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Purpose: To investigate genetics, electrophysiology, and clinical course of KCNV2-associated retinopathy in a cohort of children and adults., Study Design: This was a multicenter international clinical cohort study., Methods: Review of clinical notes and molecular genetic testing. Full-field electroretinography (ERG) recordings, incorporating the international standards, were reviewed and quantified and compared with age and recordings from control subjects., Results: In total, 230 disease-associated alleles were identified from 117 patients, corresponding to 75 different KCNV2 variants, with 28 being novel. The mean age of onset was 3.9 years old. All patients were symptomatic before 12 years of age (range, 0-11 years). Decreased visual acuity was present in all patients, and 4 other symptoms were common: reduced color vision (78.6%), photophobia (53.5%), nyctalopia (43.6%), and nystagmus (38.6%). After a mean follow-up of 8.4 years, the mean best-corrected visual acuity (BCVA ± SD) decreased from 0.81 ± 0.27 to 0.90 ± 0.31 logarithm of minimal angle of resolution. Full-field ERGs showed pathognomonic waveform features. Quantitative assessment revealed a wide range of ERG amplitudes and peak times, with a mean rate of age-associated reduction indistinguishable from the control group. Mean amplitude reductions for the dark-adapted 0.01 ERG, dark-adapted 10 ERG a-wave, and LA 3.0 30 Hz and LA3 ERG b-waves were 55%, 21%, 48%, and 74%, respectively compared with control values. Peak times showed stability across 6 decades., Conclusion: In KCNV2-associated retinopathy, full-field ERGs are diagnostic and consistent with largely stable peripheral retinal dysfunction. Report 1 highlights the severity of the clinical phenotype and established a large cohort of patients, emphasizing the unmet need for trials of novel therapeutics., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Ciliopathies are heterogeneous genetic diseases affecting primary cilium structure and function. Meckel-Gruber (MKS) and Bardet-Biedl (BBS) syndromes are severe ciliopathies characterized by skeletal and neurodevelopment anomalies, including polydactyly, cognitive impairment, and retinal degeneration. We describe the generation and molecular characterization of human induced pluripotent stem cell (iPSC)-derived retinal sheets (RSs) from controls, and MKS (TMEM67) and BBS (BBS10) cases. MKS and BBS RSs displayed significant common alterations in the expression of hundreds of developmental genes and members of the WNT and BMP pathways. Induction of crystallin molecular chaperones was prominent in MKS and BBS RSs suggesting a stress response to misfolded proteins. Unique to MKS photoreceptors was the presence of supernumerary centrioles and cilia, and aggregation of ciliary proteins. Unique to BBS photoreceptors was the accumulation of DNA damage and activation of the mitotic spindle checkpoint. This study reveals how combining cell reprogramming, organogenesis, and next-generation sequencing enables the elucidation of mechanisms involved in human ciliopathies., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Joubert syndrome (JS) is a recessive neurodevelopmental disorder defined by a characteristic cerebellar and brainstem malformation recognizable on axial brain magnetic resonance imaging as the "Molar Tooth Sign". Although defined by the neurological features, JS is associated with clinical features affecting many other organ systems, particularly progressive involvement of the retina, kidney, and liver. JS is a rare condition; therefore, many affected individuals may not have easy access to subspecialty providers familiar with JS (e.g., geneticists, neurologists, developmental pediatricians, ophthalmologists, nephrologists, hepatologists, psychiatrists, therapists, and educators). Expert recommendations can enable practitioners of all types to provide quality care to individuals with JS and know when to refer for subspecialty care. This need will only increase as precision treatments targeting specific genetic causes of JS emerge. The goal of these recommendations is to provide a resource for general practitioners, subspecialists, and families to maximize the health of individuals with JS throughout the lifespan., (© 2019 Wiley Periodicals, Inc.)

Objective: To review the effectiveness and toxicity of periocular topotecan hydrochloride in fibrin sealant (Tisseel) for the control of intraocular retinoblastoma., Methods: Retrospective medical record review of visually threatening or recurrent intraocular retinoblastoma treated with periocular topotecan., Results: Eight children (10 eyes) received 1 to 4 injections of periocular topotecan in fibrin sealant, without or with concomitant laser and/or single freeze-thaw prechemotherapy cryotherapy. Median dose was 0.18 mg/kg (3.72 mg/m(2)). The 6 children who responded to treatment had small discrete tumors (8 International Intraocular Retinoblastoma Classification group A or B eyes). Of these, prior primary treatment for 3 children (3 eyes) was laser; for 1 child (2 eyes), systemic chemotherapy with focal laser; and for 2 children (3 eyes), periocular topotecan. In 4 children (4 eyes), tumor regression was sufficient for effective focal therapy, but in 2 children (4 eyes), long-term control required systemic chemotherapy. The 2 children who did not respond each had an International Intraocular Retinoblastoma Classification group D eye treated primarily with systemic chemotherapy, focal laser, and cryotherapy and recurrent disease that was not controlled by periocular topotecan; both eyes were eventually enucleated. No ocular and minimal hematological toxic effects were observed. At 11 months' median follow-up after topotecan treatment (18 months since diagnosis), all 8 group A and B eyes were retained with ongoing focal therapy required in only 1 group B eye; the 2 group D eyes were enucleated., Conclusion: Periocular topotecan in fibrin sealant can achieve volume reduction of small and recurrent retinoblastoma sufficient to allow successful focal therapy.

