Phenotyping and genotyping inherited retinal diseases: Molecular genetics, clinical and imaging features, and therapeutics of macular dystrophies, cone and cone-rod dystrophies, rod-cone dystrophies, Leber congenital amaurosis, and cone dysfunction syndromes.

Inherited retinal diseases (IRD) are a leading cause of blindness in the working age population and in children. The scope of this review is to familiarise clinicians and scientists with the current landscape of molecular genetics, clinical phenotype, retinal imaging and therapeutic prospects/completed trials in IRD. Herein we present in a comprehensive and concise manner: (i) macular dystrophies (Stargardt disease (ABCA4), X-linked retinoschisis (RS1), Best disease (BEST1), PRPH2-associated pattern dystrophy, Sorsby fundus dystrophy (TIMP3), and autosomal dominant drusen (EFEMP1)), (ii) cone and cone-rod dystrophies (GUCA1A, PRPH2, ABCA4, KCNV2 and RPGR), (iii) predominant rod or rod-cone dystrophies (retinitis pigmentosa, enhanced S-Cone syndrome (NR2E3), Bietti crystalline corneoretinal dystrophy (CYP4V2)), (iv) Leber congenital amaurosis/early-onset severe retinal dystrophy (GUCY2D, CEP290, CRB1, RDH12, RPE65, TULP1, AIPL1 and NMNAT1), (v) cone dysfunction syndromes (achromatopsia (CNGA3, CNGB3, PDE6C, PDE6H, GNAT2, ATF6), X-linked cone dysfunction with myopia and dichromacy (Bornholm Eye disease; OPN1LW/OPN1MW array), oligocone trichromacy, and blue-cone monochromatism (OPN1LW/OPN1MW array)). Whilst we use the aforementioned classical phenotypic groupings, a key feature of IRD is that it is characterised by tremendous heterogeneity and variable expressivity, with several of the above genes associated with a range of phenotypes.

Genetic Characteristics and Clinical Manifestations of Foveal Hypoplasia in Familial Exudative Vitreoretinopathy.

PURPOSE: This study aimed to ascertain the occurrence of foveal hypoplasia (FH) in individuals diagnosed with familial exudative vitreoretinopathy (FEVR). DESIGN: Retrospective cohort study. METHODS: In this study, FEVR families and sporadic cases were diagnosed at the Eye and ENT Hospital, Fudan University, between 2017 and 2023. All patients attended routine ophthalmologic examinations and genetic screenings. The classification of FH was determined using optical coherence tomography (OCT) scans. The FH condition was classified into 2 subgroups: group A (FH being limited to the inner layers) and group B (FH affecting the outer layers). A total of 102 eyes from 58 patients were suitable for analysis. RESULTS: Forty-nine mutations in LRP5, FZD4, NDP, TSPAN12, KIF11, CTNNB1, and ZNF408 were examined and detected, with 26 of them being novel. Forty-seven eyes (46.1%) revealed FH. The majority (53.2%) were due to the typical grade 1 FH. Patients with mutations in LRP5 and KIF11 were found to exhibit a higher prevalence of FH (P = .0088). Group B displayed the lowest visual acuity compared with group A (P = .048) and the group without FH (P < .001). The retinal arteriolar angle in group B was significantly smaller than in group A (P = .001) and those without FH (P < .001). CONCLUSIONS: This study offers a new diagnostic approach and expands the spectrum of FEVR mutations. LRP5 and KIF11 were found to be more susceptible to causing FH in patients with FEVR. FEVR eyes with FH exhibited both greater visual impairment and reduced retinal arteriolar angles. The assessment of foveal status in patients with FEVR should be valued.

Novel TTLL5 Variants Associated with Cone-Rod Dystrophy and Early-Onset Severe Retinal Dystrophy.

