Bull's Eye Maculopathy Research Articles

Spectral-Domain Optical Coherence Tomography Is More Sensitive for Hydroxychloroquine-Related Structural Abnormalities Than Short-Wavelength and Near-Infrared Autofluorescence.

PurposeTo analyze the appearance of structural abnormalities due to hydroxychloroquine (HCQ) toxicity by spectral-domain optical coherence tomography (SD-OCT) and short-wavelength autofluorescence (SW-AF) and near-infrared fundus autofluorescence (NIR-AF) imaging.MethodsThis retrospective cohort study included 88 eyes from 44 patients who had a history of or were currently taking HCQ. SD-OCT, SW-AF, and NIR-AF images were analyzed by two independent graders for the detection of HCQ-associated abnormalities.ResultsSixty eyes (30 patients, 68%) presented with no abnormalities for either imaging modality. Twenty eyes (10 patients, 23%) presented with parafoveal abnormalities (ellipsoid zone attenuation and/or interdigitation zone continuity loss) in SD-OCT scans but with qualitatively normal SW-AF and NIR-AF images. Eight eyes (four patients, 9%) presented with bull's-eye maculopathy in SW-AF and NIR-AF images, with corresponding outer retinal structures disrupted parafoveally in SD-OCT scans (“flying saucer” sign). No patients presented with normal SD-OCT scans and concurrent abnormalities in SW-AF or NIR-AF images.ConclusionsSD-OCT was more sensitive in detecting structural abnormalities than either SW-AF or NIR-AF imaging, suggesting its superiority as a screening imaging modality for HCQ toxicity. Maculopathy and abnormalities in the retinal pigment epithelium from HCQ toxicity can be appreciated in both SW-AF and NIR-AF images.Translational RelevanceAlthough debate exists regarding the best imaging modalities for screening patients for potential HCQ toxicity, our study supports the use of SD-OCT over both SW-AF and NIR-AF imaging as a screening modality.

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

To investigate quantitatively lipofuscin-associated fundus autofluorescence in patients with macular and cone/cone-rod dystrophies (MD/CCRDs). Prospective, single-center, case-control study. Two hundred thirty patients with MD/CCRDs who had undergone genetic testing and 110 control participants without any eye disease. 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. The qAF8 levels. 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. 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.

Hydroxychloroquine-induced bull's eye maculopathy.

Hydroxychloroquine-induced bull's eye maculopathy.

DIFFUSE RETINAL VASCULAR LEAKAGE AND CONE-ROD DYSTROPHY IN A FAMILY WITH THE HOMOZYGOUS MISSENSE C.1429G>A (P.GLY477ARG) MUTATION IN CRB1.

To describe a specific cone-rod dystrophy phenotype in a family with the homozygous c.1429G>A; p.Gly477Arg mutation in CRB1. The detailed phenotype of subjects with this specific mutation has not been described previously. Clinical examination included full-field electroretinography and high-resolution and widefield retinal imaging and uveitis workup. Molecular genetic analysis included next-generation sequencing of known retinal dystrophy genes and Sanger sequencing for segregation analysis. Three affected male siblings (26, 16, and 8 years old) were diagnosed with cone-rod dystrophy, featuring bilateral macular hypoautofluorescent lesions. In addition, the eldest brother was found to have retinal vascular leakage throughout the retina without telangiectasia. Uveitis laboratory workup was unremarkable. The homozygous c.1429G>A; p.Gly477Arg mutation in CRB1 was found to segregate with disease in this family. To the best of our knowledge, diffuse vascular leakage without telangiectasia or exudation, with bull's eye maculopathy, has not been reported previously in CRB1-cone rod dystrophy. This expands the phenotype complexity associated with CRB1 mutations and confirms that dystrophies associated with mutations in this gene may appear with features of uveitis.

