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Convolutional neural network (CNN) models are of great promise to aid the segmentation and analysis of brain structures. Here, we tested whether CNN trained to segment normal optic chiasms from the T1w magnetic resonance imaging (MRI) image can be also applied to abnormal chiasms, specifically with optic nerve misrouting as typical for human albinism. We performed supervised training of the CNN on the T1w images of control participants ( n = 1049) from the Human Connectome Project (HCP) repository and automatically generated algorithm-based optic chiasm masks. The trained CNN was subsequently tested on data of persons with albinism (PWA; n = 9) and controls ( n = 8) from the CHIASM repository. The quality of outcome segmentation was assessed via the comparison to manually defined optic chiasm masks using the Dice similarity coefficient (DSC). The results revealed contrasting quality of masks obtained for control (mean DSC ± SEM = 0.75 ± 0.03) and PWA data (0.43 ± 0.8, few-corrected p = 0.04). The fact that the CNN recognition of the optic chiasm fails for chiasm abnormalities in PWA underlines the fundamental differences in their spatial features. This finding provides proof of concept for a novel deep-learning-based diagnostics approach of chiasmal misrouting from T1w images, as well as further analyses on chiasmal misrouting and their impact on the structure and function of the visual system.

Albinism describes a heterogeneous group of genetically determined disorders characterized by disrupted synthesis of melanin and a range of developmental ocular abnormalities. The main ocular features common to both oculocutaneous albinism (OCA), and ocular albinism (OA) include reduced visual acuity, refractive errors, foveal hypoplasia, congenital nystagmus, iris and fundus hypopigmentation and visual pathway misrouting, but clinical signs vary and there is phenotypic overlap with other pathologies. This study reviews the prevalence, genetics and ocular manifestations of OCA and OA, including abnormal development of the optic chiasm. The role of visual electrophysiology in the detection of chiasmal dysfunction and visual pathway misrouting is emphasized, highlighting how age-associated changes in visual evoked potential (VEP) test results must be considered to enable accurate diagnosis, and illustrated further by the inclusion of novel VEP data in genetically confirmed cases. Differential diagnosis is considered in the context of suspected retinal and other disorders, including rare syndromes that may masquerade as albinism.

Oculocutaneous albinism is an autosomal recessive disorder characterized by the presence of typical ocular features, such as foveal hypoplasia, iris translucency, hypopigmented fundus oculi and reduced pigmentation of skin and hair. Albino patients can show significant clinical variability; some individuals can present with only mild depigmentation and subtle ocular changes. Here, we provide a retrospective review of the standardized clinical charts of patients firstly addressed for evaluation of foveal hypoplasia and slightly subnormal visual acuity, whose diagnosis of albinism was achieved only after extensive phenotypic and genotypic characterization. Our report corroborates the pathogenicity of the two common TYR polymorphisms p.(Arg402Gln) and p.(Ser192Tyr) when both are located in trans with a pathogenic TYR variant and aims to expand the phenotypic spectrum of albinism in order to increase the detection rate of the albino phenotype. Our data also suggest that isolated foveal hypoplasia should be considered a clinical sign instead of a definitive diagnosis of an isolated clinical entity, and we recommend deep phenotypic and molecular characterization in such patients to achieve a proper diagnosis.

Mutations in receptors, ion channels, and enzymes are frequently recognized by the cellular quality control system as misfolded and retained in the endoplasmic reticulum (ER) or otherwise misrouted. Retention results in loss of function at the normal site of biological activity and disease. Pharmacoperones are target-specific small molecules that diffuse into cells and serve as folding templates that enable mutant proteins to pass the criteria of the quality control system and route to their physiologic site of action. Pharmacoperones of the gonadotropin releasing hormone receptor (GnRHR) have efficacy in cell culture systems, and their cellular and biochemical mechanisms of action are known. Here, we show the efficacy of a pharmacoperone drug in a small animal model, a knock-in mouse, expressing a mutant GnRHR. This recessive mutation (GnRHR E ⁹⁰K) causes hypogonadotropic hypogonadism (failed puberty associated with low or apulsatile luteinizing hormone) in both humans and in the mouse model described. We find that pulsatile pharmacoperone therapy restores E ⁹⁰K from ER retention to the plasma membrane, concurrently with responsiveness to the endogenous natural ligand, gonadotropin releasing hormone, and an agonist that is specific for the mutant. Spermatogenesis, proteins associated with steroid transport and steroidogenesis, and androgen levels were restored in mutant male mice following pharmacoperone therapy. These results show the efficacy of pharmacoperone therapy in vivo by using physiological, molecular, genetic, endocrine and biochemical markers and optimization of pulsatile administration. We expect that this newly appreciated approach of protein rescue will benefit other disorders sharing pathologies based on misrouting of misfolded protein mutants.

