OBJECTIVE: To investigate the distribution of genotypes and natural history of ABCA4-associated retinal disease in a large cohort of patients seen at a single institution.
METHODS: Retrospective, single-institution cohort review.
METHODS: Patients seen at the University of Iowa between November 1986 and August 2022 clinically suspected to have disease caused by sequence variations in ABCA4.
METHODS: DNA samples from participants were subjected to a tiered testing strategy progressing from allele-specific screening to whole genome sequencing. Charts were reviewed, and clinical data were tabulated. The pathogenic severity of the most common alleles was estimated by studying groups of patients who shared 1 allele. Groups of patients with shared genotypes were reviewed for evidence of modifying factor effects.
METHODS: Age at first uncorrectable vision loss, best-corrected visual acuity, and the area of the I2e isopter of the Goldmann visual field.
RESULTS: A total of 460 patients from 390 families demonstrated convincing clinical features of ABCA4-associated retinal disease. Complete genotypes were identified in 399 patients, and partial genotypes were identified in 61. The median age at first vision loss was 16 years (range, 4-76 years). Two hundred sixty-five families (68%) harbored a unique genotype, and no more than 10 patients shared any single genotype. Review of the patients with shared genotypes revealed evidence of modifying factors that in several cases resulted in a > 15-year difference in age at first vision loss. Two hundred forty-one different alleles were identified among the members of this cohort, and 161 of these (67%) were found in only a single individual.
CONCLUSIONS: ABCA4-associated retinal disease ranges from a very severe photoreceptor disease with an onset before 5 years of age to a late-onset retinal pigment epithelium-based condition resembling pattern dystrophy. Modifying factors frequently impact the ABCA4 disease phenotype to a degree that is similar in magnitude to the detectable ABCA4 alleles themselves. It is likely that most patients in any cohort will harbor a unique genotype. The latter observations taken together suggest that patients\' clinical findings in most cases will be more useful for predicting their clinical course than their genotype.
BACKGROUND: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

UNASSIGNED: To examine the potential of different head-mounted displays in the rehabilitation of individuals with visual impairment.
UNASSIGNED: This prospective explorative study conducted between September 2019 and August 2020 included participants with Stargardt disease with moderate to severe visual impairment and a relatively preserved peripheral visual field. AceSight, eSight 3, IrisVision Live, and Jordy were tested. After instruction and training, participants chose two head-mounted displays for home use for two weeks per device. The Canadian Occupational Performance Measure was used for evaluation.
UNASSIGNED: Twelve participants (aged 16-53 years) tested all head-mounted displays in the clinic. Distance visual acuity and reading distance improved with all head-mounted displays and eSight and Irisvision improved near visual acuity. Six participants decided not to test the head-mounted display at home due to lack of time or energy, dizziness and discomfort, double vision and peripheral visual field limitation, or aesthetics. After home use, the participants reported improved visual function at a distance with IrisVision, AceSight, and e-Sight, whereas only AceSight improved vision during near tasks. IrisVision and eSight improved reading ability, and none of the devices improved vision during tasks involving computers. Five participants used the devices sparingly, and five avoided public use owing to aesthetics.
UNASSIGNED: We found an improvement in distance visual acuity and increased reading distance for all tested head-mounted displays. Additionally, IrisVision and eSight improved visual function at near and eSight also improved contrast vision at distance. Despite the possibility of improving vision, social stigma and device aesthetics kept the participants from using head-mounted displays in public and limited their use at home.

