Oguchi Disease Research Articles

Loss of sheen in Oguchi disease following short wavelength exposure

Loss of sheen in Oguchi disease following short wavelength exposure

Abstract 1912 Protein Instability As a Novel Human Oguchi Disease Mechanism

Abstract 1912 Protein Instability As a Novel Human Oguchi Disease Mechanism

Localised loss of sheen in Optos pseudocolour images in Oguchi disease following prior short wavelength autofluorescence imaging

Aims/Purpose: Oguchi disease is characterized by night blindness and a striking golden retinal sheen in the light‐adapted state which disappears following prolonged dark adaptation (Mizuo‐Nakamura phenomenon). The sheen is observable clinically and on colour and pseudocolour (Optos plc) imaging. We observed a localized loss of sheen in a patient on colour/pseudocolour imaging in an area corresponding to the 30 degree square illuminated by short wavelength (488 nm) autofluorescence (AF) imaging (Heidelberg Spectralis). We explored whether other cases showed this phenomenon.Methods: Patients in our service with Oguchi disease (diagnosed phenotypically and/or with genetic confirmation) who had undergone colour or pseudocolour imaging were identified. In these patients, note was made of whether prior 30 degree short wavelength autofluorescence images had been undertaken and whether a localized square‐shaped loss of sheen was observed.Results: We identified 13 patients who had undergone colour or pseudocolour imaging. Of these, 4 patients (2 males, 2 females) had undergone prior 30 degree (and not 55 degree) short wavelength AF imaging at the same visit (ages ranging from 12 to 67). In 2 patients (a 12 year old, with variants in GRK1, and a 67 year old, not yet genotyped), a clear central square in which the sheen was absent was observed in the colour or pseudocolour images.Conclusions: The phenomenon of disappearance of the sheen in Oguchi disease following prolonged darkness is well‐described. Paradoxically, we observed loss of the sheen in 2 patients in a defined area corresponding to the field of illumination by bright blue light in 30 degree AF imaging. The blue light is preferentially absorbed by rhodopsin, which becomes bleached. It is possible that the sheen (at least in some patients) is dependent on there being a large proportion of unbleached rhodopsin as well as deficient shut‐off of activated rhodopsin.

ON–OFF electroretinogram analysis in patients with negative electroretinograms

Aims/Purpose: In a healthy population, the flash full‐field electroretinography (ffERG) includes a negative a‐wave and a positive b‐wave. The amplitude of the b‐wave is larger than the a‐wave amplitude in normal patients. In dark‐adapted ERG, the b:a ratio is about 1.6–1.8. The term “negative electroretinogram” is used when the b‐wave amplitude is smaller (negative–negative) or relatively smaller (negative–positive) than the a‐wave amplitude.This study aims to describe the differences in the ERG of patients with a negative ERG caused by genetic and acquired diseases to help better narrowing down an accurate diagnosis.Methods: The retrospective study comprised 10 patients aged 5–43 years (4 female, 6 male). ffERG was done according to the ISCEV standards. ON–OFF ERG protocol was additionally used. RETeval portable device (LKC, USA) and sensor strip palpebral electrodes were used.Results: Negative ERG was found in patients with congenital stationary night blindness (X‐linked, autosomal dominant, autosomal recessive, Oguchi disease), fundus albipunctatus, X‐linked retinoschisis, vitamin A deficiency, vigabatrin toxicity, retinal inflammation. In ON–OFF protocol differences between the function of the ON and OFF bipolar cells in the various diseases are present and will be discussed.Conclusions: ffERG with ON–OFF protocol should be done in all patients with nyctalopia or inner retina diseases. Detailed analysis of ERG may help to establish the clinical diagnose of retinal disease and to narrow the area of genetic investigation.

Multimodal analysis of two siblings with Oguchi disease

Multimodal analysis of two siblings with Oguchi disease

Oguchi's disease - Clinical image.

Oguchi's disease - Clinical image.

Mizuo–Nakamura phenomenon in a 10-year-old boy with Oguchi disease

Mizuo–Nakamura phenomenon in a 10-year-old boy with Oguchi disease

Genetic analysis and clinical features of three Chinese patients with Oguchi disease.

