Spatial distribution of metabolites in the retina and its relevance to studies of metabolic retinal disorders.

INTRODUCTION: The primate retina has evolved regional specialisations for specific visual functions. The macula is specialised towards high acuity vision and is an area that contains an increased density of cone photoreceptors and signal processing neurons. Different regions in the retina display unique susceptibility to pathology, with many retinal diseases primarily affecting the macula. OBJECTIVES: To better understand the properties of different retinal areas we studied the differential distribution of metabolites across the retina. METHODS: We conducted an untargeted metabolomics analysis on full-thickness punches from three different regions (macula, temporal peri-macula and periphery) of healthy primate retina. RESULTS: Nearly half of all metabolites identified showed differential abundance in at least one comparison between the three regions. Furthermore, mapping metabolomics results from macula-specific eye diseases onto our region-specific metabolite distributions revealed differential abundance defining systemic metabolic dysregulations that were region specific. CONCLUSIONS: The unique metabolic phenotype of different retinal regions is likely due to the differential distribution of different cell types in these regions reflecting the specific metabolic requirements of each cell type. Our results may help to better understand the pathobiology of retinal diseases with region specificity.

New variants and in silico analyses in GRK1 associated Oguchi disease.

Biallelic mutations in G-Protein coupled receptor kinase 1 (GRK1) cause Oguchi disease, a rare subtype of congenital stationary night blindness (CSNB). The purpose of this study was to identify disease causing GRK1 variants and use in-depth bioinformatic analyses to evaluate how their impact on protein structure could lead to pathogenicity. Patients' genomic DNA was sequenced by whole genome, whole exome or focused exome sequencing. Disease associated variants, published and novel, were compared to nondisease associated missense variants. The impact of GRK1 missense variants at the protein level were then predicted using a series of computational tools. We identified twelve previously unpublished cases with biallelic disease associated GRK1 variants, including eight novel variants, and reviewed all GRK1 disease associated variants. Further structure-based scoring revealed a hotspot for missense variants in the kinase domain. In addition, to aid future clinical interpretation, we identified the bioinformatics tools best able to differentiate disease associated from nondisease associated variants. We identified GRK1 variants in Oguchi disease patients and investigated how disease-causing variants may impede protein function in-silico.

Autosomal Recessive Bestrophinopathy: Clinical Features, Natural History, and Genetic Findings in Preparation for Clinical Trials.

PURPOSE: To investigate the clinical course, genetic findings, and phenotypic spectrum of autosomal recessive bestrophinopathy (ARB) in a large cohort of children and adults. DESIGN: Retrospective case series. PARTICIPANTS: Patients with a detailed clinical phenotype consistent with ARB, biallelic likely disease-causing sequence variants in the BEST1 gene, or both identified at a single tertiary referral center. METHODS: Review of case notes, retinal imaging (color fundus photography, fundus autofluorescence, OCT), electrophysiologic assessment, and molecular genetic testing. MAIN OUTCOME MEASURES: Visual acuity (VA), retinal imaging, and electrophysiologic changes over time. RESULTS: Fifty-six eyes of 28 unrelated patients were included. Compound heterozygous variants were detected in most patients (19/27), with 6 alleles recurring in apparently unrelated individuals, the most common of which was c.422G→A, p.(Arg141His; n = 4 patients). Mean presenting VA was 0.52 ± 0.36 logarithm of the minimum angle of resolution (logMAR), and final VA was 0.81 ± 0.75 logMAR (P = 0.06). The mean rate of change in VA was 0.05 ± 0.13 logMAR/year. A significant change in VA was detected in patients with a follow-up of 5 years or more (n = 18) compared with patients with a follow-up of 5 years or less (n = 10; P = 0.001). Presence of subretinal fluid and vitelliform material were early findings in most patients, and this did not change substantially over time. A reduction in central retinal thickness was detected in most eyes (80.4%) over the course of follow-up. Many patients (10/26) showed evidence of generalized rod and cone system dysfunction. These patients were older (P < 0.001) and had worse VA (P = 0.02) than those with normal full-field electroretinography results. CONCLUSIONS: Although patients with ARB are presumed to have no functioning bestrophin channels, significant phenotypic heterogeneity is evident. The clinical course is characterized by a progressive loss of vision with a slow rate of decline, providing a wide therapeutic window for anticipated future treatment strategies.

