Systemic complications of Aicardi Goutières syndrome using real-world data

Abstract

Objective: Aicardi 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.

Methods: All 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)].

Results: The 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 %).

Conclusions: AGS 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.

Keywords: Aicardi Goutières syndrome; Clinical manifestations; Genotype; Interferonopathy; Leukodystrophy.

Fig. 1.

The flow diagram represents the identification of the AGS cohorts.

Fig. 2.. Distribution of AGS Severity Scale Score at last encounter by genotype.

A single point represents each individual. Lower scores indicate greater disease severity. Kruskal-Wallis test with the Dunn test for multiple comparisons was used to compare across genotypes; the median last AGS scale in TREX1-related disease was significantly different than the median last AGS scale in ADAR-related disease (p = 0.0110). RNASEH2A, RNASEH2C, and RNU7–1 were not represented due to a limited number of patients in those genotypes.

Fig. 3.. Kaplan-Meier survival curves for the overall cohort (left) and stratified by genotype (right) for neurologic time-to-event measurements.

These curves demonstrate the probability of being affected by the clinical finding identified. A-B: Time to dystonia, C-D: Time to isolated cognitive delay, E-F: Time to isolated gross motor delay, G-H: Time to change in motor function (motor regression). For the RNASEH2-related AGS cohort, only RNASEH2B data was reported due to the small n for the other two genotypes: RNASEH2B (24 patients), RNASEH2A (6 patients), and RNASEH 2C (2 patients).

Fig. 4.. Systemic complications of AGS.

The frequency of clinical events was screened in the MDBP Natural History cohort. The area represents the total number of individuals in the natural history cohort. Dark boxes represent event noted, medium tone represents not noted, and light boxes represent unknown (individuals who were not screened or for whom the information was unavailable in the medical record).

Fig. 5.. Systemic complications of AGS.

A. Subject level description of onset of systemic and neurologic complications. The onset of systemic complications from the real-world data is shown as a timeline of systemic (yellow) and neurological (gray) symptoms. IUGR (intrauterine growth restriction) is noted as onset at birth (triangle symbol). B. Variable-level description of age at onset. Each dot represents the first time a complication was reported in each system for a specific patient. The bar represents the median, and the outer boxes represent the interquartile range (Q1 and Q3). Multiple systems become involved in a patient’s disease throughout their lifetime, starting on average with complications in the gastrointestinal system followed closely by the neurologic and visual systems. Intrauterine growth restriction is represented in the figure as 0 years, which is the standard definition of our database (because the precise date of the finding was often unavailable). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 6.. Kaplan-Meier survival curves for the overall cohort (left) and stratified by genotype (right) for systemic time-to-event measurements.

These curves demonstrate the probability of a clinical event occurring in the overall cohort (A, C) and by each genotype (B, D). A-B: Time to feeding tube; C-D: Time to chilblains. Time to the feeding tube and chilblains varied across the different genotypes.

Fig. 7.. AGS-associated multisystemic complications.

A. A brain MRI (T2) shows abnormalities of the left globe (asterisk) consistent with glaucoma in a 21-year-old patient with SAMHD1-related AGS. B–C. Brain MRI brain (T2) demonstrates an acute right middle cerebral artery (MCA) infarct in a 4-year-old patient with SAMHD1-related AGS, with secondary vasculopathy of small vessels within the circle of Willis consistent with Moyamoya syndrome. The vascular imaging improved after the MCA bypass. D. The hand X-ray of a 9-year-old boy with ADAR-related AGS demonstrates diffuse bone demineralization and severe contractures. E. Chilblains of the pinna in a 16-year-old patient with SAMHD1-related AGS. F. Pictorial diagram of the systemic burden of disease of AGS.