What causes Creutzfeldt-Jakob disease (CJD) or mad cow disease?

What Causes Creutzfeldt-Jakob Disease (CJD) and Mad Cow Disease

CJD is caused by the accumulation of misfolded prion proteins (PrPSc) in the brain, which arise through three distinct mechanisms: spontaneous misfolding in sporadic CJD (85% of cases), inherited genetic mutations in familial CJD (10-15% of cases), or external transmission through contaminated beef products in variant CJD (mad cow disease) or medical procedures in iatrogenic CJD. 1

Sporadic CJD (Most Common Form)

Sporadic CJD occurs when normal cellular prion protein (PrPc) spontaneously converts into the pathological misfolded form (PrPSc) without any identifiable genetic or environmental trigger. 1

• This represents approximately 85% of all CJD cases with an annual incidence of 1-2 cases per million population. 2
• The spontaneous posttranslational conversion happens without external exposure or inherited mutations. 3
• Peak age of onset is 55-75 years with median survival of approximately 5 months. 2
• The disease phenotype varies based on methionine/valine polymorphism at codon 129 of the prion gene and the molecular mass of PrPSc. 1

Variant CJD (Mad Cow Disease in Humans)

Variant CJD is caused by transmission of the bovine spongiform encephalopathy (BSE) prion agent from cattle to humans through dietary contamination with BSE-infected beef products. 4, 1

• BSE in cattle resulted from feeding livestock meat and bone meal (MBM) contaminated with BSE prions—essentially industrial cannibalism in cattle. 5, 6
• The BSE outbreak in the United Kingdom began in 1986 when faulty industrial practices produced prion-contaminated cattle feed. 5, 7
• Variant CJD affects younger individuals (children and young adults) compared to sporadic CJD. 4, 8
• Critical distinction: vCJD prion protein extends to lymph nodes, appendix, and tonsils, making it potentially transmissible through medical and surgical interventions involving lymphoid tissue, whereas sporadic CJD prion protein is confined to brain, spinal cord, and posterior eye. 4, 1

Familial/Genetic CJD

Familial CJD results from autosomal dominant gain-of-function mutations in the prion protein gene (PRNP), with the E200K mutation being one of the most common pathogenic variants. 1

• Approximately 10-15% of CJD cases are genetic, following autosomal dominant inheritance. 1
• Homozygosity for these mutations increases the likelihood of manifesting the disease. 3
• Phenotypic variability can obscure family history, making PRNP gene sequencing essential for all suspected CJD cases regardless of apparent family history. 1

Iatrogenic CJD (Medical Transmission)

Iatrogenic CJD results from accidental transmission through contaminated medical procedures, including neurosurgical instruments, dura mater grafts, and pituitary extracts. 4

Specific Transmission Routes:

• Contaminated dura mater grafts: 132 cases in Japan linked to a single brand (Lyodura) produced before May 1987, with incubation periods possibly exceeding 24.8 years. 9
• Human growth hormone and gonadotropin: Prepared from infected human pituitary glands. 3
• Neurosurgical instruments: Microscopic tissue traces remain on surgical instruments after standard washing and autoclaving, and prion proteins in these traces can transmit disease if inoculated into another patient. 4
• Depth electrodes: Inadequately sterilized electrodes used in epilepsy workups. 3
• Corneal transplants: From infected donors. 3

Critical Sterilization Issue:

Standard autoclaving and disinfection do not reliably eliminate prion infectivity from surgical instruments; approximately 10 successive decontamination cycles are required to reduce infectivity to negligible levels. 4, 8, 1

Pathophysiological Mechanism

Once formed, misfolded PrPSc acts as a template for conformational conversion of additional normal PrPc molecules, creating a self-propagating cascade that leads to neuronal death and characteristic spongiform changes in brain tissue. 1

• The abnormal misfolding of normal prion protein (PrPc) into pathological conformers (PrPSc) causes progressive neurodegeneration with characteristic spongiform changes. 4
• This process results in widespread cerebral hypometabolism, histopathological astrocytosis, neuronal death, and spongiform changes. 2
• The accumulation of PrPSc causes progressive neurodegeneration with pathognomonic spongiform change, and in some cases, plaque formation. 1

Common Pitfalls to Avoid

• Do not assume negative family history rules out genetic CJD: Phenotypic variability and delayed diagnosis can obscure family history; PRNP gene sequencing is essential for all suspected cases. 1
• Do not rely on standard sterilization for prion-contaminated instruments: Prions are extraordinarily resistant to conventional decontamination methods. 8
• Do not overlook the extended incubation period: Iatrogenic CJD can manifest more than 24 years after exposure to contaminated medical materials. 9
• Recognize age differences: Variant CJD affects younger patients (children and young adults) while sporadic CJD typically affects those aged 55-75 years. 2, 8