Phenotype and genotype of 197 British patients with McArdle disease: An observational single-centre study.

McArdle disease is caused by recessive mutations in PYGM gene. The condition is considered to cause a "pure" muscle phenotype with symptoms including exercise intolerance, inability to perform isometric activities, contracture, and acute rhabdomyolysis leading to acute renal failure. This is a retrospective observational study aiming to describe phenotypic and genotypic features of a large cohort of patients with McArdle disease between 2011 and 2019. Data relating to genotype and phenotype, including frequency of rhabdomyolysis, fixed muscle weakness, gout and comorbidities, inclusive of retinal disease (pattern retinal dystrophy) and thyroid disease, were collected. Data from 197 patients are presented. Seven previously unpublished PYGM mutations are described. Exercise intolerance (100%) and episodic rhabdomyolysis (75.6%) were the most common symptoms. Fixed muscle weakness was present in 82 (41.6%) subjects. Unexpectedly, ptosis was observed in 28 patients (14.2%). Hyperuricaemia was a common finding present in 88 subjects (44.7%), complicated by gout in 25% of cases. Thyroid dysfunction was described in 30 subjects (15.2%), and in 3 cases, papillary thyroid cancer was observed. Pattern retinal dystrophy was detected in 15 out of the 41 subjects that underwent an ophthalmic assessment (36.6%). In addition to fixed muscle weakness, ptosis was a relatively common finding. Surprisingly, dysfunction of thyroid and retinal abnormalities were relatively frequent comorbidities. Further studies are needed to better clarify this association, although our finding may have important implication for patient management.

DYNC2H1 hypomorphic or retina-predominant variants cause nonsyndromic retinal degeneration.

PURPOSE: Determining the role of DYNC2H1 variants in nonsyndromic inherited retinal disease (IRD). METHODS: Genome and exome sequencing were performed for five unrelated cases of IRD with no identified variant. In vitro assays were developed to validate the variants identified (fibroblast assay, induced pluripotent stem cell [iPSC] derived retinal organoids, and a dynein motility assay). RESULTS: Four novel DYNC2H1 variants (V1, g.103327020_103327021dup; V2, g.103055779A>T; V3, g.103112272C>G; V4, g.103070104A>C) and one previously reported variant (V5, g.103339363T>G) were identified. In proband 1 (V1/V2), V1 was predicted to introduce a premature termination codon (PTC), whereas V2 disrupted the exon 41 splice donor site causing incomplete skipping of exon 41. V1 and V2 impaired dynein-2 motility in vitro and perturbed IFT88 distribution within cilia. V3, homozygous in probands 2-4, is predicted to cause a PTC in a retina-predominant transcript. Analysis of retinal organoids showed that this new transcript expression increased with organoid differentiation. V4, a novel missense variant, was in trans with V5, previously associated with Jeune asphyxiating thoracic dystrophy (JATD). CONCLUSION: The DYNC2H1 variants discussed herein were either hypomorphic or affecting a retina-predominant transcript and caused nonsyndromic IRD. Dynein variants, specifically DYNC2H1 variants are reported as a cause of non syndromic IRD.

Correction: Biallelic sequence and structural variants in RAX2 are a novel cause for autosomal recessive inherited retinal disease.

The original version of this Article contained an incorrect version of Fig. 3, which included two variants initially shown in black text in Fig. 3a that the authors removed from the final manuscript. The correct version of Fig. 3 without the two variants now appears in the PDF and HTML versions of the Article.

Biallelic sequence and structural variants in RAX2 are a novel cause for autosomal recessive inherited retinal disease.

PURPOSE: RAX2 encodes a homeobox-containing transcription factor, in which four monoallelic pathogenic variants have been described in autosomal dominant cone-dominated retinal disease. METHODS: Exome sequencing in a European cohort with inherited retinal disease (IRD) (n = 2086) was combined with protein structure modeling of RAX2 missense variants, bioinformatics analysis of deletion breakpoints, haplotyping of RAX2 variant c.335dup, and clinical assessment of biallelic RAX2-positive cases and carrier family members. RESULTS: Biallelic RAX2 sequence and structural variants were found in five unrelated European index cases, displaying nonsyndromic autosomal recessive retinitis pigmentosa (ARRP) with an age of onset ranging from childhood to the mid-40s (average mid-30s). Protein structure modeling points to loss of function of the novel recessive missense variants and to a dominant-negative effect of the reported dominant RAX2 alleles. Structural variants were fine-mapped to disentangle their underlying mechanisms. Haplotyping of c.335dup in two cases suggests a common ancestry. CONCLUSION: This study supports a role for RAX2 as a novel disease gene for recessive IRD, broadening the mutation spectrum from sequence to structural variants and revealing a founder effect. The identification of biallelic RAX2 pathogenic variants in five unrelated families shows that RAX2 loss of function may be a nonnegligible cause of IRD in unsolved ARRP cases.

