Exome sequencing revealed a homozygous missense mutation (c.317C>G [p.Arg106Pro]) in POC1B, encoding POC1 centriolar protein B, in three siblings with autosomal-recessive cone dystrophy or cone-rod dystrophy and compound-heterozygous POC1B mutations (c.199_201del [p.Gln67del] and c.810+1G>T) in an unrelated person with cone-rod dystrophy. Upon overexpression of POC1B in human TERT-immortalized retinal pigment epithelium 1 cells, the encoded wild-type protein localized to the basal body of the primary cilium, whereas this localization was lost for p.Arg106Pro and p.Gln67del variant forms of POC1B. Morpholino-oligonucleotide-induced knockdown of poc1b translation in zebrafish resulted in a dose-dependent small-eye phenotype, impaired optokinetic responses, and decreased length of photoreceptor outer segments. These ocular phenotypes could partially be rescued by wild-type human POC1B mRNA, but not by c.199_201del and c.317C>G mutant human POC1B mRNAs. Yeast two-hybrid screening of a human retinal cDNA library revealed FAM161A as a binary interaction partner of POC1B. This was confirmed in coimmunoprecipitation and colocalization assays, which both showed loss of FAM161A interaction with p.Arg106Pro and p.Gln67del variant forms of POC1B. FAM161A was previously implicated in autosomal-recessive retinitis pigmentosa and shown to be located at the base of the photoreceptor connecting cilium, where it interacts with several other ciliopathy-associated proteins. Altogether, this study demonstrates that POC1B mutations result in a defect of the photoreceptor sensory cilium and thus affect cone and rod photoreceptors.

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We show that RPE atrophy represents a robust biomarker to monitor disease progression in future therapeutic trials. In contrast, the variability in terms of the course of visual acuity was high.

Refractive errors, in particular myopia, are common in IRD. The bipolar synapse and the inner and outer segments of the photoreceptor may serve as critical sites for myopia development.

These natural history data indicate differential disease progression in AMD versus late-onset STGD1. The results underline the relevance of refined phenotyping in elderly patients presenting with RPE atrophy in regard to prognosis and design of interventional trials.

Purpose To raise awareness of Stargardt disease (STGD1) patients without fundus abnormalities. Methods Medical records were evaluated for age at onset, initial symptoms and diagnosis, reason for delay of diagnosis, age at STGD1 diagnosis, best-corrected visual acuity (BCVA), ophthalmoscopy, fundus photography, fundus autofluorescence (FAF), fluorescein angiography (FA), spectral-domain optical coherence tomography (SD-OCT), full-field electroretinography (ffERG), color vision test, and the presence of ABCA4 variants. Results In 11.1% of our STGD1 cohort of 280 patients, no fundus abnormalities were observed at first ophthalmic consultation. The median age at onset was 8 years (range, 1-18). There was a median delay in diagnosis of 3 years (range, 0-19) in 27 out of 31 patients, which resulted in a median age at diagnosis of 12 years (range, 7-26). Patients were misdiagnosed with amblyopia, myopia, optic disk pathology, mental health problems, tension headache, neuritis bulbaris, and uveitis. Subtle abnormalities, such as lipofuscin accumulation, were seen on FAF at an earlier disease stage than in ophthalmoscopy. On SD-OCT, this included a thickened external limiting membrane. Color vision tests showed red-green insufficiency in 79% of patients. Reduced ERG amplitudes were only present in 26% (N = 8) and a dark choroid sign in 65% of the patients. Visual acuity considerably fluctuated in the first 5 years after onset. The majority of the patients (65%) carried a least one variant with a severe effect on ABCA4 function. Conclusions Childhood-onset STGD1 patients were diagnosed with a delay of median 3 years. The presence of accurate competence, equipment, and the possibility for genetic screening is required; therefore, we recommend to refer children with visual complaints without initial fundus abnormalities to a specialized ophthalmologic center. In particular, to diagnose patients at an early stage of disease is of increased importance with the advent of new therapeutic possibilities.

