Retinotopic cortical mapping in objective functional monitoring of macular therapy.

BACKGROUND/AIMS: To determine the suitability of functional MRI (fMRI) as an objective measure of macular function following therapeutic intervention; conventional psychophysical measures rely heavily on patient compliance. METHODS: Twenty patients with neovascular age-related macular degeneration (nAMD) were studied with high-resolution fMRI, visual acuity, reading accuracy and speed, contrast sensitivity (CS) and microperimetry (MP) before and after 3 monthly intravitreal injections of ranibizumab. Population-receptive field retinotopic maps calculated from fMRI data were compared with psychophysical measures and optical coherence tomography. RESULTS: Best-corrected visual acuity (BCVA) responders (≥5 letters) showed an increase of 29.5% in activated brain area, while non-responders showed a decrease of 0.8%. Radial histograms over eccentricity allowed quantification of the absolute number of significant voxels and thus differences before and after treatment. Responders showed increases in foveal (α<0.5°) activation, while non-responders did not. Absence of intraretinal fluid and preservation of outer retinal layers was associated with higher numbers of active V1 voxels and better BCVA. Higher voxel numbers were associated with improved reading performance and, less marked, with BCVA, CS and MP. CONCLUSION: The data show that retinotopic mapping using fMRI can successfully be applied objectively to evaluate the therapeutic response in nAMD patients treated with anti-vascular endothelial growth factor therapy. This demonstrates the ability of retinotopic mapping to provide an objective assessment of functional recovery at a cortical level; the technique can therefore be applied, in other degenerative macular diseases, to the assessment of potential therapeutic interventions such as gene therapy or cell replacement therapy.

Rationale and protocol paper for the Asia Pacific Network for inherited eye diseases.

PURPOSE: There are major gaps in our knowledge of hereditary ocular conditions in the Asia-Pacific population, which comprises approximately 60% of the world's population. Therefore, a concerted regional effort is urgently needed to close this critical knowledge gap and apply precision medicine technology to improve the quality of lives of these patients in the Asia-Pacific region. DESIGN: Multi-national, multi-center collaborative network. METHODS: The Research Standing Committee of the Asia-Pacific Academy of Ophthalmology and the Asia-Pacific Society of Eye Genetics fostered this research collaboration, which brings together renowned institutions and experts for inherited eye diseases in the Asia-Pacific region. The immediate priority of the network will be inherited retinal diseases (IRDs), where there is a lack of detailed characterization of these conditions and in the number of established registries. RESULTS: The network comprises 55 members from 35 centers, spanning 12 countries and regions, including Australia, China, India, Indonesia, Japan, South Korea, Malaysia, Nepal, Philippines, Singapore, Taiwan, and Thailand. The steering committee comprises ophthalmologists with experience in consortia for eye diseases in the Asia-Pacific region, leading ophthalmologists and vision scientists in the field of IRDs internationally, and ophthalmic geneticists. CONCLUSIONS: The Asia Pacific Inherited Eye Disease (APIED) network aims to (1) improve genotyping capabilities and expertise to increase early and accurate genetic diagnosis of IRDs, (2) harmonise deep phenotyping practices and utilization of ontological terms, and (3) establish high-quality, multi-user, federated disease registries that will facilitate patient care, genetic counseling, and research of IRDs regionally and internationally.

Diffuse retinal dysfunction following immune reconstitution uveitis in patients with prior cytomegalovirus retinitis: a novel observation.

