Relationship Between the Foveal Avascular Zone and Foveal Pit Morphology

Purpose.To assess the relationship between foveal pit morphology and size of the foveal avascular zone (FAZ). Methods. Forty-two subjects were recruited. Volumetric images of the macula were obtained using spectral domain optical coherence tomography. Images of the FAZ were obtained using either a modified fundus camera or an adaptive optics scanning light ophthalmoscope. Foveal pit metrics (depth, diameter, slope, volume, and area) were automatically extracted from retinal thickness data, whereas the FAZ was manually segmented by two observers to extract estimates of FAZ diameter and area. Results. Consistent with previous reports, the authors observed significant variation in foveal pit morphology. The average foveal pit volume was 0.081 mm3 (range, 0.022 to 0.190 mm3). The size of the FAZ was also highly variable between persons, with FAZ area ranging from 0.05 to 1.05 mm2 and FAZ diameter ranging from 0.20 to 1.08 mm. FAZ area was significantly correlated with foveal pit area, depth, and volume; deeper and broader foveal pits were associated with larger FAZs. Conclusions. Although these results are consistent with predictions from existing models of foveal development, more work is needed to confirm the developmental link between the size of the FAZ and the degree of foveal pit excavation. In addition, more work is needed to understand the relationship between these and other anatomic features of the human foveal region, including peak cone density, rod-free zone diameter, and Henle fiber layer

GUCY2D-Associated Leber Congenital Amaurosis: A Retrospective Natural History Study in Preparation for Trials of Novel Therapies

Purpose To describe the natural history of Leber congenital Amaurosis (LCA) associated with GUCY2D variants (GUCY2D-LCA) in a cohort of children and adults, in preparation for trials of novel therapies. Design Retrospective case series. Participants Patients with GUCY2D-LCA at a single referral center. Methods Review of clinical notes, retinal imaging including fundus autofluorescence (FAF), and optical coherence tomography (OCT), electroretinography (ERG), and molecular genetic testing. Main Outcome Measures Demographic data, symptoms at presentation, visual acuity, evidence of progression, OCT and FAF findings, ERG assessment and molecular genetics. Results Twenty-one subjects with GUCY2D-LCA were included, with a mean follow up ± standard deviation (SD) of 10 ± 11.85 years. Marked reduction in visual acuity (VA) and nystagmus was documented in all patients within the first 3 years of life. Fifty-four percent (n=12) exhibited photophobia and 36% (n=8) had nyctalopia. VA was worse than hand motion in 71% of the patients (n=15). Longitudinal assessment of VA showed stability in all patients, except one patient who experienced deterioration over a follow-up of 44 years. Hyperopia was reported in 13 (71%) of the 17 subjects with available refraction data. Eighteen subjects had either normal fundus appearance (n=14) or a blonde fundus (n=3), while only 4 of the eldest subjects had mild RPE atrophy (mean, 49 years; range 40 - 54 years). OCT data were available for eleven subjects and four different grades of ellipsoid zone (EZ) integrity were identified: (i) continuous/intact EZ (n=6), (ii) focally disrupted EZ (n=2), (iii) focally disrupted with RPE changes (n=2), and (iv) diffuse EZ disruption with RPE changes (n=1). All examined subjects had stable OCT findings over the long follow-up period. Full-field ERGs showed evidence of a severe cone-rod dystrophy in 5 of 6 patients, and undetectable ERGs in one subject. Novel genotype-phenotype correlations are also reported. Conclusion GUCY2D-LCA is a severe early-onset retinal dystrophy associated with very poor VA from birth. Despite the severely affected photoreceptor function, the relatively preserved photoreceptor structure based on EZ integrity till late in the disease in the majority of subjects, suggests a wide therapeutic window for gene therapy trials

