Early brain‐penetrant immunotherapy reverses interferon signature and improves motor outcome in a case of ADAR1 ‐related Aicardi‐Goutières syndrome

Objectives Aicardi‐Goutières syndrome (AGS) is a genetic interferonopathy resulting from defects in nucleic acid metabolism and subsequent enhanced type I interferon signalling. We report how an expedited genomic diagnosis in conjunction with natural history data can enable a long‐term brain‐penetrant anti‐inflammatory regimen to optimise neurodevelopmental outcomes in genetic autoinflammatory brain disorders. Methods Expedited genomic testing identified compound heterozygous ADAR1 mutations. Published natural history data from 33 patients with biallelic ADAR1 mutations reported severe disability (GMFCS V) or death in 79%. To reduce neuroinflammation, we commenced a long‐term pulsed oral dexamethasone protocol (20 mg/m 2 for 3 days every 3 weeks) from the age of 11 months, plus ruxolitinib, a Janus Kinase (JAK) inhibitor (5 mg per day). Results At the age of 24 months, the patient was crawling and walking a few steps unaided, with a GMFCS level of II. Single‐cell RNA sequencing of 41 164 leukocytes, taken before and after 3 months of treatment and compared to three age matched male controls, showed a reversal of upregulated pan‐cellular interferon pathways, with most differentially expressed genes observed in monocytes. On treatment, there was statistically significant downregulation of key autoinflammatory genes, including nucleic acid sensing ( CGAS, IFIH1, SAMHD1 ), interferon‐stimulated genes ( ISG15 and IFIF44L ) and signalling ( JAK1 ). Given the dual immune therapy, it was not possible to define whether the biological effect was related to dexamethasone or JAK inhibitor, or both. Conclusion Compared with natural history data, our data suggest that early diagnosis, and the use of early brain‐penetrant immune suppressants (dexamethasone), may improve outcomes in ADAR1 AGS.