PURPOSE: To report continuing diffuse retinal dysfunction following resolution of immune reconstitution uveitis (IRU) in patients with cytomegalovirus retinitis (CMVR). METHODS: Retrospective case series describing two patients with IRU following CMVR who underwent serial fundus photography and macular optical coherence tomography. One patient had serial electrophysiology. RESULTS: Both patients had CMVR successfully treated with antiviral medication. The affected eyes later developed IRU that resolved with steroids. However, following resolution, chronic retinal damage was evidenced by ellipsoid line loss in one case and gradual optic disc cupping in the other. Electrophysiology in both cases revealed generalized retinal dysfunction worse in the eye with more severe IRU and demonstrated objectively the efficacy of treatment intervention in the patient with serial recordings. CONCLUSIONS: Patients with IRU following CMV retinitis may have continuing diffuse retinal dysfunction despite apparent recovery and normal visual acuity. An aggressive approach to inflammation control may be warranted in such patients.

Three-Year Changes in Visual Function in the Placebo Group of a Randomized Double-Blind International Multicenter Safety Study: Analysis of Electroretinography, Perimetry, Color Vision, and Visual Acuity in Individuals With Chronic Stable Angina Pectoris.

Purpose: To determine whether significant deteriorations in objective (electroretinography [ERG]) and subjective (standard automated and semi-automated kinetic perimetry; color discrimination; and best-corrected visual acuity) tests of visual function, potentially attributable to aging, occurred in the group randomized to placebo of a 3-year prospective multicenter ocular safety study of ivabradine for chronic stable angina pectoris. Methods: The multicenter trial was conducted at 11 international ophthalmic centers. Changes in visual function between baseline and month 36 were analyzed by means of a two-tailed Wilcoxon signed-rank test, based on the Hodges and Lehman estimator of the median difference, with the 95% confidence intervals derived by Walsh averages. Results: Thirty-eight participants from the placebo group completed the study (mean [SD], age, 62.7 [8.1] years). The group exhibited in each eye small, but statistically significant, reductions in the amplitudes of the dark-adapted (DA) ERG 3.0 a-wave, and light-adapted (LA) 3.0 b-wave, as well as increases in peak time for the DA 0.01 b-wave, DA 3.0 a-wave, LA 3.0 b-wave, and LA 3.0 30-Hz flicker response and in the isopter area I3e of the visual field. Conclusions: Statistically significant deteriorations occurred in visual function over a period of 3 years, potentially attributable to age, within a group of individuals with chronic stable angina pectoris and unremarkable ophthalmological findings other than those attributable to age. Translational Relevance: A longitudinal correction factor for age-related change in visual function may be useful in future trials to determine whether an observed deterioration in visual function is related to intervention or to aging.

Macular Telangiectasia type 2: multimodal assessment of retinal function and microstructure.

PURPOSE: To assess the impact of neurodegenerative morphologic alterations due to macular telangiectasia type 2 (MacTel) on microperimetry (MP) and multifocal electroretinography (mfERG). METHODS: Thirty-five eyes of 18 patients with MacTel were examined using spectral domain optical coherence tomography (SD-OCT), fundus autofluorescence (FAF), mfERG and MP. Software was used to match SD-OCT B-scans with the corresponding retinal sensitivity map and multifocal electroretinograms (mfERGs), thus enabling direct structure/function correlation. RESULTS: Loss of the ellipsoid zone (EZ) had the strongest negative association with retinal sensitivity (16.77 dB versus 4.58 dB, adj. p < 0.001) of all parameters examined, and a limited negative effect on mfERGs (0.32 SD versus -1.97 SD adj. p = 0.121). Ellipsoid zone (EZ) irregularity was associated with reduced MP values but preserved mfERGs. There was a significant association between areas of inner retinal hyporeflectivity and loss of MP sensitivity (adj. p < 0.001) but the reduction in sensitivity was less than in locations with EZ loss. Areas of mfERG abnormality showed similar sensitivity loss with either inner retinal hyporeflectivity or EZ loss (adj. p = 0.063). In areas with EZ loss alone, preservation of the external limiting membrane (ELM) was associated with higher MP values than in areas with additional ELM loss; the integrity of the ELM alone was not associated with changes either in MP or mfERG. Increased FAF was observed in 51% of eyes, mixed/reduced FAF in 40%, and no abnormality was detected in 9% of eyes. CONCLUSION: The data suggest both MP and mfERG to be useful non-invasive modalities for detecting localised macular dysfunction in MacTel. The findings suggest a different sensitivity of the two modalities to inner and outer retinal changes in macular function and are therefore complementary.

