A Novel Case Series Of NMNAT1-Associated Early-Onset Retinal Dystrophy: Extending the Phenotypic Spectrum

PURPOSE: To report two siblings with NMNAT1-associated retinopathy presenting with a later onset and milder phenotype than previously described. METHODS: Retrospective case series of two siblings. The authors describe two cases of early-onset retinal dystrophy caused by disease-causing NMNAT1 variants. Visual acuity, clinical examination, and retinal imaging including color fundus photography, spectral domain optical coherence tomography, and fundus autofluorescence were performed. Both cases underwent full-field and pattern electroretinography incorporating the International standards. RESULTS: Two siblings were found to harbor the variants c.53A>G, p.(Asn18Ser) and c.769G>A, p.(Glu257Lys) in NMNAT1 after retinal dystrophy panel gene testing. Both had good visual acuity until the ages of 6 and 11 years, respectively, with subsequent gradual worsening into their twenties. At the ages of 10 and 16 years, respectively, electroretinograms indicated generalized rod and cone system dysfunction of moderate severity, with pattern electroretinography evidence of severe macular involvement. Repeat testing at the ages of 26 and 33 years revealed only mild worsening of rod photoreceptor function in both. CONCLUSION: NMNAT1-associated retinopathy has previously only been described as a typical form of Leber congenital amaurosis, with poor visual acuity from birth associated with nystagmus, characteristic macular atrophy, and intraretinal pigmentation from birth. Here, we present two siblings with a novel, later onset, and far milder phenotype. We suggest that this may be due to the two missense NMNAT1 variants resulting in milder reduction of NMNAT1 enzymatic activity. These cases extend the phenotypic spectrum associated with NMNAT1 and further highlight the clinical heterogeneity associated with inherited retinal diseases

Evaluation of fluocinolone acetonide 0.19 mg intravitreal implant in the management of birdshot retinochoroiditis

Purpose: To report treatment outcomes and efficacy of the fluocinolone acetonide 0.19 mg intravitreal implant (Iluvien) in controlling retinal and choroidal inflammation in 11 patients with birdshot retinochoroiditis. Methods: A single-centre, retrospective, interventional case series. The primary efficacy end point was improvement in vascular leakage on fluorescein angiography (FA), effect on cystoid macular oedema (CMO) and resolution of hypofluorescent lesions on indocyanine green angiography (ICGA); secondary measures were improvements on pattern and full-field electroretinogram (PERG; ERG) parameters. Safety outcome measures were intraocular elevation and cataractogenesis. Results: Fifteen eyes received Iluvien implant with an average follow-up of 31 months (range 12–36 months). Prior to the implant, 5 (33.3%) eyes had received dexamethasone intravitreal implant 0.7 mg (Ozurdex). FA showed evidence of vascular leakage in all eyes at baseline. Between month 6 and 12, FA showed that 73.4% of eyes had no leakage, this increased to 84.6% by month 24. Three eyes in our study had CMO at baseline. 6 months after Iluvien implant, all eyes achieved complete CMO resolution. One year after insertion of the implant, the characteristic hypofluorescent lesions on ICGA were unchanged in all cases. There was baseline ERG evidence indicating a high incidence of peripheral cone system dysfunction and most showed PERG evidence of macular dysfunction. Retinal function improved and macular function improved or was stable in the majority following treatment. Conclusions: The results show the possible therapeutic effect of Iluvien in the management of Birdshot-related vascular leakage, CMO and retinal dysfunction. However, choroidal lesions seem to persist with no detectable response to treatment

The Effect on Retinal Structure and Function of 15 Specific ABCA4 Mutations: A Detailed Examination of 82 Hemizygous Patients