Clinico- investigative profile of 7 genetically confirmed cases of neuronal ceroid lipofuscinosis: Indian perspective

To describe a cohort of genetically confirmed Neuronal Ceroid Lipofuscinoses (NCL) from a tertiary-care institute from India. A retrospective study on genetically confirmed NCL's (2017–2019). A total of 7 patients were classified into 5 subgroups based on protein and gene defect. CLN7-NCL = 2 patients, mean age of onset 3.5 years, both males, clinically had developmental delay and regression following a febrile illness. One patient had spasmus nutans and bulls eye maculopathy. Homozygous 5′ splice site variation in intron 9, c.863 + 1G > A (5′ splice site) of the MFSD8 gene(chr4:128854139C > T) was detected in one patient and deletion of exon 1 to 3 in MFSD8 gene in the other. CLN6-NCL = 2 patients, mean age of onset 9.5 years, M:F = 1:1, had developmental delay, seizures and progressive extrapyramidal manifestations. Homozygous mutations in CLN6 gene at Exon 4 c.425A > G(p.Tyr142Cys); and Exon 2 c.103G > A(p.Asp35Asn) respectively. CLN1-NCL = 1 patient, age of onset 1.5 years boy, had developmental delay, regression, hypertonia and retinitis pigmentosa. Neuroimaging showed diffuse cortical atrophy. Compound heterozygous mutations in PPT1 gene at Exon 7 c.674 T > C(p.Phe225Ser) and Exon 7 c.651_671 del(p.Asn218_Lys224del) was present. CLN3-NCL = 1, age of onset 8 years, male, had progressive vision loss, cognitive decline with autistic features. Neuroimaging showed cerebellar and cerebral atrophy. Compound heterozygous mutations noted in Intron 9 c.534-2A > G(splice site) and Exon 10 c.565G > T(p.Gly189Trp) of CLN3 gene respectively. CLN8 = 1, age of onset 5 years with regression, cerebellar and visual symptoms, genetically had homozygous mutation in CLN8 gene[c.208C > T(p.Arg70Cys)]. This study describes a cohort of genetically confirmed NCL's from our centre and demonstrates the genetic heterogeneity.

Retinal dystrophies with bull's-eye maculopathy along with negative ERGs.

The aim of this study was to examine the ophthalmological characteristics and genotypes of patients with congenital retinal pathologies, who display a bull's-eye maculopathy in the fundus, along with a negative scotopic electroretinogram. We analysed the results of five patients showing both a bull's-eye maculopathy, as well as a negative scotopic ERG evoked by a bright flash. Their median age was 39years (range 11-63years): three males and two females. All underwent a comprehensive examination with determination of distant visual acuity (ETDRS) and recording of the full-field ERG (scotopic and photopic). Fundus, OCT, and FAF images were obtained, the kinetic visual field was determined, and colour vision (D-15) was tested in most patients. Targeted gene panel sequencing was performed on peripheral blood. One patient carried a homozygous ABCA4 mutation and an additional heterozygous variant in CRX. Two of the five patients were shown to have a heterozygous mutation in the CRX gene, one of whom had an additional heterozygous ABCA4 mutation. Two patients had the common heterozygous mutation c.2413G>A;p.Arg838His in GUCY2D. In all of the patients, there was a reduction in the amplitude of the b-wave with a regular a-wave amplitude in the scotopic bright-flash ERG. The five patients with bull's-eye maculopathy along with a negative ERG had differing genotypes. Mutations were found in the CRX gene (2 patients), the ABCA4 gene (1 patient), and the GUCY2D gene (2 patients).

Incidence of blindness in a population of rheumatic patients treated with hydroxychloroquine.

ObjectiveLong-term HCQ use for the treatment of rheumatic diseases has been associated with retinopathy in a daily and cumulative dose-dependent manner by weight. We examined the incidence of ocular toxicity in a large population of patients treated with HCQ for inflammatory arthritis and SLE and followed long term in a tertiary centre.MethodsOur retrospective longitudinal review identified 2867 rheumatic patients from 1999 to August 2017 who had a prescription written for HCQ. Thirty-one patients were identified as having a diagnosis of blindness or toxic maculopathy in their electronic medical record, and we carried out an extensive chart review.ResultsOf our 31 patients with a diagnosis of blindness or toxic maculopathy, 11 had documented blindness, in all cases attributed to a cause other than HCQ-related ocular toxicity: stroke (27%), pre-existing macular disease (18%), diabetic retinopathy (18%), hypertensive retinopathy (9%) and cataracts (9%). Seventeen of 31 patients had visual impairment that was multifactorial and unrelated to HCQ. We identified two patients with bull’s eye maculopathy [person-time incidence rate, 0.12 cases per 1000 person-years (95% CI: 0.01, 0.43)] and one with early HCQ toxic maculopathy [person-time incidence rate, 0.06 cases per 1000 person-years (95% CI: 0.002, 0.33)]. All three patients received HCQ for >18 years, and none had functional vision loss at diagnosis.ConclusionHCQ-induced macular toxicity is rare in routine clinical practice, seems to require prolonged HCQ therapy (>18 years) and is not necessarily associated with functional visual loss. Our findings suggest that co-morbid conditions that are common in RA and SLE contribute substantially to vision loss and should not be ignored.