Background: Visual evoked potentials (VEPs) are used to detect chiasmal misrouting associated with albinism. However, VEPs are only performed in specialist centres and typically have long waiting lists. The portable electrophysiology device RETeval® shows promise as a clinical screening tool across a range of ophthalmic conditions. Here, we explore its utility in detecting chiasmal abnormalities associated with albinism. Methods: Flash VEPs were recorded on the RETeval® and by standard ISCEV techniques for 27 patients with suspected albinism and 40 control patients as part of routine appointments. We retrospectively investigated the agreeability between the two methods. The amplitude/latency of the main component was measured for standard VEPs whilst a correlation value of interhemispheric difference was calculated for the RETeval® data. Results: We demonstrate a significant difference between albinism patients and controls (p < 0.001) with respect to the interhemispheric difference identified by the RETeval®. By applying a threshold of 0.001865 to the correlation value, the RETeval® detected chiasmal misrouting in all 27 patients with albinism and had 97% agreeability to standard testing. Conclusions: This study shows the potential of using the RETeval® as a clinical tool for the diagnosis of chiasmal anomalies in albinism. The RETeval® has significant time/cost savings which could hasten diagnoses.

Biallelic pathogenic variants in solute carrier family 38 member 8, SLC38A8, cause a pan-ocular autosomal recessive condition known as foveal hypoplasia 2, FVH2, characterised by foveal hypoplasia, nystagmus and optic nerve chiasmal misrouting. Patients are often clinically diagnosed with ocular albinism, but foveal hypoplasia can occur in several other ocular disorders. Here we describe nine patients from seven families who had molecularly confirmed biallelic recessive variants in SLC38A8 identified through whole genome sequencing or targeted gene panel testing. We identified four novel sequence variants (p.(Tyr88*), p.(Trp145*), p.(Glu233Gly) and c.632+1G>A). All patients presented with foveal hypoplasia, nystagmus and reduced visual acuity; however, one patient did not exhibit any signs of chiasmal misrouting, and three patients had features of anterior segment dysgenesis. We highlight these findings in the context of 30 other families reported to date. This study reinforces the importance of obtaining a molecular diagnosis in patients whose phenotype overlap with other inherited ocular conditions, in order to support genetic counselling, clinical prognosis and family planning. We expand the spectrum of SLC38A8 mutations which will be relevant for treatment through future genetic-based therapies.

Albinism encompasses a group of hereditary disorders characterized by reduced or absent ocular pigment and variable skin and/or hair involvement, with syndromic forms such as Hermansky–Pudlak syndrome and Chédiak–Higashi syndrome. Autosomal recessive oculocutaneous albinism (OCA) is phenotypically and genetically heterogenous (associated with seven genes). X-linked ocular albinism (OA) is associated with only one gene, GPR143. We report the clinical and genetic outcomes of 44 patients, from 40 unrelated families of diverse ethnicities, with query albinism presenting to the ocular genetics service at Moorfields Eye Hospital NHS Foundation Trust between November 2017 and October 2019. Thirty-six were children (≤ 16 years) with a median age of 31 months (range 2–186), and eight adults with a median age of 33 years (range 17–39); 52.3% (n = 23) were male. Genetic testing using whole genome sequencing (WGS, n = 9) or a targeted gene panel (n = 31) gave an overall diagnostic rate of 42.5% (44.4% (4/9) with WGS and 41.9% (13/31) with panel testing). Seventeen families had confirmed mutations in TYR (n = 9), OCA2, (n = 4), HPS1 (n = 1), HPS3 (n = 1), HPS6 (n = 1), and GPR143 (n = 1). Molecular diagnosis of albinism remains challenging due to factors such as missing heritability. Differential diagnoses must include SLC38A8-associated foveal hypoplasia and syndromic forms of albinism.

