Inherited retinal dystrophies (IRDs) are a group of heterogeneous diseases caused by genetic mutations that specifically affect the function of the rod, cone, or bipolar cells in the retina. Electroretinography (ERG) is a diagnostic tool that measures the electrical activity of the retina in response to light stimuli, and it can help to determine the function of these cells. A normal ERG response consists of two waves, the a-wave and the b-wave, which reflect the activity of the photoreceptor cells and the bipolar and Muller cells, respectively. Despite the growing availability of next-generation sequencing (NGS) technology, identifying the precise genetic mutation causing an IRD can be challenging and costly. However, certain types of IRDs present with unique ERG features that can help guide genetic testing. By combining these ERG findings with other clinical information, such as on family history and retinal imaging, physicians can effectively narrow down the list of candidate genes to be sequenced, thereby reducing the cost of genetic testing. This review article focuses on certain types of IRDs with unique ERG features. We will discuss the pathophysiology and clinical presentation of, and ERG findings on, these disorders, emphasizing the unique role ERG plays in their diagnosis and genetic testing.

Enhanced S-cone syndrome (ESCS) is a rare type of retinal dystrophy disorder that is linked to NR2E3 gene mutation and NRL gene mutations less widely. The disease is characterized by increased S-cones number and marked degeneration in rods and M- and L-cone receptors. The patient suffers from night blindness from an early age. Examination of the fundus of the eye shows nummular pigmented lesions, but they are not specific to ESCS. The diagnosis can be confirmed with electroretinography. We report a case of a four-year-old girl suspected of having ESCS based on her clinical picture, fundus examination, and electroretinography.

NR2E3 is a nuclear hormone receptor gene required for the correct development of the retinal rod photoreceptors. Expression of NR2E3 protein in rod cell precursors suppresses cone-specific gene expression and, in concert with other transcription factors including NRL, activates the expression of rod-specific genes. Pathogenic variants involving NR2E3 cause a spectrum of retinopathies, including enhanced S-cone syndrome, Goldmann-Favre syndrome, retinitis pigmentosa, and clumped pigmentary retinal degeneration, with limited evidence of genotype-phenotype correlations. A common feature of NR2E3-related disease is an abnormally high number of cone photoreceptors that are sensitive to short wavelength light, the S-cones. This characteristic has been supported by mouse studies, which have also revealed that loss of Nr2e3 function causes photoreceptors to develop as cells that are intermediate between rods and cones. While there is currently no available cure for NR2E3-related retinopathies, there are a number of emerging therapeutic strategies under investigation, including the use of viral gene therapy and gene editing, that have shown promise for the future treatment of patients with NR2E3 variants and other inherited retinal diseases. This review provides a detailed overview of the current understanding of the role of NR2E3 in normal development and disease, and the associated clinical phenotypes, animal models, and therapeutic studies.

Introduction: Goldmann Favre Syndrome (GFS) is a vitreoretinal degenerative disease with macular retinoschisis. The current treatment of foveoschisis is topical and oral carbonic anhydrase inhibitors.Case: A 22-year-old male diagnosed with GFS presented a progressive decrease in vision of the right eye. The optical coherence tomography showed a significant macular schisis. A medical treatment with topical and oral carbonic anhydrase inhibitors was ineffective. We performed a pars plana vitrectomy and silicone oil placement which led to an improvement of the visual acuity and a reduction of the foveoschisis.Conclusion: We describe here the first case of surgical treatment for macular schisis in a patient with GFS.

