The inherent autofluorescence (AF) of the fundus originates from RPE lipofuscin. While RPE lipofuscin is amassed even in healthy eyes, homozygous mutations in ABCA4 are well known to confer accelerated formation of these fluorophores. Moreover, imaging of fundus AF by confocal scanning laser ophthalmoscopy (cSLO) has shown that the patterns and intensities of AF deviate from normal in several retinal disorders. Thus we aim to demonstrate that a standardized approach to quantifying fundus AF (qAF) can assist in the diagnosis of retinal disease, in the monitoring of disease progression and in the assessment of therapeutic outcomes. To enable this investigation we have gathered normative qAF data from a large number of participants with healthy eye status (aged 6-60) so as to establish ranges of qAF values with respect to age, gender and ethnicity. Going forward we will use these normal values to examine for genotype/phenotype correlations between specific ABCA4 alleles and fundus AF levels (qAF) in patients diagnosed with ABCA4- associated disease (Aim 1.1). In longitudinal studies we will measure changes in qAF values after 1 and 2 year follow-up of ABCA4-affected individuals (Aim 1.2). We will determine whether the carrier state (heterozygous) of ABCA4 is associated with elevated RPE lipofuscin, the latter being measured as qAF and compared to age-matched normals (Aim 1.3). We will also investigate the cellular basis of retinal flecks (Aim 1.4).
In Aim 2, we will determine whether the quantification of fundus SW-AF can aid in differentiating between pattern dystrophy (PD) associated with PRPH2/RDS mutations versus similar phenotypes observed with ABCA4 variants (Aim 2.1). We will also compare qAF values in individuals presenting with bull's eye macular dystrophy that is of ABCA4- versus non-ABCA4 origin (Aim 2.2). In patients with RP, we will measure qAF over the autofluorescent rings that are often a feature of this disorder. qAF Intensities inside, within and outside the rings will be compared to levels in our normal controls so as to further the use of fundus AF imaging to monitor disease progression in RP.
In Aim 4, we will determine whether elevated fundus AF is a factor influencing the onset and progression of AMD when controlling for specific CFH and ARMS2 alleles. In summary, the studies proposed in this application will examine the contribution that the lipofuscin of retina makes to the onset and progression of several retinal diseases and will demonstrate that quantitation of fundus AF facilitates the diagnosis and monitoring of some retinal disorders.

Public Health Relevance

Retinal degeneration remains a major cause of legal blindness. Despite advances in the genetics of retinal degeneration, associated pathogenic processes largely defy elucidation. The work proposed in this application will address disease mechanisms that may be influential in both early onset and age-related macular degeneration and in some forms of retinitis pigmentosa.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BDCN-H (02))
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Shen, Grace L
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Columbia University
Schools of Medicine
New York
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Tanaka, Koji; Lee, Winston; Zernant, Jana et al. (2018) The Rapid-Onset Chorioretinopathy Phenotype of ABCA4 Disease. Ophthalmology 125:89-99
Duncker, Tobias; Lee, Winston; Jiang, Fan et al. (2018) ACUTE ZONAL OCCULT OUTER RETINOPATHY: Structural and Functional Analysis Across the Transition Zone Between Healthy and Diseased Retina. Retina 38:118-127
Paavo, Maarjaliis; Zhao, Jin; Kim, Hye Jin et al. (2018) Mutations in GPR143/OA1 and ABCA4 Inform Interpretations of Short-Wavelength and Near-Infrared Fundus Autofluorescence. Invest Ophthalmol Vis Sci 59:2459-2469
Schuerch, Kaspar; Woods, Russell L; Lee, Winston et al. (2017) Quantifying Fundus Autofluorescence in Patients With Retinitis Pigmentosa. Invest Ophthalmol Vis Sci 58:1843-1855
Zernant, Jana; Lee, Winston; Collison, Frederick T et al. (2017) Frequent hypomorphic alleles account for a significant fraction of ABCA4 disease and distinguish it from age-related macular degeneration. J Med Genet 54:404-412
Sparrow, Janet R (2017) Quantitative Fundus Autofluorescence. JAMA Ophthalmol 135:403
Boudreault, Katherine A; Schuerch, Kaspar; Zhao, Jin et al. (2017) Quantitative Autofluorescence Intensities in Acute Zonal Occult Outer Retinopathy vs Healthy Eyes. JAMA Ophthalmol 135:1330-1338
Lee, Winston; Schuerch, Kaspar; Zernant, Jana et al. (2017) Genotypic spectrum and phenotype correlations of ABCA4-associated disease in patients of south Asian descent. Eur J Hum Genet 25:735-743
Paavo, Maarjaliis; Lee, Winston; Merriam, John et al. (2017) Intraretinal Correlates of Reticular Pseudodrusen Revealed by Autofluorescence and En Face OCT. Invest Ophthalmol Vis Sci 58:4769-4777
De Rojas, Joaquin O; Schuerch, Kaspar; Mathews, Priya M et al. (2017) Evaluating Structural Progression of Retinitis Pigmentosa After Cataract Surgery. Am J Ophthalmol 180:117-123

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