Oguchi Disease Research Articles

Signs of Oguchi Disease and Pigmentary Degeneration from Early in Life

Signs of Oguchi Disease and Pigmentary Degeneration from Early in Life

Pathogenic mutation in a patient with Oguchi disease

Objective To identify the pathogenic mutation in a patient with Oguchi disease. Methods A Japanese patient with Oguchi disease was enrolled in this study, and underwent a comprehensive medical history assessment and multiple ophthalmic examinations, including BCVA, OCT, color fundus photography and full field electroretinogram. Genomic deoxyribonucleic acid (DNA) was extracted from peripheral blood samples for whole exome sequencing. The gene mutation was detected, and the analysis software was used to determine the conservation of the mutation and the possible structural changes. Results The patient, 71 years old, with consanguineous parents, complained of night blindness since early childhood. BCVA in both eyes was 0.7 and the golden-yellowish reflex appeared in the grey retina. The scotopic 0.01 ERGs showed a extinguished reaction in both eyes. The scotopic 3.0 ERGs showed a negative configuration with a significantly reduced a wave and a nearly absent b wave. A homozygous deletion mutation in the SAG gene (c.924delA, p.N309Tfs*12) in this patient was founded by DNA sequencing, which was predicted to generate prematurely truncated SAG protein and result in severe structural change. Homology analysis of the protein sequence indicated that the mutation resulted in an altered amino acid which was evolutionarily highly conserved among different species, strongly suggesting the potential pathogenicity of this homozygous mutation. Conclusion The mutation c.924delA(309Tfs*12) in SAG cause Oguchi disease in this patient. Key words: Retinal diseases/genetics; Frameshift mutation; Exome; Oguchi disease; SAG gene

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.

Progression from Classical Oguchi Disease to Retinitis Pigmentosa after 50 Years

Fundus photograph of a 77-year-old Japanese man with retinitis pigmentosa (RP) and homozygous c.636delT in S-antigen (SAG) (Fig A). The patient’s condition had been reported as Oguchi disease (Fig B) with Mizuo-Nakamura phenomenon at the 20th International Congress of Ophthalmology held at Munich in 1966. Fundus photograph of the same patient taken around that time (age ∼23) showed metallic sheen covering the posterior pole with no sign of retinal degeneration. These photographs mark the first example of progression of classical juvenile Oguchi disease to RP.

Phenotypic Features of Oguchi Disease and Retinitis Pigmentosa in Patients with S-Antigen Mutations: A Long-Term Follow-up Study

To present phenotypic features of 22 patients with S-antigen (SAG) mutations. Retrospective cohort study. Twenty-one Japanese patients from 16 families with a homozygous c.924delA mutation and 1 patient with a homozygous c.636delT mutation in the SAG gene. Clinical records on symptoms; best-corrected visual acuity; and Goldmann perimetry, fundus photography, fundus autofluorescence (FAF), OCT, and electroretinography results were reviewed. Best-corrected visual acuity, Goldmann perimetry results, imaging findings, and electroretinography results. Ten patients had Oguchi disease and 12 had retinitis pigmentosa (RP) with mean follow-up periods of 13.8 and 10.2 years, respectively. Retinitis pigmentosa patients were older (mean age, 56.0 years) than those with Oguchi disease (mean age, 22.1 years; P < 0.001) at the initial visit. Night blindness noted in childhood was the most common initial symptom for both Oguchi disease (80.0%) and RP (91.7%) patients. Best-corrected visual acuity in the logarithm of the minimum angle of resolution (logMAR) was well preserved in Oguchi disease patients (mean, 0.02 logMAR in both eyes) but reduced in most RP patients (mean, 1.32 logMAR [right eye] and 1.35 logMAR [left eye]). Similarly, the visual field in the retinal area was preserved in Oguchi disease patients (mean, 677 mm2 right eye and 667 mm2 left eye) and reduced in RP patients (mean, 369 mm2 right eye and 294 mm2 left eye). Fundus images revealed a characteristic golden sheen with no retinal degeneration in Oguchi disease patients, excluding 2 with macular degeneration detected by FAF, OCT, or both and 1 with mild retinal degeneration confirmed by OCT and fluorescein angiography. Pigmentary retinal degeneration most evident posteriorly was observed in RP patients, accompanied by a characteristic golden sheen in 12 of 14 patients undergoing ultra-widefield fundus imaging. OCT showed disrupted macular structure, and FAF revealed variable hypofluorescence. Electroretinography identified absent rod responses in both diseases, along with relative preservation of cone responses in Oguchi disease patients. Three patients showed progressive loss of the golden sheen based on fundus images, including 1 who demonstrated RP 26 years after the initial diagnosis of Oguchi disease. Retinitis pigmentosa with SAG mutations often shows a characteristic golden sheen surrounding posterior pigmentary retinal degeneration. Oguchi disease can show progressive degeneration in adulthood, rarely resulting in RP.