Variants of the TTLL5 gene, which encodes tubulin tyrosine ligase-like family member five, are a rare cause of cone dystrophy (COD) or cone-rod dystrophy (CORD). To date, only a few TTLL5 patients have been clinically and genetically described. In this study, we report five patients harbouring biallelic variants of TTLL5. Four adult patients presented either COD or CORD with onset in the late teenage years. The youngest patient had a phenotype of early onset severe retinal dystrophy (EOSRD). Genetic analysis was performed by targeted next generation sequencing of gene panels and assessment of copy number variants (CNV). We identified eight variants, of which six were novel, including two large multiexon deletions in patients with COD or CORD, while the EOSRD patient harboured the novel homozygous p.(Trp640*) variant and three distinct USH2A variants, which might explain the observed rod involvement. Our study highlights the role of TTLL5 in COD/CORD and the importance of large deletions. These findings suggest that COD or CORD patients lacking variants in known genes may harbour CNVs to be discovered in TTLL5, previously undetected by classical sequencing methods. In addition, variable phenotypes in TTLL5-associated patients might be due to the presence of additional gene defects.

Characterization of the Spectrum of Ophthalmic Changes in Patients With Alagille Syndrome.

Purpose: The purpose of this study was to characterize the phenotypic spectrum of ophthalmic findings in patients with Alagille syndrome. Methods: We conducted a retrospective, observational, multicenter, study on 46 eyes of 23 subjects with Alagille syndrome. We reviewed systemic and ophthalmologic data extracted from medical records, color fundus photography, fundus autofluorescence, optical coherence tomography, visual fields, electrophysiological assessments, and molecular genetic findings. Results: Cardiovascular abnormalities were found in 83% of all cases (of those, 74% had cardiac murmur), whereas 61% had a positive history of hepatobiliary issues, and musculoskeletal anomalies were present in 61% of all patients. Dysmorphic facies were present in 16 patients, with a broad forehead being the most frequent feature. Ocular symptoms were found in 91%, with peripheral vision loss being the most frequent complaint. Median (range) Snellen visual acuity of all eyes was 20/25 (20/20 to hand motion [HM]). Anterior segment abnormalities were present in 74% of the patients; of those, posterior embryotoxon was the most frequent finding. Abnormalities of the optic disc were found in 52%, and peripheral retinal abnormalities were the most frequent ocular finding in this series, found in 96% of all patients. Fifteen JAG1 mutations were identified in 16 individuals; of those, 6 were novel. Conclusions: This study reports a cohort of patients with Alagille syndrome in which peripheral chorioretinal changes were more frequent than posterior embryotoxon, the most frequent ocular finding according to a number of previous studies. We propose that these peripheral chorioretinal changes are a new hallmark to help diagnose this syndrome.

Phenotypic and Genetic Spectrum of Autosomal Recessive Bestrophinopathy and Best Vitelliform Macular Dystrophy.

Purpose: Autosomal recessive bestrophinopathy (ARB) and vitelliform macular dystrophy (VMD) are distinct phenotypes, typically inherited through recessive and dominant patterns, respectively. Recessively inherited VMD (arVMD) has been reported, suggesting that dominant and recessive BEST1-related retinopathies represent a single disease spectrum. This study compares adVMD, arVMD, and ARB to determine whether a continuum exists and to define clinical and genetic features to aid diagnosis and management. Methods: One arVMD patient and nine ARB patients underwent standard ophthalmic examination, imaging, electrophysiology, and genetic assessments. A meta-analysis of reported BEST1 variants was compiled, and clinical parameters were analyzed with regard to inheritance and phenotype. Results: Among 10 patients with biallelic BEST1 variants, three novel ARB variants (p.Asp118Ala, p.Leu224Gln, p.Val273del) were discovered. A patient with homozygous p.Glu35Lys was clinically unique, presenting with VMD, including hyperautofluorescence extending beyond the macula, peripheral punctate lesions, and shortened axial-length. A tritan-axis color vision deficit was seen in three of six (50%) of ARB patients. Attempts to distinguish recessively-inherited ARB and dominantly-inherited VMD genotypically, by variant frequency and residue location, did not yield significant differences. Literature meta-analysis with principle component analysis of clinical features demonstrated a spectrum of disease with arVMD falling between adVMD and ARB. Conclusions: This study suggests that arVMD is part of a continuum of autosomal recessive and dominant BEST1-related retinopathies. Detailed clinical and molecular assessments of this cohort and the literature are corroborated by unsupervised analysis, highlighting the overlapping heterogeneity among BEST1-associated clinical diagnoses. Tritan-axis color vision deficit is a previously unreported finding associated with ARB.