Loss-of-Function Mutations in the CFH Gene Affecting Alternatively Encoded Factor H-like 1 Protein Cause Dominant Early-Onset Macular Drusen.

PURPOSE: To characterize the molecular mechanism underpinning early-onset macular drusen (EOMD), a phenotypically severe subtype of age-related macular degeneration (AMD), in a subgroup of patients. DESIGN: Multicenter case series, in vitro experimentation, and retrospective analysis of previously reported variants. PARTICIPANTS: Seven families with apparently autosomal dominant EOMD. METHODS: Patients underwent a comprehensive ophthalmic assessment. Affected individuals from families A, B, and E underwent whole exome sequencing. The probands from families C, D, F, and G underwent Sanger sequencing analysis of the complement factor H (CFH) gene. Mutant recombinant factor H like-1 (FHL-1) proteins were expressed in HEK293 cells to assess the impact on FHL-1 expression and function. Previously reported EOMD-causing variants in CFH were reviewed. MAIN OUTCOME MEASURES: Detailed clinical phenotypes, genomic findings, in vitro characterization of mutation effect on protein function, and postulation of the pathomechanism underpinning EOMD. RESULTS: All affected participants demonstrated bilateral drusen. The earliest reported age of onset was 16 years (median, 46 years). Ultra-rare (minor allele frequency [MAF], ≤0.0001) CFH variants were identified as the cause of disease in each family: CFH c.1243del, p.(Ala415ProfsTer39) het; c.350+1G→T het; c.619+1G→A het, c.380G→A, p.(Arg127His) het; c.694C→T p.(Arg232Ter) het (identified in 2 unrelated families in this cohort); and c.1291T→A, p.(Cys431Ser). All mutations affect complement control protein domains 2 through 7, and thus are predicted to impact both FHL-1, the predominant isoform in Bruch's membrane (BrM) of the macula, and factor H (FH). In vitro analysis of recombinant proteins FHL-1R127H, FHL-1A415f/s, and FHL-1C431S demonstrated that they are not secreted, and thus are loss-of-function proteins. Review of 29 previously reported EOMD-causing mutations found that 75.8% (22/29) impact FHL-1 and FH. In total, 86.2% (25/29) of EOMD-associated variants cause haploinsufficiency of FH or FHL-1. CONCLUSIONS: Early-onset macular drusen is an underrecognized, phenotypically severe subtype of AMD. We propose that haploinsufficiency of FHL-1, the main regulator of the complement pathway in BrM, where drusen develop, is an important mechanism underpinning the development of EOMD in a number of cases. Understanding the molecular basis of EOMD will shed light on AMD pathogenesis given their pathologic similarities.

Early Patterns of Macular Degeneration in ABCA4-Associated Retinopathy.

