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

TY - JOUR

T1 - Quantitative Fundus Autofluorescence and Genetic Associations in Macular, Cone, and Cone-Rod Dystrophies

AU - Gliem, Martin

AU - Müller, Philipp L

AU - Birtel, Johannes

AU - Herrmann, Philipp

AU - McGuinness, Myra B

AU - Holz, Frank G

AU - Charbel Issa, Peter

N1 - Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

PY - 2020/7

Y1 - 2020/7

N2 - 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.

AB - 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.

KW - Adolescent

KW - Adult

KW - Case-Control Studies

KW - Child

KW - Cone-Rod Dystrophies/genetics

KW - Cross-Sectional Studies

KW - DNA/genetics

KW - DNA Mutational Analysis

KW - Eye Proteins/genetics

KW - Female

KW - Fluorescein Angiography/methods

KW - Fundus Oculi

KW - Humans

KW - Male

KW - Middle Aged

KW - Mutation

KW - Ophthalmoscopy/methods

KW - Pedigree

KW - Prospective Studies

KW - Retinal Cone Photoreceptor Cells/pathology

KW - Retinal Pigment Epithelium/pathology

KW - Tomography, Optical Coherence/methods

KW - Young Adult

U2 - 10.1016/j.oret.2020.02.009

DO - 10.1016/j.oret.2020.02.009

M3 - SCORING: Journal article

C2 - 32646556

VL - 4

SP - 737

EP - 749

JO - OPHTHALMOL RETINA

JF - OPHTHALMOL RETINA

SN - 2468-6530

IS - 7

ER -