Complete congenital stationary night blindness associated with a novel NYX variant (p.Asn216Lys) in middle-aged and older adult patients.

BACKGROUND: Complete congenital stationary night blindness (CSNB) is a retinal disorder thought to be non-progressive. The purpose of this study was to characterize the clinical and genetic findings of middle-aged and older adult patients with X-linked complete CSNB. METHODS: Three male CSNB patients (aged 62, 72, and 51 years) and one unaffected female carrier in a Japanese family were included in this study. Whole-exome sequencing (WES) was performed to determine the disease-causing variants. Co-segregation was confirmed in the family members. We performed a comprehensive ophthalmic examination on each patient. RESULTS: In the 62-year-old patient, a novel hemizygous variant (c.648 C > A; p.Asn216Lys) of the NYX gene was identified by WES analysis. The other two patients carried the variant hemizygously, and the unaffected carrier harbored the variant heterozygously. The clinical and electroretinography (ERG) findings were very similar among all three patients. Fundus images exhibited high myopic chorioretinal atrophy with long axial length. Ultra-wide field fundus autofluorescence images showed no retinal degenerative changes except for changes resulting from high myopia and previous retinal diseases. The ERG findings showed no response in rod ERG, electronegative configuration with preserved a-waves in standard/bright-flash ERG, and preserved responses in cone and 30-Hz flicker ERG, which were compared with age-matched controls with high myopia. CONCLUSIONS: We identified a novel missense NYX variant in a Japanese family with complete CSNB. Our clinical findings indicated that photoreceptor mediated ERG responses are well preserved even in middle-aged and older adult patients.

Restoration of mGluR6 Localization Following AAV-Mediated Delivery in a Mouse Model of Congenital Stationary Night Blindness.

Purpose: Complete congenital stationary night blindness (cCSNB) is an incurable inherited retinal disorder characterized by an ON-bipolar cell (ON-BC) defect. GRM6 mutations are the third most prevalent cause of cCSNB. The Grm6-/- mouse model mimics the human phenotype, showing no b-wave in the electroretinogram (ERG) and a loss of mGluR6 and other proteins of the same cascade at the outer plexiform layer (OPL). Our aim was to restore protein localization and function in Grm6-/- adult mice targeting specifically ON-BCs or the whole retina. Methods: Adeno-associated virus-encoding Grm6 under two different promoters (GRM6-Grm6 and CAG-Grm6) were injected intravitreally in P15 Grm6-/- mice. ERG recordings at 2 and 4 months were performed in Grm6+/+, untreated and treated Grm6-/- mice. Similarly, immunolocalization studies were performed on retinal slices before or after treatment using antibodies against mGluR6, TRPM1, GPR179, RGS7, RGS11, Gß5, and dystrophin. Results: Following treatment, mGluR6 was localized to the dendritic tips of ON-BCs when expressed with either promoter. The relocalization efficiency in mGluR6-transduced retinas at the OPL was 2.5% versus 11% when the GRM6-Grm6 and CAG-Grm6 were used, respectively. Albeit no functional rescue was seen in ERGs, relocalization of TRPM1, GPR179, and Gß5 was also noted using both constructs. The restoration of the localization of RGS7, RGS11, and dystrophin was more obvious in retinas treated with GRM6-Grm6 than in retinas treated with CAG-Grm6. Conclusions: Our findings show the potential of treating cCSNB with GRM6 mutations; however, it appears that the transduction rate must be improved to restore visual function.

