Quantitative Fundus Autofluorescence and Genetic Associations in Macular, Cone, and Cone-Rod Dystrophies

Purpose: To investigate quantitatively lipofuscin-associated fundus autofluorescence in patients with macular and cone/cone-rod dystrophies (MD/CCRDs).

Design: Prospective, single-center, case-control study.

Participants: Two hundred thirty patients with MD/CCRDs who had undergone genetic testing and 110 control participants without any eye disease.

Methods: Participants were examined using quantitative fundus autofluorescence (qAF) imaging with a modified confocal scanning laser ophthalmoscope equipped with an internal fluorescent reference (modified Spectralis HRA-OCT; Heidelberg Engineering, Heidelberg, Germany). Mean qAF values were obtained by averaging measurements from an 8-segment ring centered on the fovea (qAF₈) and compared with controls.

Main outcome measures: The qAF₈ levels.

Results: Elevated qAF₈ values were a frequent finding (n = 105 [45%]) and associated with ABCA4 (n = 73 [70%]), PRPH2 (n = 9 [9%]), CERKL (n = 3 [3%]), PROM1 (n = 2 [2%]), CRX (n = 1 [1%]), and CDHR1 (n = 1 [1%]) mutations. Reduced qAF₈ values were rare (n = 15 [7%]) and found predominantly among patients with MERTK (n = 3 [20%]) and RDH5 (n = 2 [13%]) mutations. Patients with normal qAF₈ values (n = 110 [48%]) showed high genotypic heterogeneity. For various genes including ABCA4, PRPH2, CDHR1, and PROM1, higher qAF₈ measures were associated with specific phenotypes and genotypes. For instance, qAF₈ values were normal in PRPH2-related central areolar chorioretinal dystrophy but increased in PRPH2-related Stargardt-like retinopathy. Accordingly, high qAF₈ levels were associated with specific genetic causes and mutation detection rates in characteristic but genetically heterogenous clinical phenotypes, such as a Stargardt-like flecked fundus, bull's eye maculopathy, or pattern dystrophy. In genetically unsolved cases (16 with elevated, 35 with normal, 7 with reduced qAF values), qAF₈ was used to support or reject ambiguous results of genetic testing, to suggest underlying pathogenic pathways, and to predict disease in otherwise healthy participants.

Conclusions: Quantitative fundus autofluorescence imaging revealed characteristic qAF levels in association with certain gene mutations and in participants without detected mutations. These findings indicate that qAF may facilitate differential diagnostics of MD/CCRDs and may offer novel pathogenetic insights that may be of particular value for the assessment of future treatment approaches.