Pathogenic NR2F1 variants cause a developmental ocular phenotype recapitulated in a mutant mouse model.

Pathogenic NR2F1 variants cause a rare autosomal dominant neurodevelopmental disorder referred to as the Bosch-Boonstra-Schaaf Optic Atrophy Syndrome. Although visual loss is a prominent feature seen in affected individuals, the molecular and cellular mechanisms contributing to visual impairment are still poorly characterized. We conducted a deep phenotyping study on a cohort of 22 individuals carrying pathogenic NR2F1 variants to document the neurodevelopmental and ophthalmological manifestations, in particular the structural and functional changes within the retina and the optic nerve, which have not been detailed previously. The visual impairment became apparent in early childhood with small and/or tilted hypoplastic optic nerves observed in 10 cases. High-resolution optical coherence tomography imaging confirmed significant loss of retinal ganglion cells with thinning of the ganglion cell layer, consistent with electrophysiological evidence of retinal ganglion cells dysfunction. Interestingly, for those individuals with available longitudinal ophthalmological data, there was no significant deterioration in visual function during the period of follow-up. Diffusion tensor imaging tractography studies showed defective connections and disorganization of the extracortical visual pathways. To further investigate how pathogenic NR2F1 variants impact on retinal and optic nerve development, we took advantage of an Nr2f1 mutant mouse disease model. Abnormal retinogenesis in early stages of development was observed in Nr2f1 mutant mice with decreased retinal ganglion cell density and disruption of retinal ganglion cell axonal guidance from the neural retina into the optic stalk, accounting for the development of optic nerve hypoplasia. The mutant mice showed significantly reduced visual acuity based on electrophysiological parameters with marked conduction delay and decreased amplitude of the recordings in the superficial layers of the visual cortex. The clinical observations in our study cohort, supported by the mouse data, suggest an early neurodevelopmental origin for the retinal and optic nerve head defects caused by NR2F1 pathogenic variants, resulting in congenital vision loss that seems to be non-progressive. We propose NR2F1 as a major gene that orchestrates early retinal and optic nerve head development, playing a key role in the maturation of the visual system.

cGMP-grade human iPSC-derived retinal photoreceptor precursor cells rescue cone photoreceptor damage in non-human primates.

BACKGROUND: Retinal regenerative therapies hold great promise for the treatment of inherited retinal degenerations (IRDs). Studies in preclinical lower mammal models of IRDs have suggested visual improvement following retinal photoreceptor precursors transplantation, but there is limited evidence on the ability of these transplants to rescue retinal damage in higher mammals. The purpose of this study was to evaluate the therapeutic potential of photoreceptor precursors derived from clinically compliant induced pluripotent stem cells (iPSCs). METHODS: Photoreceptor precursors were sub-retinally transplanted into non-human primates (Macaca fascicularis). The cells were transplanted both in naïve and cobalt chloride-induced retinal degeneration models who had been receiving systemic immunosuppression for one week prior to the procedure. Optical coherence tomography, fundus autofluorescence imaging, electroretinography, ex vivo histology and immunofluorescence staining were used to evaluate retinal structure, function and survival of transplanted cells. RESULTS: There were no adverse effects of iPSC-derived photoreceptor precursors on retinal structure or function in naïve NHP models, indicating good biocompatibility. In addition, photoreceptor precursors injected into cobalt chloride-induced retinal degeneration NHP models demonstrated an ability both to survive and to mature into cone photoreceptors at 3 months post-transplant. Optical coherence tomography showed restoration of retinal ellipsoid zone post-transplantation. CONCLUSIONS: These findings demonstrate the safety and therapeutic potential of clinically compliant iPSC-derived photoreceptor precursors as a cell replacement source for future clinical trials.