Purpose: To investigate intersibling phenotypic concordance in Stargardt disease (STGD1). Design: Retrospective cohort study. Participants: Siblings with genetically confirmed STGD1 and at least 1 available fundus autofluorescence (FAF) image of both eyes.Methods: We compared age at onset within families. Disease duration was matched to investigate differences in best-corrected visual acuity (BCVA) and compared the survival time for reaching severe visual impairment (<20/200 Snellen or >1.0 logarithm of the minimum angle of resolution [logMAR]). Central retinal atrophy area was quantified independently by 2 experienced graders using semiautomated software and compared between siblings. Both graders performed qualitative assessment of FAF and spectral-domain (SD) OCT images to identify phenotypic differences.Main Outcome Measures: Differences in age at onset, disease duration-matched BCVA, time to severe visual impairment development, FAF atrophy area, FAF patterns, and genotypes.Results: Substantial differences in age at onset were present in 5 of 17 families, ranging from 13 to 39 years. Median BCVA at baseline was 0.60 logMAR (range, e0.20 to 2.30 logMAR; Snellen equivalent, 20/80 [range, 20/12ehand movements]) in the right eye and 0.50 logMAR (range, e0.20 to 2.30 logMAR; Snellen equivalent, 20/63 [range, 20/12ehand movements]) in the left eye. Disease duration-matched BCVA was investigated in 12 of 17 families, and the median difference was 0.41 logMAR (range, 0.00e1.10 logMAR) for the right eye and 0.41 logMAR (range, 0.00e1.08 logMAR) for the left eye. We observed notable differences in time to severe visual impairment development in 7 families, ranging from 1 to 29 years. Median central retinal atrophy area was 11.38 mm 2 in the right eye (range, 1.98e44.78 mm 2 ) and 10.59 mm 2 in the left eye (range, 1.61e40.59 mm 2 ) and highly comparable between siblings. Similarly, qualitative FAF and SD OCT phenotypes were highly comparable between siblings.Conclusions: Phenotypic discordance between siblings with STGD1 carrying the same ABCA4 variants is a prevalent phenomenon. Although the FAF phenotypes are highly comparable between siblings, functional outcomes differ substantially. This complicates both sibling-based prognosis and genotype-phenotype correlations and has important implications for patient care and management.

BackgroundEach inherited retinal disorder is rare, but together, they affect millions of people worldwide. No treatment is currently available for these blinding diseases, but promising new options—including gene therapy—are emerging. Arguably, the most prevalent retinal dystrophy is Stargardt disease. In each case, the specific combination of ABCA4 variants (> 900 identified to date) and modifying factors is virtually unique. It accounts for the vast phenotypic heterogeneity including variable rates of functional and structural progression, thereby potentially limiting the ability of phase I/II clinical trials to assess efficacy of novel therapies with few patients. To accommodate this problem, we developed and validated a sensitive and reliable composite clinical trial endpoint for disease progression based on structural measurements of retinal degeneration.Methods and findingsWe used longitudinal data from early-onset Stargardt patients from the Netherlands (development cohort, n = 14) and the United Kingdom (external validation cohort, n = 18). The composite endpoint was derived from best-corrected visual acuity, fundus autofluorescence, and spectral-domain optical coherence tomography. Weighting optimization techniques excluded visual acuity from the composite endpoint. After optimization, the endpoint outperformed each univariable outcome, and showed an average progression of 0.41° retinal eccentricity per year (95% confidence interval, 0.30–0.52). Comparing with actual longitudinal values, the model accurately predicted progression (R2, 0.904). These properties were largely preserved in the validation cohort (0.43°/year [0.33–0.53]; prediction: R2, 0.872). We subsequently ran a two-year trial simulation with the composite endpoint, which detected a 25% decrease in disease progression with 80% statistical power using only 14 patients.ConclusionsThese results suggest that a multimodal endpoint, reflecting structural macular changes, provides a sensitive measurement of disease progression in Stargardt disease. It can be very useful in the evaluation of novel therapeutic modalities in rare disorders.