Axenfeld-Rieger Syndrome: From Zebrafish Models to Clinical Outcomes

PURPOSE: To investigate genetics and outcomes in Axenfeld-Rieger Syndrome (ARS) METHODS: Retrospective cohort study of ARS patients diagnosed 1970-2023. Ocular diagnoses, surgeries, genetic information, and exam findings were collected. Surgery success was defined as IOP of 5-20 mmHg, no additional IOP-lowering surgery, and no visually devastating complications. Live-imaging and histological zebrafish studies were performed to study FOXC1 variants RESULTS: 66 patients (31 males) presented at median 4.1 years [IQR 0.4,13.1] and were classified into 4 ARS phenotypes: deep anterior chamber (n=55), shallow anterior chamber (n=4), corneal opacification (n=3), and iridogoniodysgenesis (n=4). 42 patients (64%) were diagnosed with glaucoma at median 4.2 years [IQR 0.3,13.3] and 58 eyes of 33 patients required IOP-lowering surgery. Patients with glaucoma had higher initial IOP (p<.0001) and worse final BCVA (p<.01) compared to patients without glaucoma. At final follow-up (median 6.1 years [IQR 1.6,10.1]), patients with glaucoma showed decreased IOP (p<.0001), but increased glaucoma medications (p<.001). Ten-year survival rates were greatest for trabeculectomy with mitomycin C (76% with 95%CI[47,91]) and Baerveldt devices (71% with 95%CI[47,86]. Final BCVA was linearly associated with number of glaucoma surgeries (ß=0.15, p<.01, R2=0.12). Foxc1a zebrafish morpholino oligonucleotide knockdown, which disrupted ocular and craniofacial development, was rescued by human wildtype FOXC1 mRNA, but not mutant FOXC1 mRNA containing clinically identified variants. CONCLUSIONS: In ARS, patients with glaucoma had worse final BCVA and often required angle bypass surgery. Further, our zebrafish model recapitulated ARS and verified clinically identified FOXC1 variants.