.

Unknown, few studies have been performed due to limited cases

(mostly isolated to Papua New Guinea in the 1950s)

Fatal Familial Insomnia In patients aged 23–73:

Progressive insomnia 

Loss of normal circadian sleep-activity pattern

Myoclonus

Ataxia

Dysautonomia

Death within 1 year of symptom onset.

Unclear, post-mortem brain biopsy
Gerstmann-Straussler-Scheinker syndrome In patients mid/late 40s: 

Progressive cerebellar degeneration

  • Clumsiness, incoordination, ataxia

Dementia

Death within 5 years of symptom onset.

Post-mortem brain biopsy

Management

  • Unfortunately, no curative measures exist and the diseases are universally fatal.

Clinical Relevance

Differential diagnosis includes disease that are associated with rapidly progressing dementia including.

  • Dementia with Lewy bodies:
    • Can be rapidly progressing
    • Associated with dementia, visual hallucinations, and syncope
    • Histologic findings: intracellular Lewy bodies (⍺-synuclein)
  • Frontotemporal dementia (Pick disease):
    • Associated with early changes in personality and behavior that progress to parkinsonism-like movement
    • MRI: frontotemporal lobe degeneration
  • Vascular dementia:
    • Generally stepwise decline in neurological function with late-onset memory impairment
    • MRI: multiple cortical infarctions
  • Alzheimer disease:
    • Most common cause of dementia in the elderly
    • Symptoms often develop gradually
    • MRI: cortical and hippocampal atrophy
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