Purpose: To determine the effect of 15 individual ABCA4 mutations on disease severity. Methods: Eighty-two patients harboring 15 distinct ABCA4 mutations in trans with null (hemizygous), 10 homozygous, and 20 nullizygous patients were recruited. Age of onset was determined from medical histories. Electroretinography (ERG) responses were classified into three groups (normal; cone dysfunction; cone and rod dysfunction). The dark-adapted bright-flash (DA 10.0) a-wave amplitudes and the light-adapted flicker ERG (LA 3.0 30 Hz) amplitudes were plotted against age and compared with the nullizygous patients. Fundus autofluorescence imaging (FAF) was assessed when available. Results: Patients hemizygous for p.G1961E and p.R2030Q had normal ERGs. Patients harboring p.R24H, p.R212C, p.G863A/delG, p.R1108C, p.P1380L, p.L2027F, and c.5714+5G>A had abnormal ERGs (ERG group 2 or 3) at older ages, in most cases with significantly higher amplitudes than nullizygous patients. Mutations p.L541P+A1038V, p.E1022K, p.C1490Y, p.E1087K, p.T1526M, and p.C2150Y were associated with abnormal ERGs (group 2 or 3) and amplitudes comparable to those of nullizygous patients. The majority of patients, including those harboring p.G1961E, had foveal atrophy; while both patients harboring p.R2030Q had foveal sparing. Most patients harboring intermediate and null-like mutations displayed FAF abnormalities extending beyond the vascular arcades. Conclusions: In the hemizygous state, 2/15 ABCA4 alleles retain preserved peripheral retinal function; 7/15 are associated with either preserved or only mildly abnormal retinal function, worse in older patients; 6/15 behave like null mutations. These data help characterize the degree of dysfunction conferred by specific mutant ABCA4 proteins in the human retina

Extending the phenotypic spectrum of PRPF8, PRPH2, RP1 and RPGR, and the genotypic spectrum of early-onset severe retinal dystrophy

PURPOSE: To present the detailed retinal phenotype of patients with Leber Congenital Amaurosis/Early-Onset Severe Retinal Dystrophy (LCA/EOSRD) caused by sequence variants in four genes, either not (n = 1) or very rarely (n = 3) previously associated with the disease. METHODS: Retrospective case series of LCA/EOSRD from four pedigrees. Chart review of clinical notes, multimodal retinal imaging, electrophysiology, and molecular genetic testing at a single tertiary referral center (Moorfields Eye Hospital, London, UK). RESULTS: The mean age of presentation was 3 months of age, with disease onset in the first year of life in all cases. Molecular genetic testing revealed the following disease-causing variants: PRPF8 (heterozygous c.5804G > A), PRPH2 (homozygous c.620_627delinsTA, novel variant), RP1 (homozygous c.4147_4151delGGATT, novel variant) and RPGR (heterozygous c.1894_1897delGACA). PRPF8, PRPH2, and RP1 variants have very rarely been reported, either as unique cases or case reports, with limited clinical data presented. RPGR variants have not previously been associated with LCA/EOSRD. Clinical history and detailed retinal imaging are presented. CONCLUSIONS: The reported cases extend the phenotypic spectrum of PRPF8-, PRPH2-, RP1-, and RPGR-associated disease, and the genotypic spectrum of LCA/EOSRD. The study highlights the importance of retinal and functional phenotyping, and the importance of specific genetic diagnosis to potential future therapy

Ophthalmological Manifestations of Oculocutaneous and Ocular Albinism: Current Perspectives

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

ISCEV standard for clinical multifocal electroretinography (mfERG) (2021 update)

The multifocal electroretinogram (mfERG) is an electrophysiological test that allows the function of multiple discrete areas of the retina to be tested simultaneously. This document, from the International Society for Clinical Electrophysiology of Vision (ISCEV), presents an updated and revised ISCEV standard for clinical mfERG and defines minimum protocols for basic clinical mfERG recording and reporting so that responses can be recognized and compared from different laboratories worldwide. The major changes compared with the previous mfERG standard relate to the minimum length of m-sequences used for recording, reporting of results and a change in document format, to be more consistent with other ISCEV standards

Leber Congenital Amaurosis Associated with Mutations in CEP290, Clinical Phenotype, and Natural History in Preparation for Trials of Novel Therapies

PURPOSE: To investigate and describe in detail the demographics, functional and anatomic characteristics, and clinical course of Leber congenital amaurosis (LCA) associated with mutations in the CEP290 gene (LCA-CEP290) in a large cohort of adults and children. DESIGN: Retrospective case series. PARTICIPANTS: Patients with mutations in CEP290 identified at a single UK referral center. METHODS: Review of case notes and results of retinal imaging (color fundus photography, fundus autofluorescence [FAF] imaging, OCT), electrophysiologic assessment, and molecular genetic testing. MAIN OUTCOME MEASURES: Molecular genetic testing, clinical findings including visual acuity and retinal imaging, and electrophysiologic assessment. RESULTS: Forty patients with LCA-CEP290 were identified. The deep intronic mutation c.2991+1655 A>G was the most common disease-causing variant (23/40 patients) identified in the compound heterozygous state in 20 patients (50%) and homozygous in 2 patients (5%). Visual acuity (VA) varied from 6/9 to no perception of light, and only 2 of 12 patients with longitudinal VA data showed deterioration in VA in their better-seeing eye over time. A normal fundus was found at diagnosis in younger patients (mean age, 1.9 years), with older patients showing white flecks (mean age, 5.9 years) or pigmentary retinopathy (mean age, 21.7 years). Eleven of 12 patients (92%) with OCT imaging had preservation of foveal architecture. Ten of 12 patients (83%) with FAF imaging had a perifoveal hyperautofluorescent ring. Having 2 nonsense CEP290 mutations was associated with worse final VA and the presence of nonocular features. CONCLUSIONS: Detailed analysis of the clinical phenotype of LCA-CEP290 in a large cohort confirms that there is a window of opportunity in childhood for therapeutic intervention based on relative structural preservation in the central cone-rich retina in a significant proportion of patients, with the majority harboring the deep intronic variant potentially tractable to several planned gene editing approaches