A Mixture of U.S. Food and Drug Administration-Approved Monoaminergic Drugs Protects the Retina From Light Damage in Diverse Models of Night Blindness.

PurposeThe purpose of this study was to test the extent of light damage in different models of night blindness and apply these paradigms in testing the therapeutic efficacy of combination therapy by drugs acting on the Gi, Gs, and Gq protein-coupled receptors.MethodsAcute bright light exposure was used to test susceptibility to light damage in mice lacking the following crucial phototransduction proteins: rod transducin (GNAT1), cone transducin (GNAT2), visual arrestin 1 (ARR1), and rhodopsin kinase 1 (GRK1). Mice were intraperitoneally injected with either vehicle or drug combination consisting of metoprolol (β1-receptor antagonist), bromocriptine (dopamine family-2 receptor agonist) and tamsulosin (α1-receptor antagonist) before bright light exposure. Light damage was primarily assessed with optical coherence tomography and inspection of cone population in retinal whole mounts. Retinal inflammation was assessed in a subset of experiments using autofluorescence imaging by scanning laser ophthalmoscopy and by postmortem inspection of microglia and astrocyte activity.ResultsThe Gnat1−/− mice showed slightly increased susceptibility to rod light damage, whereas the Gnat2−/− mice were very resistant. The Arr1−/− and Grk1−/− mice were sensitive for both rod and cone light damage and showed robust retinal inflammation 7 days after bright light exposure. Pretreatment with metoprolol + bromocriptine + tamsulosin rescued the retina in all genetic backgrounds, starting at doses of 0.2 mg/kg metoprolol, 0.02 mg/kg bromocriptine, and 0.01 mg/kg tamsulosin in the Gnat1−/− mice. The therapeutic drug doses increased in parallel with light-damage severity.ConclusionsOur results suggest that congenital stationary night blindness and Oguchi disease patients can be at an elevated risk of the toxic effects of bright light. Furthermore, systems pharmacology drug regimens that stimulate Gi signaling and attenuate Gs and Gq signaling present a promising disease-modifying therapy for photoreceptor degenerative diseases.

Oguchi Disease: The Chameleon in the Retina

Oguchi Disease: The Chameleon in the Retina

Mizuo-Nakamura phenomenon in an Indian male.

Key Clinical Message The authors present a 20‐year‐old myopic male who showed golden color of fundus (Mizuo‐Nakamura phenomenon) in light and normal color after long dark adaptation. This phenomenon is associated with an abnormally slow dark adaptation and is typically noted in Oguchi disease, a variant of congenital stationary night blindness.

Oguchi type I caused by a homozygous missense variation in the SAG gene

Oguchi disease, is a very rare form of night blindness caused by biallelic variations in the SAG or GRK1 genes, both involved in rod restoration after light stimuli. Here we report the clinical and genetic findings of an 8-year old boy with a history of reduced visual acuity, nyctalpia and hemeralopia. Clinical findings, in particular the Mizuo-Nakamura phenomenon, were compatible with a diagnosis of Oguchi disease. Genetic testing revealed a novel missense homozygous variation in the SAG gene. This is the first evidence that the disease can be caused by missense variations in this gene.