Submacular integration of hESC-RPE monolayer xenografts in a surgical non-human primate model.

BACKGROUND: Human pluripotent stem cells (hPSCs) provide a promising cell source for retinal cell replacement therapy but often lack standardized cell production and live-cell shipment logistics as well as rigorous analyses of surgical procedures for cell transplantation in the delicate macula area. We have previously established a xeno- and feeder cell-free production system for hPSC differentiated retinal pigment epithelial (RPE) cells, and herein, a novel immunosuppressed non-human primate (NHP) model with a disrupted ocular immune privilege is presented for transplanting human embryonic stem cell (hESC)-derived RPE on a scaffold, and the safety and submacular graft integration are assessed. Furthermore, the feasibility of intercontinental shipment of live hESC-RPE is examined. METHODS: Cynomolgus monkeys were systemically immunosuppressed and implanted with a hESC-RPE monolayer on a permeable polyester-terephthalate (PET) scaffold. Microscope-integrated intraoperative optical coherence tomography (miOCT)-guided surgery, postoperative follow-up incorporated scanning laser ophthalmoscopy, spectral domain (SD-) OCT, and full-field electroretinography (ERG) were used as outcome measures. In addition, histology was performed after a 28-day follow-up. RESULTS: Intercontinental cell shipment, which took >30 h from the manufacturing to the transplantation site, did not alter the hESC-RPE quality. The submacular hESC-RPE xenotransplantation was performed in 11 macaques. The miOCT typically revealed foveal disruption. ERG showed amplitude and peak time preservation in cases with favorable surgical outcomes. Histology confirmed photoreceptor preservation above the grafts and in vivo phagocytosis by hESC-RPE, albeit evidence of cytoplasmic redistribution of opsin in photoreceptors and glia hypertrophy. The immunosuppression protocol efficiently suppressed retinal T cell infiltration and microglia activation. CONCLUSION: These results suggest both structural and functional submacular integrations of hESC-RPE xenografts. It is anticipated that surgical technique refinement will further improve the engraftment of macular cell therapeutics with significant translational relevance to improve future clinical trials.

Retinal Pigment Epithelium Transplantation in a Non-human Primate Model for Degenerative Retinal Diseases.

Retinal pigment epithelial (RPE) transplantation holds great promise for the treatment of inherited and acquired retinal degenerative diseases. These conditions include retinitis pigmentosa (RP) and advanced forms of age-related macular degeneration (AMD), such as geographic atrophy (GA). Together, these disorders represent a significant proportion of currently untreatable blindness globally. These unmet medical needs have generated heightened academic interest in developing methods of RPE replacement. Among the animal models commonly utilized for preclinical testing of therapeutics, the non-human primate (NHP) is the only animal model that has a macula. As it shares this anatomical similarity with the human eye, the NHP eye is an important and appropriate preclinical animal model for the development of advanced therapy medicinal products (ATMPs) such as RPE cell therapy. This manuscript describes a method for the submacular transplantation of an RPE monolayer, cultured on a polyethylene terephthalate (PET) cell carrier, underneath the macula onto a surgically created RPE wound in immunosuppressed NHPs. The fovea-the central avascular portion of the macula-is the site of the greatest mechanical weakness during the transplantation. Foveal trauma will occur if the initial subretinal fluid injection generates an excessive force on the retina. Hence, slow injection under perfluorocarbon liquid (PFCL) vitreous tamponade is recommended with a dual-bore subretinal injection cannula at low intraocular pressure (IOP) settings to create a retinal bleb. Pretreatment with an intravitreal plasminogen injection to release parafoveal RPE-photoreceptor adhesions is also advised. These combined strategies can reduce the likelihood of foveal tears when compared to conventional techniques. The NHP is a key animal model in the preclinical phase of RPE cell therapy development. This protocol addresses the technical challenges associated with the delivery of RPE cellular therapy in the NHP eye.