Steroid resistant focal segmental glomerulosclerosis: effect of arterial hyalinosis on outcome: single center study.

Background. Few data with adequate evidence exists as regards the effect of Cyclosporine (CsA) and mycophenolate mofetil (MMF) on pathological prognostic parameters in patients with steroid resistant focal segmental glomerulosclerosis (FSGS). The purpose of the present study is to compare the effect of cyclosporin and mycophenolate mofetil in addition to steroids on functional and histopathologic renal parameters in patients with steroid resistant FSGS one year after treatment.Material and methods. Thirty-seven adults with primary FSGS patients resistant to steroid therapy consecutively randomized to treatment with either MMF or cyclosporine. Low dose prednisolone added to both groups. Glomerular filtration rate (GFR) and blood pressure (BP) were determined at all examinations and a second renal biopsy was taken 12 months after treatment with either of cyclosporin and mycophenolate mofetil.Results. GFR significantly increased in MMF group p < 0.01 after 6 months and unchanged after 12 months. On the other hand, GFR significantly decrease in CsA group p < 0.001 after 6 months and reduced more after 12 months p < 0.001 compared to base line levels. There was a significant difference of GFR between the 2 groups at 6 months p < 0.001. The extent of proteinuria decreased significantly in CsA group after 12 months p < 0.001. The extent of arteriolar hyalinosis increased significantly in CsA group (0.78 to 1.81 score, p < 0.001) but was unchanged in MMF group (0.93 to 0.96 score), whereas interstitial fibrosis increased to same level in both groups (grade 3).Conclusion. Conversion to MMF in those patients may be superior to CsA as regards GFR after 12 months after treatment in spite of the presence of greater level of protein excretion. The increased arteriolar hyalinosis during CsA treatment most likely results in higher BP compared to MMF treatment in patients with FSGS resistant to steroids.

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.

ENHANCED S-CONE SYNDROME: VISUAL FUNCTION, CROSS-SECTIONAL IMAGING, AND CELLULAR STRUCTURE WITH ADAPTIVE OPTICS OPHTHALMOSCOPY.

PURPOSE: To describe in detail the phenotype of a patient with enhanced S-cone syndrome. METHODS: We describe a 13-year-old boy who presented with blurred vision, vitreous cells, cystoid macular edema refractory to steroid treatment, and a negative uveitic workup. The patient underwent a complete ophthalmic examination, full-field electroretinograms (ffERG), automatic static perimetry and multimodal imaging with spectral domain optical coherence tomography, and adaptive optics scanning laser ophthalmoscopy (AOSLO). RESULTS: Spectral domain optical coherence tomography demonstrated cystoid macular edema and a hyperthick, delaminated midperipheral retina. Fluorescein angiography did not demonstrate macular leakage. Rod-mediated ffERGs were undetectable, and there was a supernormal response to short-wavelength stimuli compared with photopically matched longer wavelengths of light consistent with enhanced S-cone syndrome. Gene screening was positive for compound heterozygous mutations NR2E3: a known (c.119-2 A>C) and a novel (c.119-1G>A) mutation. By perimetry, sensitivities were normal or above normal for short-wavelength stimuli; there was no detectable rod-mediated vision. AOSLO demonstrated higher than normal cone densities in the perifoveal retina and evidence for smaller outer segment cone diameters. CONCLUSION: Evidence for supernumerary cones (at least twice the normal complement) by AOSLO and spectral domain optical coherence tomography was associated with supernormal S-cone sensitivities and electroretinogram responses confirming previous in vivo findings in postmortem human specimens. Smaller than normal cones in enhanced S-cone syndrome may represent "hybrid" photoreceptors analogous to the rd7/rd7 murine model of the disease.

