What is the recommended management approach for an infant diagnosed with Aicardi-Goutières disease (AGS)?

Management of Aicardi-Goutières Syndrome in Infants

There is no established curative treatment for Aicardi-Goutières syndrome (AGS), so management focuses on supportive care, early symptom recognition, and emerging immunomodulatory therapies targeting the interferon pathway, with JAK inhibitors showing the most promise in recent studies. 1

Diagnostic Confirmation

• Confirm diagnosis through molecular genetic testing for mutations in AGS-associated genes (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, IFIH1) 2, 3
• Measure interferon-alpha levels in cerebrospinal fluid (CSF), which are characteristically elevated and higher in CSF than serum, suggesting intrathecal synthesis 2
• Document CSF lymphocytosis, a cardinal feature of AGS 2
• Obtain brain CT to identify basal ganglia calcifications (often bilateral and symmetrical) and MRI to assess leukoencephalopathy and cerebral atrophy 2
• Monitor for elevated C26:0 lysophosphatidylcholine on newborn screening, which may identify AGS cases before symptom onset 4

Supportive Care Framework

Neurological Management

• Monitor head circumference serially to track acquired microcephaly progression 2
• Manage spasticity and extrapyramidal signs with physical therapy and antispasticity medications as clinically indicated 2, 3
• Coordinate developmental intervention with consistent caregivers to maximize interpersonal experiences and minimize overstimulation 5
• Plan procedures (bathing, venipuncture, suctioning) during periods when the infant shows readiness to interact, avoiding interruption of deep sleep cycles 5

Nutritional Support

• Provide adequate caloric intake to support growth, with realistic expectations given that weight gain is often slow with frequent setbacks 5
• Monitor for gastroesophageal reflux, which is common in neurologically impaired infants, and treat with H2-receptor antagonists or proton pump inhibitors when diagnosed 5
• Consider thickened feedings if reflux is problematic, but avoid in preterm infants due to necrotizing enterocolitis risk 5
• Supplement with iron (2-3 mg/kg/day) if receiving human milk or fortified human milk 5

Electrolyte and Mineral Homeostasis

• Provide sodium 4-7 mEq/kg/day and potassium 2-4 mEq/kg/day, adjusted based on clinical monitoring 5
• Ensure adequate calcium (120-230 mg/kg/day enterally), phosphorus (60-140 mg/kg/day), and magnesium (7.9-15 mg/kg/day) intake 5
• Supplement vitamin D at 150-400 IU/kg/day (maximum 800 IU/kg/day) with adequate mineral intake 5

Emerging Immunomodulatory Therapies

JAK Inhibitors (Most Promising)

• Consider Janus kinase (JAK) inhibitors as the most promising therapeutic strategy, targeting the interferon signaling pathway that drives AGS pathology 1
• These agents directly inhibit the type I interferon response that characterizes AGS 1

Alternative Immunomodulatory Options

• Reverse transcriptase inhibitors may be considered based on the role of nucleic acid metabolism in AGS pathogenesis 1
• Anti-interferon-alpha antibodies represent a direct approach to neutralizing elevated IFN-α 1
• Antimalarial drugs (hydroxychloroquine) have immunomodulatory properties that may benefit some patients 1, 3
• cGAS inhibitors are under investigation as they target upstream interferon production 1

Important caveat: The efficacy of these immunomodulatory therapies remains unproven in large-scale trials, and their use should be considered experimental 1

Monitoring and Follow-Up

• Perform serial neuroimaging to track progression of calcifications, leukoencephalopathy, and atrophy 2
• Measure CSF interferon-alpha levels periodically, recognizing that levels decrease with age 2
• Monitor for non-neurological manifestations including chilblains (which may precede neurological symptoms by months) 3
• Assess developmental milestones at regular intervals (at least quarterly) 5
• Screen for seizures and manage with appropriate anticonvulsants if they develop 2

Timing Considerations

• Recognize that while AGS typically manifests by 4 months of age, late-onset presentations can occur after 12 months 3, 6
• Abnormal neuroimaging and chilblains may be present many months before neurological symptoms appear 3
• Interferon signature on newborn screening blood spots can identify affected infants before symptom onset, allowing earlier intervention 4
• CSF abnormalities (including elevated IFN-α) may normalize with age in milder cases, so early testing is critical 6

Genetic Counseling and Family Planning

• Provide genetic counseling regarding the autosomal recessive inheritance pattern 2, 3
• Test at-risk siblings, as they may be identified before symptom onset based on laboratory and imaging findings alone 3
• Discuss recurrence risk (25% for each pregnancy) with parents 2