Oguchi disease is a rare autosomal recessive form of congenital stationary night blindness caused by disease-causing variants in the rhodopsin kinase gene (GRK1) or the arrestin gene (SAG). Our study aims to describe the clinical features and identify the genetic defects for three Chinese patients with Oguchi disease. We conducted detailed ophthalmologic examinations for three patients from three unrelated non-consanguineous Chinese families. Targeted next-generation sequencing (targeted NGS) and copy number variations (CNVs) analysis were applied to screen pathogenic variants. Sanger sequencing validation, quantitative real-time PCR (qPCR), and segregation analysis were further performed for confirmation. Subsequently, a combined genetic and structural biology approach was used to infer the likely functional consequences of novel variants. All three patients presented with typical clinical features of Oguchi disease, including night blindness, characteristic fundus appearance (Mizuo-Nakamura phenomenon), attenuated rod responses, and negative ERG waveforms. Their visual acuity and visual field were normal. Genetic analysis revealed two pathogenic variants in SAG and four pathogenic variants in GRK1. Patient 1 was identified to harbor compound heterozygous SAG variants c.874C > T (p.R292*) and exon2 deletion. Compound heterozygous GRK1 variants c.55C > T (p.R19*) and c.1412delC (p.P471Lfs*52) were found in patient 2. In patient 3, compound heterozygous GRK1 variants c.946C > A (p.R316S) and c.1388T > C (p. L463P) were detected. We reported the first two Chinese Oguchi patients with novel GRK1 pathogenic variants (P471Lfs*52, R316S, L463P) and one Oguchi case with SAG, indicating both GRK1 and SAG are important causative genes in Chinese Oguchi patients.

Deletion of Protein Phosphatase 2A Accelerates Retinal Degeneration in GRK1- and Arr1-Deficient Mice.

PurposeLight detection in retinal rod photoreceptors is initiated by activation of the visual pigment rhodopsin. A critical, yet often-overlooked, step enabling efficient perception of light is rhodopsin dephosphorylation mediated by protein phosphatase 2A (PP2A). PP2A deficiency has been reported to impair rhodopsin regeneration after phosphorylation by G protein receptor kinase 1 (GRK1) and binding of arrestin (Arr1), thereby delaying rod dark adaptation. However, its effects on the viability of photoreceptors in the absence of GRK1 and Arr1 remain unclear. Here, we investigated the effects of PP2A deficiency in the absence of GRK1 or Arr1, both of which have been implicated in Oguchi disease, a form of night blindness.MethodsRod-specific mice lacking the predominant catalytic Cα-subunit of PP2A were crossed with the Grk1−/− or Arr1−/− strains to obtain double knockout lines. Rod photoreceptor viability was analyzed in histological cross-sections of the retina stained with hematoxylin and eosin, and rod function was evaluated by ex vivo electroretinography.ResultsPP2A deficiency alone did not impair photoreceptor viability up to 12 months of age. Retinal degeneration was more pronounced in rods lacking GRK1 compared to rods lacking Arr1, and degeneration was accelerated in both Grk1−/− or Arr1−/− strains where PP2A was also deleted. In Arr1−/− mice, rod maximal photoresponse amplitudes were reduced by 80% at 3 months, and this diminution was enhanced further with concomitant PP2A deficiency.ConclusionsThese results suggest that although PP2A is not required for the survival of rods, its deletion accelerates the degeneration induced by the absence of either GRK1 or Arr1.

Mutation analysis reveals novel and known mutations in SAG gene in first two Egyptian families with Oguchi disease

BackgroundOguchi disease is a rare type of congenital stationary night blindness associated with an abnormal fundus appearance. It is inherited in an autosomal recessive manner where two types exist according to the gene affected; type 1 associated with S-antigen (SAG) gene mutations and type 2 associated with rhodopsin kinase (GRK1) gene mutations.PurposeThe aim of this work was to describe the clinical and genetic findings of the first two reported families of Oguchi disease in Egypt and African region.MethodsFour members of two consanguineous Egyptian families with history of night blindness since childhood underwent complete ophthalmological examination, standard automated static perimetry, fundus color photography, fundus autofluorescence (FAF), fundus fluorescein angiography (FFA) in light-adapted state and spectral-domain optical coherence tomography (SD-OCT) of both the macula and the optic nerve head as well as central corneal thickness with repeated fundus photography following prolonged dark adaptation. Mutation screening of 7 coding exons of GRK1 gene and 15 coding exons of SAG gene as well as some flanking regions were performed using Sanger sequencing technique. The variants were tested for pathogenicity using different in silico functional analysis tools.ResultsThe clinical examination and investigations confirmed Oguchi disease phenotype. One patient showed p.R193* (c.577C > T) which is a previously reported SAG gene mutation in a homozygous form. The other three patients from a different family showed (c.649–1 G > C), a novel canonical splice site SAG gene mutation in a homozygous form.ConclusionThe identification of the novel canonical splice site SAG gene variant in three members of the same family with clinically confirmed Oguchi disease reinforces its pathogenicity. A fourth patient from another family carried a previously reported mutation in the same gene. SAG gene variants may be the underlying genetic cause for Oguchi disease in Egypt. Our findings have expanded the spectrum of Oguchi disease-associated mutations in SAG gene and may serve as a basis for genetic diagnosis for Oguchi disease.