ISCEV extended protocol for the dark-adapted red flash ERG

The International Society for Clinical Electrophysiology of Vision (ISCEV) standard for full-field electroretinography (ERG) describes a minimum procedure, but encourages more extensive testing. This ISCEV extended protocol describes an extension to the ERG standard, namely the dark-adapted (DA) red flash ERG. The DA red flash ERG can be incorporated conveniently within the ISCEV standard ERG protocol after a minimum of 20-min DA and recorded after the DA 0.01 ERG to a flash strength of 0.3 phot cd s m−2, eliciting a waveform with two positive peaks in healthy individuals. The first positive component is the cone-mediated x-wave with a peak at 30–50 ms; the second is a rod-mediated b-wave with a peak time of approximately 100 ms. Shorter DA times may be desirable to shorten the recording time or to alter the prominence of the early cone-mediated x-wave relative to the rod-mediated b-wave. The DA red flash ERG is used to aid the diagnosis of achromatopsia (rod monochromacy), cone dystrophy and other forms of cone system dysfunction, including “Bradyopsia” (RGS9/R9AP-retinopathy), when the DA red flash ERG x-wave is preserved in the absence of ISCEV standard LA ERGs. The DA red flash ERG can also help determine the origin of residual DA ERGs in cases of severe rod dysfunction, for example in disorders such as vitamin A deficiency, fundus albipunctatus (RDH5-retinopathy), Oguchi disease (SAG- or GRK1-retinopathy) and some rod-cone dystrophies. To shorter DA periods, the x-wave may be elicited without the following rod b-wave, shown to be helpful in abbreviated protocols for children.

A Novel Dominant Mutation in SAG, the Arrestin-1 Gene, Is a Common Cause of Retinitis Pigmentosa in Hispanic Families in the Southwestern United States.

PurposeTo identify the causes of autosomal dominant retinitis pigmentosa (adRP) in a cohort of families without mutations in known adRP genes and consequently to characterize a novel dominant-acting missense mutation in SAG.MethodsPatients underwent ophthalmologic testing and were screened for mutations using targeted-capture and whole-exome next-generation sequencing. Confirmation and additional screening were done by Sanger sequencing. Haplotypes segregating with the mutation were determined using short tandem repeat and single nucleotide variant polymorphisms. Genealogies were established by interviews of family members.ResultsEight families in a cohort of 300 adRP families, and four additional families, were found to have a novel heterozygous mutation in the SAG gene, c.440G>T; p.Cys147Phe. Patients exhibited symptoms of retinitis pigmentosa and none showed symptoms characteristic of Oguchi disease. All families are of Hispanic descent and most were ascertained in Texas or California. A single haplotype including the SAG mutation was identified in all families. The mutation dramatically alters a conserved amino acid, is extremely rare in global databases, and was not found in 4000+ exomes from Hispanic controls. Molecular modeling based on the crystal structure of bovine arrestin-1 predicts protein misfolding/instability.ConclusionsThis is the first dominant-acting mutation identified in SAG, a founder mutation possibly originating in Mexico several centuries ago. The phenotype is clearly adRP and is distinct from the previously reported phenotypes of recessive null mutations, that is, Oguchi disease and recessive RP. The mutation accounts for 3% of the 300 families in the adRP Cohort and 36% of Hispanic families in this cohort.

