Normal and abnormal foveal development

Normal foveal development begins in utero at midgestation with centrifugal displacement of inner retinal layers (IRLs) from the location of the incipient fovea. The outer retinal changes such as increase in cone cell bodies, cone elongation and packing mainly occur after birth and continue until 13 years of age. The maturity of the fovea can be assessed invivo using optical coherence tomography, which in normal development would show a well-developed foveal pit, extrusion of IRLs, thickened outer nuclear layer and long outer segments. Developmental abnormalities of various degrees can result in foveal hypoplasia (FH). This is a characteristic feature for example in albinism, aniridia, prematurity, foveal hypoplasia with optic nerve decussation defects with or without anterior segment dysgenesis without albinism (FHONDA) and optic nerve hypoplasia. In achromatopsia, there is disruption of the outer retinal layers with atypical FH. Similarly, in retinal dystrophies, there is abnormal lamination of the IRLs sometimes with persistent IRLs. Morphology of FH provides clues to diagnoses, and grading correlates to visual acuity. The outer segment thickness is a surrogate marker for cone density and in foveal hypoplasia this correlates strongly with visual acuity. In preverbal children grading FH can help predict future visual acuity

Home-based screening tools for amblyopia: a systematic review protocol

Introduction Amblyopia is an important public health concern associated with functional vision loss and detrimental impact on the physical and mental well-being of children. The gold standard for diagnosis of amblyogenic conditions currently involves screening by orthoptists and/or ophthalmologists. The bloom of technology enables the use of home-based screening tools to detect these conditions at an early stage by the layperson in community, which could reduce the burden of screening in the community, especially during restrictions associated with the COVID-19 pandemic. Here, we propose a systematic review aiming to evaluate the accuracy and reliability of home-based screening tools compared with the existing gold standard. Methods and analysis We aim to search for studies involving home-based screening tools for amblyopia among children aged under 18 years. Oxford Centre for Evidence-Based Medicine Level 4 evidence and above will be included, without language or time restrictions. The following platforms will be searched from inception to 31 August 2021: PubMed, Medline, The Cochrane Library, Embase, Web of Science Core Collection and Clinicaltrials.gov. Two independent reviewers will identify studies for inclusion based on a screening questionnaire. The search and screening will start on 14 August 2021 until 1 October 2021. We aim to complete our data analysis by 30 November 2021. Risk of bias will be assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool for diagnostic accuracy studies only. Our primary outcome measure is the diagnostic accuracy of home-based screening tools, while secondary outcome measures include validity, feasibility, reproducibility and cost-effectiveness, where available. Ethics and dissemination Ethical approval is not necessary as no primary data will be collected. The findings will be disseminated through presentations at scientific meetings and peer-reviewed journal publication. PROSPERO registration number CRD42021233511.</div

Current and Emerging Treatments for Albinism

Albinism is a group of rare inherited disorders arising from impairment of melanin biosynthesis. The reduction of melanin synthesis leads to hypopigmentation of skin and eyes. A wide range of ophthalmic manifestations arise from albinism, including reduction of visual acuity, nystagmus, strabismus, iris translucency, foveal hypoplasia, fundus hypopigmentation, and abnormal decussation of retinal ganglion cell axons at the optic chiasm. Currently, albinism is incurable, and treatment aims either surgically or pharmacologically to optimize vision and protect skin; however, novel therapies that aim to directly address the molecular errors of albinism, such as L-dihydroxyphenylalanine (L-DOPA) and nitisinone, are being developed and have entered human trials though with limited success. Experimental gene-based strategies for editing the genetic errors in albinism have also met early success in animal models. The emergence of these new therapeutic modalities represents a new era in the management of albinism. We focus on the known genetic subtypes, clinical assessment, existing and emerging therapeutic options for the non-syndromic forms of albinism

