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Background: KCNV2-associated retinopathy causes a phenotype reported as "cone dystrophy with nyctalopia and supernormal rod responses (CDSRR; OMIM# 610356)," featuring pathognomonic findings on electroretinography (ERG). Here, we report the clinical courses of two siblings with CDSRR. Case reports: Patient 1: A 3-year-old boy with intermittent exophoria was referred to our hospital. The patient's decimal best-corrected visual acuity (BCVA) at age 6 was 0.7 and 0.7 in the right and left eyes, respectively. Photophobia and night blindness were also observed. Because the ERG showed a delayed and supernormal b-wave with a "squaring (trough-flattened)" a-wave in the DA-30 ERG, and CDSRR was diagnosed. The patient's vision gradually worsened, and faint bilateral bull's eye maculopathy was observed at the age of 27 years, although the fundi were initially unremarkable. Genetic examination revealed a homozygous missense variant, c.529T > C (p.Cys177Arg), in the KCNV2 gene. Patient 2: The second patient was Patient 1's younger sister, who was brought to our hospital at 3 years of age. The patient presented with exotropia, mild nystagmus, photophobia, night blindness, and color vision abnormalities. The patients' decimal BCVA at age 13 was 0.6 and 0.4 in the right and left eyes, respectively, and BCVA gradually decreased until the age of 24 years. The fundi were unremarkable. The siblings had similar ERG findings and the same homozygous missense variant in the KCNV2 gene. Conclusions: The siblings had clinical findings typical of CDSRR. High-intense flash ERG is recommended for identifying pathognomonic "squaring" a-waves in patients with CDSRR. [ABSTRACT FROM AUTHOR]

Fat-soluble vitamins, including vitamins A, D, E and K, are molecules with no energy value that are essential to the body's functioning and to life. Their intake is almost exclusively exogenous, i.e. dietary. Deficiency or excess of fat-soluble vitamins is responsible for a variety of more or less specific clinical symptoms. The fact that the functions performed by these vitamins are both ubiquitous and vital explains the wide variety of clinical manifestations and their potential seriousness. Some syndromes are typical of a deficiency in fat-soluble vitamins, such as: the combination of ophthalmological and immunity impairment in the case of vitamin A; a haemorrhagic syndrome and osteopenia in the case of vitamin E; and osteomalacia, muscular weakness, even falls, and rickets in the case of vitamin D. Diagnosis of a deficiency in one of the fat-soluble vitamins is based on blood tests, which are not always essential for routine use. In this case, a therapeutic test may be suggested. [ABSTRACT FROM AUTHOR]

IntroductionNight blindness is the first sign of vitamin A deficiency (VAD), which can lead to blindness if left untreated. University students may be at risk of VAD-related night blindness due to unhealthy eating attitudes and inadequate vitamin A intake. This study aimed to determine the relationship between knowledge and attitudes toward vitamin A consumption affecting night blindness in university students.MethodsThis cross-sectional study involved 409 third-year university students of Universitas Islam Sultan Agung, Semarang, Indonesia. Participants completed questionnaires about socio-demographics, their knowledge of vitamin A, and attitudes toward vitamin A consumption. Night blindness symptoms among university students were assessed using the Low Luminance Questionnaire (LLQ), followed by a bivariate analysis of the Chi-Square test. Multivariate binary logistic regressions were used to determine whether the independent variables were associated with night blindness. A p-value less than 0.05 indicated significance.ResultsThe prevalence of high-symptom night blindness was higher among males (26.4%) than females (5.7%). Out of 409 university students, 48 from the non-medicine cluster of the study program had a night blindness symptom. The prevalence was lower in students who studied in the medicine cluster program. The level of knowledge on vitamin A had a significant relationship with symptoms of night blindness [prevalence ratio (PR) = 2.239 (95% CI = 1.110–4.516)]. The attitudes toward vitamin A consumption were significantly associated with night blindness (PR = 2.560, 95% CI = 1.215–5.392).DiscussionThe results of this study show that the risk of night blindness in university students can be prevented by increasing their knowledge and attitudes toward consuming vitamin A-rich food. The university can provide health promotion and vitamin A supplementation to avoid night blindness among academia.