Oguchi disease due to a novel mutation in the GRK1 gene

PurposeTo present the phenotype and genotype of a patient with Oguchi disease, a rare autosomal recessive form of congenital stationary night blindness.MethodsA 20‐year old lady of Indian ethnicity presented with a history of congenital nyctalopia. She underwent an extensive ophthalmological and genetic work‐up.ResultsBCVA was 6/6 in both eyes. Slit‐lamp examination was unremarkable. Fundoscopy revealed a bilateral, widespread golden‐yellow discoloration and peripheral patches of normal, darker pigmentation. Blue‐light fundus autofluorescence imaging and visual field testing were normal. Spectral domain OCT showed a normal anatomic retinal structure, however with hyperreflectivity and blending of the ISe, COST and RPE layers. Absent rod responses in the dark‐adapted state, electronegative maximal combined responses and subnormal light‐adapted responses were detected on full‐field ERG. After prolonged dark‐adaptation, the fundus appearance was normal (Mizuo‐Nakamura phenomenon) with partial recovery of the rod‐specific ERG responses. DNA analysis confirmed the clinical diagnosis of Oguchi disease and revealed homozygosity for a novel deletion in the GRK1 gene (c.1549_1559del – p.Pro517Glyfs*).ConclusionsA patient with Oguchi disease due to homozygosity for a novel mutation in the GRK1 gene is described, increasing the total number of causative mutations and confirming the role of GRK1 in the pathogenesis of this very rare disorder.

A novel missense mutation of the GRK1 gene in Oguchi disease.

Oguchi disease is a rare form of congenital stationary night blindness with an autosomal recessive inheritance pattern. The presence of S-antigen (SAG) and G-protein-dependent receptor kinase 1 (GRK1) mutations were investigated in the family members with Oguchi disease. All exons of the SAG and GRK1 genes were amplified by polymerase chain reaction and sequenced. The patients were shown to have characteristic clinical features of Oguchi disease. Gene analysis determined a novel GRK1 mutation c.923T>C, which caused Oguchi disease in all siblings. This mutation, was demonstrated by amino acid alignment analysis to be in a phylogenetically conserved region and resulted in an amino acid change from leucine to proline at position 308. Thus, the present study reports a novel missense mutation of GRK1 in the affected members of a consanguineous Turkish family. Homozygosity at position 308, which resides in the catalytic domain of the GRK1 gene, is the cause of Oguchi disease in this Turkish family.

Association of Retinal Artery and Other Inner Retinal Structures With Distribution of Tapetal-like Reflex in Oguchi's Disease.

To report novel ophthalmoscopic features of patients with Oguchi's disease, and to describe how they may be related to the unusual tapetal-like fundus appearance. Twenty-one eyes of 11 patients who were diagnosed with Oguchi's disease were investigated. Genetic screening of seven cases showed homozygous mutations in the SAG gene (c.926delA). The retinal appearance was retrospectively assessed in the fundus photographs, and the optical coherence tomographic (OCT) and fundus autofluorescence (AF) images. In 11 eyes of 7 patients, clearly demarcated dark regions without tapetal-like reflex were observed in the midperipheral retinal regions. In the dark regions, OCT showed lower reflectances in the photoreceptor layer but the AF images had normal reflectances. In nine eyes of six patients, the dark regions were partially demarcated by retinal arteries but not by veins. In nine eyes of five patients, the extent of the dark regions either increased or decreased during the course of the disease process, and these changes were not due to the state of adaptation or a posterior vitreous detachment. In all eyes, the peripheral retinal arteries but not veins had either high or low reflective regions along one side. Although the alterations of the outer retinal layers are believed to be most responsible for the abnormal tapetal-like reflex in patients with Oguchi's disease, these ophthalmoscopic features cannot be explained solely by the abnormality of the outer retina. Our findings suggest that the appearance of tapetal-like reflex is strongly affected by alterations of structures in the inner retinal layers.

Not So Hot Rods: Mutations in Rhodopsin Kinase in Regards to Oguchi Disease

The average person's eyes adapt to darkness within minutes. For those with Oguchi's disease, adaptation can be slowed to several hours. Oguchi disease is an autosomal recessive disorder that results in greatly slowed phototransduction. Phototransduction is a cascade reaction beginning with a photon activating rhodopsin in the rod and leading to hyperpolarization of the cell. Oguchi disease is caused by mutations in rhodopsin kinase which prevent the phosphorylation of rhodopsin, lowering rhodopsin's affinity for arrestin. This reduced ability to bind arrestin decreases the speed in which rhodopsin is deactivated and prepped to reactivate. After a long period in a dark environment, the rhodopsin is eventually deactivated by arrestin, allowing it to be recycled. The Hartford Union High School SMART (Students Modelling a Research Topic) Team has designed a model of rhodopsin kinase to investigate its structure‐function relationship. Oguchi disease can be caused by two different mutations in rhodopsin kinase: large deletion or point mutation. In our 3D model, we will highlight the complete deletion of exon five, the partial deletion at the C‐terminus, and point mutations in the catalytic domain (Val380Asp and Pro391His) that cause Oguchi disease. Understanding the structure‐function relationships of rhodopsin kinase could shed more light on night blindness. This program is supported by a grant from NIH and CTSA.