PURPOSE: To describe the earliest features of ABCA4-associated retinopathy. DESIGN: Case series. PARTICIPANTS: Children with a clinical and molecular diagnosis of ABCA4-associated retinopathy without evidence of macular atrophy. METHODS: The retinal phenotype was characterized by color fundus photography, OCT, fundus autofluorescence (FAF) imaging, electroretinography, and in 2 patients, adaptive optics scanning laser ophthalmoscopy (AOSLO). Sequencing of the ABCA4 gene was performed in all patients. MAIN OUTCOME MEASURES: Visual acuity, OCT, FAF, electroretinography, and AOSLO results. RESULTS: Eight children with ABCA4-associated retinopathy without macular atrophy were identified. Biallelic variants in ABCA4 were identified in all patients. Four children were asymptomatic, and 4 reported loss of VA. Patients were young (median age, 8.5 years; interquartile range, 6.8 years) with good visual acuity (median, 0.155 logarithm of the minimum angle of resolution [logMAR]; interquartile range, 0.29 logMAR). At presentation, the macula appeared normal (n = 3), had a subtly altered foveal reflex (n = 4), or demonstrated manifest fine yellow dots (n = 1). Fundus autofluorescence identified hyperautofluorescent dots in the central macula in 3 patients, 2 of whom showed a normal fundus appearance. Only 1 child had widespread hyperautofluorescent retinal flecks at presentation. OCT imaging identified hyperreflectivity at the base of the outer nuclear layer in all 8 patients. Where loss of outer nuclear volume was evident, this appeared to occur preferentially at a perifoveal locus. Longitudinal split-detector AOSLO imaging in 2 individuals confirmed that the greatest change in cone spacing occurred in the perifoveal, and not foveolar, photoreceptors. Electroretinography showed a reduced B-wave-to-A-wave ratio in 3 of 5 patients tested; in 2 children, recordings clearly showed electronegative results. CONCLUSIONS: In childhood-onset ABCA4-associated retinopathy, the earliest stages of macular atrophy involve the parafovea and spare the foveola. In some cases, these changes are predated by tiny, foveal, yellow, hyperautofluorescent dots. Hyperreflectivity at the base of the outer nuclear layer, previously described as thickening of the external limiting membrane, is likely to represent a structural change at the level of the foveal cone nuclei. Electroretinography suggests that the initial site of retinal dysfunction may occur after phototransduction.

THE FUNDUS PHENOTYPE ASSOCIATED WITH THE p.Ala243Val BEST1 MUTATION.

PURPOSE: To describe a highly recognizable and reproducible retinal phenotype associated with a specific BEST1 mutation-p.Ala243Val. METHODS: Retrospective review of consecutive cases where genetic testing has identified p.Ala243Val BEST1 as the cause of disease. Electronic patient records were used to extract demographic, as well as functional and anatomical data. These data were compared with those observed with the most common BEST1 genotype, p.Arg218Cys. RESULTS: Eight individuals (six families) were identified with the p.Ala243Val BEST1 mutation and seven patients with the pathologic variant p.Arg218Cys. No patients with mutation of codon 243 knowingly had a family history of retinal disease, whereas all patients with the p.Arg218Cys variant did. The maculopathy was bilateral in all cases. The p.Ala243Val mutation was associated with a pattern dystrophy-type appearance, most visible with near-infrared reflectance and fundus autofluorescence imaging. This phenotype was never observed with any other genotype. This mutation was associated with an older median age of symptom onset (median = 42, interquartile range = 22) compared with those harboring the p.Arg218Cys mutation (median = 18, interquartile range = 12; Mann-Whitney U test; P < 0.05). Despite their older age, the final recorded acuity seemed to be better in the p.Ala243Val group (median = 0.55, interquartile range = 0.6475; median = 0.33, interquartile range = 0.358), although this did not reach statistical significance (Mann-Whitney U test; P > 0.05). CONCLUSION: The mutation p.Ala243Val is associated with highly recognizable and reproducible pattern dystrophy-like phenotype. Patients develop symptoms at a later age and tend to have better preservation of electrooculogram amplitudes.

NORMAL ELECTROOCULOGRAPHY IN BEST DISEASE AND AUTOSOMAL RECESSIVE BESTROPHINOPATHY.

PURPOSE: To evaluate the electrooculogram (EOG) in a large series of patients with Best disease and autosomal recessive bestrophinopathy. METHODS: A retrospective review of consecutive cases at Moorfields Eye Hospital, London, United Kingdom. Patients with Best disease or autosomal recessive bestrophinopathy who, after electrophysiologic testing, had a normal or atypical EOG light rise were identified. Main outcome measure was EOG amplitude, clinical phenotype and genotype. RESULTS: One hundred thirteen patients were identified with likely disease-causing sequence variants in BEST1 (99 Best disease and 14 autosomal recessive bestrophinopathy). Electrooculograms had been performed in 75 patients. Twenty patients (27%) had no detectable light rise (Arden ratio of 100%) and 49 (65%) had Arden ratios of between 100% to 165%. Six patients (8%) were found to have an EOG light rise of >165%. No cases demonstrated significant interocular asymmetry in EOG amplitude. CONCLUSION: The current work provides significant clinical evidence that the EOG phenotype in Best disease and autosomal recessive bestrophinopathy is more variable than currently appreciated. As a normal EOG may occur in the presence of a classical fundus appearance, the consequences of BEST1 mutation may be independently expressed, possibly mediated through differential effects on intracellular calcium homeostasis.