Background: This report describes the study design and baseline characteristics of patients with Stargardt disease (STGD1) enrolled in the STArgardt Remofuscin Treatment Trial (STARTT). Methods: In total, 87 patients with genetically confirmed STGD1 were randomized in a double-masked, placebo-controlled proof of concept trial to evaluate the safety and efficacy of 20 milligram oral remofuscin for 24 months. The primary outcome measure is change in mean quantitative autofluorescence value of an 8-segment ring centred on the fovea (qAF 8). Secondary efficacy variables are best corrected visual acuity (BCVA), low-luminance visual acuity (LLVA), mesopic microperimetry (mMP),  spectral domain optical coherence tomography (SD-OCT), reading speed on Radner reading charts, and patient-reported visual function as assessed by the National Eye Institute Visual Functioning Questionnaire 25 (NEI VFQ-25) and Functional Reading Independence (FRI) Index. Results: Mean age of participants was 35±11 years with 49 (56%) female. Median qAF 8 value was 438 Units (range 210-729). Median BCVA and LLVA in decimal units were 0.50 (range 0.13-0.80) and 0.20 (range 0.06-0.63), respectively. The median of the mean retinal sensitivity with mMP was 20.4 dB (range 0.0-28.8). SD-OCT showed median central subfield retinal thickness of 142 µm (range 72-265) and median macular volume of 1.65 mm 3 (range 1.13-2.19). Compared to persons without vision impairment, both reading performance and patient-reported visual function were significantly lower (p<0.001, one sample t-test). Mean reading speed was 108±39 words/minute with logRAD-score of 0.45±0.28. Mean VFQ-25 composite score was 72±13. Mean FRI Index score 2.8±0.6. Conclusions: This trial design may serve as reference for future clinical trials as it explores the utility of qAF 8 as primary outcome measure. The baseline data represent the largest, multi-national, STGD1 cohort to date that underwent standardized qAF imaging, reading speed assessment and vision-related quality of life measures which all contribute to the characterization of STGD1. EudraCT registration: 2018-001496-20 (09/05/2019).

OBJECTIVE: Late-onset Stargardt disease is a subtype of Stargardt disease type 1 (STGD1), defined by an age of onset of 45 years or older. We describe the disease characteristics, underlying genetics, and disease progression of late-onset STGD1 and highlight the differences from geographic atrophy.
METHODS: Retrospective cohort study.
METHODS: Seventy-one patients with late-onset STGD1.
METHODS: Medical files were reviewed for clinical data including age at onset, initial symptoms, and best-corrected visual acuity. A quantitative and qualitative assessment of retinal pigment epithelium (RPE) atrophy was performed on fundus autofluorescence images and OCT scans.
METHODS: Age at onset, genotype, visual acuity, atrophy growth rates, and loss of external limiting membrane, ellipsoid zone, and RPE.
RESULTS: Median age at onset was 55.0 years (range, 45-82 years). A combination of a mild and severe variant in ATP-binding cassette subfamily A member 4 (ABCA4) was the most common genotype (n = 49 [69.0%]). The most frequent allele, c.5603A→T (p.Asn1868Ile), was present in 43 of 71 patients (60.6%). No combination of 2 severe variants was found. At first presentation, all patients have flecks. Foveal-sparing atrophy was present in 33.3% of eyes, whereas 21.1% had atrophy with foveal involvement. Extrafoveal atrophy was present in 38.9% of eyes, and no atrophy was evident in 6.7% of eyes. Time-to-event curves showed a median duration of 15.4 years (95% confidence interval, 11.1-19.6 years) from onset to foveal involvement. The median visual acuity decline was -0.03 Snellen decimal per year (interquartile range [IQR], -0.07 to 0.00 Snellen decimal; 0.03 logarithm of the minimum angle of resolution). Median atrophy growth was 0.590 mm2/year (IQR, 0.046-1.641 mm2/year) for definitely decreased autofluorescence and 0.650 mm2/year (IQR, 0.299-1.729 mm2/year) for total decreased autofluorescence.
CONCLUSIONS: Late-onset STGD1 is a subtype of STGD1 with most commonly 1 severe and 1 mild ABCA4 variant. The general patient presents with typical fundus flecks and retinal atrophy in a foveal-sparing pattern with preserved central vision. Misdiagnosis as age-related macular degeneration should be avoided to prevent futile invasive treatments with potential complications. In addition, correct diagnosis lends patients with late-onset STGD1 the opportunity to participate in potentially beneficial therapeutic trials for STGD1.
BACKGROUND: The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Inherited retinal dystrophies (IRDs) are genetic disorders that lead to the bilateral degeneration of the retina, causing irreversible vision loss. These conditions often manifest during the first and second decades of life, and their primary symptoms can be non-specific. Diagnostic processes encompass assessments of best-corrected visual acuity, fundoscopy, optical coherence tomography, fundus autofluorescence, fluorescein angiography, electrophysiological tests, and genetic testing. This study focuses on the application of adaptive optics (AO), a non-invasive retinal examination, for the assessment of patients with IRDs. AO facilitates the high-quality, detailed observation of retinal photoreceptor structures (cones and rods) and enables the quantitative analysis of parameters such as cone density (DM), cone spacing (SM), cone regularity (REG), and Voronoi analysis (N%6). AO examinations were conducted on eyes diagnosed with Stargardt disease (STGD, N=36), cone dystrophy (CD, N=9), and cone-rod dystrophy (CRD, N=8), and on healthy eyes (N=14). There were significant differences in the DM, SM, REG, and N%6 parameters between the healthy and IRD-affected eyes (p<0.001 for DM, SM, and REG; p=0.008 for N%6). The mean DM in the CD, CRD, and STGD groups was 8900.39/mm2, 9296.32/mm2, and 16,209.66/mm2, respectively, with a significant inter-group difference (p=0.006). The mean SM in the CD, CRD, and STGD groups was 12.37 μm, 14.82 μm, and 9.65 μm, respectively, with a significant difference observed between groups (p=0.002). However, no significant difference was found in REG and N%6 among the CD, CRD, and STGD groups. Significant differences were found in SM and DM between CD and STGD (p=0.014 for SM; p=0.003 for DM) and between CRD and STGD (p=0.027 for SM; p=0.003 for DM). Our findings suggest that AO holds significant potential as an impactful diagnostic tool for IRDs.