BackgroundThe clinical manifestations of vitamin A deficiency (VAD) involve night blindness, bitot’s spots, corneal xerosis, and corneal scars. It is the most important cause of preventable childhood blindness among children and causes morbidity and mortality. Even though Ethiopia implemented high-potency vitamin A supplements, the occurrence of VAD remains significant. This study was to identify determinants of clinical VAD among preschool-aged children (PSC) in southwest Ethiopia.MethodA community-based survey was conducted among 411 randomly selected PSCs. A pretested and structured questionnaire coupled with clinical observation for signs of vitamin A deficiency by a trained ophthalmologist was used to collect the data. An anthropometric measurement of height was taken and analyzed using WHO Anthro to calculate Z-scores for each index. The public health significance of VAD was declared after comparison with international references. A bi-variable and multi-variable logistic analysis was done. We reported the adjusted odds ratio (AOR), 95% confidence interval, and p-value.ResultA total of 411 children were screened for clinical VAD, and the overall prevalence was 2.2% (95% CI: 1.5–2.5). Of which, night blindness affects 1.2%, bitot’s spots affects 0.7%, and corneal xerosis affects 0.2%, indicating a major public health problem compared to the international reference. The odds of clinical VAD were 81% lower among children who received vitamin A supplementation (VAS; AOR = 0.19, 95% CI: 0.04–0.92). On the other hand, PSC of mothers who had attended ANC visits were 89% less likely to develop clinical VAD (AOR = 0.11, 95% CI: 0.02–0.53). In addition, the study revealed that the odds of developing clinical VAD are 82% lower among PSC aged 36 to 47 months (AOR = 0.18; 95% CI: 0.03–0.97).ConclusionThe prevalence of clinical VAD among PSC is a public health problem and is associated with ANC visits, VAS status, and the age of the child, which could be used to target interventions to further reduce existing VAD. Further studies using reliable dietary intake and biomarker data could further depict the burden of subclinical VAD.

It is of utmost importance to define the molecular diagnosis of patients with retinitis pigmentosa (RP) due to existing targeted therapeutic option: voretigene neparvovec. We provide clinical evidence for pathogenicity reclassification of variants of uncertain significance (VUSs) RPE65 c.1580A>G (p.His527Arg). A case report of a 10-year-old boy with progressive vision loss. The patient manifested disease highly suggestive of RPE65 retinal dystrophy: nyctalopia, fairly good central vision, severely depressed full-field electroretinography responses and complete loss of peripheral fundus aut ofluorescence. Invitae Inherited Retinal Disorders Panel identified likely pathogenic mutation RPE65 c.499G>T (p.Asp167Tyr) and RPE65 c.1580A>G (p.His527Arg), variant of uncertain significance. Segregation analysis confirmed that these variants are in trans. We conclude that the variant RPE65 c.1580A>G (p.His527Arg) has contributed to the pathologic phenotype, demonstrating its significance clearly in the case presented, and should be reclassified according to the criteria of evidence as pathogenic. Therefore, patients with this specific variant in homozygous or compound heterozygous form would likely benefit from genetic treatment based on recombinant adeno-associated virus vector, providing a working RPE65 gene to act in place of a mutated RPE65 gene. [ABSTRACT FROM AUTHOR]

