Human Spongiform Encephalopathies

Prion diseases belong to a group of related diseases known as the transmissible spongiform encephalopathies (TSEs). The causative agents of these diseases are thought to have very similar characteristics. All cause fatal spongiform changes in the brain.

The neuropathology of the human TSEs is characteristic:

1. neuronal cell death
2. spongiform changes of the brain (invariably present)
3. gliosis
4. astrocytosis
5. but no inflammatory responses
6. amyloid plaques are not always observed; the plaques contain the protease resistant core of PrPSc
7. usually many brain regions are affected

Human prion infection transmission occurs via three routes:

1. Acquired by ingestion (ex., Kuru and human vCJD: similar to the mode of BSE transmission)
2. Acquired by an iatrogenic route (surgery, growth hormone injection, corneal transplant)
3. Hereditary transmission as an autosomal, dominant trait (familial TSEs)

click on figure for 26k version describing and showing PrP mutations associated with human TSE's; CJD, GSSD, FFI

for a comparison of different human TSE presented in Tabular format

click on the figure to learn about the location of lesions in the human brain

click of the figure to learn a little about the functions of the human brain

Creutzfeldt-Jakob disease (CJD)

CJD is the most common clinicopathological subtype of human TSE. CJD was first described in 1920. It occurs in inherited, acquired and sporadic forms.

• The inherited forms, including familial CJD, are autosomal dominant disorders associated with coding mutations in the prion protein gene.
• Acquired prion diseases include iatrogenic CJD (acquired from human cadaver-derived growth hormone) and kuru (transmitted by cannibalistic funeral rituals).
• The remaining 85% of human prion disease occurs as a randomly distributed illness of unknown cause (sporadic CJD).

Classically, sporadic CJD occurs in those >65 years of age. Sporadic CJD presents as rapidly progressive dementia with myoclonus (shock-like contractions of isolated muscles), characteristic EEG (pseudoperiodic sharp complexes), and progress via loss of movement sensation (akinetic mutisim) to death in less than 6 months (once clinical symptoms become evident).

Characteristic EEG changes occur in 60-70% of patients (triphasic spike signal at 1 cycle/sec).
Death commonly follows hypostatic pneumonia.
In the 1960's, CJD was shown to be transmissible in the laboratory.
Iatrogenic CJD has been recognized for the last 30 years.

Some 8 polymorphisms in the PrP gene have been associated with familial CJD in different families.
In contrast to Scrapie in sheep, familial CJD is inherited in an autosomal dominant fashion .

CJD

Variant CJD, linked to BSE, was described in 1996.
A description of the vCJD symptoms and contact information for the United Kingdom, National Creutzfeldt-Jakob Disease Surveillance Unit are available through the British Medical Journal

The incidence of CJD is 1/1,000,000 population (at any one point in time). This translates into a lifetime risk: 1/10,000.

The duration of CJD, once clinical signs become evident, ranges from 1-11 years

Clinical signs of CJD and GSSD vary depending on the strain and time of onset but may include:

• early
  • depression, tiredness, sleep disturbances, abnormal sweating and appetiti, weight loss, diarrhea and headaches
• later signs
  • myoclonus - convulsive action of the muscles
  • dizziness
  • tremors - involuntary movement of the body or limbs
  • dysarthria - defective speaking
  • ataxia - confusion, disorderliness
  • pyramidal signs
  • dysarthria
  • Parkinsonism
  • presenile dementia
  • late stage dementia - failure or loss of the mental powers
  • death

Gerstmann-Straussier-Scheinker syndrome and Fatal Familial Insomnia

GSS was described in 1936. In the early 1960's GSS was known to be familial (inherited); the gene was not described but it was known to be autosomal and dominant. FFI was described in 1986.

The incidence of GSS is about 2% that of the rate of CJD.
GSS is differentiated from CJD in that it occurs in the 40s or 50s, and is characterized by cerebellar ataxia and motor problems. Dementia is less common than with CJD.

The disease course once clinical symptoms are evident is several years (1 to 12). GSS occurs in both familial and sporadic forms.

GSS diagnosis is confirmed by histopathological examination of the brain postmortem. Characteristics include non-inflammatory lesions, vacuoles, amyloid protein deposits, and astrogliosis.

FFI is characterized by severe selective atrophy of the thalamus.

 

Kuru Kuru was described and intensively studied in the 1950s after it was identified in isolated tribes in the Fore highlands of Papua, New Guinea restricted to the Okapa area. The tribe practiced cannabalism, especially women and children. The brain tissue of dead tribesmen were ground into a pale grey soup, heated and eaten, thus transmitting and propagating the disease. The similarities between human kuru and sheep scrapie (both transmissible and naturally infectious TSEs) was recognized in the early 1960's. Clinical signs of this pure human cerebellar syndrome include: headaches and limb pains cerebellar ataxia titubation - staggering astasia - inability to stand behavioral changes tremors - involuntary movement of the body or limbs dysarthria - defective speaking death The clinical course in adults ranged from 12 to 18 months and in children from 3 to 12 months. There was no evidence of vertical transmission (example: from mother to baby by breastfeeding) Investigations of Kuru were the first to demonstrate that TSEs can be transmitted orally.