Congenital Retinal Diseases Research Articles

Association of mood disorders, substance abuse, and anxiety disorders in children and teens with eye disease

We sought to evaluate the association between 5 eye diseases (including glaucoma, cataract, congenital optic nerve disease, congenital retinal disease, and blindness/low vision) and mental illness in a pediatric population.

Association of Mood Disorders, Substance Abuse, and Anxiety Disorders in Children and Teens With Serious Structural Eye Diseases

We sought to evaluate the association between 5 eye diseases (including glaucoma, cataract, congenital optic nerve disease, congenital retinal disease, and blindness/low vision) and mental illness in a pediatric population. Cross-sectional study. A de-identified commercial insurance claims database, OptumLabs Data Warehouse, between January 1, 2007, and December 31, 2018, was used. Children and teens less than 19 years of age at the time of eye diagnosis were included. Demographics and mental illness claims were compared, looking at the association of mental illness and eye disease claims. A total of 11,832,850 children and teens were included in this study with mean age of 8.04 ± 5.94 years at the first claim. Of the patients with at least 1 of the 5 eye diseases (n=180,297), 30.5% had glaucoma (n=54,954), 9.5% had cataract (n=17,214), 21.4% had congenital optic nerve disease (n=38,555), 26.9% had congenital retinal disease (n=48,562), and 25.9% had blindness or low vision (n=46,778). There was a statistically significant association, after adjusting for confounding variables, between at least 1 of the 5 eye diseases and schizophrenia disorder (OR=1.54, 95% CI=1.48-1.61, P < .001), anxiety disorder (OR=1.45, 95% CI=1.43-1.48, P < .001), depressive disorder (OR=1.27, 95% CI=1.25-1.29, P < .001), and bipolar disorder (OR=1.27, 95% CI=1.21-1.31, P < .001), but a reversed association with substance use disorder (OR=0.88, 95% CI=0.86-0.90, P < .001). We found associations between eye disease in children and teens and mental illness. Understanding these relationships may improve mental illness screening and treatment in the pediatric population.

Clinical Characterization of 66 Patients With Congenital Retinal Disease Due to the Deep-Intronic c.2991+1655A>G Mutation in CEP290.

To describe the phenotypic spectrum of retinal disease caused by the c.2991+1655A>G mutation in CEP290 and to compare disease severity between homozygous and compound heterozygous patients. Medical records were reviewed for best-corrected visual acuity (BCVA), age of onset, fundoscopy descriptions. Foveal outer nuclear layer (ONL) and ellipsoid zone (EZ) presence was assessed using spectral-domain optical coherence tomography (SD-OCT). Differences between compound heterozygous and homozygous patients were analyzed based on visual performance and visual development. A total of 66 patients were included. The majority of patients had either light perception or no light perception. In the remaining group of 14 patients, median BCVA was 20/195 Snellen (0.99 LogMAR; range 0.12-1.90) for the right eye, and 20/148 Snellen (0.87 LogMAR; range 0.22-1.90) for the left. Homozygous patients tended to be more likely to develop light perception compared to more severely affected compound heterozygous patients (P = 0.080) and are more likely to improve from no light perception to light perception (P = 0.022) before the age of 6 years. OCT data were available in 12 patients, 11 of whom had retained foveal ONL and EZ integrity up to 48 years (median 23 years) of age. Homozygous patients seem less severely affected compared to their compound-heterozygous peers. Improvement of visual function may occur in the early years of life, suggesting a time window for therapeutic intervention up to the approximate age of 17 years. This period may be extended by an intact foveal ONL and EZ on OCT.

Identification of Target Binding Site in Photoreceptor Guanylyl Cyclase-activating Protein 1 (GCAP1)

Retinal guanylyl cyclase (RetGC)-activating proteins (GCAPs) regulate visual photoresponse and trigger congenital retinal diseases in humans, but GCAP interaction with its target enzyme remains obscure. We mapped GCAP1 residues comprising the RetGC1 binding site by mutagenizing the entire surface of GCAP1 and testing the ability of each mutant to bind RetGC1 in a cell-based assay and to activate it in vitro. Mutations that most strongly affected the activation of RetGC1 localized to a distinct patch formed by the surface of non-metal-binding EF-hand 1, the loop and the exiting helix of EF-hand 2, and the entering helix of EF-hand 3. Mutations in the binding patch completely blocked activation of the cyclase without affecting Ca(2+) binding stoichiometry of GCAP1 or its tertiary fold. Exposed residues in the C-terminal portion of GCAP1, including EF-hand 4 and the helix connecting it with the N-terminal lobe of GCAP1, are not critical for activation of the cyclase. GCAP1 mutants that failed to activate RetGC1 in vitro were GFP-tagged and co-expressed in HEK293 cells with mOrange-tagged RetGC1 to test their direct binding in cyto. Most of the GCAP1 mutations introduced into the "binding patch" prevented co-localization with RetGC1, except for Met-26, Lys-85, and Trp-94. With these residues mutated, GCAP1 completely failed to stimulate cyclase activity but still bound RetGC1 and competed with the wild type GCAP1. Thus, RetGC1 activation by GCAP1 involves establishing a tight complex through the binding patch with an additional activation step involving Met-26, Lys-85, and Trp-94.

