Treatment of Aicardi-Goutières Syndrome
There is no cure for Aicardi-Goutières syndrome, but JAK inhibitors (ruxolitinib, baricitinib, tofacitinib) represent the most promising disease-modifying therapy, with reverse transcriptase inhibitors and supportive symptomatic management forming the current treatment approach.
Disease-Modifying Therapies
JAK Inhibitors (Primary Emerging Treatment)
- Ruxolitinib, baricitinib, and tofacitinib are non-toxic to neural stem cells and show promise in targeting the type I interferon pathway that drives AGS pathogenesis 1, 2
- These agents directly inhibit the overactive interferon signaling that characterizes AGS as a type I interferonopathy 1, 3
- Avoid pacritinib specifically, as it demonstrates cytotoxicity to neural stem cells in AGS patients 2
- Clinical trials and case series are ongoing, though definitive efficacy data remain limited 1
Reverse Transcriptase Inhibitors
- Abacavir and lamivudine are safe options with no demonstrated neural stem cell cytotoxicity 2
- Avoid zidovudine, particularly in AGS2 patients (RNASEH2B mutations), due to selective toxicity in patient-derived cells 2
- These agents target the accumulation of self-nucleic acids that trigger interferon overproduction 1, 3
Other Immunomodulatory Approaches Under Investigation
- Anti-interferon-alpha antibodies are being studied to directly neutralize the elevated IFN-α characteristic of AGS 1
- Antimalarial drugs and cGAS inhibitors represent additional experimental strategies 1
- Anti-interleukin antibodies are under evaluation 1
Symptomatic and Supportive Management
Corticosteroids
- Glucocorticoids are safe for neural tissue and do not compromise neural stem cell viability in AGS patients 2
- Use for managing inflammatory manifestations and neurological symptoms 2
Thiopurines (Use with Caution)
- Avoid thioguanine due to demonstrated cytotoxicity in AGS neural stem cells 2
- Mercaptopurine appears safer if immunosuppression is needed 2
Clinical Monitoring Requirements
Neurological Surveillance
- Monitor for progressive encephalopathy, developmental arrest, and motor disability (spasticity, dystonia) 4, 5
- Serial neuroimaging to assess cerebral calcification (particularly basal ganglia), leukoencephalopathy, and cerebral atrophy 4, 3
- Watch for bilateral striatal necrosis, particularly in ADAR-related AGS6 5
Laboratory Monitoring
- Serial CSF analysis for chronic lymphocytosis and elevated interferon-alpha levels 4, 3
- Serum IFN-α levels to assess disease activity 3
- In ADAR-related AGS6, monitor liver transaminases for recurrent transaminitis episodes 5
Genetic Subtype Considerations
The nine causative genes (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, IFIH1, LSM11, RNU7-1) all lead to accumulation of self-nucleic acids or aberrant sensing, triggering type I interferon overproduction 3. Treatment approach remains similar across subtypes, though:
- AGS2 (RNASEH2B) patients should specifically avoid zidovudine 2
- AGS6 (ADAR) patients require hepatic monitoring for transaminitis 5
Critical Diagnostic Exclusions
Before confirming AGS and initiating therapy, rigorously exclude congenital infections (TORCH) that can mimic AGS with similar neurological sequelae, CSF lymphocytosis, and calcifications 4. AGS diagnosis requires progressive encephalopathy with early onset (typically first year of life), characteristic neuroimaging, and chronic CSF lymphocytosis 4.
Treatment Limitations and Prognosis
Current therapies remain largely symptomatic and supportive, as no treatment has proven efficacy in reversing established neurological damage 1. JAK inhibitors and RTIs represent the most evidence-based disease-modifying approaches, though their long-term efficacy requires further validation through clinical trials 1, 2.