Mizuo–Nakamura phenomenon in X-linked retinoschisis

PurposeTo determine whether the Mizuo–Nakamura phenomenon, which is an important diagnostic sign of Oguchi's disease, also occurs in patients with genetically proven X-linked retinoschisis (XLRS). MethodsWe examined three patients with a clinical and genetic diagnosis of XLRS and one patient who was clinically diagnosed with Oguchi's disease, with an emphasis on the Mizuo–Nakamura phenomenon. We obtained color fundus photographs, especially in the fully dark-adapted state, using the non-mydriatic mode on a digital retinal camera and infrared observation monitor to avoid the bleaching effects caused by the viewing light, which alters the fundus color in a short time. ResultsThe Mizuo–Nakamura phenomenon was observed in all patients with molecularly proven XLRS, similar to that in the patient with Oguchi's disease. The sets of photographs were obtained in the light- and dark-adapted states using our newly devised techniques needed to witness the Mizuo-Nakamura phenomenon. Conclusions and ImportanceThe Mizuo–Nakamura phenomenon was identified in three patients with genetically proven XLRS. To the best of our knowledge, this study provided the first genetic evidence of the Mizuo–Nakamura phenomenon in a patient with molecularly proven XLRS without the causative genetic abnormalities for Oguchi's disease. Our findings suggest that XLRS is responsible for the Mizuo–Nakamura phenomenon and its presence in XLRS is not a rare exception but may be a consistent manifestation of XLRS.

A compound heterozygous mutation in the S-Antigen Visual Arrestin SAG gene in a Chinese patient with Oguchi type one: a case report

BackgroundOguchi disease is a rare autosomal recessive form of congenital quiescent night blindness. Oguchi disease has been found to be associated with gene mutations in SAG and GRK1, which are vital factors in the recovery phase of phototransduction after light stimuli. We report a case of Oguchi disease with novel heterozygous mutations in SAG.Case presentationA 7-year-old girl with a history of night blindness since childhood, was referred to our hospital. Ophthalmologic examinations included visual acuity, fundus examinations, fundus photography, spectral-domain optical coherence tomography, electroretinographic (ERG). Mutation screening of the SAG and GRK1 genes was performed. This patient exhibited typical clinical characteristics of Oguchi disease, including night blindness, golden fundus with the Mizuo–Nakamura phenomenon, packed structure of the parafovea in optical coherence tomography and reduced a-waves and b-waves in scotopic 3.0 ERG. Genetic testing revealed a heterozygous change in nucleotide c.72_75+15delATCGGTGAGTGGTGCACAA in exon 2 of the SAG gene in this patient, her unaffected mother and younger brother. A splicing alteration of nucleotide c.376-2A>C was identified in exon 6 of the SAG gene with heterozygous status in this patient and her unaffected father.ConclusionsCompound heterozygosity of a nonsense p.S25X mutation in exon 2 and a splicing alteration in exon 6 of the SAG gene is the cause of this patient with Oguchi type 1 disease in China.

Swept-source optical coherence tomography in Oguchi disease

Swept-source optical coherence tomography in Oguchi disease

Oguchi's disease: two cases and literature review.

Oguchi's disease is a rare form of congenital stationary night blindness, associated with light-dependent golden fundus discoloration. In this report, we describe two cases of Oguchi's disease, both of which had two characteristic features: congenital stationary night blindness and fundoscopic manifestation of the Mizuo–Nakamura phenomenon. In both patients, fundus examination revealed a metallic sheen throughout the retina, which disappeared after 2.5 hours of dark adaptation, suggestive of the Mizuo–Nakamura phenomenon. The characteristic electroretinogram (ERG) changes (i.e., un-recordable rod response and reductions of maximal response, oscillatory potentials, and flicker response) in these patients confirmed the clinical diagnosis of Oguchi's disease. Furthermore, we discuss the results of our literature search for evidence concerning the diagnosis and pathogenesis of this rare disease. Further studies regarding the genes involved in phototransduction and light adaptation are needed to determine the pathogenesis of this rare disease.

Cover, Volume 42, Issue 2

The back cover image is based on the Research Article New variants and in silico analyses in GRK1 associated Oguchi disease by James A. Poulter et al., https://doi.org/10.1002/humu.24140.

Oguchi Disease Associated with Keratoconus.

This is a Photo Essay and does not have an abstract. Please download the PDF or view the article in HTML.