Long-term natural history studies are important in rare disease research. This study aimed to assess electrophysiological and fundus autofluorescence (FAF) progression rate in 18 genetically confirmed Stargardt disease (STGD1) patients with a minimum follow-up of 10 years. Age at the first and last exams, age at onset, Snellen decimal visual acuity (VA), electroretinography (ERG), and FAF images were evaluated. Patients were classified into four Fishman stages and three electroretinography groups, and areas of definitely decreased autofluorescence (DDAF) were measured. Patients were further substratified based on genotype, and phenotype-genotype correlations were performed. The median follow-up was 18 (range 10-26) years. The median yearly VA loss was 0.009 (range 0.002-0.071), while the median progression rate of the DDAF area was 0.354 (range 0.002-4.359) mm2 per year. Patients harbouring p.(Gly1961Glu) or p.(Asn1868Ile) allele had significantly slower DDAF area progression when compared to patients with other genotypes (0.07 mm2 vs. 1.03 mm2, respectively), as well as significantly later age at onset (20 years vs. 13 years, respectively). Results showed that structural and functional parameters, together with genotype, should be considered when counselling patients regarding prognosis and monitoring disease progression. Patients harbouring hypomorphic variants p.(Gly1961Glu) or p.(Asn1868Ile) presented with overall milder disease than patients with other genotypes.

The retina-specific ATP-binding cassette transporter protein ABCA4 is responsible for properly continuing the visual cycle by removing toxic retinoid byproducts of phototransduction. Functional impairment caused by ABCA4 sequence variations is the leading cause of autosomal recessive inherited retinal disorders, including Stargardt disease, retinitis pigmentosa, and cone-rod dystrophy. To date, more than 3000 ABCA4 genetic variants have been identified, approximately 40 percent of which have not been able to be classified for pathogenicity assessments. This study examined 30 missense ABCA4 variants using AlphaFold2 protein modeling and computational structure analysis for pathogenicity prediction. All variants classified as pathogenic (n = 10) were found to have deleterious structural consequences. Eight of the ten benign variants were structurally neutral, while the remaining two resulted in mild structural changes. This study\'s results provided multiple lines of computational pathogenicity evidence for eight ABCA4 variants of uncertain clinical significance. Overall, in silico analyses of ABCA4 can provide a valuable tool for understanding the molecular mechanisms of retinal degeneration and their pathogenic impact.