PurposeTo describe the trans-occipital asymmetries of pattern and flash visual evoked potentials (VEPs), in an infant with MRI findings of unilateral optic nerve aplasia and hemi-chiasm dysplasia.MethodsA child with suspected left cystic microphthalmia, left microcornea, left unilateral optic nerve aplasia, and hemi-chiasm underwent a multi-channel VEP assessment with pattern reversal, pattern onset, and flash stimulation at the age of 16 weeks.ResultsThere was no VEP evidence of any post-retinal visual pathway activation from left eye with optic nerve aplasia. The VEP trans-occipital distribution from the functional right eye was skewed markedly across the midline, in keeping with significant misrouting of optic nerve fibres at the chiasm. This was supported by the anatomical trajectory of the optic chiasm and tracts seen on MRI.ConclusionThis infant has chiasmal misrouting in association with unilateral optic nerve aplasia and unilateral microphthalmos. Chiasmal misrouting has not been found in patients with microphthalmos or anophthalmos, but has been reported after early eye loss in animal models. Our findings contribute to our understanding of the discrepancy between the visual pathway physiology of human unilateral microphthalmia and animal models.

PurposeTo characterize the clinical and genetic features of a Japanese male patient with foveal hypoplasia caused by a homozygous single nucleotide duplication in the SLC38A8 gene.MethodsWe performed a comprehensive ophthalmic examination including full-field electroretinography (FF-ERG) and pattern-reversal visual evoked potentials (PR-VEPs). Whole-exome sequencing (WES) was performed to identify the disease-causing variant; Sanger sequencing was used for confirmation.ResultsIn the WES analysis, a homozygous single nucleotide duplication (c.995dupG; p.Trp333MetfsTer35) was identified in SLC38A8 of the patient. His unaffected mother carried the variant heterozygously. The patient exhibited hyperopia, congenital nystagmus, low visual acuity, and grade 4 foveal hypoplasia. Slit-lamp examination revealed mild posterior embryotoxon and goniodysgenesis. Fundus examination revealed the absence of foveal hyperpigmentation and foveal avascularity, but there were no retinal degenerative lesions. In the FF-ERG, the amplitudes of rod ERG, standard-flash, and bright-flash ERG were within the normal range; cone-mediated responses also showed nearly normal amplitudes. The PR-VEP findings revealed delayed P100 latencies and decreased amplitudes of the P100 components, but no chiasmal misrouting.ConclusionsThis report is the first report on the clinical and genetic characteristics of SLC38A8-associated foveal hypoplasia in the Japanese population. This is also the first report of normal rod- and cone-mediated responses in a patient with this disorder.

In albinism, with the use of optical coherence tomography (OCT), a thinning of the macular ganglion cell layer was recently reported. As a consequence, the relevant OCT measure, i.e., a reduction of the temporal/nasal ganglion cell layer thickness quotient (GCLTQ), is a strong candidate for a novel biomarker of albinism. However, nystagmus is a common trait in albinism and is known as a potential confound of imaging techniques. Therefore, there is a need to determine the impact of nystagmus without albinism on the GCLTQ. In this bi-center study, the retinal GCLTQ was determined (OCT Spectralis, Heidelberg Engineering, Heidelberg, Germany) for healthy controls (n = 5, 10 eyes) vs. participants with nystagmus and albinism (Nalbinism, n = 8, 15 eyes), and with nystagmus of other origins (Nother, n = 11, 17 eyes). Macular OCT with 25 horizontal B scans 20 × 20° with 9 automated real time tracking (ART) frames centered on the retina was obtained for each group. From the sectoral GCLTs of the early treatment diabetic retinopathy study (ETDRS) circular thickness maps, i.e., 3 mm and 6 mm ETDRS rings, GCLTQ I and GCLTQ II were determined. Both GCLTQs were reduced in Nalbinism (GCLTQ I and II: 0.78 and 0.77, p < 0.001) compared to Nother (0.91 and 0.93) and healthy controls (0.89 and 0.95). The discrimination of Nalbinism from Nother via GCLTQ I and II had an area under the curve of 80 and 82% with an optimal cutoff point of 0.86 and 0.88, respectively. In conclusion, lower GCLTQ in Nalbinism appears as a distinguished feature in albinism-related nystagmus as opposed to other causes of nystagmus.