Long term follow-up of a family with GUCY2D dominant cone dystrophy.

To describe long term follow-up in a family with GUCY2D dominant cone dystrophy. Optical coherence tomography scans and fundus autofluorescence images were obtained. Flash and pattern electroretinograms (ERGs) and occipital pattern reversal visual evoked potentials were recorded. Two members of the same family (father and son) were identified to have the heterozygous R838C mutation in the GUCY2D gene. The father presented at the age of 45 with bilateral bull's eye maculopathy and temporal disc pallor. Over 13y of serial follow up visits, the bull's eye maculopathy progressed gradually into macular atrophy. Electrophysiological tests were significantly degraded suggesting poor macular function. Spectral-domain optical coherence tomography (SD-OCT) scans showed progressive loss and disruption of the ellipsoid layer at the foveal level. His son presented at the age of 16 with bilateral granular retinal pigment epithelial changes in both maculae. Electrophysiological testing was initially borderline normal but has gradually deteriorated to show reduced cone ERGs and macula function. SD-OCT demonstrated gradual macular thinning and atrophy bilaterally. Unlike his father, there was no disruption of the ellipsoid layer. Both family members exhibited gradual changes in their fundi, electrophysiological testing and multimodal imaging. Changes were milder than those observed in other mutations of the same gene.

Novel clinical findings in autosomal recessive NR2E3-related retinal dystrophy.

To evaluate the clinical phenotype of autosomal recessive NR2E3-related retinal dystrophy. We retrospectively studied 11 patients carrying out at least 2 NR2E3 mutations; they had undergone comprehensive ophthalmological examination, fundus photography, optical coherence tomography, electrophysiological testing, and visual field at the Regional Reference Center for Hereditary Retinal Degenerations of the Eye Clinic in Florence. Five females and six males with a diagnosis of NR2E3-related retinal dystrophy were included in the study. All patients complained of nyctalopia. Visual acuity ranged from 0.00 logMAR to hand motion. Two patients presented bull's eye maculopathy, and one of these was characterized by a triple hyper-autofluorescent ring at the fundus autofluorescence examination. Three patients showed small yellowish dots and spots at the mid-periphery. One patient was characterized by widespread subretinal drusenoid deposits (SDD) at the posterior pole. Four patients showed vitreous abnormalities. Optical coherence tomography (OCT) examinations detected variable degrees of abnormal retinal lamination and schitic changes. Seven patients were compound heterozygous and four were homozygous for mutations in NR2E3. Our study confirmed high variable phenotype in autosomal recessive NR2E3-related retinal dystrophy. Bull's eye maculopathy, subretinal drusenoid deposits, and foveal hypoplasia represent novel clinical findings in NR2E3-related retinal dystrophy. Macular involvement was detectable in all the patients, and the abnormal foveal avascular zone (FAZ) supports the role of NR2E3 in retinal development.

Next generation sequencing in the diagnosis of Stargardt's disease

Abstract Introduction Stargardt's disease is the most frequent form of inherited macular dystrophy in children and adults. It is a genetic eye disorder caused by mutations in ABCA4 gene with an autosomal recessive inheritance. ABCA4 is a very polymorphic and large gene containing 50 exons. The development of next generation sequencing (NGS) can be used for the genetic diagnosis of this disease. Patients and methods A report is presented on two patients with a clinical diagnosis of Stargardt's disease whose genetic confirmation was performed by a NGS panel of 298 genes. Results Clinically, the patients showed bull's eye maculopathy and absence of flecks, and genetically they shared the Gly1961Glu mutation that could explain their common phenotype, together with c.C3056T:p.T1019M for case 1, and c.287del:p.Asn96Thrfs*19 for case 2. Conclusions NGS is particularly useful in the diagnosis of Stargardt's disease as ABCA4 is a large gene with a high allelic heterogeneity that causes a wide range of clinical manifestations.