Spectral tuning of visual pigments often facilitates adaptation to new environments, and it is intriguing to study the visual ecology of pelagic sharks with secondarily expanded habitats. The whale shark, which dives into the deep sea of nearly 2,000 meters besides near-surface filter feeding, was previously shown to possess the ‘blueshifted’ rhodopsin (RHO), which is a signature of deep-sea adaptation. In this study, our spectroscopy of recombinant whale shark RHO mutants revealed that this blue shift is caused dominantly by an unprecedented spectral tuning site 94. In humans, the mutation at the site causes congenital stationary night blindness (CSNB) by reducing the thermal stability of RHO. Similarly, the RHO of deep-diving whale shark has reduced thermal stability, which was experimentally shown to be achieved by site 178 and 94. RHOs having the natural substitution at site 94 are also found in some Antarctic fishes, suggesting that the blue shift by the substitution at the CSNB site associated with the reduction in thermal stability might be allowed in cold-water deep-sea habitats. [ABSTRACT FROM AUTHOR]

Vitamin-A deficiency associated with night blindness in children is a global health problem that could be prevented or reduced by promoting the intake of β-carotene in food. The fortification of β-carotene in yogurt using pumpkin flesh (PF) could be a very cost-effective public health intervention. The current study aimed to analyze the proximate, functional, microbial, textural, and sensory properties of yogurt fortified with PF to evaluate its suitability as a β-carotene enriched food. The research was conducted with three treatments, control set-type yogurt (CSY) with no PF, 15% PF-fortified set-type yogurt (15PFSY), and 20% PF-fortified set-type yogurts (20PFSY) followed by pumpkin pie spice and ground pumpkin seed to improve consumer acceptability. The fortified yogurt with 20PFSY and 15PFSY contained a higher amount of β-carotene, protein, fiber, and ash, and lower carbohydrate, fat, and energy in compression with CSY, which might attract health-conscious people. In addition, viable bacterial count, firmness, consistency, cohesiveness, and viscosity index were found better in fortified yogurt. Based on reports of sensory panellists, 15PFSY achieved a significantly (p

PURPOSE: The 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. METHODS: Acute 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. RESULTS: The 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. CONCLUSIONS: Our 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.

A 60-year-old male patient admitted to our clinic with complaints of decreased vision, nyctalopia, and metamorphopsia in both eyes, mainly in the left eye. The best-corrected visual acuity was determined as 20/25 on the right and 20/200 on the left eye with the Snellen chart. Anterior segment examination was normal. Fundus examination revealed chorioretinal atrophic areas and bone spicules around all vascular arcades in both eyes. Optical coherence tomography displayed normal foveal architecture in the right eye; however, retinal pigment epithelial detachment, intraretinal cysts, subretinal fluid, and subretinal hyperreflective material were detected in the left eye. Examination findings and fluorescein angiography were supported by visual field and electrophysiological tests, and the patient was diagnosed as pigmented paravenous chorioretinal atrophy (PPCRA) with Type 1 macular neovascularization. We aimed to present the co-occurrence of PPCRA and macular neovascularization to the best of our knowledge, which has not been reported previously. [ABSTRACT FROM AUTHOR]

Precise genetic diagnosis in RPE65-mediated retinitis pigmentosa (RP) is necessary to establish eligibility for genetic treatment with voretigene neparvovec: a recombinant adeno-associated viral vector providing a functional RPE65 gene. This case report aims to report a novel RP-related point mutation RPE65 c.353G>A, p.(Arg118Lys), a variant of uncertain significance associated with a severe clinical presentation and the striking phenotypic feature of complete macular atrophy. We report the case of a 40-year-old male with inherited retinal dystrophy, all features typical for the RPE65-associated RP, and marked macular atrophy. Genetic testing identified that the patient was a compound heterozygote in trans form with two heterozygous variants: RPE65 c.499G>T, p.(Asp167Tyr) and RPE65 c.353G>A, p.(Arg118Lys). Furthermore, short-wavelength and near-infrared autofluorescence patterns exhibited deficiencies specific to mutations in the visual cycle genes. To the best of our knowledge, RPE65 c.353G>A, p.(Arg118Lys) is the first described point mutation on this locus, among all other reported insertional mutations, currently classified as likely benign and of uncertain significance. We concluded that this variant contributed to the pathological phenotype, demonstrating its significance clearly to be reclassified as likely pathogenic. This being the case, patients with this specific variant in homozygous or compound heterozygous form would be likely candidates for genetic treatment with voretigene neparvovec. [ABSTRACT FROM AUTHOR]