Objectives: To investigate retinal microstructure of patients affected with malattia leventinese (MLVT) and mutation in the EFEMP1 gene using high-resolution optical coherence tomography (OCT)., Methods: Patients diagnosed with MLVT received a comprehensive eye exam, full-field and multifocal electroretinogram testing and imaging with a high-resolution Fourier domain OCT (Fd-OCT, UC Davis Medical Center, Davis, USA; axial resolution: 4.5 microm, acquisition speed: 9 frames s(-1), 1000 A scans s(-1)) combined with a flexible scanning head (Bioptigen Inc. Durham, NC, USA)., Results: Two related patients aged 30 and 60 years, with MLVT and identified c.R345W mutation in the EFEMP1 gene, were tested. Mother and daughter showed a variable phenotype with reduced vision function in the younger patient, whereas the mother had a 'form frustre'. Fd-OCT revealed extensive or focal sub-retinal pigment epithelium (RPE) deposits, separation of RPE and Bruch's membrane, and disruption of the photoreceptor outer and inner segment layers. No outer retinal changes were visible outside areas with sub-RPE deposits., Conclusion: Retinal structure in EFEMP1 retinal dystrophy is reflected by morphological changes within the RPE/Bruch's membrane complex with accumulation of sub-RPE material associated with disrupted photoreceptor integrity. The pattern of microstructural retinal abnormalities is similar but with a different extent in patients with variable phenotypes.

Purpose: To review the current literature on the detection and measurement of antiretinal antibodies., Design: Collaborative essay., Methods: Literature review and interpretation., Results: There is strong evidence to suggest a role for antiretinal antibodies, particularly those targeting recoverin and alpha-enolase, in the pathogenesis of autoimmune retinopathy (AIR). Additionally, numerous other autoantibodies have been described as putative mediators of retinal degeneration and more remain to be discovered. However, assay methods described in the literature by many laboratories for the detection of circulating antiretinal antibodies have been varied and diverse, making it difficult to interpret and compare their results., Conclusions: There is currently little standardization of laboratory methods used to detect and monitor antiretinal antibodies. To measure and monitor levels of circulating antiretinal antibodies optimally in patients with AIR, development of standardized assays with stringent internal controls is required. A multicenter collaborative and validation effort is encouraged to reach a consensus on this issue.

Objective: To investigate the retinal microstructure and lamination of patients affected with X-linked retinoschisis (XLRS) using high-resolution imaging modalities., Methods: Patients diagnosed as having XLRS underwent assessment. Visual function testing included visual acuity, color vision, and full-field electroretinography. We used a high-resolution Fourier-domain optical coherence tomography (FD-OCT) system (4.5-mum axial resolution; 9 frames/s; 1000 A-scans per frame) combined with a handheld scanner. Macular image evaluation included schisis localization and retinal layer integrity., Results: Six patients with XLRS and identified mutations in the XLRS1 gene underwent testing. Visual acuity ranged from 0.2 to 1.6 logMAR (logarithm of the minimum angle of resolution). Results of FD-OCT revealed foveal schisis extending from the outer to the inner plexiform layer in 4 of 6 patients. Bullous foveal schisis was associated with younger age. All patients showed extrafoveal schisis within the outer and inner nuclear and ganglion cell layer, alone or in combination. Photoreceptor outer and inner segment layers were disrupted and irregular in all patients., Conclusions: Retinal dystrophy in XLRS is reflected by morphological changes within the inner and outer retinal layers. Disturbed foveal photoreceptor integrity was identified in all patients. Retinal layer abnormalities correlated with age but did not appear to correlate with visual acuity or genotypic variation.