Photoreceptor Structure in GNAT2-Associated Achromatopsia

Purpose: The purpose of this study was to report GNAT2-associated achromatopsia (GNAT2-ACHM) natural history, characterize photoreceptor mosaic, and determine a therapeutic window for potential intervention. Methods: Patients with GNAT2-ACHM were recruited from a single tertiary referral eye center (Moorfields Eye Hospital, London, UK). We performed longitudinal clinical evaluation and ophthalmic examination, and multimodal retinal imaging, including adaptive optics scanning light ophthalmoscopy, quantitative analysis of the cone mosaic, and outer nuclear layer (ONL) thickness, including cone densities evaluation in selected regions of interest and comparison with reported healthy controls. Results: All nine subjects (3 women) presented with nystagmus, decreased visual acuity (VA), light sensitivity, and highly variable color vision loss. One patient had normal color vision and better VA. Mean VA was 1.01 (±0.10) logarithms of the minimal angle of resolution (LogMAR) at baseline, and 1.04 (±0.10) LogMAR after a mean follow-up (range) of 7.6 years (1.7-12.8 years). Optical coherence tomography showed preservation of the foveal ellipsoid zone (EZ; n = 8; 88.9%), and EZ disruption (n = 1; 11.1%). Mean ONL thickness (range, ± SD) was 84.72 µm (28.57-113.33, ± 25.46 µm) and 86.47 µm (28.57-113.33, ± 24.65 µm) for right and left eyes, respectively. Mean cone densities (±SD) at 190 µm, 350 µm, and 500 µm from the foveal center, were 48.4 (±24.6), 37.8 (±14.7), and 30.7 (±9.9), ×103 cones/mm2, respectively. Mean cone densities were lower than these of unaffected individuals, but with an overlap. Conclusions: The cone mosaic in GNAT2-ACHM is relatively well preserved, potentially allowing for a wide therapeutic window for cone-directed interventions

Novel disease-causing variant in RDH12 presenting with autosomal dominant retinitis pigmentosa

Aim: To describe the clinical and molecular features of a novel, autosomal dominant RDH12-retinopathy. Methods: Retrospective cross-sectional study. Twelve individuals from a four-generation British pedigree underwent ophthalmic examination, genotyping using next generation sequencing, including whole genome sequencing and multimodal retinal imaging including fundus photography, optical coherence tomography (OCT), autofluorescence imaging and adaptive optics (AO) scanning light ophthalmoscopy were performed. Visual electrophysiology was performed in a subset. Results: Eight family members were confirmed as affected by genotyping heterozygous for RDH12 c.763delG. Visual acuity ranged from −0.1 to 0.2 logMAR. Affected individuals had constricted visual fields. A parafoveal and peripapillary ring of hyper-autofluorescence was seen initially, and with progression the area of perifoveal hypo-autofluorescence increased to involve the parafoveal area. Mild retinal thinning was identified on OCT imaging with reduction in both foveal total retinal and outer nuclear layer thickness. Cone densities along the temporal meridian were reduced in affected individuals compared with normative values at all temporal eccentricities studied. One individual with incomplete penetrance, was identified as clinically affected primarily on the basis of AO imaging. Full-field electroretinography demonstrated a rod-cone pattern of dysfunction and large-field pattern electroretinography identified peripheral macular dysfunction. Conclusions: This novel heterozygous variant RDH12 c.763delG is associated with a rod-cone dystrophy with variable expression. Determination of the degree of penetrance may depend on the modality employed to phenotypically characterise an individual. This rare and specific heterozygous (dominant) variant is predicted to result in a gain of function, that causes disease in a gene typically associated with biallelic (recessive) variants

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