Inherited retinal dystrophies (IRDs) are a heterogeneous group of degenerative disorders of the retina. Retinitis Pigmentosa (RP) is a common type of IRD that causes night blindness and loss of peripheral vision and may progress to blindness. Mutations in more than 300 genes have been associated with syndromic and non-syndromic IRDs. Recessive forms are more frequent in populations where endogamy is a social preference, such as Pakistan. The aim of this study was to identify molecular determinants of IRDs with the common presentation of night blindness in consanguineous Pakistani families. This study included nine consanguineous IRD-affected families that presented autosomal recessive inheritance of the night blindness phenotype. DNA was extracted from blood samples. Targeted exome sequencing of 344 known genes for retinal dystrophies was performed. Screening of nine affected families revealed two novel (c.5571_5576delinsCTAGATand c.471dup in EYS and SPATA7 genes, respectively) and six reported pathogenic mutations (c.304C>A, c.187C>T, c.1560C>A, c.547C>T, c.109del and c.9911_11550del in PDE6A, USH2A, USH2A, NMNAT1, PAX6 and ALMS1 genes, respectively) segregating with disease phenotype in each respective family. Molecular determinants of hereditary retinal dystrophies were identified in all screened families. Identification of novel variants aid future diagnosis of retinal dystrophies and help to provide genetic counseling to affected families. [ABSTRACT FROM AUTHOR]

A middle-aged homemaker, known sickle cell anaemia patient presented with complaints of reduced vision and night blindness since childhood along with recent-onset hearing impairment in both ears. Anterior segment findings revealed lens opacities more in the left eye, whereas fundus findings showed widespread bone spicule pigmentation in both eyes. Pure-tone audiometry indicated bilateral sensorineural hearing loss. With improvement in visual acuity after refraction, the corrective spectacle was prescribed along with a hearing aid. She presently maintains a follow-up appointment with the sickle cell, ophthalmology, and ear, nose, and throat clinics for a routine checkup. She has improved in her general health and has been crisis-free since the presentation.

Retinal dystrophies (RD) refer to a group of clinically and genetically heterogenous degenerative conditions of the retina. We aim to summarize emerging gene therapies for RD and their efficacy in restoring photoreceptor or bipolar cell functions. In patients with retinitis pigmentosa, injection of adeno-associated virus containing RPE65, RPGR or MERTK results in improvements in outcomes of the multi-luminal mobility test and full-field light sensitivity threshold test. In animal models of congenital stationary night blindness, gene augmentation of Cacn1f, LRIT3 or Nyx increases ON-bipolar cell signaling cascade and preserves retinal morphology. Patients with achromatopsia show improved visual acuity, contrast sensitivity, and cone responses after injection of a vector comprising CNGA3 or CNGB3. In patients with Leber congenital amaurosis, administration of a vector containing RPE65 or RDH12 results in improved full-field sensitivity to white light and photoreceptors responses, particularly in pediatric populations. Some patients have improved dark-adapted spectral sensitivities and pupillary light responses after injection of vectors. For choroideremia, REP1 gene therapy has been shown to improve visual acuity and retinal sensitivity. Nonetheless, voretigene neparvovec-ryzl (Luxturna) remains to be the only approved gene therapy in patients with biallelic RPE65 mutation. In the Chinese population, RPGR, Lrit3, Nyx, CNGA3, RPE65, RDH12, and CHM gene therapies may be beneficial, because the mutated genes are compatible with the genes investigated in previous clinical trials. A thorough understanding of gene therapies for different RD subtypes may allow more personalized management of retinal degeneration. [ABSTRACT FROM AUTHOR]