Abnormal foveal morphology in carriers of oculocutaneous albinism

To investigate the foveal morphology in carriers of oculocutaneous albinism (OCA) using spectral domain optical coherence tomography (SD-OCT). A cross-sectional, observational study.Handheld SD-OCT (Envisu C2300) was used to acquire horizontal scans through the centre of the fovea in biological parents of patients with OCA (n=28; mean age±SD=40.43±8.07 years) and age-matched and ethnicity-matched controls (n=28; mean age±SD=38.04±10.27 years). Sequence analysis was performed for variants in known genes associated with OCA. Best-corrected visual acuity (BCVA), presence of foveal hypoplasia and grade, foveal, parafoveal and perifoveal thickness measurements of total retinal layers (TRL), inner retinal layers (IRL) and outer retinal layers (ORL) thickness were measured.Foveal hypoplasia was identified in 32.14% of OCA carriers; grade 1 in all cases. OCA carriers demonstrated significant thicker TRL thickness (median difference: 13.46 µm, p=0.009) and IRL thickness (mean difference: 8.98 µm, pTYR, OCA2 and SLC45A2, novel OCA2 variants (n=3) and heterozygosity of the pathogenic TYR haplotype.We have, for the first time, identified foveal abnormalities in OCA carriers. This provides clinical value, particularly in cases where limited phenotype data are available. Our findings raise the possibility that previously reported mild cases of foveal hypoplasia or isolated foveal hypoplasia could correspond to OCA carrier status.</p

Zebrafish Optokinetic Reflex: Minimal Reporting Guidelines and Recommendations

Optokinetic reflex (OKR) assays in zebrafish models are a valuable tool for studying a diverse range of ophthalmological and neurological conditions. Despite its increasing popularity in recent years, there are no clear reporting guidelines for the assay. Following reporting guidelines in research enhances reproducibility, reduces bias, and mitigates underreporting and poor methodologies in published works. To better understand optimal reporting standards for an OKR assay in zebrafish, we performed a systematic literature review exploring the animal, environmental, and technical factors that should be considered. Using search criteria from three online databases, a total of 109 research papers were selected for review. Multiple crucial factors were identified, including larval characteristics, sample size, fixing method, OKR set-up, distance of stimulus, detailed stimulus parameters, eye recording, and eye movement analysis. The outcome of the literature analysis highlighted the insufficient information provided in past research papers and the lack of a systematic way to present the parameters related to each of the experimental factors. To circumvent any future errors and champion robust transparent research, we have created the zebrafish optokinetic (ZOK) reflex minimal reporting guideline

SLC38A8 mutations result in arrested retinal development with loss of cone photoreceptor specialisation.

Foveal hypoplasia, optic nerve decussation defects and anterior segment dysgenesis is an autosomal recessive disorder arising from SLC38A8 mutations. SLC38A8 is a putative glutamine transporter with strong expression within the photoreceptor layer in the retina. Previous studies have been limited due to lack of quantitative data on retinal development and nystagmus characteristics. In this multi-centre study, a custom-targeted next generation sequencing (NGS) gene panel was used to identify SLC38A8 mutations from a cohort of 511 nystagmus patients. We report 16 novel SLC38A8 mutations. The sixth transmembrane domain is most frequently disrupted by missense SLC38A8 mutations. Ninety percent of our cases were initially misdiagnosed as PAX6-related phenotype or ocular albinism prior to NGS. We characterized the retinal development in vivo in patients with SLC38A8 mutations using high-resolution optical coherence tomography. All patients had severe grades of arrested retinal development with lack of a foveal pit and no cone photoreceptor outer segment lengthening. Loss of foveal specialization features such as outer segment lengthening implies reduced foveal cone density, which contributes to reduced visual acuity. Unlike other disorders (such as albinism or PAX6 mutations) which exhibit a spectrum of foveal hypoplasia, SLC38A8 mutations have arrest of retinal development at an earlier stage resulting in a more under-developed retina and severe phenotype