Systemic complications of Aicardi Goutières syndrome using real-world data.

objectiveAicardi Goutières Syndrome (AGS) is a rare genetic interferonopathy associated with diverse multisystemic complications. A critical gap exists in our understanding of its longitudinal, systemic disease burden, complicated by delayed diagnosis. To address this need, real-world data extracted from existing medical records were used to characterize the longitudinal disease burden.

methodsAll subjects (n = 167) with genetically confirmed AGS enrolled in the Myelin Disorders Biorepository Project (MDBP) were included. As available in medical records, information was collected on subject demographics, age of onset, and disease complications. Information from published cases of AGS (2007-2022; n = 129) with individual-level data was also collected. Neurologic severity at the last available encounter was determined by retrospectively assigning the AGS Severity Scale [severe (0-3), moderate (4-8), and mild (9-11)].

resultsThe genotype frequency in the natural history cohort was TREX1 (n = 26, 15.6 %), RNASEH2B (n = 50, 29.9 %), RNASEH2C (n = 3, 1.8 %), RNASEH2A (n = 7, 4.2 %), SAMHD1 (n = 25, 15.0 %), ADAR (n = 34, 20.4 %), IFIH1 (n = 19, 11.4 %), and RNU7-1 (n = 3, 1.8 %). The median age of systemic onset was 0.15 years [IQR = 0.67 years; median range by genotype: 0 (TREX1) - 0.62 (ADAR) years], while the median neurological onset was 0.33 years [IQR = 0.82 years; median range by genotype: 0.08 (TREX1) - 0.90 (ADAR) year]. The most common early systemic complications were gastrointestinal, including dysphagia or feeding intolerance (n = 124) and liver abnormalities (n = 67). Among postnatal complications, thrombocytopenia appeared earliest (n = 29, median 0.06 years). Tone abnormalities (axial hypotonia: n = 145, 86.8 %; dystonia: n = 123, 73.7 %), irritability (n = 115, 68.9 %), and gross motor delay (n = 112, 7.1 %) emerged as the most prevalent neurological symptoms. Previously published case reports demonstrated similar patterns. The median AGS score for the entire cohort was 4 (IQR = 7). The most severe neurologic phenotype occurred in TREX1-related AGS (n = 19, median AGS severity score 2, IQR = 2). Time to feeding tube placement, chilblains, early gross motor delay, early cognitive delay, and motor regression were significantly associated with genotype (Fleming-Harrington log-rank: p = 0.0002, p < 0.0001, p = 0.0038, p < 0.0001, p = 0.0001, respectively). Microcephaly, feeding tube placement, and seizures were associated with lower AGS scores (All: Wilcoxon rank sum test, p < 0.0001). Among the qualifying case reports (n = 129), tone abnormalities were the most prevalent disease feature, with spastic quadriplegia reported in 37 of 96 cases (38.5 %) and dystonia in 30 of 96 cases (31.2 %).

conclusionsAGS is a heterogeneous disease with multi-organ system dysfunction that compounds throughout the clinical course, resulting in profound neurological and extra-neurological disease impact. Systemic symptoms precede neurologic disease features in most cases. Disease onset before the age of one year, microcephaly, feeding tube placement, and seizures were associated with worse neurological outcomes. This work will inform evidence-based clinical monitoring guidelines and clinical trial design.