DETAILED RETINAL IMAGING IN CARRIERS OF OCULAR ALBINISM.

BACKGROUND: Albinism refers to a group of disorders primarily characterized by hypopigmentation. Affected individuals usually manifest both ocular and cutaneous features of the disease, but occasionally hair and skin pigmentation may appear normal. This is the case in ocular albinism, an X chromosome linked disorder resulting from mutation of GPR143. Female carriers may be recognized by a "mud-splatter" appearance in the peripheral retina. The macula is thought to be normal, however. METHODS: Obligate female carriers of pathogenic GPR143 alleles were recruited. Molecular confirmation of disease was performed only for atypical cases. Detailed retinal imaging was performed (colour fundus photography, optical coherence tomography, fundus autofluorescence. RESULTS: Eight individuals were ascertained. A novel GPR143 mutation was identified in one family (p.Gln328Ter). Foveal fundus autofluorescence was subjectively reduced in 6/6 patients imaged. A "tapetal-like" pattern of autofluorescence was visible at the macula in 3/6. Persistence of the inner retinal layers at the fovea was observed in 6/8 females. CONCLUSION: Female carriers of ocular albinism may manifest signs of retinal pigment epithelium mosaicism at the macula and the peripheral fundus. A tapetal-like reflex on fundus autofluorescence may be considered the macular correlate of "mud-splatter."

FUNCTIONAL AND ANATOMICAL OUTCOMES OF CHOROIDAL NEOVASCULARIZATION COMPLICATING BEST1-RELATED RETINOPATHY.

PURPOSE: To describe the presenting features and functional outcomes in a series of patients with choroidal neovascular membrane complicating BEST1-related retinopathy (Best disease and autosomal recessive bestrophinopathy). METHODS: Retrospective review of consecutive cases at a tertiary care eye hospital. Patients were identified retrospectively over an 11-year period. Records were reviewed to extract demographic as well as functional and anatomical outcome data. RESULTS: Fourteen eyes of 12 patients were identified (11 Best disease and 1 autosomal recessive bestrophinopathy). Median follow-up was 2.8 years (range 0.8-6). The median age at choroidal neovascular membrane discovery was 15.5 years (range 6-72). Choroidal neovascular membranes were active early in the disease course before vitelliruption. Seven eyes were treated with intravitreal bevacizumab, 7 eyes were monitored by observation alone. On average, patients required a single treatment (median = 1, range 1-10). The median gain in visual acuity was greater in the treated versus the observed group-0.46 versus 0.17 decimalized units of Snellen acuity, respectively (P < 0.05 Mann-Whitney U test). Although a significant reduction in central macular thickness was evident in both groups, 150 µm (treated) and 104 µm (observed), active treatment was not associated with greater thinning than observation (P > 0.05 Mann-Whitney U test). CONCLUSION: There is a high rate of spontaneous recovery of BEST1-related choroidal neovascular membrane, and overall the authors observed a gain in visual acuity associated with a reduction in central macular thickness. Active treatment, here with intravitreal bevacizumab, is associated with better functional outcomes than observation alone.

Clinical and Genetic Features of Choroideremia in Childhood.

PURPOSE: To review the functional and anatomic characteristics of choroideremia in the pediatric population, aiming to describe the earliest features of the disease and to identify biomarkers useful for monitoring disease progression. DESIGN: Retrospective case series. PARTICIPANTS: Children diagnosed with choroideremia at a single institution. METHODS: Patients were identified using an electronic patient record system. Case notes and retinal imaging (color fundus photography [CFP], spectral-domain [SD] optical coherence tomography [OCT], and fundus autofluorescence [FAF]) then were reviewed. The results of genetic testing also were recorded. MAIN OUTCOME MEASURES: Presenting symptoms, visual acuity, fundus changes (CFP, SD OCT, FAF), and CHM sequencing results. RESULTS: Twenty-nine patients were identified with a mean age at referral of 9 years (range, 3-16 years). CHM mutations were identified in 15 of 19 patients tested. Nyctalopia was the predominant symptom (66%). Five of 29 patients were asymptomatic at presentation. At the final follow-up visit (mean age, 16 years; range, 7-26 years), most maintained excellent visual acuity (mean, 0.98±0.13 decimalized Snellen acuity). The first sign of retinopathy was widespread pigment clumping at the level of the retinal pigment epithelium (RPE). This later evolved to chorioretinal atrophy, most marked in the mid-peripheral retina. Peripapillary atrophy also was an early feature and was progressive in nature. Three different zones of FAF change were visible. Persistence of the inner retinal layers, detected by SD OCT, was visible at presentation in 15 of 27 patients. Subfoveal choroidal thickness decreased with age, whereas central retinal thickness increased over a similar interval. Four patients in whom visual acuity decreased over the follow-up period recorded a reduction in central retinal thickness. CONCLUSIONS: Progressive structural changes occur at a time when central visual function is maintained. Pigmentary changes at the level of the RPE occur early in the disease course. Peripapillary chorioretinal atrophy, central retinal thickness, and subfoveal choroidal thickness are likely to be valuable in monitoring disease progression and should be considered as potential biomarkers in future therapeutic trials.