Severe retinal vasculitis in systemic lupus erythematosus leading to vision threatening paracentral acute middle maculopathy.

Systemic lupus erythematosus can affect any organ system at presentation and throughout its course. Lupus retinal vasculitis is responsible for the visual loss of variable severity and typically ascribed to the involvement of pre-capillary superficial arterial vasculature. Using multimodal imaging techniques and electrophysiology, we demonstrate the first-ever case of severe lupus retinal vasculitis resulting in the rare association of paracentral acute middle maculopathy. The findings showcase the involvement of both superficial and deep retinal capillary vasculature and the localisation of retinal dysfunction. This precise evaluation facilitated the timely use of combination immunomodulatory therapy with localised pan-retinal laser photocoagulation, resulting in the preservation of vision.

Surgical Transplantation of Human RPE Stem Cell-Derived RPE Monolayers into Non-Human Primates with Immunosuppression.

Recent trials of retinal pigment epithelium (RPE) transplantation for the treatment of disorders such as age-related macular degeneration have been promising. However, limitations of existing strategies include the uncertain survival of RPE cells delivered by cell suspension and the inherent risk of uncontrolled cell proliferation in the vitreous cavity. Human RPE stem cell-derived RPE (hRPESC-RPE) transplantation can rescue vision in a rat model of retinal dystrophy and survive in the rabbit retina for at least 1 month. The present study placed hRPESC-RPE monolayers under the macula of a non-human primate model for 3 months. The transplant was able to recover in vivo and maintained healthy photoreceptors. Importantly, there was no evidence that subretinally transplanted monolayers underwent an epithelial-mesenchymal transition. Neither gliosis in adjacent retina nor epiretinal membranes were observed. These findings suggest that hRPESC-RPE monolayers are safe and may be a useful source for RPE cell replacement therapy.

ACUTE SYPHILITIC POSTERIOR PLACOID CHORIORETINITIS: MULTIMODAL IMAGING AND ELECTROPHYSIOLOGIC FINDINGS BEFORE AND AFTER TREATMENT.

PURPOSE: To describe the clinical course of acute syphilitic posterior placoid chorioretinitis (ASPPC) in the preplacoid stage, placoid stage, and after treatment with penicillin. METHOD: A retrospective case report of serial multimodal imaging and electrophysiology studies of a patient with ASPPC, with 18 months of follow-up. RESULTS: A 47-year-old man presented with bilateral panuveitis. The patient defaulted follow-up and returned when his vision deteriorated. Tests for neurosyphilis and retroviral disease were positive, and treatment was initiated. The earliest change on serial optical coherence tomography was loss of the signal from the reflective band corresponding to the ellipsoid zone. In the placoid stage, there was nodular thickening of the retinal pigment epithelium. The ellipsoid zone signals reappeared after treatment. Fundus fluorescein angiogram at presentation showed peripapillary vasculitis and disk leakage; indocyanine green angiography revealed multiple hypofluorescent spots in the peripapillary region and posterior pole that was not visible clinically. The angiographic abnormalities resolved after treatment. Electrophysiology demonstrated bilateral maculopathy and reduction of both a- and b-waves from dark-adapted and light-adapted responses at presentation. The b-waves (inner retina) recovered partially with treatment. CONCLUSION: To the best of our knowledge, this is the first case report of the multimodal imaging and electrophysiology findings in a patient with acute syphilitic posterior placoid chorioretinitis, before the development of the classic placoid lesion. Improvement of structural and functional pathology after systemic treatment is demonstrated.

Quality Control Procedures and Baseline Values for Electroretinography, Perimetry, Color Vision, and Visual Acuity in an International Multicenter Study: Observations from a Safety Trial in Chronic Stable Angina Pectoris.

