Anne B. Fulton

CEP290-associated retinal diseases span a broad phenotypic spectrum, from Leber congenital amaurosis to milder retinal dystrophies to syndromic ciliopathies. Herein, we describe a non-syndromic 18-year-old woman with compound heterozygous pathogenic variants in CEP290 whose ophthalmic features are infantile-onset nystagmus, benign and stable fundus appearance, and lack of cone-mediated visual and retinal function. Serial examinations from infancy onward document stable achromatopsia-like ophthalmic features. No cone-mediated vision or retinal function was demonstrated. By optical coherence tomography, foveal architecture was preserved and central retinal thickness was stable for more than a decade (median 246 µm, range 232-257 µm). Testing for common CNGA3 and CNGB3 variants in early childhood was negative, as was further testing via an eight-gene achromatopsia panel. Trio exome sequencing identified compound heterozygous pathogenic CEP290 variants in trans: c.4723A>T (p.Lys1575Ter) and c.6277del (p.Val2093SerfsTer4). Notably, c.4723A>T is a nonsense variant previously shown to undergo nonsense-associated exon skipping, consistent with a hypomorphic effect that has been associated with milder CEP290-related retinal disease. These findings suggest a selective impairment of cone-mediated function with relative preservation of rod function.

To score real-world fundus autofluorescence (FAF) images of pediatric patients with ABCA4-related Stargardt disease (STGD1), in a way that is automatable, scales with the disease progression, and is applicable to a wide time interval in the natural history of the disease. We developed the score based on a series of Optos wide-field FAF images of pediatric STGD1 patients (73 images; 14 individuals) and controls (27 images; 8 individuals). The patients' images were obtained over up to 6 years, and the controls over up to 5 years. In each image, we manually selected an artifact-free region, within which we evaluated an average of the pixel-level intensity score, constructed so that the average increases with progression of the disease. The score we propose provides a statistically robust measure of disease progression (91% Spearman correlation with the absolute age, 97% with the estimated time from onset, when averaged over both eyes), comparable across timepoints and patients. FAF is a reliable tool in STGD1 diagnostics, but its quantitative description must be modified to be applicable to tracking the disease progression. Analyzing images obtained in the course of clinical care of pediatric patients poses special challenges that make complete automation difficult. Our methodology provides a quantitative tool for investigating the natural progression of the Stargardt disease, and, potentially, the effects of genotype, environment, and therapeutic intervention on its course.

Pediatric macular disorders are a diverse group of inherited retinal diseases characterized by central vision loss due to dysfunction and degeneration of the macula, the region of the retina responsible for high-acuity vision. Common disorders in this category include Stargardt disease, Best vitelliform macular dystrophy, and X-linked retinoschisis. These conditions often manifest during childhood or adolescence, with symptoms such as progressive central vision loss, photophobia, and difficulty with fine visual tasks. Underlying mechanisms involve genetic mutations that disrupt photoreceptor and retinal pigment epithelium function, accumulating toxic byproducts, impaired ion channel activity, or structural degeneration. Advances in imaging modalities like optical coherence tomography and fundus autofluorescence have improved diagnostic accuracy and disease monitoring. Emerging therapies are transforming the treatment landscape. Gene therapy and genome editing hold promise for addressing the genetic basis of these disorders, while stem cell-based approaches and pharmacological interventions aim to restore retinal function and mitigate damage. Personalized medicine, driven by genomic sequencing, offers the potential for tailored interventions. Despite current challenges, ongoing research into molecular mechanisms, advanced imaging, and innovative therapies provides hope for improving outcomes and quality of life in children with macular disorders.

Stargardt disease (STGD1), associated with biallelic variants in the ABCA4 gene, is the most common heritable macular dystrophy and is currently untreatable. To identify potential treatment targets, we characterized surviving STGD1 photoreceptors. We used clinical data to identify macular regions with surviving STGD1 photoreceptors. We compared the hyperreflective bands in the optical coherence tomographic (OCT) images that correspond to structures in the STGD1 photoreceptor inner segments to those in controls. We used adaptive optics scanning light ophthalmoscopy (AO-SLO) to study the distribution of cones and AO-OCT to evaluate the interface of photoreceptors and retinal pigment epithelium (RPE). We found that the profile of the hyperreflective bands differed dramatically between patients with STGD1 and controls. AO-SLOs showed patches in which cone densities were similar to those in healthy retinas and others in which the cone population was sparse. In regions replete with cones, there was no debris at the photoreceptor-RPE interface. In regions with sparse cones, there was abundant debris. Our results raise the possibility that pharmaceutical means may protect surviving photoreceptors and so mitigate vision loss in patients with STGD1.