Outcome of Cataract Surgery in Patients With Retinitis Pigmentosa.

PURPOSE: To assess the visual outcome of cataract surgery in patients with retinitis pigmentosa (RP). DESIGN: Retrospective, noncomparative clinical study. METHODS: Preoperative, intraoperative, and postoperative data of patients with RP who were undergoing cataract surgery were collected from several expertise centers across Europe. RESULTS: In total, 295 eyes of 226 patients were included in the study. The mean age at surgery of the first eye was 56.1 ± 17.9 years. Following surgery, best-corrected visual acuity (BCVA) improved significantly from 1.03 to 0.81 logMAR (ie, 20/214 to 20/129 Snellen) in the first treated eye (-0.22 logMAR; 95% CI = -0.31 to -0.13; P < .001) and from 0.80 to 0.56 logMAR (ie, 20/126 to 20/73 Snellen) in the second treated eye (-0.24 logMAR; 95% CI = -0.32 to -0.15; P < .001). Marked BCVA improvements (postoperative change in BCVA of ≥0.3 logMAR) were observed in 87 of 226 patients (39%). Greater odds for marked visual improvements were observed in patients with moderate visual impairment or worse. The most common complications were zonular dialysis (n = 15; 5%) and (exacerbation of) cystoid macular edema (n = 14; 5%), respectively. Postoperative posterior capsular opacifications were present in 111 of 295 eyes (38%). CONCLUSION: Significant improvements in BCVA are observed in most patients with RP following cataract surgery. Baseline BCVA is a predictor of visual outcome. Preoperative evaluation should include the assessment of potential zonular insufficiency and the presence of CME, as they are relatively common and may increase the risk of complications.

Panel-based genetic testing for inherited retinal disease screening 176 genes.

BACKGROUND: This case series reports the performance of a next-generation sequencing (NGS) panel of 176 retinal genes (NGS 176) in patients with inherited retinal disease (IRD). METHODS: Subjects are patients who underwent genetic testing between 1 August 2016 and 1 January 2018 at Moorfields Eye Hospital, London, UK. Panel-based genetic testing was performed unless a specific gene (e.g., RS1) or small group of genes (e.g., ABCA4, PRPH2) were suspected. If a novel variant was identified, a further comment on their predicted pathogenicity and evolutionary conservation was offered and segregation studies performed. The main outcome measure is the likelihood of obtaining a genetic diagnosis using NGS 176. RESULTS: 488 patients were included. A molecular diagnosis was obtained for 59.4% of patients. Younger patients were more likely to receive a molecular diagnosis; with 92% of children under the age of 6 years receiving a conclusive result. There was a change in their initially assigned inheritance pattern in 8.4% of patients following genetic testing. Selected IRD diagnoses (e.g., achromatopsia, congenital stationary night blindness) were associated with high diagnostic yields. CONCLUSION: This study confirms that NGS 176 is a useful first-tier genetic test for most IRD patients. Age and initial clinical diagnosis were strongly associated with diagnostic yield.

Macular dystrophies: clinical and imaging features, molecular genetics and therapeutic options.