Advances in gene therapy technologies to treat retinitis pigmentosa

Retinitis pigmentosa (RP) is a class of diseases that leads to progressive degeneration of the retina. Experimental approaches to gene therapy for the treatment of inherited retinal dystrophies have advanced in recent years, inclusive of the safe delivery of genes to the human retina. This review is focused on the development of gene therapy for RP using recombinant adenoassociated viral vectors, which show a positive safety record and have so far been successful in several clinical trials for congenital retinal disease. Gene therapy for RP is under development in a variety of animal models, and the results raise expectations of future clinical application. Nonetheless, the translation of such strategies to the bedside requires further understanding of the mutations and mechanisms that cause visual defects, as well as thorough examination of potential adverse effects.

Correct interpretation and evaluation of the results of clinical trials of gene therapy for Leber congenital amaurosis

The treatment of hereditary retinal disease is still one of the contemporary scientific problems. Leber congenital amaurosis （LCA） is one type of congenital retinal diseases. Desirable results have been achieved in ongoing clinical trials of gene therapy for LCA, and the efficacy and safety in the intraocular injection of a gene inserted in an adeno-associated virus （AAV） have been verified abroad. These results bring hope and opportunity to LCA patients. China has more hereditary retinal disease patients, but gene therapy for hereditary retinal disease and LCA is lacking. Rightly interpreting and objectively evaluating the clinical trials of gene therapy of LCA will provide us with many important references and useful clues to further help us organize and implement clinical trials of gene therapy for hereditary retinal disease in the future. Key words: Leber congenital amaurosis; Hereditary retinal disease; Gene therapy; Clinical trial

Enzymatic Relay Mechanism Stimulates Cyclic GMP Synthesis in Rod Photoresponse: Biochemical and Physiological Study in Guanylyl Cyclase Activating Protein 1 Knockout Mice

Regulation of cGMP synthesis by retinal membrane guanylyl cyclase isozymes (RetGC1 and RetGC2) in rod and cone photoreceptors by calcium-sensitive guanylyl cyclase activating proteins (GCAP1 and GCAP2) is one of the key molecular mechanisms affecting the response to light and is involved in congenital retinal diseases. The objective of this study was to identify the physiological sequence of events underlying RetGC activation in vivo, by studying the electrophysiological and biochemical properties of mouse rods in a new genetic model lacking GCAP1. The GCAP1−/− retinas expressed normal levels of RetGC isozymes and other phototransduction proteins, with the exception of GCAP2, whose expression was elevated in a compensatory fashion. RetGC activity in GCAP1−/− retinas became more sensitive to Ca2+ and slightly increased. The bright flash response in electroretinogram (ERG) recordings recovered quickly in GCAP1−/−, as well as in RetGC1−/−GCAP1−/−, and RetGC2−/−GCAP1−/− hybrid rods, indicating that GCAP2 activates both RetGC isozymes in vivo. Individual GCAP1−/− rod responses varied in size and shape, likely reflecting variable endogenous GCAP2 levels between different cells, but single-photon response (SPR) amplitude and time-to-peak were typically increased, while recovery kinetics remained faster than in wild type. Recovery from bright flashes in GCAP1−/− was prominently biphasic, because rare, aberrant SPRs producing the slower tail component were magnified. These data provide strong physiological evidence that rod photoresponse recovery is shaped by the sequential recruitment of RetGC isozyme activation by GCAPs according to the different GCAP sensitivities for Ca2+ and specificities toward RetGC isozymes. GCAP1 is the ‘first-response’ sensor protein that stimulates RetGC1 early in the response and thus limits the SPR amplitude, followed by activation of GCAP2 that adds stimulation of both RetGC1 and RetGC2 to speed-up photoreceptor recovery.