A rare case of oguchi disease exhibiting the classic Mizuo-Nakamura phenomenon

Oguchi disease also called congenital stationary night blindness is an autosomal recessive genetic condition first identified in Japan with a few cases reported in other countries like Europe, America, India and Pakistan. We report one such case exhibiting the Mizuo-Nakamura phenomenon with a reduced amplitude on the b-wave of the rod electroretinogram advocating this diagnosis. A 40-year-old man presented with complaints of non-progressive decrease in vision as the day progressed for 6 months with normal vision during the day in both eyes. There was no history of trauma or any other ocular or systemic disease. His parents had a second-degree consanguineous marriage and his father experienced similar symptoms. Visual acuity for distance was 6/6 and N6 for near in both eyes. His anterior segment and posterior segments were normal. When the patient was put to dark adaptation for 3 hours, there was a change in his fundus background colour from grey to red (Mizuo-Nakamura phenomenon). The b-wave amplitude was decreased on the rod electroretinogram. The cone electroretinogram on the other hand was normal. All this was confirmed by his genetic study which favoured this diagnosis.This disease presents with features similar to retinitis pigmentosa in terms of mutations in the SAG gene This highlights the importance of the Mizou-Nakamura phenomenon in formulating a confirmatory diagnosis and treatment protocol.

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

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

Clinical Findings in Four Siblings with Genetically Proven Oguchi Disease.

Purpose:To assess the clinical findings in normal daylight status and 3 h of dark-adapted status in family members with Oguchi disease (OD).Methods:Four siblings with OD and their parents were included in this case series. The presence of disease was confirmed with genetic analysis and comprehensive clinical evaluation. Corrected distant visual acuity (CDVA), automated visual field analysis (VFA), optical coherence tomography (OCT), OCT angiography (OCTA), colored fundus photography, fundus autofluorescence (FAF), fundus fluorescein angiography (FFA), electroretinography (ERG), and dark adaptation test (DAT) results were obtained in normal daylight status. On the next day, after 3 h of dark adaptation, the patients were re-evaluated. The findings obtained in normal daylight status and 3 h dark-adapted status were compared.Results:The mean age of the four sibling subjects was 15.25 ± 2.2 years. All subjects had 20/20 CDVA and normal VFA. There was no abnormality in OCT and OCTA in normal daylight status and 3 h of dark-adapted status. Colored fundus photographs showed characteristic golden-yellow colored reflex in the mid-peripheral retina in normal daylight status, and discoloration in 3 h of dark-adapted status. In FAF and FFA, no abnormal pattern was observed in normal daylight status and 3 h of dark-adapted status. ERG showed rod function alterations and normal cone function. DAT showed delayed rod adaptation and normal cone adaptation. ERG and DAT findings remained unchanged after 3 h of dark adaptation.Conclusion:After 3 h of dark adaptation, golden-yellow fundus color returns to normal in patients with OD; however, rod function alterations and normal cone function in ERG, as well as delayed rod adaptation and normal cone adaptation in DAT remain unchanged.

A Homozygote Mutation in S-Antigen Visual Arrestin SAG Gene in an Iranian Patient with Oguchi Type One: A Case Report

Oguchi disease is a rare autosomal recessive form of congenital stationary night blindness (CSNB) characterized by specific features such as golden-brown discoloration of the fundus called Mizuo-Nakamura phenomenon which is distinguishable by fundoscopy, and retinography. Clinical diagnosis is confirmed through genetic test. Two known genes in pathogenesis of Oguchi disease are SAG and GRK1. A 35-year-old Iranian male exhibiting the clinical features of congenital stationary night blindness, was referred to the genetic clinic of Dr. Farhud, Tehran, Iran in 2012 and examined. Ophthalmic examination including slit-lamp biomicroscopy, perimetry and funduscopy was performed. Additionally, the full-field electroretinography and molecular testing for congenital stationary night blindness were performed. Molecular genetic tests, including the analysis of GSK1 and SAG genes exon-intron boundaries were performed for this patient and his family. According to the sequencing results, we did not find any mutation in GSK1 gene. However, a new homozygote mutation at location chr2:233320735, c.517delC, p.P96LfsX28 was identified in exon four of SAG gene. This deletion causes a frame shift mutation, and premature stop codon that results in deletion of about 281 amino acid residues of S-antigen visual arrestin protein (from entire C-terminal). This mutation was also found in patient's parents and one of his sister as heterozygote form. This is the first molecular evidence for SAG gene mutation in an Iranian family affected with Oguchi disease type 1. The identification of the new c.517delC, p.P96LfsX28 mutation in this family with Oguchi disease can confirm the pathogenicity of this variant.