Pigmented Paravenous Chorioretinal Atrophy: Clinical Spectrum and Multimodal Imaging Characteristics.

PURPOSE: To investigate the clinical findings and natural course of patients with pigmented paravenous chorioretinal atrophy (PPCRA) using multimodal imaging. DESIGN: Retrospective, observational case series. METHODS: We reviewed the records of consecutive patients diagnosed with PPCRA at a single center and assessed serial fundus photographs, fundus autofluorescence (FAF), and spectral-domain optical coherence tomography images. Electrophysiological findings and visual field analysis were also reviewed. RESULTS: The study included 50 eyes in 25 patients. The mean age of the population was 51.6 ± 14.6 years. Nine patients (36.0%) were asymptomatic and 9 (36.0%) complained of nyctalopia. We divided fundus appearance into one of 3 groups: paravenous (58.0%), focal (16.0%), and confluent (26.0%). Of the 50 eyes, macular involvement was present in 13 eyes (26.0%). Fifteen patients (60.0%) demonstrated a symmetric fundus appearance, whereas 10 (40.0%) had marked asymmetry. Eight eyes (16.0%) exhibited apparent changes in fundus findings, over a mean follow-up period of 8.8 years. FAF imaging was most sensitive to evaluate the extent of lesions. Sixteen eyes (44.4%) showed progressive visual field loss during the follow-up period. Most patients maintained stable vision, and 36 eyes (72.0%) had a final visual acuity of 20/50 or better. Nevertheless, some eyes with macular involvement experienced severe deterioration in vision. Electrophysiological data were variable, and interocular asymmetry was common (45.8%). CONCLUSIONS: PPCRA can present with a more variable expressivity than previously described. Multimodal imaging can provide insights into its clinical characteristics to facilitate the diagnosis, classification, and follow-up of these patients.

A large deletion spanning PITX2 and PANCR in a Chinese family with Axenfeld-Rieger syndrome.

Purpose: To identify the genetic cause in a four-generation Chinese family with Axenfeld-Rieger syndrome (ARS). Methods: The family members received clinical examinations of the eye, tooth, periumbilical skin, and heart. Sanger sequencing and whole-exome sequencing (WES) were performed to screen potential mutations. The genomic deletion region around the PITX2 gene was estimated from single nucleotide polymorphism (SNP) data from WES and then confirmed with "quantitative PCR (qPCR) using a set of primers. The DNA breakpoint was further identified with long-range PCR and Sanger sequencing. Results: Symptoms including anterior segment dysplasia of the eye (iris dysplasia, multiple pupils, and posterior embryotoxon), dental dysplasia, and periumbilical skin redundancy were present in all of the affected individuals. Three of them had glaucoma. Corneal abnormalities (inferior sclerocornea, corneal endothelial dystrophy, and central corneal scar) were seen in most of the affected individuals. Cataract, limited eye movement, electrocardiographic abnormalities, intellectual disability, and recurrent miscarriages were observed in some of the affected individuals. No mutations in the coding and exon-intron adjacent regions of the PITX2 and FOXC1 genes were identified with Sanger sequencing. According to the SNP data from WES, we suspected that there might be a deletion region (at most 1.6 Mb) around the PITX2 gene. With the use of qPCR and long-range PCR, we identified a 53,840 bp deletion (chr4: 111,535,454-111,588,933) spanning PITX2 and PANCR. The genomic deletion cosegregated with the major ARS symptoms observed in the family members. Conclusions: With the help of WES, qPCR, and long-range PCR, we identified a genomic deletion encompassing PITX2 and the adjacent noncoding gene PANCR in a Chinese family with ARS. The clinical features of the affected individuals are reported. This work may broaden understanding of the phenotypic and mutational spectrums related to ARS.

Electronegative Electroretinograms in the United Arab Emirates.

