Axenfeld-Rieger Syndrome: From Zebrafish Models to Clinical Outcomes

To investigate genetics and outcomes in Axenfeld-Rieger Syndrome (ARS).

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.

A total of 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). Total 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.

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. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.