What is the cause of Jakob-Creutzfeldt disease?

Cause of Creutzfeldt-Jakob Disease

Creutzfeldt-Jakob disease (CJD) is caused by misfolded prion proteins (PrPSc) that accumulate in the brain, leading to fatal neurodegeneration with characteristic spongiform changes in brain tissue. 1, 2

Pathophysiology of CJD

• The disease results from the abnormal misfolding of normal prion protein (PrPc) into pathological conformers called prions (PrPSc) that act as templates for further protein misfolding 2
• These misfolded prions accumulate in the brain, causing neuronal death and the characteristic spongiform changes seen in brain tissue 2
• The misfolded prion proteins are resistant to normal protein degradation mechanisms, allowing them to progressively accumulate 1
• The process leads to rapidly progressive neurodegeneration, resulting in fatal outcomes typically within months of symptom onset 1, 3

Types of CJD Based on Etiology

Sporadic CJD (sCJD)

• Most common form, accounting for approximately 90% of all CJD cases 1
• Occurs with an incidence of 1.5-2.0 cases per million person-years 1
• Associated with spontaneous misfolding of prion protein without any known triggering factor 1
• Different phenotypes are associated with Methionine/Valine (M/V) polymorphism at Codon 129 of the prion gene (PRNP) and with molecular mass of PrPSc (glycotype 1 and 2) 1

Genetic/Familial CJD

• Caused by autosomal dominant protein-altering variants in the PRNP gene located on chromosome 20p13 2
• Common pathogenic variants include E200K, P102L, D178N, and various octapeptide repeat insertions 2
• Other genetic prion diseases include Gerstmann-Sträussler-Scheinker syndrome (GSS) and fatal familial insomnia (FFI) 2

Acquired CJD

• Iatrogenic transmission through contaminated surgical instruments, cadaveric brain-derived products, and infected donor tissues (including dura mater and corneas) 4
• Variant CJD (vCJD) linked to consumption of bovine spongiform encephalopathy (BSE) contaminated beef products 5
• Transmission occurs through direct contact with infectious prion-containing tissue 4

Diagnostic Confirmation

• Real-time Quaking Induced Conversion (RT-QuIC) assay of CSF has revolutionized diagnosis with excellent sensitivity and specificity 1, 3
• Brain MRI with diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) sequences shows characteristic changes in gray matter structures 3
• CSF analysis for 14-3-3 protein and total Tau serves as supportive biomarkers 1, 3
• EEG may show characteristic periodic sharp wave complexes in later stages 3

Clinical Implications

• CJD is invariably fatal, with sporadic CJD having a median survival of approximately 5 months from symptom onset 3, 2
• Early symptoms can be non-specific and variable, making diagnosis challenging 6
• Common presentations include rapidly progressive dementia, cerebellar ataxia, myoclonus, and visual disturbances 1, 2
• Atypical presentations may include isolated visual symptoms, aphasia, or seizures, which can delay diagnosis 6

Important Considerations

• Stringent infection control measures are necessary when handling tissues or fluids from patients with suspected or confirmed CJD 4
• Brain, ocular, and central nervous system tissues are highly infectious and require special containment or incineration 4
• Genetic counseling should be offered to all families with a case of prion disease, regardless of apparent family history 2
• Currently, there are no effective disease-modifying treatments for CJD 1, 7