Architecture for in-space robotic assembly of a modular space telescope

An architecture and conceptual design for a robotically assembled, modular space telescope (RAMST) that enables extremely large space telescopes to be conceived is presented. The distinguishing features of the RAMST architecture compared with prior concepts include the use of a modular deployable structure, a general-purpose robot, and advanced metrology, with the option of formation flying. To demonstrate the feasibility of the robotic assembly concept, we present a reference design using the RAMST architecture for a formation flying 100-m telescope that is assembled in Earth orbit and operated at the Sun–Earth Lagrange Point 2

Challenges to optimizing a telescope system to detect and characterize exo-solar planetary systems

Novel optical design and engineering ideas are needed to build the large space telescopes for the direct detection and characterization of exo-solar system planets. For example, the Terrestrial Planet Finder Coronagraph requires a primary mirror 4 x 8 meters in size that is >10 x smoother than the 2.8 meter HST mirror and have a uniform reflectivity across the mirror to within 0.1%. The telescope system will need to control scattered light to within a part in 10 billion. The Terrestrial Planet Finder Interferometer will be a white-light, broadband infrared interferometer with a baseline in excess of 50 meters. In addition to direct imaging, planets masses and orbits can be derived from very precise measurements of the position of a star as it moves across the background. Interferometers provide the highest accuracy measurements of relative positions We will show that the optical design and the mechanical layout & configuration for these new telescopes need to be optimized for polarization as well as scattered light. Material science and coating technology plays an important role in the optimization of these systems. Stress across the surface of a mirror and stress within the optical thin film introduces polarization dependent scattered light. A new method to measure the anisotropy of the polarization-reflectivity of thin metal films on large astronomical mirrors is described

Patients and animal models of CNGβ1-deficient retinitis pigmentosa support gene augmentation approach.

Retinitis pigmentosa (RP) is a major cause of blindness that affects 1.5 million people worldwide. Mutations in cyclic nucleotide-gated channel β 1 (CNGB1) cause approximately 4% of autosomal recessive RP. Gene augmentation therapy shows promise for treating inherited retinal degenerations; however, relevant animal models and biomarkers of progression in patients with RP are needed to assess therapeutic outcomes. Here, we evaluated RP patients with CNGB1 mutations for potential biomarkers of progression and compared human phenotypes with those of mouse and dog models of the disease. Additionally, we used gene augmentation therapy in a CNGβ1-deficient dog model to evaluate potential translation to patients. CNGB1-deficient RP patients and mouse and dog models had a similar phenotype characterized by early loss of rod function and slow rod photoreceptor loss with a secondary decline in cone function. Advanced imaging showed promise for evaluating RP progression in human patients, and gene augmentation using adeno-associated virus vectors robustly sustained the rescue of rod function and preserved retinal structure in the dog model. Together, our results reveal an early loss of rod function in CNGB1-deficient patients and a wide window for therapeutic intervention. Moreover, the identification of potential biomarkers of outcome measures, availability of relevant animal models, and robust functional rescue from gene augmentation therapy support future work to move CNGB1-RP therapies toward clinical trials

Evaluating Outer Segment Length as A Surrogate Measure of Peak Foveal Cone Density

Adaptive optics (AO) imaging tools enable direct visualization of the cone photoreceptor mosaic, which facilitates quantitative measurements such as cone density. However, in many individuals, low image quality or excessive eye movements precludes making such measures. As foveal cone specialization is associated with both increased density and outer segment (OS) elongation, we sought to examine whether OS length could be used as a surrogate measure of foveal cone density. The retinas of 43 subjects (23 normal and 20 albinism; aged 6–67 years) were examined. Peak foveal cone density was measured using confocal adaptive optics scanning light ophthalmoscopy (AOSLO), and OS length was measured using optical coherence tomography (OCT) and longitudinal reflectivity profile-based approach. Peak cone density ranged from 29,200 to 214,000 cones/mm2(111,700 ± 46,300 cones/mm2); OS length ranged from 26.3 to 54.5 μm (40.5 ± 7.7 μm). Density was significantly correlated with OS length in albinism (p \u3c 0.0001), but not normals (p = 0.99). A cubic model of density as a function of OS length was created based on histology and optimized to fit the albinism data. The model includes triangular cone packing, a cylindrical OS with a fixed volume of 136.6 μm3, and a ratio of OS to inner segment width that increased linearly with increasing OS length (R2 = 0.72). Normal subjects showed no apparent relationship between cone density and OS length. In the absence of adequate AOSLO imagery, OS length may be used to estimate cone density in patients with albinism. Whether this relationship exists in other patient populations with foveal hypoplasia (e.g., premature birth, aniridia, isolated foveal hypoplasia) remains to be seen