PURPOSE: An electronegative electroretinogram (ERG), defined as having a b:a wave ratio ≤1 in the scotopic flash ERG response, indicates relative inner retinal dysfunction. Causes vary depending upon the study population. In the Arabian Gulf, where inherited retinal disease is relatively prevalent, common diagnoses associated with electronegative ERGs have not been described. In this study, we report the frequency and causes of electronegative ERGs in a cohort of Emirati patients with inherited retinal disease. METHODS: A retrospective review was performed of all full-field ERGs done for Emirati patients in the Ocular Genetics Service of Cleveland Clinic Abu Dhabi from January 2017 to December 2019. Those who had an electronegative ERG in at least one eye were included in the study. RESULTS: Out of 137 patients, 9 probands (6.6%) had an electronegative ERG. The mean age at presentation was 24 years (range 5-48 years), and five patients (55.6%) were male. The final clinical diagnoses were congenital stationary night blindness (CSNB) (two TRPM1-related and one Oguchi disease), X-linked retinoschisis (XLRS) (one genetically confirmed and two not genetically tested), cone-rod dystrophy (one CRX-related and one not genetically tested), and enhanced S-cone syndrome (ESCS) (one NRL-related). The one patient who did not have bilateral electronegative ERGs was a male with XLRS whose fellow eye had an unrecordable ERG. CONCLUSIONS: In this series of Emirati patients, an electronegative ERG was most commonly associated with the inherited retinal diseases recessive CSNB and XLRS. An electronegative ERG was noted in a case of NRL-related ESCS.

Differential adaptations in rod outer segment disc membranes in different models of congenital stationary night blindness.

Rod photoreceptor cells initiate scotopic vision when the light receptor rhodopsin absorbs a photon of light to initiate phototransduction. These photoreceptor cells are exquisitely sensitive and have adaptive mechanisms in place to maintain optimal function and to overcome dysfunctional states. One adaptation rod photoreceptor cells exhibit is in the packing properties of rhodopsin within the membrane. The mechanism underlying these adaptations is unclear. Mouse models of congenital stationary night blindness with different molecular causes were investigated to determine which signals are important for adaptations in rod photoreceptor cells. Night blindness in these mice is caused by dysfunction in either rod photoreceptor cell signaling or bipolar cell signaling. Changes in the packing of rhodopsin within photoreceptor cell membranes were examined by atomic force microscopy. Mice expressing constitutively active rhodopsin did not exhibit any adaptations, even under constant dark conditions. Mice with disrupted bipolar cell signaling exhibited adaptations, however, they were distinct from those in mice with disrupted phototransduction. These differential adaptations demonstrate that although multiple molecular defects can lead to a similar primary defect causing disease (i.e., night blindness), they can cause different secondary effects (i.e., adaptations). The lighting environment or signaling defects present from birth and during early rearing can condition mice and affect the adaptations occurring in more mature animals. A comparison of effects in wild-type mice, mice with defective phototransduction, and mice with defective bipolar cell signaling, indicated that bipolar cell signaling plays a role in this conditioning but is not required for adaptations in more mature animals.

Surgical outcomes of Glaucoma associated with Axenfeld-Rieger syndrome.