To highlight recognizable patterns of subretinal fibrosis in enhanced S-cone syndrome (ESCS).
Retrospective case series.
Forty-seven patients with subretinal fibrosis identified from 101 patients with clinically diagnosed ESCS, confirmed by full-field electroretinography (35/47), genetic testing (34/47), or both.
Multimodal retinal imaging, electroretinography, and genetic analysis.
Patterns of subretinal fibrosis with angiographic, OCT, and genetic correlations.
Eighty-five eyes of 47 patients (24 male patients; 36 unrelated consanguineous families) had subretinal fibrosis. Mean age at presentation was 14 years. Best-corrected visual acuity ranged from 20/20 to hand movements. All 34 genetically tested patients were homozygous for pathogenic NR2E3 variants. Subretinal fibrosis was always in the macular area, although it extended beyond in some patients. Six recurrent patterns of submacular fibrosis were noted: central unifocal nodular, circumferential unifocal nodular, multifocal nodular, arcuate, helicoid, and thick geographic. Some patients showed a combination of patterns. Previous misdiagnosis as inflammatory disease was common. Fibrosis was fairly symmetrical in a given patient but not always present or identical in other affected individuals with a given homozygous mutation from the same or other families.
These recognizable patterns of submacular fibrosis are part of the ESCS phenotypic spectrum and strongly suggest the disease. In addition to facilitating diagnosis, recognition of these patterns can spare patients unnecessary workup for an inflammatory cause.

NR2E3-associated recessive disease in humans is historically defined by congenital night blinding retinopathy, characterized by an initial increase in short-wavelength (S)-cone sensitivity and progressive loss of rod and cone function. The retinal degeneration 7 (rd7) murine model, harboring a recessive mutation in the mouse ortholog of NR2E3, has been a well-studied disease model and recently evaluated as a therapeutic model for NR2E3-associated retinal degenerations. This study aims to draw parallels between human and mouse NR2E3-related disease through examination of spectral domain optical coherence tomography (SD-OCT) imaging between different stage of human disease and its murine counterpart. We propose that SD-OCT is a useful non-invasive diagnostic tool to compare human clinical dystrophy presentation with that of the rd7 mouse and make inference that may be of therapeutically relevance. Additionally, a longitudinal assessment of rd7 disease progression, utilizing available clinical data from our patients as well as extensive retrospective analysis of visual acuity data from published cases of human NR2E3-related disease, was curated to identify further valuable correlates between human and mouse Nr2e3 disease. Results of this study validate the slow progression of NR2E3-associated disease in humans and the rd7 mice and identify SD-OCT characteristics in patients at or near the vascular arcades that correlate well with the whorls and rosettes that are seen also in the rd7 mouse and point to imaging features that appear to be associated with better preserved S-cone mediated retinal function. The correlation of histological findings between rd7 mice and human imaging provides a solid foundation for diagnostic use of pathophysiological and prognostic information to further define characteristics and a relevant timeline for therapeutic intervention in the field of NR2E3-associated retinopathies.

NR2E3 encodes an orphan nuclear receptor that plays a dual function as both transcriptional activator and repressor in photoreceptors, being necessary for cone fate inhibition as well as rod differentiation and homeostasis. Mutations in this gene cause retinitis pigmentosa (RP), enhanced S cone syndrome (ESCS) and Goldmann-Favre syndrome (GFS). There is one reported Nr2e3 isoform that contains all 8 exons and a second -previously unreported- shorter isoform, which only spans the first 7 exons and whose function is still unknown. In this data article, we designed and generated two new mouse models by targeting exon 8 of Nr2e3 using the CRISPR/Cas9-D10A nickase in order to dissect the role of the two isoforms in Nr2e3 function and elucidate the different disease mechanisms caused by NR2E3 mutations. This strategy generated several modified alleles that altered the coding sequence of the last exon thereby affecting functional domains of the transcription factor. Allele Δ27 is an in-frame deletion of 27 bp that ablates the dimerization domain, whereas allele ΔE8 (full deletion of exon 8), produces only the short isoform that lacks the dimerization and repressor domains. Morphological and functional alterations of both Δ27 and ΔE8 mutants are reported in the associated research article \"Nr2e3 functional domain ablation by CRISPR-Cas9D10A identifies a new isoform and generated Retinitis Pigmentosa and Enhanced S-cone Syndrome models\" (Aísa-Marín et al., 2020).

