Search Results (101)

Retinitis pigmentosa is a group of inherited retinal dystrophies characterized by progressive photoreceptor cell loss leading to irreversible vision loss. Affecting approximately 1 in 4000 individuals worldwide, retinitis pigmentosa exhibits significant genetic heterogeneity, with mutations in genes such as RHO, PRPF31, RPE65, USH2A, and NR2E3, which contribute to its diverse clinical presentation. This review outlines the genetic basis of retinitis pigmentosa and explores cutting-edge gene-based therapeutic strategies. Luxturna (voretigene neparvovec-rzyl), the first FDA-approved gene therapy targeting RPE65 mutations, represents a milestone in precision ophthalmology, while OCU400 is a gene-independent therapy that uses a modified NR2E3 construct to modulate retinal homeostasis across different RP genotypes. Additionally, CRISPR–Cas genome-editing technologies offer future potential for the personalized correction of specific mutations, though concerns about off-target effects and delivery challenges remain. The article also highlights MCO-010, a novel optogenetic therapy that bypasses defective phototransduction pathways, showing promise for patients regardless of their genetic profile. Moreover, QR-1123, a mutation-specific antisense oligonucleotide targeting the P23H variant in the RHO gene, is under clinical investigation for autosomal dominant RP and has shown encouraging preclinical results in reducing toxic protein accumulation and preserving photoreceptors. SPVN06, another promising candidate, is a mutation-agnostic gene therapy delivering RdCVF and RdCVFL via AAV to support cone viability and delay degeneration, currently being evaluated in a multicenter Phase I/II trial for patients with various rod–cone dystrophies. Collectively, these advances illustrate the transition from symptom management toward targeted, mutation-specific therapies, marking a major advancement in the treatment of RP and inherited retinal diseases. Full article

Background: The prevalence of foveal hypoplasia in different inherited retinal diseases (IRDs) has not been compared in a large patient cohort. We aimed to investigate the prevalence and visual significance of foveal hypoplasia in IRDs. Methods: Participants included patients with IRDs and control subjects. All patients had macular optical coherence tomography (OCT). Results: Among our 357 patients, 123 had rod-cone dystrophy (34.5%), 22 had cone/cone-rod dystrophy (6.2%), 30 had macular dystrophy (8.4%), and 182 (51%) were controls. Having a phenotype of rod-cone (OR = 12.9, p < 0.001) or cone/cone-rod dystrophy (OR = 10.2, p < 0.001) was associated with higher odds of having foveal hypoplasia. Males had higher odds of having foveal hypoplasia (OR = 2.4, p = 0.006). The prevalence of foveal hypoplasia in the retinitis pigmentosa GTPase regulator (RPGR) group (8/15 (53.3%)) was significantly higher than in matched controls (0/15, 0.0%) (p = 0.002). Atypical foveal hypoplasia had the highest LogMAR of 0.50 (±0.37), which was higher than grade one 0.16 (±0.17) (p = 0.038). Grade one LogMAR was not different from normal fovea 0.20 (±0.28) (p = 0.572). Conclusions: We report that rod-cone and cone/cone-rod IRDs are associated with foveal hypoplasia. Based on our findings, detection of foveal hypoplasia in a patient with reduced vision should prompt consideration of an IRD. Full article

Bardet–Biedl syndrome (BBS) is a rare multisystem ciliopathy characterized by early-onset retinal degeneration and other vision-threatening ophthalmologic manifestations. This review synthesizes current knowledge on the ocular phenotype of BBS as well as emerging therapeutic approaches aimed at preserving visual function. Retinal degeneration, particularly early macular involvement and rod–cone dystrophy, remains the hallmark of BBS-related vision loss. Additional ocular manifestations, such as refractive errors, nystagmus, optic nerve abnormalities, and cataracts further contribute to visual morbidity. Experimental therapies—including gene-based interventions and pharmacologic strategies such as nonsense suppression and antioxidant approaches—have shown promise in preclinical models but require further validation. Early ophthalmologic care, including routine visual assessments, refractive correction, and low-vision rehabilitation, remains the standard of management. However, there are currently no effective therapies to halt or reverse retinal degeneration, which underscores the importance of emerging molecular and genetic interventions. Timely recognition and comprehensive ophthalmologic evaluation are essential to mitigate visual decline in BBS. Future efforts should focus on translating these approaches into clinical practice, enhancing early diagnosis, and promoting multidisciplinary collaboration to improve long-term outcomes for patients with BBS. Full article