Bardet-Biedl Syndrome (BBS) is a rare autosomal recessive ciliopathy. Within corneal development, primary cilia serve a critical role. We sought to investigate the association of BBS with corneal astigmatism among a cohort of patients with BBS. This was a cross-sectional, retrospective study performed at a pediatric ophthalmology department of a tertiary hospital. The study enrolled 45 patients with genetically confirmed Bardet-Biedl syndrome, encompassing a total of 90 eyes observed from February 2011 to August 2021. Spherical and cylindrical refractive errors and keratometry outcome measures, including diopter (D) values at the flattest and steepest axes, were recorded. Corneal astigmatism of greater than 3D is considered extreme corneal astigmatism based on previously published data. Among 45 patients (M:26; F:19), the mean age was 16.4 ± 8.2 years, and the mean best-corrected visual acuity was 20/60. The most common molecular diagnosis was BBS1, seen in 24 of 45 (53.3%). Among all the patients, the mean spherical refractive error was -2.9 ± 3.8D. The mean cylindrical refractive error was 2.6 ± 1.5D. The mean keratometry values at the flattest axis was 43.5 ± 5.3D (39.4-75.0) and at the steepest axis was 47.2 ± 7.3D(41.5-84.0). Among all the patients with BBS, the mean corneal astigmatism was 3.7 ± 1.0D(0.5-7.1), which is considered extreme. A cohort of individuals with BBS demonstrated high corneal astigmatism. These results suggest an association between corneal astigmatism and primary ciliary dysfunction and may assist in clinical management and future therapeutic targets among BBS and other corneal disorders.

Tubulin, one of the most abundant cytoskeletal building blocks, has numerous isotypes in metazoans encoded by different conserved genes. Whether these distinct isotypes form cell type– and context-specific microtubule structures is poorly understood. Based on a cohort of 12 patients with primary ciliary dyskinesia as well as mouse mutants, we identified and characterized variants in the TUBB4B isotype that specifically perturbed centriole and cilium biogenesis. Distinct TUBB4B variants differentially affected microtubule dynamics and cilia formation in a dominant-negative manner. Structure-function studies revealed that different TUBB4B variants disrupted distinct tubulin interfaces, thereby enabling stratification of patients into three classes of ciliopathic diseases. These findings show that specific tubulin isotypes have distinct and nonredundant subcellular functions and establish a link between tubulinopathies and ciliopathies.

Purpose: The purpose of this study was to test the hypothesis that retinopathy of prematurity (ROP) prolongs development of rod-mediated thresholds for detection of stimuli at 10 degrees but not 30 degrees eccentricity. In addition, to evaluate the thresholds at each site for an association with visual acuity (VA) and spherical equivalent (SE). Methods: We estimated rod-mediated dark-adapted thresholds (DATs) for the detection of 2 degree diameter, 50 ms, blue (λ < 510 nm) flashes at 10 degrees and 30 degrees eccentric in former preterm subjects (n = 111), stratified by ROP severity: None (n = 32), Mild (n = 66), and Severe (n = 13). We also tested Term-born (n = 28) controls. To determine the age at half-maximal sensitivity (Age_half) for each group and eccentricity, we fit DATs to logistic growth curves. We obtained VA and SE for Preterm subjects and evaluated the course of threshold development at 10 degrees and 30 degrees for significant association with VA and SE predicted at age 10 years. Results: DAT development at 10 degrees was significantly delayed in ROP (Mild and Severe); ROP did not significantly alter DAT development at 30 degrees. At age 10 years, among Preterm subjects, both VA and SE were significantly associated with group (None, Mild, and Severe). SE was predicted by the course of DAT development at 30 degrees. VA was not associated with the course of DAT development at 10 degrees. Conclusions: At 10 degrees, ROP—whether mild or severe—is associated with significant delays in DAT development, evidence that the late-maturing central retina is vulnerable to ROP. The association of 30 degree threshold and myopia are evidence that more peripheral retina is important to refractive development.