Retinal dystrophy in Bardet-Biedl Syndrome (BBS) is caused by defective genes that are expressed within ciliated cells such as photoreceptors. The purpose of this study was to characterize and compare the retinal structure and lamination of two groups of patients, carrying mutations in BBS1 or BBS10. Eight patients with BBS (ages 11.9-28.5 years) and mutations in BBS1 (4/8) or BBS10 (4/8) were tested. A high-resolution hand-held probe Fourier-domain optical coherence tomography system (Fd-OCT) was used for retinal image acquisition. Macular scans were evaluated with respect to structure, retinal layering and photoreceptor integrity. Micro-structural in-vivo analysis showed abnormalities within retinal layers but preserved retinal lamination. Photoreceptor integrity was disrupted in all patients. Macular scans from patients with BBS10 mutations most often showed 'deposits' adjacent and anterior to Bruch's membrane. Age, genotype and presence of macular changes did not correlate with the structural changes observed. Retinal dystrophy in BBS is reflected by major changes in the outer retinal layers. This is the first report of in-vivo micro-structural analysis of retinal layers in patients with BBS. Mutations in different BBS genes seem to be associated with similar micro-structural changes in retinal layers.

Purpose: To assess central retinal function in patients with advanced retinitis pigmentosa (RP) using the multifocal (mf)ERG and static perimetry., Methods: Patients with RP; a nonrecordable, full-field (ff)ERG; and visual acuity (VA) of

Accurate interpretation of electroretinograms (ERGs) requires knowledge of effects of axial myopia on ERG responses. Our purpose was to derive expected changes of ERG responses according to axial length, to stimulus conditions that conform to the International Society for Clinical Electrophysiology of Vision (ISCEV) Standard for Electroretinography. ERGs from 60 subjects were recorded. The subjects were assigned to one of three groups according to the level of myopia. Thirty-three subjects had high myopia (-6.00 D to -14.50 D; mean age, 31 years), eight had mild myopia (-3.00 D to -5.00; mean age, 28 years), and 19 had a small refractive error (+0.75 D to -2.75 D; mean age, 27 years). No subjects had myopic retinopathy. Stimulus-response curves were fitted to dark-adapted b-wave amplitudes and maximum amplitude and semi-saturation constants derived. Axial lengths, measured with A scan ultrasound, ranged from 22.2 mm to 30.0 mm. Analysis of variance and post hoc t-tests revealed significant difference between subjects with high myopia and subjects with small refractive error for ERG amplitude data. There were no significant differences between the three groups for implicit times, the ratio of b- to a-wave and semi-saturation constant. There is linear reduction in the logarithmic transform of ERG amplitude with increasing axial length, related more to axial length than refractive error. We provide relative slope and intercept values, allowing labs to derive expected ERG amplitudes according to axial length. These derivations are valid for persons with no retinopathy.

Purpose: Dystrophin, the Duchenne muscular dystrophy gene product, has been localized to the outer plexiform layer of normal human retina. The purpose of this study is to define completely the ocular phenotype associated with mutations at Xp21, the Duchenne muscular dystrophy gene locus., Methods: Twenty-one patients with a diagnosis of Duchenne muscular dystrophy and five patients with Becker muscular dystrophy had ophthalmologic examinations, including electroretinograms (ERGs). Electroretinogram results were correlated with respect to patient DNA analysis., Results: Twenty-three (88%) patients had reduced scotopic b-wave amplitudes to bright-white flash stimulus, including nine with negative-shaped ERGs. Rod-isolated responses were reduced or not recordable above noise in 14 (67%) patients. Most isolated cone responses (92%) were normal. Flicker amplitudes were reduced in seven patients. Two of these patients with proximal (5' end) deletions had normal scotopic b-waves to dim blue and bright-white flash stimulus. Patients with deletions toward the middle of the gene had greater reductions in their scotopic b-wave amplitudes than patients with deletions located toward the 5' end. Most patients had normal color vision, extraocular muscle function, and Snellen visual acuity. Increased macular pigmentation was seen in 16 patients with Duchenne muscular dystrophy., Conclusion: Most patients with Duchenne or Becker muscular dystrophy have evidence of abnormal scotopic ERGs. Patients with deletions in the central region of the gene had the most severe ERG changes. This study supports previous suggestions that dystrophin may play a role in retinal neurotransmission. The presence of increased macular pigmentation and normal photopic ERGs distinguishes patients with Duchenne muscular dystrophy mutations from other X-linked retinal disorders with negative-shaped ERGs.

Ciliopathies, a growing pleotropic class of diseases due to mutations in genes that play an important role in primary cilia function. These highly conserved organelles are key to cell signaling. We now know, that mutations in one gene may lead to more than one ciliopathy phenotype and that one ciliopathy phenotype may be due to mutations in more than one gene. We studied the case of a female child with a novel ciliopathy phenotype and identified two novel mutations in the gene IFT80. Previously, mutations in IFT80 have been associated with a very narrow rib cage and failure of the lungs. Bone anomalies are also part of this IFT80‐condition but with no vision problems documented. Our case had none of the features known to be associated with IFT80 mutations and had retinal degeneration (RD). This work broadens the IFT80‐phenotype spectrum and also shows RD can be a feature of many ciliopathies. [ABSTRACT FROM AUTHOR]