Transmissible spongiform encephalopathies (Prion diseases)

• Includes;
  • Creutzfeldt-Jakob disease
  • Gerstmann-Straussler-Scheinker syndrome
  • Fatal familial insomnia
  • Kuru
  • Scrapie (sheep and goats)
  • Bovine spongioform encephalopathy (BSE)
• All associated with abnormal forms of PrP (prion protein) and are both infectious and transmissible
• Predominantly associated with spongiform change – intracellular vacuoles in neurones and glia
• Clinically most of these patients develop progressive dementia
• Most common is CJD, sporadic form, accounts for 90%, has an incidence of 1 in 1000,000.
• Familial and transmitted forms make up the rest

 

Pathogenesis

 

• PrP is a normal cellular protein present in neurones
• Disease occurs when the normal a-helix-containing isoform undergoes a conformational change to form the abnormal b-pleated sheet isoform which is protease resistant
• PrP^res then facilitates the transformation of other PrP^c
• You can transmit the disease by inoculation with PrP^res
• A gene on chromosome 20 termed PRNP encodes for PrP^c and mutations are associated with disease
• Pathology is causes by PrP^res although how is not known

 

Morphology

 

• Progression of dementia in CJD is usually so rapid there is little evidence macroscopically of atrophy
• Microscopically there is spongiform transformation of the cerebral cortex and often in the basal ganglia – small, empty microscopic vacuoles within neurones
• In advanced cases there is severe neuronal loss, reactive gliosis and sometimes expansion of the spaces into cyst-like spaces
• No inflammatory infiltrate is present
• Kuru plaques are extracellular deposits of aggregated abnormal protein and are congo red as well as PAS positive

 

Creutzfeldt-Jakob Disease

• Rare, clinically develops into a rapidly progressive dementia
• 85% of cases are sporadic
• Peak incidence of disease in the 7^th decade
• Cases of iatrogenic transmission due to corneal transplantation, deep implantation electrodes and human derived growth hormone
• Initially there is subtle changes in memory and behaviour followed by rapidly progressive dementia
• There is often involuntary jerking muscle contractions on sudden stimulation – startle myoclonus
• Disease is fatal with an average duration of 7mth

 

Variant Creutzfeldt-Jacob Disease (vCJD)

• Affects young adults
• Behavioural disorders early in disease
• Neuropathy develops more slowly than other forms of CJD
• Pathologically characterised by extensive cortical plaques with a surrounding halo or spongiform change
• May be associated with BSE

 

Gerstmann-Straussler-Scheinker Syndrome

• Inherited disease with mutations of the PRNP gene
• Typically begins with chronic cerebellar ataxia followed by progressive dementia
• Clinical course is slower than CJD, progression to death takes several years
• As well as being associated with spongiform encephalopy, it is also associated with numerous plaques of PrP^res and neurofibrillary tangles

 

Fatal Familial Insomnia

• Named due to the sleep disturbances that characterise the initial stages
• In the course of the illness, which takes around 3 years, patients develop other neurological signs;
  • Ataxia
  • Autonomic disturbance
  • Stupor
  • Finally coma
• Pathologically does not show spongiform change
• Instead there is neuronal loss and gliosis in the anterior ventral and dorsomedial nuclei of the thalamus and the inferior olivary nuclei
• PrP^res is detectable