Genotype-phenotype characterization of novel variants in six Italian patients with familial exudative vitreoretinopathy

Familial exudative vitreoretinopathy (FEVR) is a complex disorder characterized by incomplete development of the retinal vasculature. Here, we report the results obtained on the spectrum of genetic variations and correlated phenotypes found in a cohort of Italian FEVR patients. Eight probands (age range 7-19 years) were assessed by genetic analysis and comprehensive age-appropriate ophthalmic examination. Genetic testing investigated the genes most widely associated in literature with FEVR: FZD4, LRP5, TSPAN12, and NDP. Clinical and genetic evaluations were extended to relatives of probands positive to genetic testing. Six out of eight probands (75%) showed a genetic variation probably related to the phenotype. We identified four novel genetic variants, one variant already described in association with Norrie disease and one previously described linked to autosomal dominant FEVR. Pedigree analysis of patients led to the classification of four autosomal dominant cases of FEVR (caused by FZD4 and TSPAN12 variants) and two X-linked FEVR probands (NDP variants). None of the patients showed variants in the LRP5 gene. This study represents the largest cohort study in Italian FEVR patients. Our findings are in agreement with the previous literature confirming that FEVR is a clinically and genetically heterogeneous retinal disorder, even when it manifests in the same family

Identification of the Photoreceptor Transcriptional Co-Repressor SAMD11 as Novel Cause of Autosomal Recessive Retinitis Pigmentosa

Retinitis pigmentosa (RP), the most frequent form of inherited retinal dystrophy is characterized by progressive photoreceptor degeneration. Many genes have been implicated in RP development, but several others remain to be identified. Using a combination of homozygosity mapping, whole-exome and targeted next-generation sequencing, we found a novel homozygous nonsense mutation in SAMD11 in five individuals diagnosed with adult-onset RP from two unrelated consanguineous Spanish families. SAMD11 is ortholog to the mouse major retinal SAM domain (mr-s) protein that is implicated in CRX-mediated transcriptional regulation in the retina. Accordingly, protein-protein network analysis revealed a significant interaction of SAMD11 with CRX. Immunoblotting analysis confirmed strong expression of SAMD11 in human retina. Immunolocalization studies revealed SAMD11 was detected in the three nuclear layers of the human retina and interestingly differential expression between cone and rod photoreceptors was observed. Our study strongly implicates SAMD11 as novel cause of RP playing an important role in the pathogenesis of human degeneration of photoreceptors.This work was supported by several grants from the Spanish Centre for Biomedical Network Research on Rare Diseases (CIBERER)(06/07/0036), Instituto de Salud Carlos III (ISCIII, Spanish Ministry of Health)/FEDER, including FIS (PI013/00226) and RETICS (RD09/0076/00101 and RD12/0034/0010), Ministry of Economy and Competitiveness (MINECO), including FEDER (BFU2012-36845), and BIO2011-27069, Conselleria de Educació of the Valencia Community (PROMETEOII/2014/025), Spanish National Organization of the Blind (ONCE) and the Spanish Fighting Blindness Foundation (FUNDALUCE). M.C. was sponsored by the Miguel Servet Program for Researchers in the Spanish National Health Service (CP12/03256) and RSA by Sara Borrel Postdoctoral Program (CD12/00676), both from the ISCIII/FEDER. A.A-F. was sponsored by CIBERER, RPC is supported by Fundación Conchita Rábago (FCR), L.C is sponsored by RETICS (RD12/0034/0010) from ISCIII and L.d.S. was supported by CAPES Foundation, Ministry of Education of Brazil