Molecular Mechanisms of Disease for Mutations at Gly-90 in Rhodopsin

Two different mutations at Gly-90 in the second transmembrane helix of the photoreceptor protein rhodopsin have been proposed to lead to different phenotypes. G90D has been classically associated with congenital night blindness, whereas the newly reported G90V substitution was linked to a retinitis pigmentosa phenotype. Here, we used Val/Asp replacements of the native Gly at position 90 to unravel the structure/function divergences caused by these mutations and the potential molecular mechanisms of inherited retinal disease. The G90V and G90D mutants have a similar conformation around the Schiff base linkage region in the dark state and same regeneration kinetics with 11-cis-retinal, but G90V has dramatically reduced thermal stability when compared with the G90D mutant rhodopsin. The G90V mutant also shows, like G90D, an altered photobleaching pattern and capacity to activate Gt in the opsin state. Furthermore, the regeneration of the G90V mutant with 9-cis-retinal was improved, achieving the same A(280)/A(500) as wild type isorhodopsin. Hydroxylamine resistance was also recovered, indicating a compact structure around the Schiff base linkage, and the thermal stability was substantially improved when compared with the 11-cis-regenerated mutant. These results support the role of thermal instability and/or abnormal photoproduct formation in eliciting a retinitis pigmentosa phenotype. The improved stability and more compact structure of the G90V mutant when it was regenerated with 9-cis-retinal brings about the possibility that this isomer or other modified retinoid analogues might be used in potential treatment strategies for mutants showing the same structural features.

Multifocal electroretinography: update on clinical application and future development

Multifocal electroretinography (mfERG) is a tool that can provide topographic objective functional assessment of the retina. With the use of cross-correlation techniques, mfERG allows the stimulation and recording of multiple electroretinographic responses from individual locations in the macula over a short period of time. This article aims to provide an update on the clinical applications of mfERG and will focus in particular on studies published in the last 2 years. The clinical applications of mfERG for both acquired and congenital retinal diseases will be discussed.

In Utero Gene Therapy Rescues Vision in a Murine Model of Congenital Blindness

The congenital retinal blindness known as Leber congenital amaurosis (LCA) can be caused by mutations in the RPE65 gene. RPE65 plays a critical role in the visual cycle that produces the photosensitive pigment rhodopsin. Recent evidence from human studies of LCA indicates that earlier rather than later intervention may be more likely to restore vision. We determined the impact of in utero delivery of the human RPE65 cDNA to retinal pigment epithelium cells in a murine model of LCA, the Rpe65−/− mouse, using a serotype 2 adeno-associated virus packaged within an AAV1 capsid (AAV2/1). Delivery of AAV2/1-CMV-hRPE65 to fetuses (embryonic day 14) resulted in efficient transduction of retinal pigment epithelium, restoration of visual function, and measurable rhodopsin. The results demonstrate AAV-mediated correction of the deficit and suggest that in utero retinal gene delivery may be a useful approach for treating a variety of blinding congenital retinal diseases.

Factors that affect regulation of cGMP synthesis in vertebrate photoreceptors and their genetic link to human retinal degeneration.

Cyclic GMP is essential for the ability of rods and cones to respond to the light stimuli. Light triggers hydrolysis of cGMP and stops the influx of sodium and calcium through the cGMP-gated ion channels. The consequence of this event is 2-fold: first, the decrease in the inward sodium current plays the major role in an abrupt hyperpolarization of the cellular membrane; secondly, the decrease in the Ca2+ influx diminishes the free intracellular Ca2+ concentration. While the former constitutes the essence of the phototransduction pathway in rods and cones, the latter gives rise to a potent feedback mechanism that accelerates photoreceptor recovery and adaptation to background light. One of the most important events by which Ca2+ feedback controls recovery and light adaptation is synthesis of cGMP by guanylyl cyclase. Two isozymes of membrane photoreceptor guanylyl cyclase (retGC) have been identified in rods and cones that are regulated by Ca2+-binding proteins, GCAPs. At low intracellular concentrations of Ca2+ typical for light-adapted rods and cones GCAPs activate RetGC, but concentrations above 500 nM typical for dark-adapted photoreceptors turn them into inhibitors of retGC. A variety of mutations found in GCAP and retGC genes have been linked to several forms of human congenital retinal diseases, such as dominant cone degeneration, cone-rod dystrophy and Leber congenital amaurosis.

Pupillary constriction to darkness.