La secuenciación masiva (NGS) como método diagnóstico en la enfermedad de Stargardt

IntroductionStargardt‘s disease is the most frequent form of inherited macular dystrophy in children and adults. It is a genetic eye disorder caused by mutations in ABCA4 gene with an autosomal recessive inheritance. ABCA4 is a very polymorphic and large gene containing 50 exons. The development of next generation sequencing (NGS) can be used for the genetic diagnosis of this disease. Patients and methodsA report is presented on two patients with a clinical diagnosis of Stargardt's disease whose genetic confirmation was performed by a NGS panel of 298 genes. ResultsClinically, the patients showed bull's eye maculopathy and absence of flecks, and genetically they shared the Gly1961Glu mutation that could explain their common phenotype, together with c.C3056T:p.T1019M for case 1, and c.287del:p.Asn96Thrfs*19 for case 2. ConclusionsNGS is particularly useful in the diagnosis of Stargardt's disease as ABCA4 is a large gene with a high allelic heterogeneity that causes a wide range of clinical manifestations.

A neurodevelopmental disorder with a nonsense mutation in the Ox-2 antigen domain of the amyloid precursor protein (APP) gene

ABSTRACTWe report a patient, an infant with a neurodevelopmental disorder manifesting intractable complex partial epilepsy, bull's eye maculopathy, microcephaly, bilateral cataracts, truncal hypotonia, and spasticity of all four extremities. Sequencing of genomic DNA revealed mutations in (a) exon 8 (Ox-2 antigen domain) of the amyloid precursor protein (APP) gene: c.1075C>T, p.Arg359* (b) exon 8 of the senataxin (SETX) gene: c.4738C>T, p.Arg1580Cys, and (c) exon 2 of the ceroid-lipofuscinosis, neuronal 8 (CLN8) gene: c.685C>G, p.Pro229Ala. Using a quantitative method for measurement of various APP-mRNA isoforms, we found that the APP-mRNA isoform of 624 bp with a deletion starting after 49 bp of the 5′ end of exon 3 followed by a complete deletion of exons 4–15, mutations in exon 1: c.22C>T, p.L18F, and exon 3: c.269A>G, p.Q90R encoding APP207 isoform was the most abundant one, and would appear to be responsible for the clinical manifestations. This is the first example that may underline the role of the epigenetic regulation in the expression of APP gene leading to a neurodevelopmental disorder resulting from a nonsense mutation in the Ox-2 antigen domain.

Case series of Stargardt's disease: Our experience

Stargardt disease is the most common form of juvenile macular degeneration. Clinically, it is characterized by pisciform flecks at lhe level of the retinal pigment epithelium and a bull's-eye maculopathy. Inheritance is usually autosomal recessive, although dominantly inherited case have been described. Both sexes are affected equally. We reported here three cases of Stargardt's macular dystrophy, who are siblings and daughters of non consanguineous parents. In case-1,2 and 3 we found the typical presentation with almost same findings.

Hydroxychloroquine Induced Toxicity Presenting As Bulls Eye Maculopathy: A Case Report

Hydroxychloroquine Induced Toxicity Presenting As Bulls Eye Maculopathy: A Case Report

Recessive Stargardt disease phenocopying hydroxychloroquine retinopathy.

To describe a series of patients with Stargardt disease (STGD1) exhibiting a phenotype usually associated with hydroxychloroquine (HCQ) retinopathy on spectral domain-optical coherence tomography (SD-OCT). Observational case series from Columbia University Medical Center involving eight patients with genetically-confirmed STGD1. Patients selected for the study presented no history of HCQ use. Horizontal macular SD-OCT scans and accompanying 488-nm autofluorescence (AF) images, color fundus photographs, and full-field electroretinograms were analyzed. All study patients exhibited an abrupt thinning of the parafoveal region or disruption of the outer retinal layers on SD-OCT resembling the transient HCQ retinopathy phenotype. Funduscopy and AF imaging revealed variations of bull's eye maculopathy (BEM). Five patients exhibited local fleck-like deposits around the lesion. Genetic screening confirmed two disease-causing ABCA4 mutations in five patients and one mutation in three patients. A transient SD-OCT phenotype ascribed to patients with HCQ retinopathy is associated with an early subtype of STGD1. This finding may also present with HCQ retinopathy-like BEM lesions on AF imaging and funduscopy. A possible phenotypic overlap is unsurprising, given certain shared mechanistic disease processes between the two conditions. A thorough work-up, including screening of genes that are causal in retinal dystrophies associated with foveal sparing, may prevent misdiagnosis of more ambiguous cases.

