Quantitative Fundus Autofluorescence and Optical Coherence Tomography in PRPH2/RDS- and ABCA4-Associated Disease Exhibiting Phenotypic Overlap.

Recessive Stargardt disease (STGD1), caused by mutations in the gene ABCA4,1 follows an autosomal recessive mode of inheritance and usually manifests in the first two decades of life,2 although late-onset forms of STGD1 also exist.3 Typical phenotypic features of STGD1 include intensely fluorescent foci (flecks) that emerge with disease progression, mottling of the retinal pigment epithelium (RPE), and central atrophy.4,5 These fundus changes can be confined to the macula or extend beyond the vascular arcades. Another fundus feature that is considered pathognomonic for ABCA4-related disease is relative sparing of the peripapillary area from flecks and atrophy.6,7 However, peripapillary sparing does not necessarily persist with ABCA4-related disease progression.8 Foveal atrophy is common in STGD1 patients, even at young ages, although in some patients the fovea is spared.9 On fluorescein angiography, STGD1 patients also often, but not always, exhibit a “dark choroid.”10 Despite the frequency with which STGD1 can be defined by these features, the phenotype is not necessarily exclusive to STGD1. For instance, peripapillary sparing can also be present in cases of pattern dystrophy (PD) without ABCA4 mutations,11 and both STGD1 and PD can present with pigmentary changes identified as flecks and mottling.12 Pattern dystrophy refers to a genetically heterogeneous group of retinal disorders, with mutations in PRPH2/RDS being the most common cause.4 Pattern dystrophy is usually inherited in an autosomal dominant manner and usually manifests in midlife with mild-to-moderate vision loss.13,14 In PD with an absence of ABCA4 mutations, foveal atrophy is generally found only in late stages of the disease.13 Histopathological studies, spectrophotometric analysis, and studies in mouse models have demonstrated over many years that the formation of RPE cell lipofuscin is augmented and pathogenic in ABCA4-associated disease.15–18 Retinal pigment epithelium lipofuscin, a mixture of fluorophores with spectral features that reflect its bisretinoid constituents,19 is the primary source of fundus AF, with a minor contribution from Bruch's membrane.20 We recently demonstrated that the increase in RPE lipofuscin in STGD1 can be measured indirectly by quantifying fundus autofluorescence intensities in images acquired by confocal scanning laser ophthalmoscope (cSLO).21,22 Quantitative fundus autofluorescence (qAF) was also shown to be a valuable tool for distinguishing ABCA4-related from non-ABCA4-related bull's-eye maculopathy (BEM).23 Here we present a patient cohort that, because they presented with clinical features of STGD1, were referred to our medical center for ABCA4 genetic screening. In all patients the clinical evaluation included qAF imaging and analysis. We report that some of these patients were ultimately found to carry mutations in PRPH2/RDS. The inheritance pattern of PD can often not be readily discerned because incomplete penetrance24 and variable expression can mask dominant inheritance. Whether PRPH2/RDS patients exhibit increased lipofuscin levels has been a matter of debate.4,25 Thus our objective was to consider whether qAF can assist in distinguishing ABCA4-related disease from disease caused by mutations in PRPH2/RDS and other unknown genes. Given the phenotypic overlap between some cases of ABCA4- and PRPH2/RDS-associated disease,4,5 we also assessed AF and spectral-domain optical coherence tomography (SD-OCT) images qualitatively to attempt to identify characteristic fundus features that may aid in the differentiation of these diseases. PRPH2/RDS-associated PD is generally considered to have a better prognosis than ABCA4-associated disease; thus it is important to differentiate the two conditions clinically.