Aicardi-Goutières Syndrome
Aicardi-Goutières Syndrome (AGS)
Aicardi-Goutières syndrome is a rare genetic encephalopathy characterized by early-onset progressive brain dysfunction, intracranial calcifications, and chronic cerebrospinal fluid (CSF) lymphocytosis. It features increased interferon-alpha activity and mimics congenital viral infections.
Key Points
- Genetic interferonopathy
- Multiple causative genes identified
- Autosomal recessive/dominant inheritance
- Type I interferon signature
- Presents with neurological deterioration
- Often misdiagnosed as viral infection
Epidemiology
- Rare disorder: <1/100,000 births
- All ethnic groups affected
- No gender predominance
- Higher prevalence in consanguineous families
- Approximately 400 cases reported worldwide
Historical Context
- 1984: First described by Aicardi and Goutières
- 2006: First gene (TREX1) identified
- 2007-2014: Additional genes discovered
- 2014: Recognition as type I interferonopathy
- Ongoing research into pathogenesis
Clinical Features
Disease Onset Patterns
- Early-Onset Form:
- Presents in first few months
- Often after normal early development
- Rapid neurological deterioration
- Severe developmental regression
- Poor prognosis
- Later-Onset Form:
- Presents after several months
- More gradual progression
- Variable severity
- Better outcomes possible
Neurological Manifestations
- Central Nervous System:
- Progressive microcephaly
- Spastic quadriplegia
- Dystonia
- Seizures
- Developmental regression
- Intellectual disability
- Neuroradiological Features:
- Intracranial calcifications
- White matter abnormalities
- Cerebral atrophy
- Basal ganglia involvement
Extraneurological Features
- Skin Manifestations:
- Chilblain lesions
- Periungual inflammation
- Cutaneous vasculitis
- Digital necrosis
- Systemic Features:
- Hepatosplenomegaly
- Thrombocytopenia
- Elevated liver enzymes
- Autoimmune phenomena
Associated Features
- Growth retardation
- Feeding difficulties
- Visual problems
- Hearing impairment
- Joint contractures
- Gastrointestinal issues
Diagnosis & Genetics
Diagnostic Criteria
- Core Features:
- Early-onset encephalopathy
- Intracranial calcifications
- CSF lymphocytosis
- Elevated interferon-alpha
- Negative TORCH studies
- Supporting Features:
- Progressive microcephaly
- White matter abnormalities
- Chilblain lesions
- Family history
Genetic Testing
- Known Causative Genes:
- TREX1 (AGS1)
- RNASEH2B (AGS2)
- RNASEH2C (AGS3)
- RNASEH2A (AGS4)
- SAMHD1 (AGS5)
- ADAR1 (AGS6)
- IFIH1 (AGS7)
- Testing Strategy:
- Multi-gene panel testing
- Whole exome sequencing
- Deletion/duplication analysis
- Family studies
Molecular Mechanisms
Pathophysiology
- Interferon Pathway:
- Upregulation of type I interferons
- Activation of innate immunity
- Inflammatory response
- Autoimmune features
- Nucleic Acid Metabolism:
- Defective DNA/RNA processing
- Accumulation of nucleic acids
- Cellular stress response
- Immune activation
Biomarkers
- Interferon signature
- Neopterin levels
- CSF markers
- Inflammatory mediators
Management
Treatment Approach
- Medical Management:
- JAK inhibitors
- Immunosuppressive therapy
- Anti-inflammatory agents
- Antiepileptic drugs
- Pain management
- Supportive Care:
- Physical therapy
- Occupational therapy
- Speech therapy
- Feeding support
- Respiratory care
Multidisciplinary Care
- Core Team:
- Neurologist
- Geneticist
- Rheumatologist
- Developmental pediatrician
- Physical medicine specialist
- Support Services:
- Genetic counseling
- Social work
- Psychological support
- Educational services
Research & Advances
Current Research
- Therapeutic Development:
- JAK inhibitor trials
- Anti-interferon therapies
- Novel drug development
- Biomarker studies
- Clinical Research:
- Natural history studies
- International registries
- Treatment outcomes
- Quality of life research
Future Directions
- Gene therapy approaches
- Targeted treatments
- Early intervention studies
- Prevention strategies
Prognosis & Support
Long-term Outcomes
- Early-Onset Form:
- Severe neurological impairment
- Limited life expectancy
- High dependency needs
- Later-Onset Form:
- Variable outcomes
- Better survival rates
- Some achieve independence
Monitoring Guidelines
- Regular neurological assessment
- Developmental monitoring
- Imaging surveillance
- Laboratory monitoring
- Growth parameters