Purpose: To describe quality control procedures and baseline values of electroretinography (ERG), kinetic and static perimetry, color discrimination, and best-corrected visual acuity from a multicenter ocular safety study. Methods: A multicenter prospective longitudinal randomized placebo-controlled study was conducted at 11 ophthalmic centers that had received certification following training, instruction, and monitoring. ERGs were obtained with the Espion E2 Ganzfeld console, perimetry with the Octopus 101 perimeter, color discrimination with the Lanthony desaturated D15 test, and best-corrected visual acuity with the Early Treatment Diabetic Retinopathy Study chart. Ophthalmic eligibility required satisfactory outcomes for ERG and perimetry by the second or third pre-inclusion attempts, respectively. Quality control for the ERG was undertaken by two central readers. Results: The mean (SD) age of the 97 individuals was 63.5 (7.9) range, 44-83 years. The overall coefficients of variation (CVs) for the ERG peak times were less than those of the only comparable single-center study. The CV for the mean defect of standard automated perimetry was approximately one-third that of the Ocular Hypertension Treatment Study. With increasing age, ERG peak times and color discrimination Total Error Score increased while ERG amplitudes and isopter area all decreased. Conclusions: The data illustrate the benefit of identical equipment, stringent on-site instruction and training, quality control, certification, and validation methods. The latter are recommended for planning and conducting multicenter trials using ERG and perimetry to monitor safety and/or efficacy of treatment intervention. Translational Relevance: Stringent quality control procedures and reliable reference values are indispensable prerequisites for informative clinical trials.

ISCEV extended protocol for the S-cone ERG.

The International Society for Clinical Electrophysiology of Vision (ISCEV) standard for full-field electroretinography (ERG) describes a minimum procedure for testing generalized retinal function but encourages more extensive testing. This extended protocol describes a method of assessing the function of the short-wavelength-sensitive cone (S-cone) retinal pathway, using a short-wavelength flash superimposed on a background that saturates the rods and adapts the L/M-cones to elicit a response, known as the S-cone ERG. Stimulus parameters such as the strength and luminance of the flash and background, respectively, and their spectral and temporal characteristics are specified. As a complement to the ISCEV standard, testing the S-cone ERG enables further characterization of light-adapted retinal function and may refine diagnosis of some retinal disorders. Typical applications are described including use in the diagnosis of rod monochromacy and S-cone monochromacy, identification and investigation of cone On-bipolar cell dysfunction and use of the technique to confirm the diagnosis of enhanced S-cone syndrome.

Isolated rod dysfunction associated with a novel genotype of CNGB1.

PURPOSE: To describe the clinical and electrophysiological features of an unusual retinopathy in a patient with a novel genotype of CNGB1, mutations in which are implicated in autosomal recessive retinitis pigmentosa (rod-cone dystrophy). OBSERVATIONS: A 61-year old asymptomatic woman was referred to the inherited retinal disorders clinic because of peripheral retinal pigmentary changes. She had normal visual acuity and color vision. Clinical examination and detailed imaging of the macula were normal, but there was atrophy of the outer retina in the periphery with sparse intra-retinal pigmentation. Electroretinography (ERG) revealed undetectable rod responses, with normal cone-mediated responses. The pattern ERG was normal. Genetic analysis identified two previously unreported variants in CNGB1: (c.2258T > A, p.[Leu753*] and c.807G > C, p.[Gln269His]), shown to be in trans. CONCLUSIONS AND IMPORTANCE: This report describes a functionally cone-isolated retina in an adult, apparently hemizygous for a novel missense mutation in CNGB1, a novel phenotype for this gene. The p.[Gln269His] allele is the first missense change, within the glutamic acid-rich protein (GARP) domain of CNGB1, to be associated with retinal disease in humans.

Retinal-detachment repair and vitreous-like-body reformation via a thermogelling polymer endotamponade.

