Amanda Jan1, Isabella Peixoto de Barcelos1, Nicholson Modesti1, Sarah Woidill1, Francesco Gavazzi1, David Isaacs1, Russell D'Aiello1, Anjana Sevagamoorthy1, Amy Pizzino1, Johanna Schmidt1, Keith Van Haren2, Stephanie Keller3, Florian Eichler4, Lisa Emrick5, Jamie Fraser6, Justine Shults7, Adeline Vanderver1, Laura Adang1
1Division of Neurology, Children's Hospital of Philadelphia, 2Department of Neurology, Stanford University, 3Division of Pediatric Neurology, Emory University, 4Deptartment of Neurology, Massachusetts General Hospital, 5Department of Neurology & Developmental Neuroscience, Baylor College of Medicine, 6Rare Disease Institute, Division of Genetics and Metabolism, Children's National Medical Center, 7Department of Statistics, University of Pennsylvania
Objective:
To chronicle the natural history of AGS, especially its systemic manifestations, in relation to key variables such as genotype.
Background:
Aicardi Goutières Syndrome (AGS) is a heritable interferonopathy that results in variable neurologic disability and systemic complications. Key variables (e.g., genotype, age at onset) only partially correlate with neurologic function, and little is known about their association with systemic symptoms.
Design/Methods:
Clinical data from subjects with confirmed AGS were extracted from the Myelin Disorders Biorepository Project on demographics, age of onset, and neurological and systemic complications associated with AGS. Neurologic severity was assessed using a disease-specific scale (AGS Severity Scale).
Results:
The cohort included 167 subjects of all known AGS genotypes except LSM-11. The median age of systemic onset was 0.15 years [IQR 0, 0.67], while neurological onset was 0.33 years [IQR 0.08, 0.90]. Neurologic severity correlated significantly with age of systemic symptom onset. Gastrointestinal abnormalities (n=139), dysphagia/feeding intolerance (n=124), and liver dysfunction (n=67) were the most frequent systemic symptoms and occurred early in patients’ disease course. The time to some systemic events, such as feeding tube placement and chilblains, were significantly associated with genotype (Fleming-Harrington log-rank: p=0.0002, p<0.0001, respectively), with TREX1 often having earlier median onset of events. Other events, such as glaucoma and retinopathy, were more likely to occur at different points in a patient’s life, with glaucoma more likely after the first year of life (58.3%) and retinopathy within the first year (75.0%).
Conclusions:
AGS is a heterogeneous disease with a large systemic burden and an unmet need for natural history data, which is further amplified by new therapeutics trials. Our data highlights that the frequency and time course of systemic inflammatory events varies among AGS genotypes. Systemic symptoms largely precede neurological ones. These data show the importance of tailoring clinical screening guidelines to a patient’s age, disease onset, and genotype.