BACKGROUND: The surgical management of glaucoma associated with Axenfeld-Rieger Syndrome (ARS) is poorly described in the literature. The goal of this study is to compare the effectiveness of various glaucoma surgeries on intraocular pressure (IOP) management in ARS. METHODS: Retrospective cohort study at a university hospital-based practice of patients diagnosed with ARS between 1973 and 2018. Exclusion criterion was follow-up less than 1 year. The number of eyes with glaucoma (IOP ≥ 21 mmHg with corneal edema, Haabs striae, optic nerve cupping or buphthalmos) requiring surgery was determined. The success and survival rates of goniotomy, trabeculotomy±trabeculectomy (no antifibrotics), cycloablation, trabeculectomy with anti-fibrotics, and glaucoma drainage device placement were assessed. Success was defined as IOP of 5-20 mmHg and no additional IOP-lowering surgery or visually devastating complications. Kaplan-Meier survival curves and the Wilcoxon test were used for statistical analysis. RESULTS: In 32 patients identified with ARS (median age at presentation 6.9 years, 0-58.7 years; median follow-up 5.4 years, 1.1-43.7 years), 23 (71.9%) patients were diagnosed with glaucoma at median age 6.3 years (0-57.9 years). In glaucomatous eyes (46 eyes), mean IOP at presentation was 21.8 ± 9.3 mmHg (median 20 mmHg, 4-45 mmHg) on 1.0 ± 1.6 glaucoma medications. Thirty-one eyes of 18 patients required glaucoma surgery with 2.2 ± 1.2 IOP-lowering surgeries per eye. Goniotomy (6 eyes) showed 43% success with 4.3 ± 3.9 years of IOP control. Trabeculotomy±trabeculectomy (6 eyes) had 17% success rate with 14.8 ± 12.7 years of IOP control. Trabeculectomy with anti-fibrotics (14 eyes) showed 57% success with 16.5 ± 13.5 years of IOP control. Ahmed© (FP7 or FP8) valve placement (8 eyes) had 25% success rate with 1.7 ± 1.9 years of IOP control. Baerveldt© (250 or 350) device placement (8 eyes) showed 70% success with 1.9 ± 2.3 years of IOP control. Cycloablation (4 eyes) had 33% success rate with 2.7 ± 3.5 years of IOP control. At final follow-up, mean IOP (12.6 ± 3.8 mmHg, median 11.8 mmHg, 7-19 mmHg) in glaucomatous eyes was significantly decreased (p < 0.0001), but there was no difference in number of glaucoma medications (1.6 ± 1.5, p = 0.1). CONCLUSIONS: In our series, greater than 70% of patients with ARS have secondary glaucoma that often requires multiple surgeries. Trabeculectomy with anti-fibrotics and Baerveldt glaucoma drainage devices showed the greatest success in obtaining IOP control.

Oguchi disease caused by a homozygous novel SAG splicing alteration associated with the multiple evanescent white dot syndrome: A 15-month follow-up.

PURPOSE: We report a 15-month follow-up case on a Chinese patient with Oguchi disease associated with the multiple evanescent white dot syndrome (MEWDS). METHODS: The patient's clinical presentation and follow-up visits were documented via decimal best-corrected visual acuity, fundus photography, fundus autofluorescence (FAF) imaging, near-infrared FAF, spectral domain optical coherence tomography, Humphrey's visual fields, microperimetry, and multifocal electroretinography. We also performed whole exome sequencing for screening variation in the patient and her relatives. RESULTS: The patient had typical clinical characteristic of Oguchi disease, including night blindness, the Mizuo-Nakamura phenomenon (a golden yellow discoloration of the fundus that disappears in the prolonged dark adaptation [DA]) and typical full-field electroretinogram changes (nearly undetected b-wave in 0.01 and 0.03 ERGs that can partially recover only after prolonged DA). Aside from Oguchi disease, the patient was also diagnosed with the MEWDS based on clinical detections, including suddenly reduced visual acuity, appeared white dots, blurred ellipsoid zone and disrupted interdigitation zone, enlarged blind spot, and reduced macular sensitivity. A series of investigations revealed that along with the 15-month follow-up after onset, the visual acuity enhanced, the numerous white dots disappeared, and the macular structure returned to normal. Moreover, the novel homozygous splicing alteration c.181 + 1G > A was identified in the SAG gene. CONCLUSIONS: This work is the first long-term case study of a patient with Oguchi disease associated with the MEWDS. The recovery period of symptoms caused by the MEWDS was much longer than that in typical patients with MEWDS. Molecular genetics demonstrate that this is the first case of Oguchi disease caused by splicing alterations in the SAG gene.