Mizuo-Nakamura phenomenon (a rare ocular phenomenon)

Oguchi disease, first described in 1907, is a rare autosomal recessive disorder characterized by congenital stationary night blindness with a unique morphological and functional abnormality of the retina. The cause, though largely unknown, is associated with ARRESTIN and RHODOPSIN KINASE gene defects. This is a case report of a 20 yr old male patient of Oguchi disease who presented with classical symptoms and morphological features in the form of Mizuo phenomenon.

Assessing Retinal Structure in Complete Congenital Stationary Night Blindness and Oguchi Disease

To examine retinal structure and changes in photoreceptor intensity after dark adaptation in patients with complete congenital stationary night blindness and Oguchi disease. Prospective, observational case series. We recruited 3 patients with complete congenital stationary night blindness caused by mutations in GRM6, 2 brothers with Oguchi disease caused by mutations in GRK1, and 1 normal control. Retinal thickness was measured from optical coherence tomography images. Integrity of the rod and cone mosaic was assessed using adaptive optics scanning light ophthalmoscopy. We imaged 5 of the patients after a period of dark adaptation and examined layer reflectivity on optical coherence tomography in a patient with Oguchi disease under light- and dark-adapted conditions. Retinal thickness was reduced in the parafoveal region in patients with GRM6 mutations as a result of decreased thickness of the inner retinal layers. All patients had normal photoreceptor density at all locations analyzed. On removal from dark adaptation, the intensity of the rods (but not cones) in the patients with Oguchi disease gradually and significantly increased. In 1 Oguchi disease patient, the outer segment layer contrast on optical coherence tomography was 4-fold higher under dark-adapted versus light-adapted conditions. The selective thinning of the inner retinal layers in patients with GRM6 mutations suggests either reduced bipolar or ganglion cell numbers or altered synaptic structure in the inner retina. Our finding that rods, but not cones, change intensity after dark adaptation suggests that fundus changes in Oguchi disease are the result of changes within the rods as opposed to changes at a different retinal locus.

Oguchi disease masked by retinitis pigmentosa

The purpose of this study was to report a patient with Oguchi disease whose ophthalmological characteristics were masked by retinitis pigmentosa (RP). The method used in this study was case report. A 53-year-old man had a progressive decrease in his visual acuity and was diagnosed with RP because of night blindness, fundoscopic findings, ring scotoma, and extinguished single-flash electroretinograms (ERGs). However, a faint golden-yellowish reflex of the retina prompted us to make a more detailed examination of the fundus after a long period of dark adaptation, ERGs, and genetic analysis. Examinations showed the Mizuo-Nakamura phenomenon, relative intact photopic ERGs, and a SAG mutation, and the patient was diagnosed with RP associated with Oguchi disease. When RP accompanies Oguchi disease, the clinical characteristics of Oguchi disease might be masked. In such a situation, the correct diagnosis is difficult. However, careful analysis of clinical findings will suggest Oguchi disease, which can be confirmed by molecular genetics.

Mizuo-Nakamura phenomenon in Oguchi disease due to a homozygous nonsense mutation in the SAG gene

Mizuo-Nakamura phenomenon in Oguchi disease due to a homozygous nonsense mutation in the SAG gene

Spectral-Domain Optical Coherence Tomography Findings in the Mizuo–Nakamura Phenomenon of Oguchi Disease

Spectral-Domain Optical Coherence Tomography Findings in the Mizuo–Nakamura Phenomenon of Oguchi Disease