This study assesses the repeatability of quantitative autofluorescence (qAF) in a multicenter setting and evaluates qAF as the end point for clinical trials in recessive Stargardt disease 1 (STGD1).
A total of 102 patients with STGD1 underwent qAF imaging as part of the Stargardt Remofuscin Treatment Trial (STARTT; EudraCT No. 2018-001496-20). For 166 eyes, we obtained qAF imaging at 2 visits, with 2 recordings per visit. The qAF8 values were independently determined by the study site and a central reading center. Intra- and inter-visit reproducibility, as well as interobserver (study site versus reading center) reproducibility were obtained using intraclass correlation (ICC), one-sample t-test, and Bland-Altman coefficient of repeatability.
The qAF repeatability was ± 26.1% for intra-visit, ± 40.5% for inter-visit, and ± 20.2% for the interobserver reproducibility measures. Intra-visit repeatability was good to excellent for all sites (ICC of 0.88-0.96). Variability between visits was higher with an overall ICC of 0.76 (0.69-0.81). We observed no significant difference in qAF values across sites between visits (7.06 ± 93.33, P = 0.238).
Real-life test-retest variability of qAF is higher in this set of data than previously reported in single center settings. With improved operator training and by selecting the better of two recordings for evaluation, qAF serves as a useful method for assessing changes in autofluorescence signal.
The qAF can be adopted as a clinical trial end point, but steps to counterbalance variability should be considered.

To assess the safety of injecting human embryonic stem cell retinal pigment epithelial cell dose to treat Stargardt disease.
In this prospective, Phase I clinical trial, human embryonic stem cell retinal pigment epithelial cells in suspension were injected into the subretinal space in eyes with the worse best-corrected visual acuity (BCVA). After vitrectomy/posterior hyaloid removal, a partial retinal detachment was created and the human embryonic stem cell retinal pigment epithelial cells were administered. Phacoemulsification with intraocular lens implantation was performed in eyes with lens opacity. All procedures were optical coherence tomography-guided. The 12-month follow-up included retinal imaging, optical coherence tomography, visual field/electrophysiologic testing, and systemic evaluation. The main outcome was the absence of ocular/systemic inflammation or rejection, tumor formation, or toxicity during follow-up.
The mean baseline BCVAs in the phacoemulsification and no phacoemulsification groups were similar (1.950 ± 0.446 and 1.575 ± 0.303, respectively). One year postoperatively, treated eyes showed a nonsignificant increase in BCVA. No adverse effects occurred during follow-up. Intraoperative optical coherence tomography was important for guiding all procedures.
This surgical procedure was feasible and safe without cellular migration, rejection, inflammation, or development of ocular or systemic tumors during follow-up.

To evaluate the nature and association of different phenotypes associated with ABCA4 mutations in Chinese.
All patients were recruited from our pediatric and genetic eye clinic. Detailed ocular phenotypes were characterized. The disease course was evaluated by long-term follow-up observation, with a focus on fundus changes. Cox regression was used to identify the factors associated with disease progression.
A systematic review of genetic and clinical data for 228 patients and follow-up data for 42 patients indicated specific features in patients with two ABCA4 variants. Of 185 patients with available fundus images, 107 (57.8%) showed focal lesions restricted to the central macula without flecks. Among these 107 patients, 30 patients (28.0%) initially presented with relatively preserved visual acuity and inconspicuous performance on routine fundus screening. A pigmentary change in the posterior pole was observed in 22 of 185 patients (11.9%), and this change mimicked retinitis pigmentosa in 10 cases (45.5%). Follow-up visits and sibling comparisons demonstrated disease progression from cone-rod dystrophy, Stargardt disease, to retinitis pigmentosa. An earlier age of onset was associated with a more rapid decrease in visual acuity (P = 0.03). Patients with two truncation variants had an earlier age of onset.
Phenotypic variation in ABCA4-associated retinopathy may represent sequential changes in a single disease: early-stage Stargardt disease may resemble cone-rod dystrophy, whereas the presence of diffuse pigmentation in the late stage may mimic retinitis pigmentosa. Recognizing the natural progression of fundus changes, especially those visualized by wide-field fundus autofluorescence, is valuable for diagnostics and therapeutic decision-making.