What is prion disease?

Prion Disease: A Rare and Fatal Neurodegenerative Disorder

Prion disease is a rare, fatal neurodegenerative disorder caused by the misfolding of prion proteins in the brain, leading to rapid cognitive decline with an invariably fatal outcome and no effective treatments currently available. 1

Definition and Pathophysiology

Prion diseases are characterized by:

• Abnormal misfolding of the normal prion protein (PrP or PrPc) into pathological conformers called prions (PrPSc) that act as templates for further protein misfolding 1
• Accumulation of these misfolded proteins in the brain causing neurodegeneration with characteristic spongiform changes in brain tissue 1
• Self-propagation of the misfolded proteins, which can spread from cell to cell throughout the brain 2

Epidemiology

• Incidence of 1-2 cases per million population per year 1
• Accounts for approximately 1 in 6000 deaths 1
• Most cases occur in individuals between 55-75 years of age 1

Classification and Types

Prion diseases occur in three main forms:

1. Sporadic (85% of cases)

• Most common form with no known genetic or environmental trigger 1
• Includes sporadic Creutzfeldt-Jakob disease (CJD) 3

2. Genetic (10-15% of cases)

• Caused by autosomal dominant protein-altering variants in the PRNP gene located on chromosome 20p13 1
• Main types include:
  • Genetic Creutzfeldt-Jakob disease
  • Gerstmann-Sträussler-Scheinker syndrome (GSS)
  • Fatal familial insomnia (FFI) 1, 3
• Most common pathogenic variants include E200K, P102L, D178N, and various octapeptide repeat insertions 1

3. Acquired (rare)

• Includes variant CJD (linked to bovine spongiform encephalopathy or "mad cow disease"), iatrogenic CJD, and kuru 3, 4
• Transmission occurs through exposure to infected tissues via ingestion, injection, or transplantation 2

Clinical Presentation

• Rapidly progressive dementia is the hallmark presentation, especially in sporadic CJD 1
• Early symptoms vary widely but typically progress to profound cognitive impairment 1
• Median survival of approximately 5 months for sporadic CJD 1
• Other common symptoms include:
  • Myoclonic jerks
  • Ataxia
  • Akinetic mutism (late stage)
  • Visual disturbances 1, 3
• Some genetic forms may progress more slowly over decades 3

Diagnosis

Diagnosis is multifactorial and includes:

• Clinical history and neurological examination 1
• Magnetic resonance imaging (MRI) - preferred over CT for detecting characteristic patterns 1, 5
• Cerebrospinal fluid analysis for:
  • Real-time quaking-induced conversion assay (RT-QuIC) - offers >90% sensitivity and specificity 1, 5
  • 14-3-3 protein
  • Tau protein 1
• Electroencephalography (EEG) 1
• Genetic testing for PRNP mutations, particularly important even without apparent family history 1
• Definitive diagnosis requires neuropathological examination of brain tissue, though this is rarely performed antemortem 4, 5

Treatment and Prognosis

• Currently no effective treatments that significantly alter disease progression 5
• All prion diseases are ultimately fatal 4
• Clinical trials to date have failed to show survival benefit 3
• Early diagnosis remains important for:
  • Patient care planning
  • Infection control measures
  • Genetic counseling for families 5

Special Considerations

• Prions are uniquely resistant to normal decontamination procedures, requiring special infection control protocols 4
• More than half of genetic cases lack a documented family history due to:
  • De novo mutations
  • Incomplete penetrance
  • Misdiagnosis in previous generations
  • Early death from other causes 1
• Genetic counseling should be offered to all families with a case of prion disease, regardless of apparent family history 1