Quantitative Fundus Autofluorescence and Optical Coherence Tomography inPRPH2/RDS- andABCA4-Associated Disease Exhibiting Phenotypic Overlap

To assess whether quantitative fundus autofluorescence (qAF), a measure of RPE lipofuscin, and spectral-domain optical coherence tomography (SD-OCT) can aid in the differentiation of patients with fundus features that could either be related to ABCA4 mutations or be part of the phenotypic spectrum of pattern dystrophies. Autofluorescence images (30°, 488-nm excitation) from 39 patients (67 eyes) were acquired with a confocal scanning laser ophthalmoscope equipped with an internal fluorescent reference and were quantified as previously described. In addition, horizontal SD-OCT images through the fovea were obtained. Patients were screened for ABCA4 and PRPH2/RDS mutations. ABCA4 mutations were identified in 19 patients (mean age, 37 ± 12 years) and PRPH2/RDS mutations in 8 patients (mean age, 48 ± 13 years); no known ABCA4 or PRPH2/RDS mutations were found in 12 patients (mean age, 48 ± 9 years). Differentiation of the groups using phenotypic SD-OCT and AF features (e.g., peripapillary sparing, foveal sparing) was not reliable. However, patients with ABCA4 mutations could be discriminated reasonably well from other patients when qAF values were corrected for age and race. In general, ABCA4 patients had higher qAF values than PRPH2/RDS patients, while most patients without mutations in PRPH2/RDS or ABCA4 had qAF levels within the normal range. The high qAF levels of ABCA4-positive patients are a hallmark of ABCA4-related disease. The reason for high qAF among many PRPH2/RDS-positive patients is not known; higher RPE lipofuscin accumulation may be a primary or secondary effect of the PRPH2/RDS mutation.

Bull's Eye Maculopathy in an HIV-Positive Patient Receiving Ritonavir

Retinal toxicity involving the macula as a complication of the antiretroviral protease inhibitor ritonavir has been described in a few cases. We report retinal pigment epitheliopathy involving the macula with a bull's eye pattern in a 36-year-old man with well-controlled HIV receiving ritonavir with gradually progressive bilateral vision loss.

New mutations in the RAB28 gene in 2 Spanish families with cone-rod dystrophy.

The families evaluated in this study represent the second report of cone-rod dystrophy (CRD) cases caused by mutations in RAB28, a recently discovered gene associated with CRD. To determine the disease-causing gene in 2 families of Spanish descent presenting with CRD who do not have ABCA4 mutations. Molecular genetics and observational case studies of 2 families, each with 1 affected proband with CRD and 3 or 5 unaffected family members. The affected individual from each family received a complete ophthalmic examination including assessment of refractive errors and best-corrected visual acuity, biomicroscopy, color fundus photography, electroretinography analysis, and visual-evoked potential analysis. After complete sequencing of the ABCA4 gene with negative results, the screening for disease-causing mutations was performed by whole-exome sequencing. Possible disease-associated variants were determined by filtering based on minor allele frequency, predicted pathogenicity, and segregation analysis in all family members. The appearance of the macula was evaluated by clinical examination, fundus photography, and fundus autofluorescence imaging, and visual function was assessed by electroretinography. Disease-causing mutations were assessed by sequence analyses. Ophthalmologic findings included markedly reduced visual acuity, bull's eye maculopathy, foveal hyperpigmentation, peripapillary atrophy, dyschromatopsia, extinguished photopic responses, and reduced scotopic responses observed on electroretinography consistent with the CRD phenotype often associated with ABCA4 mutations. Although no ABCA4 mutations were detected in either patient, whole-exome sequencing analysis identified 2 new homozygous mutations in the recently described RAB28 gene, the c.172 + 1G>C splice site variant in IVS2 and the missense c.T651G:p.C217W substitution. Both variants were determined as deleterious by predictive programs and were segregated with the disease in both families. Sequencing of 107 additional patients of Spanish descent with CRD did not reveal other cases with RAB28 mutations. Deleterious mutations in RAB28 result in a classic CRD phenotype and are an infrequent cause of CRD in the Spanish population.

