What are prion diseases and how are they managed?

Prion Diseases: Understanding and Management

Prion diseases are rare, fatal neurodegenerative disorders characterized by the misfolding of normal prion proteins (PrP or PrPc) into pathogenic conformers (PrPSc) that accumulate in the brain, leading to rapid neurodegeneration and death with no currently available disease-modifying treatments. 1, 2

Types and Epidemiology

Prion diseases affect both humans and animals with an incidence of 1-2 cases per million population per year, accounting for approximately 1 in 6000 deaths. They can be classified into three categories:

• Sporadic (85%): No known genetic or environmental trigger
• Genetic (10-15%): Caused by autosomal dominant variants in the PRNP gene
• Acquired (<1%): Transmitted through extraordinary circumstances (e.g., medical procedures with contaminated instruments, consumption of infected tissues)

Human Prion Disease Subtypes

1. Creutzfeldt-Jakob Disease (CJD)

   • Most common form
   • Rapidly progressive dementia
   • Median survival of approximately 5 months for sporadic CJD

2. Gerstmann-Sträussler-Scheinker Disease (GSS)

   • Prominent cerebellar ataxia
   • Often slower progression than CJD

3. Fatal Familial Insomnia (FFI)

   • Characterized by sleep dysregulation
   • Sympathetic overactivity and endocrine abnormalities

4. Variably Protease-Sensitive Prionopathy

   • More recently discovered sporadic form
   • Similar clinical presentation to other prion diseases 3

Clinical Presentation

Prion diseases present with diverse symptoms that typically progress rapidly:

• Cognitive symptoms: Memory decline, progressive dementia, confusion, disorientation, language difficulties, impaired concentration
• Motor symptoms: Cerebellar ataxia, myoclonus, pyramidal and extrapyramidal signs, muscle weakness, parkinsonism
• Psychiatric manifestations: Personality changes, apathy, disinhibition, hallucinations, delusions, depression, anxiety
• Autonomic dysfunction: Sleep dysregulation (particularly in FFI), sympathetic overactivity, endocrine abnormalities

The disease typically follows a pattern of:

1. Initial subtle symptoms
2. Rapid progression affecting multiple neurological domains
3. Advanced stage with profound dementia and akinetic mutism
4. Death (typically within months to a few years) 2

Genetic Basis

Genetic prion diseases are caused by protein-altering variants in the PRNP gene located on chromosome 20p13. These include:

• Missense variants: Most common type of pathogenic variants
• Octapeptide repeat insertion (OPRI) variants
• Truncating and frameshift variants (rare)

The most common highly penetrant variants include:

• E200K
• P102L
• D178N
• 6-OPRI
• 5-OPRI
• A117V
• P105L 1

Importantly, more than half of genetic prion disease cases lack a documented family history, which can be due to:

• De novo pathogenic variants
• Incomplete penetrance
• Misattributed parenthood
• Adoption or estrangement
• Early death by other causes
• Misdiagnosis of previous generations 1

Diagnostic Approach

Diagnosis of prion disease is often delayed unless the patient is seen by a neurologist familiar with the disease. The diagnostic workup should include:

1. Neuroimaging:

   • MRI showing characteristic findings

2. Cerebrospinal Fluid Analysis:

   • Presence of 14-3-3 protein
   • Real-time quaking-induced conversion (RT-QuIC) assay (>90% sensitivity and specificity for sporadic forms)

3. Genetic Testing:

   • PRNP gene sequencing should be routinely offered for all suspected cases of prion disease, regardless of family history
   • Particularly important when RT-QuIC has reduced sensitivity for some genetic subtypes

4. Other Tests (historically used):

   • Electroencephalogram
   • Nonspecific fluid biomarkers of neuronal damage
   • Brain biopsy (currently discouraged) 1, 2

Management

Unfortunately, despite numerous treatment efforts, prion diseases remain fatal with no effective disease-modifying therapies currently available. Management focuses on:

1. Supportive Care:

   • Symptom management
   • Maintaining quality of life
   • Addressing complications

2. Genetic Counseling:

   • Essential for patients with genetic forms and their families
   • Should address:
     • Disease presentation and course
     • Genetics and inheritance patterns
     • Psychosocial aspects
     • Available resources

3. Emerging Therapeutic Approaches (under investigation):

   • Antibody-based treatments targeting PrP conversion
   • RNA interference
   • Antisense oligonucleotides
   • Anti-aggregation compounds
   • β-sheet breakers
   • Stem cell-based therapies 4

Important Counseling Points

When counseling patients and families about prion diseases, it's crucial to address:

1. Transmission Risk:

   • Prion disease is not transmitted through normal activities including:
     • Sharing a household
     • Intimate contact
     • Caretaking activities
     • Routine medical or dental care
   • Transmission occurs only through extraordinary circumstances such as brain-to-brain contact in medical procedures
   • In genetic prion disease families, the disease tracks strictly with inheritance of the pathogenic variant
   • No evidence suggests prions are passed through breastfeeding or pregnancy

2. Blood Donation:

   • Individuals with family history of prion disease or known pathogenic PRNP variants may be ineligible to donate blood
   • This reflects an abundance of caution rather than established risk
   • Blood-based transmission has only been reported for variant CJD (acquired form), not genetic forms
   • Blood is considered a "no detectable infectivity" tissue by WHO even at symptomatic stage 1

Prognosis

The prognosis for prion diseases is poor:

• Most patients have a life expectancy of less than a year after symptom onset
• Median survival for sporadic CJD is approximately 5 months
• Some genetic forms may progress more slowly over years
• Phenotypic variability exists, with symptoms varying widely even within the same genetic variant and between affected family members 2, 4

Resources for Patients and Families

Despite the rarity of prion diseases, affected patients and families are well-organized, and the disease is well-understood by an active research community. Clinicians should connect patients and families with resources to:

• Reduce isolation
• Access information
• Stay informed about progress toward meaningful therapies 1

Prevention

For acquired forms, prevention focuses on:

• Strict infection control measures in healthcare settings
• Surveillance of animal populations for prion diseases
• Proper decontamination procedures for surgical instruments
• Screening of blood and tissue donors 5

For genetic forms, genetic counseling and testing can help individuals make informed reproductive decisions.