Fundus Autofluorescence as a Sensitive Biomarker of Disease Progression in Bietti Crystalline Dystrophy

Purpose: To characterize the natural history of Bietti crystalline dystrophy (BCD), and to identify reliable outcome measures for detecting disease progression.Design: Multicenter, prospective observational study.Participants: Patients with genetically confirmed BCD carrying biallelic pathogenic CYP4V2 variants, recruited from six academic centers in Japan, with a best-corrected visual acuity (BCVA) of 1.0 logMAR or better in at least one eye at baseline.Methods: Multimodal imaging and functional assessments included BCVA, static perimetry (Humphrey 10-2), fundus autofluorescence (FAF), and optical coherence tomography (OCT).Main Outcome Measures: Longitudinal changes in BCVA; hypo-autofluorescent (hypo-AF) area; and static perimetry parameters, such as mean deviation (MD), absolute scotoma points (ASP), transitional zone retinal sensitivity (TZRS) and central subfield thickness (CST). Results:Thirteen patients with genetically confirmed BCD were followed prospectively over a median of 2.5 years (range: 2.5-3 years).Longitudinal analysis showed progression in hypo-AF area (12.0 mm/year, 95% CI: 7.1 to 16.9, P = 0.003), CST (-4.3 m/year, 95% CI: -6.6 to -2.1, P < 0.001), MD (-1.0 dB/year, 95% CI: -1.7 to -0.3, P = 0.02), ASP (2.4 points/year, 95% CI: 1.8 to 3.0, P < 0.001), TZRS (-2.1 dB/year, 95% CI: -2.8 to -1.4,P < 0.001) and BCVA (0.04 logMAR/year, 95% CI: 0.01 to 0.07, P = 0.01).Hypo-AF area showed the biggest annual change rate (21.6%) and highest SNR (1.10; signal-to-noise ratio) among all parameters.Linear mixed-effects models revealed that hypo-AF area progression was significantly associated with faster loss of MD (P = 0.01) and ASP (P = 0.004), but not with BCVA, TZRS and CST changes. Conclusions:This prospective natural history study suggests that hypo-AF area may serve as a useful structural measure for detecting disease progression in BCD clinical trials, warranting further validation in larger prospective studies.