The diagnosis and phacoemulsification in combination with intraocular lens implantation for an Axenfeld-Rieger syndrome patient with small cornea: a case report.

BACKGROUND: Axenfeld-Rieger syndrome (ARS) is a congenital disease with a series of developmental abnormalities, and no case of ARS with cataract and small cornea has been reported in previous studies. In the present report, we aimed to describe the diagnosis and phacoemulsification of an ARS patient with small cornea. CASE PRESENTATION: A 58-year-old Han Chinese male patient who was referred to Eye Center of the Second Affiliated Hospital of Zhejiang University Medical College was diagnosed with ARS. Systemic and ophthalmic examination and genetic testing were performed. The slit-lamp microscopic examination of anterior segment showed obvious nuclear cataract, iris lesions, and the abnormal cornea of both eyes with small transversal and longitudinal diameters. ARS with bilateral complicated cataract and small cornea was diagnosed. Microincision-phacoemulsification in combination with intraocular lens implantation was performed on his left eye. After successful surgery of his left eye, the best-corrected visual acuity (BCVA) was obviously improved from 2 to 0.5 (LogMAR). A transient elevation of intraocular pressure (IOP) was controlled with medication. CONCLUSIONS: Through genetic testing, a known pathogenic mutation NM_153427.2:c.272G > A was detected on the PITX2 gene; and an unknown mutation NM_001453.2:c.1063C > T was detected on FOXC1 gene. For the ARS patient with complicated cataract, the visual acuity was increased by phacoemulsificasion in combination with microincision.

Wide-field true-colour imaging and clinical characterization of a novel GRK1 mutation in Oguchi disease.

PURPOSE: The available literature regarding Oguchi disease is limited, with around 50 cases described to date. Caused by mutations to either the SAG gene coding for arrestin (Hayashi et al. in Ophthalmic Res 46:175-180, 2011) or the GRK1 gene coding for rhodopsin kinase (Yamamoto et al. in Nat Genet 15:175-178. https://doi.org/10.1038/ng0297-175 , 1997), Oguchi disease is an autosomal recessive condition with a good visual prognosis. The clinical diagnosis of the condition is based on the presence of night blindness (nyctalopia), as well as fundoscopic observation of the Mizuo-Nakamura phenomenon. The Mizuo-Nakamura phenomenon refers to a fundus discolouration described as a golden-brown colour with a yellow-grey metallic sheen most prominent in the peripheral retina; after prolonged dark adaptation, the fundus appears normal. The prevalence of Oguchi disease is highest in Japan, particularly with SAG mutations (Nakazawa et al. in Retina 17:17-22, 1997), although patients from Europe, Pakistan and India have also been described. Formal diagnosis requires genetic testing. METHODS: Wide-field fundus images were obtained in both dark-adapted and light-adapted retina. Optical coherence tomography and dark-adapted electroretinography responses were used to further characterize the clinical phenotype. RESULTS: Existing descriptions of Oguchi disease have been limited by available technology. The flashes required for 45°-montage photographs in a dark-adapted eye quickly cause light adaptation. Recent advances in technology enable the capture of larger retinal areas in a single image. Wide-field 133° images were obtained of the native and dark-adapted fundus in natural colour. To our knowledge, these represent the first reported single-wide-field images of Oguchi disease, showing the characteristic Mizuo-Nakamura phenomenon in true colour. Genetic testing revealed a novel homozygous mutation in GRK1. CONCLUSIONS: Here, we demonstrate how characterizing this condition with single-shot true-colour wide-field imaging has distinct advantages over scanning laser technology, which applies artificial colouration, or stitched true-colour images. Images captured with wide-field systems create a much better representation of the native and dark-adapted fundus than can be observed by the ophthalmologist using direct fundoscopy and are essential in the clinical characterization of new mutations.