Internal-tamponade agents are crucial surgical adjuncts in vitreoretinal surgery. Clinically used endotamponade agents act through buoyancy forces, yet can result in prolonged post-operative positioning, temporary loss of vision, raised intra-ocular pressure, cataract formation or the need for additional removal surgery. Here, we describe a thermogelling polymer that provides an internal tamponade effect through surface tension and swelling counter-forces. We tested the long-term biocompatibility of the polymer endotamponade in rabbit vitrectomy models, and its surgical efficacy and biocompatibility in a non-human primate retinal-detachment model. We also show that, while the thermogel biodegrades during the three months following surgery, it promotes the reformation of a vitreous-like body that mimics the biophysical properties of the natural vitreous. The thermogelling endotamponade might serve as a long-term vitreous substitute.

Unilateral pigmentary retinopathy: a retrospective case series.

PURPOSE: To review the clinical characteristics and address the aetiology in a group of patients presenting with unilateral retinal pigmentary changes, best described as unilateral pigmentary retinopathy (UPR). METHODS: The cohort of 42 patients was identified retrospectively from the Moorfields Eye Hospital electrophysiology database. All had undergone full-field [electroretinography (ERG)] and pattern electroretinography (PERG), with 13 additionally having multifocal ERG (mfERG). The clinical findings, fundus photographs and fundus autofluorescence (AF) images were reviewed. RESULTS: All index eyes showed ERG evidence of generalized photoreceptor dysfunction with most showing a similar degree of rod and cone involvement. However, although the fellow eyes all had a normal fundus examination, there were bilateral but asymmetrical ERG abnormalities in eight patients and a further four patients had PERG evidence of macular dysfunction in the fellow eye. A relevant medical history or the diagnosis of an ophthalmologic entity that might be related to the unilateral fundus changes was ascertained in 15 cases (~36%) including acute zonal occult outer retinopathy, trauma, systemic malignancy or autoimmune disease, retinal vasculitis, presumed pregnancy-related choroidal ischaemia and meningitis. Two patients had a family history of retinitis pigmentosa (RP; 4.8%). CONCLUSION: The underlying aetiology in most cases of UPR cannot accurately be identified, but an heritable cause is unlikely. Aspects of the history clearly suggest an acquired disorder in some patients. Twenty-five patients (60%) with nongenetic UPR did not adhere to the pattern of rod greater than cone dysfunction that occurs in RP (rod-cone dystrophy), and the pattern of rod > cone dysfunction seen in true RP is thus not a feature of most patients with UPR.

Macular maldevelopment in ATF6-mediated retinal dysfunction.

Background: Achromatopsia has been previously associated with mutations in the ATF6 gene. Rod-monochromatism, foveal hypoplasia, and disruption of the subfoveal photoreceptor layer are described as phenotypical features. We report detailed structural and electrophysiological assessment of two patients from two families, one manifesting severe macular maldevelopment and one with foveal hypoplasia.Materials and methods: The patients underwent a complete ophthalmic examination including electroretinography (ERG), spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence, and fundus photography. Genetic testing was performed by next-generation sequencing.Results: In one patient, fundoscopy and SD-OCT revealed well-demarcated coloboma-like excavated lesions at the central macula of both eyes. Genetic analysis identified a novel homozygous p.Asp140Ter mutation in the ATF6 gene. The second patient had foveal hypoplasia in association with a homozygous ATF6 mutation affecting a splice donor site (c.1187 + 5G>C). In both patients, electrophysiological assessment showed normal rod-specific (DA 0.01) and dark-adapted bright white-flash ERGs (DA 10.0). 30 Hz flicker ERGs were undetectable. There were low-amplitude single-flash photopic ERGs (LA 3.0) with timing and shape suggesting S-cone origin.Conclusions: The findings, particularly a case with severe macular maldevelopment, may expand on the phenotype previously associated with ATF6-mediated achromatopsia. In addition, the comprehensive electrophysiological assessment suggests that preserved S-cone activity can be detected in this particular molecular sub-type of cone dysfunction.