Patients with congenital achromatopsia and congenital stationary night blindness have been known to show a transient pupillary constriction to darkness. We examined 50 normal subjects and 108 patients with retinal and optic nerve dysfunction to see if any had an initial pupillary constriction to darkness. We used a new infrared television apparatus. Four patients with congenital stationary night blindness, four with achromatopsia, two with bilateral optic neuritis, and one with dominant optic atrophy showed the phenomenon. In the patients who showed this unusual pupillary response to darkness it was the first observable event every time the lights were turned off. The constriction could usually be seen with a handlight, and it was similar in latency to the normal pupillary dilatation to darkness. Pupillary constriction to darkness is a clinically valuable sign that can be used in the detection of congenital retinal disease in children with poor vision.

Retinal Diseases in Children.

This volume consists of contributions by ten authors covering topics of interest to both pediatrician and ophthalmologist. A listing of the specific chapter headings describes the great variety of material presented and includes congenital retinal diseases, abnormalities of the posterior pole and pigmentary retinal disorders, retinal tumors, Coat's disease, the phakomatoses, retrolental fibroplasia, juvenile retinal detachment, the lipidoses, ocular inflammation, and the retina in rubella. The chapters on tumors, retrolental fibroplasia, and the lipidoses were particularly well written and informative. It was good to see retrolental fibroplasia reemphasized again as a pediatric eye problem. Catheterization of the umbilical artery with monitoring of the arterial Po₂content from 60-90 mm until respiratory distress seems unlikely appears to be a better approach to the prevention of retrolental fibroplasia than limiting the flow of oxygen to 40% as was the general rule in the past decade. The chapter on the lipidoses is

Abnormalities accompanying some congenital eye diseases.

It is well known that the congenital eye diseases are often accompanied by various abnormalities in other parts of the body. However, few observations have been made on the meaning of this fact or on the relation to the original diseases. Expecting to find out some developmental relationship between the appearance of these abnormalities and congenital diseases by observing many cases, the author examined 511 students of seven blind schools in Tokai district for their abnormal traits (_??_ 331, _??_ 180).1) Comparison of the abnormalities in the congenital blind with those in the acuired blind: qThe abnormalities of the head form, countenance, ear, lip, palate, foot, fingers and toes were found with statistical significance more frequently in the congenital blind than in the acquired. Especially as to the abnormalities of the head form and limbs the difference was remarkable.2) A bnormalities accompanying each disease:In the cases of microphthalmia many abnormalities were seen regarding head form, countenance, ear, lip, palate and finger: they were generally concentrated in the headregion and some cases showed fissure formation. In cases of congenital retinal diseases short stature, obesity hypoplasia of genital organs, deformity of finger and cleft-palatewere frequently observed. Since these signs resemble the so-called diencephalonsyndrome, this fact suggests that the congenital retinal diseases as well as Laurence-Biedrp syndrome have close connections with the diencephalon. Besides, it was found that this condition is often associated with the fissure formation such as cleft-palate, an interesting fact to be studied from the embryological standpoint, to which, due attention has not been paid.3) The relation between degenerative signs of body and mental ability:The examined were classified into two groups, superior and inferior, according to their school records, and the number of the recognized degenerative signs in each group were compared. But the comparison cannot claim much significance because the degenerative signs are in itself rare to occur. Nevertheless, the number of the degenerative signs per student in the group I was evidently larger than that of group S.4) The comparison of degree of constitutional growth in the congenital and acquired blind:The disturbance of the growth in length' and breadth was more remarkable in thecongenital blind than in the acquired. The disturbance in length was most frequently observed common to both groups. As to the Rohrer's index no difference was seen between the two groups, while their figures were larger than those of the normal tudents.5) Abnormalities associated with the cleft-palate, congenital pectoralis defect and lingua plicata:Uvula bifida was frequently seen, associated with insufficiency of suture as well as asymmetry at cranium, coloboma of the iris and syndactyly. In congenital pectoralis defect, deformities of muscles and bones on the chest, i. e. loose shoulder, bending. of spine, deformity of thorax etc. were often observed.6) Blind students due to consanguineous marriage of parents:The cases numbered 32, (6.26%). Of these the pigment degeneration was seen mostfrequently. Some students in this were low in school records, and, degenerative signs. were evidently more often observed in this group than the other.Resume: it is notable that the congenital eye diseases are of ten associated with deformities of head form and limbs and the disturbance of somatic growth especially in length. These abnormalities presumably are not accidental coincidence. They bought to be further studied with embryological correlation in view