What is the cause of Creutzfeldt-Jakob disease (CJD)?

Causes of Creutzfeldt-Jakob Disease (CJD)

Creutzfeldt-Jakob disease is caused by abnormal prions, which are infectious proteins that misfold and accumulate in the brain, leading to progressive neurodegeneration and ultimately death. 1, 2

Types and Etiologies of CJD

CJD can be acquired through several distinct mechanisms:

1. Sporadic CJD (sCJD)

• Most common form (approximately 90% of cases) with an incidence of 1.5-2.0 per million person-years 1
• Believed to occur spontaneously through posttranslational conversion of normal prion protein (PrP^c) into pathological variant (PrP^Sc) 3
• No identifiable source of infection or genetic mutation
• Associated with polymorphism at codon 129 of the prion protein gene (PRNP) and molecular mass of PrP^Sc (glycotype 1 and 2) 1

2. Familial/Genetic CJD

• Inherited in an autosomal dominant pattern
• Caused by specific mutations in the PRNP gene
• Notable mutations include:
  • D178N mutation (as reported in the first kindred from South-East Asia) 4
  • Codon 200 mutations 3
• Homozygosity for these mutations increases disease manifestation risk 3

3. Acquired CJD

• Iatrogenic CJD: Transmitted through medical procedures including:

  • Corneal transplants from infected donors
  • Human growth hormone and gonadotropin from infected pituitary glands
  • Inadequately sterilized neurosurgical instruments (depth electrodes)
  • Contaminated dura mater grafts used in neurosurgical procedures 3

• Variant CJD (vCJD):

  • Caused by the same prion protein that causes Bovine Spongiform Encephalopathy (BSE) in cattle 1
  • Differs from sporadic CJD in that prion proteins are found not only in brain, spinal cord, and posterior eye, but also in lymph nodes, appendix, and tonsils 1

• Kuru:

  • Historically acquired through ritual cannibalism (no longer practiced) 3

Pathophysiology

• CJD belongs to a group of disorders called Transmissible Spongiform Encephalopathies (TSEs) 1
• The disease process involves:
  1. Conversion of normal cellular prion protein (PrP^c) to pathological scrapie prion protein (PrP^Sc)
  2. Accumulation of misfolded proteins in neurons
  3. Progressive neurodegeneration without typical inflammatory response 5
• Prion proteins become detectable in tissues during later incubation periods and reach higher concentrations once the disease manifests 1

Transmission Risks

• Prions are highly resistant to standard sterilization procedures
• Microscopic tissue traces on surgical instruments can remain infectious even after washing and autoclaving 1
• Successive washing reduces concentration of infectious material (after approximately 10 decontamination cycles, infectivity becomes negligible) 1
• Tissues with high infectivity include brain, spinal cord, and posterior eye (for sporadic CJD) 1
• Medium infectivity tissues include lymphoid tissue, including adenoid and tonsil (particularly for vCJD) 1
• Unproven transmission routes include blood transfusion, surgical sutures, tonometers, and consumption of certain animal organs 3

Diagnostic Considerations

• Definitive diagnosis requires neuropathological confirmation 1
• RT-QuIC testing of CSF has high specificity (near 100%) and sensitivity (73-97%) 2
• MRI with DWI and FLAIR sequences showing cortical ribboning and basal ganglia/thalamic hyperintensities 2
• CSF biomarkers include 14-3-3 protein and elevated total Tau protein 1, 2
• EEG may show characteristic periodic sharp-wave complexes (PSWCs) 2

CJD is universally fatal, with median survival of only 5 months after symptom onset, with most patients dying within one year of diagnosis 2.