The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy.

Hydroxychloroquine sulfate is widely used for the long-term treatment of autoimmune conditions but can cause irreversible toxic retinopathy. Prior estimations of risk were low but were based largely on short-term users or severe retinal toxicity (bull's eye maculopathy). The risk may be much higher because retinopathy can be detected earlier when using more sensitive screening techniques. To reassess the prevalence of and risk factors for hydroxychloroquine retinal toxicity and to determine dosage levels that facilitate safe use of the drug. Retrospective case-control study in an integrated health organization of approximately 3.4 million members among 2361 patients who had used hydroxychloroquine continuously for at least 5 years according to pharmacy records and who were evaluated with visual field testing or spectral-domain optical coherence tomography. Hydroxychloroquine use for at least 5 years. Retinal toxicity as determined by characteristic visual field loss or retinal thinning and photoreceptor damage, as well as statistical measures of risk factors and prevalence. Real body weight predicted risk better than ideal body weight and was used for all calculations. The overall prevalence of hydroxychloroquine retinopathy was 7.5% but varied with daily consumption (odds ratio, 5.67; 95% CI, 4.14-7.79 for >5.0 mg/kg) and with duration of use (odds ratio, 3.22; 95% CI, 2.20-4.70 for >10 years). For daily consumption of 4.0 to 5.0 mg/kg, the prevalence of retinal toxicity remained less than 2% within the first 10 years of use but rose to almost 20% after 20 years of use. Other major risk factors include kidney disease (odds ratio, 2.08; 95% CI, 1.44-3.01) and concurrent tamoxifen citrate therapy (odds ratio, 4.59; 95% CI, 2.05-10.27). These data suggest that hydroxychloroquine retinopathy is more common than previously recognized, especially at high dosages and long duration of use. While no completely safe dosage is identified from this study, daily consumption of 5.0 mg/kg of real body weight or less is associated with a low risk for up to 10 years. Knowledge of these data and risk factors should help physicians prescribe hydroxychloroquine in a manner that will minimize the likelihood of vision loss.

Quantitative Fundus Autofluorescence Distinguishes ABCA4-Associated and Non–ABCA4-Associated Bull's-Eye Maculopathy

Quantitative fundus autofluorescence (qAF) and spectral-domain optical coherence tomography (SD OCT) were performed in patients with bull's-eye maculopathy (BEM) to identify phenotypic markers that can aid in the differentiation of ABCA4-associated and non-ABCA4-associated disease. Prospective cross-sectional study at an academic referral center. Thirty-seven BEM patients (age range, 8-60 years) were studied. All patients exhibited a localized macular lesion exhibiting a smooth contour and qualitatively normal-appearing surrounding retina without flecks. Control values consisted of previously published data from 277 healthy subjects (374 eyes; age range, 5-60 years) without a family history of retinal dystrophy. Autofluorescence (AF) images (30°, 488-nm excitation) were acquired with a confocal scanning laser ophthalmoscope equipped with an internal fluorescent reference to account for variable laser power and detector sensitivity. The grey levels (GLs) from 8 circularly arranged segments positioned at an eccentricity of approximately 7° to 9° in each image were calibrated to the reference (0 GL), magnification, and normative optical media density to yield qAF. In addition, horizontal SD OCT images through the fovea were obtained. All patients were screened for ABCA4 mutations using the ABCR600 microarray, next-generation sequencing, or both. Quantitative AF, correlations between AF and SD OCT, and genotyping for ABCA4 variants. ABCA4 mutations were identified in 22 patients, who tended to be younger (mean age, 21.9±8.3 years) than patients without ABCA4 mutations (mean age, 42.1±14.9 years). Whereas phenotypic differences were not obvious on the basis of qualitative fundus AF and SD OCT imaging, with qAF, the 2 groups of patients were clearly distinguishable. In the ABCA4-positive group, 37 of 41 eyes (19 of 22 patients) had qAF8 of more than the 95% confidence interval for age. Conversely, in the ABCA4-negative group, 22 of 26 eyes (13 of 15 patients) had qAF8 within the normal range. The qAF method can differentiate between ABCA4-associated and non-ABCA4-associated BEM and may guide clinical diagnosis and genetic testing.