A retrospective review of the clinical records of patients seen at the Oxford Eye Hospital identified as having NR2E3 mutations was performed. The data included symptoms, best-corrected visual acuity, multimodal retinal imaging, visual fields and electrophysiology testing. Three participants were identified with biallelic NR2E3 pathogenic sequence variants detected using a targeted NGS gene panel, two of which were novel. Participant I was a Nepalese male aged 68 years, and participants II and III were white Caucasian females aged 69 and 10 years old, respectively. All three had childhood onset nyctalopia, a progressive decrease in central vision, and visual field loss. Patients I and III had photopsia, patient II had photosensitivity and patient III also had photophobia. Visual acuities in patients I and II were preserved even into the seventh decade, with the worst visual acuity measured at 6/36. Visual field constriction was severe in participant I, less so in II, and fields were full to bright targets targets in participant III. Electrophysiology testing in all three demonstrated loss of rod function. The three patients share some of the typical distinctive features of NR2E3 retinopathies, as well as a novel clinical observation of foveal ellipsoid thickening.

Mutations in NR2E3 cause retinitis pigmentosa (RP) and enhanced S-cone syndrome (ESCS) in humans. This gene produces a large isoform encoded in 8 exons and a previously unreported shorter isoform of 7 exons, whose function is unknown. We generated two mouse models by targeting exon 8 of Nr2e3 using CRISPR/Cas9-D10A nickase. Allele Δ27 is an in-frame deletion of 27 bp that ablates the dimerization domain H10, whereas allele ΔE8 (full deletion of exon 8) produces only the short isoform, which lacks the C-terminal part of the ligand binding domain (LBD) that encodes both H10 and the AF2 domain involved in the Nr2e3 repressor activity. The Δ27 mutant shows developmental alterations and a non-progressive electrophysiological dysfunction that resembles the ESCS phenotype. The ΔE8 mutant exhibits progressive retinal degeneration, as occurs in human RP patients. Our mutants suggest a role for Nr2e3 as a cone-patterning regulator and provide valuable models for studying mechanisms of NR2E3-associated retinal dystrophies and evaluating potential therapies.

To describe the detailed phenotype, long-term clinical course, clinical variability, and genotype of patients with enhanced S-cone syndrome (ESCS).
Retrospective case series.
Fifty-six patients with ESCS.
Clinical history, examination, imaging, and electrophysiologic findings of 56 patients (age range, 1-75 years) diagnosed with ESCS were reviewed. Diagnosis was established by molecular confirmation of disease-causing variants in the NR2E3 gene (n = 38) or by diagnostic full-field electroretinography findings (n = 18).
Age at onset of visual symptoms, best-corrected visual acuity (BCVA), quantitative age-related electrophysiologic decline, and imaging findings.
Mean age at onset of visual symptoms was 4.0 years, and median age at presentation was 20.5 years, with mean follow-up interval being 6.1 years. Six patients were assessed once. Disease-causing variants in NR2E3 were identified in 38 patients. Mean BCVA of the better-seeing eye was 0.32 logarithm of the minimum angle of resolution (logMAR) at baseline and 0.39 logMAR at follow-up. In most eyes (76% [76/100]), BCVA remained stable, with a mean BCVA change of 0.07 logMAR during follow-up. Nyctalopia was the most common initial symptom, reported in 92.9% of patients (52/56). Clinical findings were highly variable and included foveomacular schisis (41.1% [26/56]), yellow-white dots (57.1% [32/56]), nummular pigmentation (85.7% [48/56]), torpedo-like lesions (10.7% [6/56]), and circumferential subretinal fibrosis (7.1% [4/56]). Macular and peripheral patterns of autofluorescence were classified as (1) minimal change, (2) hypoautofluorescent (mild diffuse, moderate speckled, moderate diffuse, or advanced), or (3) hyperautofluorescent flecks. One patient showed undetectable electroretinography findings; quantification of main electroretinography components in all other patients revealed amplitude and peak time variability but with pathognomonic electroretinography features. The main electroretinography components showed evidence of age-related worsening over 6.7 decades, at a rate indistinguishable from that seen in unaffected control participants. Eighteen sequence variants in NR2E3 were identified, including 4 novel missense changes.
Enhanced S-cone syndrome has a highly variable phenotype with relative clinical and imaging stability over time. Most electroretinography findings have pathognomonic features, but quantitative assessment reveals variability and a normal mean rate of age-related decline, consistent with largely nonprogressive peripheral retinal dysfunction.