Macular dystrophies (MDs) consist of a heterogeneous group of disorders that are characterised by bilateral symmetrical central visual loss. Advances in genetic testing over the last decade have led to improved knowledge of the underlying molecular basis. The developments in high-resolution multimodal retinal imaging have also transformed our ability to make accurate and more timely diagnoses and more sensitive quantitative assessment of disease progression, and allowed the design of optimised clinical trial endpoints for novel therapeutic interventions. The aim of this review was to provide an update on MDs, including Stargardt disease, Best disease, X-linked r etinoschisis, pattern dystrophy, Sorsby fundus dystrophy and autosomal dominant drusen. It highlights the range of innovations in retinal imaging, genotype-phenotype and structure-function associations, animal models of disease and the multiple treatment strategies that are currently in clinical trial or planned in the near future, which are anticipated to lead to significant changes in the management of patients with MDs.

Quantifying the Separation Between the Retinal Pigment Epithelium and Bruch's Membrane using Optical Coherence Tomography in Patients with Inherited Macular Degeneration.

Purpose: To describe and quantify Bruch's membrane (BM) and retinal pigment epithelium (RPE) separation using spectral-domain (SD) optical coherence tomography (OCT) in patients affected by inherited macular degenerations associated with BM thickening. Methods: Patients with molecularly confirmed Sorsby fundus dystrophy (SFD), dominant drusen (DD), and late-onset retinal degeneration (L-ORD) were included in this retrospective study. Each disease was classed as early stage if subjects were asymptomatic, intermediate stage if they had nyctalopia alone, and late stage if they described loss of central vision. The main outcome was measurement of BM-RPE separation on SD-OCT. The BM-RPE separation measurements were compared against those in normal age-matched controls. Results: Seventeen patients with SFD, 22 with DD, and eight with L-ORD were included. BM-RPE separation on SD-OCT demonstrated a high test-retest and interobserver reproducibility (intraclass correlation coefficients >0.9). BM-RPE separation was not identified in normal subjects. In SFD, there was greater BM-RPE separation in late-stage disease compared with intermediate-stage patients both at subfoveal (P < 0.05) and juxtafoveal (P < 0.01) locations. In DD, there was increased BM-RPE separation in late-stage disease compared with early stage at subfoveal (P < 0.001) and juxtafoveal (P < 0.05) topographies. There was no significant difference in BM-RPE separation between disease stages in L-ORD. Conclusions: BM-RPE separation is a novel, quantifiable phenotype in the three monogenic macular dystrophies studied, and may be an optical correlate of the histopathological thickening in BM that is known to occur. BM-RPE separation, as measured by OCT, varies with stage of disease in SFD and DD, but not in L-ORD. Translational Relevance: SFD, DD, and L-ORD are associated with BM thickening. In this group of patients, OCT assessment of macular structure identifies a separation of the usually single, hyperreflective line thought to represent BM and the overlying RPE. This separation is a novel and quantifiable feature of disease staging in SFD and DD.

Systemic lipid dysregulation is a risk factor for macular neurodegenerative disease.

Macular Telangiectasia type 2 (MacTel) is an uncommon bilateral retinal disease, in which glial cell and photoreceptor degeneration leads to central vision loss. The causative disease mechanism is largely unknown, and no treatment is currently available. A previous study found variants in genes associated with glycine-serine metabolism (PSPH, PHGDH and CPS1) to be associated with MacTel, and showed low levels of glycine and serine in the serum of MacTel patients. Recently, a causative role of deoxysphingolipids in MacTel disease has been established. However, little is known about possible other metabolic dysregulation. Here we used a global metabolomics platform in a case-control study to comprehensively profile serum from 60 MacTel patients and 58 controls. Analysis of the data, using innovative computational approaches, revealed a detailed, disease-associated metabolic profile with broad changes in multiple metabolic pathways. This included alterations in the levels of several metabolites that are directly or indirectly linked to glycine-serine metabolism, further validating our previous genetic findings. We also found changes unrelated to PSPH, PHGDH and CPS1 activity. Most pronounced, levels of several lipid groups were altered, with increased phosphatidylethanolamines being the most affected lipid group. Assessing correlations between different metabolites across our samples revealed putative functional connections. Correlations between phosphatidylethanolamines and sphingomyelin, and glycine-serine and sphingomyelin, observed in controls, were reduced in MacTel patients, suggesting metabolic re-wiring of sphingomyelin metabolism in MacTel patients. Our findings provide novel insights into metabolic changes associated with MacTel and implicate altered lipid metabolism as a contributor to this retinal neurodegenerative disease.