Optic Atrophy in Wolfram Syndrome Type 1: A Retrospective Analysis of Visual Outcomes and Biomarker Correlates

BACKGROUND: Wolfram syndrome type 1 (WS1) is a rare autosomal recessive disorder classically associated with diabetes mellitus (DM) and optic atrophy (OA). We aimed to characterize OA in WS1 and evaluate optical coherence tomography (OCT) and genetic biomarkers as tools for disease monitoring and prognostication. METHODS: We conducted a retrospective chart review of genetically confirmed patients with WS1 seen at Washington University or Indiana University neuro-ophthalmology clinics between July 2017 and 2024. Data included demographics, clinical history, best corrected visual acuity (BCVA), OCT retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) thickness, and WFS1 mutation severity scores. Linear regression analyses assessed correlations between BCVA and clinical, structural, and genetic variables. RESULTS: Thirty-six patients (22 women, 14 men; median age 20 years) were identified. Median mutation severity score was 3.5. Vision loss occurred in 31 patients; in 3 patients it was the only major symptom, in 5 patients it preceded DM, and in 6 patients it occurred without DM. Mean and median BCVA were 20/125 and 20/80, respectively. BCVA correlated inversely with RNFL thickness ( P = 0.0017, R 2 = 0.14), GCC thickness ( P = 0.0018, R 2 = 0.29), and mutation severity score ( P = 0.031, R 2 = 0.14). CONCLUSIONS: OA was the most common and sometimes earliest WS1 manifestation. Correlations between BCVA, OCT metrics, and mutation severity score support their potential value as biomarkers and prognostic tools. Findings also support considering genetic screening for WFS1 mutations in patients presenting with otherwise unexplained OA.