Vitamin A deficiency is highly prevalent and remains the major cause of nutritional blindness in children in low-and middle-income countries, despite supplementation programmes. Xeropthalmia (severe drying and thickening of the conjunctiva) is caused by vitamin A deficiency and leads to irreversible blindness. Vitamin A supplementation programmes effectively reduce vitamin A deficiency but many rural children are not reached. Home food production may help prevent rural children's vitamin A deficiency. We aimed to systematically review trials assessing effects of home food production (also called homestead food production and agricultural interventions) on xeropthalmia, nightblindness, stunting, wasting, underweight and mortality (primary outcomes). We searched Medline, Embase, Scopus, Cochrane CENTRAL and trials registers to February 2019. Inclusion of studies, data extraction and risk of bias were assessed independently in duplicate. Random-effects meta-analysis, sensitivity analyses, subgrouping and GRADE were used. We included 16 trials randomizing 2498 children, none reported xerophthalmia, night-blindness or mortality. Home food production may slightly reduce stunting (mean difference (MD) 0.13 (z-score), 95% CI 0.01 to 0.24), wasting (MD 0.05 (z-score), 95% CI −0.04 to 0.14) and underweight (MD 0.07 (z-score), 95% CI −0.01 to 0.15) in young children (all GRADE low-consistency evidence), and increase dietary diversity (standardized mean difference (SMD) 0.24, 95% CI 0.15 to 0.34). Home food production may usefully complement vitamin A supplementation for rural children. Large, long-duration trials with good randomization, allocation concealment and correct adjustment for clustering are needed to assess effectiveness of home food production on nutritional blindness in young children. [ABSTRACT FROM AUTHOR]

Our robust visual experience is based on the reliable transfer of information from our photoreceptor cells, the rods and cones, to higher brain centers. At the very first synapse of the visual system, information is split into two separate pathways, ON and OFF, which encode increments and decrements in light intensity, respectively. The importance of this segregation is borne out in the fact that receptive fields in higher visual centers maintain a separation between ON and OFF regions. In the past decade, the molecular mechanisms underlying the generation of ON signals have been identified, which are unique in their use of a G-protein signaling cascade. In this review, we consider advances in our understanding of G-protein signaling in ON-bipolar cell (BC) dendrites and how insights about signaling have emerged from visual deficits, mostly night blindness. Studies of G-protein signaling in ON-BCs reveal an intricate mechanism that permits the regulation of visual sensitivity over a wide dynamic range.

BackgroundCongenital stationary night-blindness (CSNB) is a recessive autosomal defect in low-light vision in Appaloosa and other horse breeds. This condition has been mapped by linkage analysis to a gene coding for the Transient Receptor Potential cation channel Member 1 (TRPM1). TRPM1 is normally expressed in the ON-bipolar cells of the inner nuclear layer of the retina. Down-regulation of TRPM1 expression in CSNB results from a transposon-like insertion in intron 1 of the TRPM1 gene. Stop transcription signals in this transposon significantly reduce TRPM1 primary transcript levels in CSNB horses. This study describes additional contributions by a second mutation of the TRPM1 gene, the ECA1 108,249,293 C > T SNP, to down-regulation of transcription of the TRPM1 gene in night-blind horses. This TRPM1 SNP introduces a consensus binding site for neuro-oncological ventral antigen 1 (Nova-1) protein in the primary transcript. Nova-1 binding disrupts normal splicing signals, producing unstable, non-functional mRNA transcripts.ResultsRetinal bipolar cells express both TRPM1 and Nova-1 proteins. In vitro addition of Nova-1 protein retards electrophoretic migration of TRPM1 RNA containing the ECA1 108,249,293 C > T SNP. Up-regulating Nova-1 expression in primary cultures of choroidal melanocytes carrying the intron 11 SNP caused an average log 2-fold reduction of ~6 (64-fold) of TRPM1 mRNA expression.ConclusionsThese finding suggest that the equine TRPM1 SNP can act independently to reduce survival of TRPM1 mRNA escaping the intron 1 transcriptional stop signals in CSNB horses. Coexistence and co-inheritance of two independent TRPM1 mutations across 1000 equine generations suggests a selective advantage for the apparently deleterious CSNB trait.