The Na,K-ATPase is a heterodimeric ion pump consisting of various combinations of a catalytic α-subunit (α1, α2, α3, or α4, encoded by ATP1A1–ATP1A4) and a β-subunit (β1, β2, or β3, encoded by ATP1B1–ATP1B3). We have previously shown that Atp1b2 knock-out (ko) mice exhibit rapid photoreceptor cell degeneration, whereas Atp1b2^Atp1b1 knock-in (ki) mice, which express the β1-subunit instead of the β2-subunit under regulatory elements of the Atp1b2 gene, exhibit slowly progressive retinal dystrophy. Here, we performed a detailed analysis of the retinal phenotype of the Atp1b2^Atp1b1 ki mouse. We found that the number of cone photoreceptor cells in the mutant retinas was significantly reduced by postnatal day 28. The retinas of 4-month-old mice were almost devoid of cones. The early onset and rapid loss of cones was followed by a slowly progressive degeneration of rods. Other retinal cell types were unaffected. Nonradioactive in situ hybridization and immunohistochemistry revealed that wild-type photoreceptors expressed β3 and high levels of β2, while Atp1b2^Atp1b1 ki photoreceptor cells expressed β3 and low levels of transgenic β1. Additionally, levels of retinoschisin, a secreted retina-specific protein that interacts directly with the β2-subunit, were greatly reduced in mutant retinas. The results demonstrate that the β1-subunit can functionally compensate, at least in part, for the absence of the β2-subunit. The results also show that cones are more susceptible to Na,K-ATPase dysfunction than rods. Taken together, the present study identifies the Atp1b2^Atp1b1 ki mutant as a novel animal model of an early-onset and rapidly progressive cone–rod dystrophy. Full article

In the past, only Oguchi disease was reported as a hereditary retinal disease from Japan. Dr. Chuuta Oguch was a Professor of Nagoya University in Japan. During the past 40 years, four new clinical entities in hereditary retinal disorders have been detected by the Miyake group from Nagoya, Japan. All disorders show essentially normal fundi, and the diagnosis was made mainly by the analysis of an electroretinogram (ERG). Gene mutations are detected in three of them. Bipolar cell (BP) dysfunction syndrome: Congenital stationary night blindness (CSNB) with negative ERG (a-wave is larger than b-wave) was named as the Schubert–Bornschein type in 1952 and considered to be an independent clinical entity. In 1986, Miyake group classified ninety patients with the Schubert–Bornschein type into two types (complete and incomplete type). The complete type of CSNB (CSNB1) showed no rod function, but the incomplete type CSNB (CSNB2) showed remaining rod function in both subjective dark adaptation and rod ERG. In order to investigate the pathogenesis, these two types of CSNB were analyzed by comparing the monkey ERGs using different glutamate analogs to the retina. The ERG analysis demonstrated that CSNB1 has a complete functional defect in the ON type BP, while CSNB2 has incomplete functional defects in the ON and OFF type BP in both rod and cone visual pathways. Evidence of several different genetic heterogeneities was reported in both diseases, indicating CSNB1 and CSNB2 are independent clinical entities. Another entity, showing total complete defect of both ON and OFF BP, was detected in 1974 and was reported by Miyake group in a brother and younger sister, showing severe photophobia, nystagmus, extremely low visual acuity, and disappearance of color vision (total color blindness). This disorder is a congenital stational condition, and subjective visual functions were severely deteriorated from birth but remained unchanged through life. This disease was termed “Total complete bipolar cell dysfunction syndrome (CSNB3)”. The relationship between BP and subjective visual function was unknown. These three kinds of BP diseases can provide information on how BP relates to subjective visual functions. Occult macular dystrophy (OMD): Occult macular dystrophy (OMD) was discovered by Miyake group in 1989. This disease shows an unusual, inherited macular dystrophy characterized by progressive decrease visual acuity due to macular dysfunction, but the fundus and fluorescein angiography are essentially normal. The full-field rod and cone ERG do not show any abnormality, but the focal macular ERG (FERG) or multifocal ERG is abnormal and the only method for diagnosis. Many pedigrees of this disorder suggest autosomal dominant heredity, showing a genetic mutation of RP1L1. This disease was termed “occult macular dystrophy”. “Occult” means “hidden from sight”. Recently, it has been called “Miyake disease”. Full article

Dark adaptometry is a non-invasive functional test that assesses the retina’s ability to recover sensitivity in low-light conditions following photobleaching. This review explores the physiological mechanisms underlying dark adaptation (DA), including photopigment regeneration and the critical role of the retinal pigment epithelium in the visual cycle. We detail clinical protocols for dark adaptometry using modern instruments such as the AdaptDx, highlighting methodological advances that improve testing efficiency and reproducibility. The clinical utility of dark adaptometry is examined across a range of inherited and acquired retinal disorders, including age-related macular degeneration (AMD), retinitis pigmentosa (RP), Stargardt disease, diabetic retinopathy (DR), cone–rod dystrophy (CRD), vitamin A deficiency, and congenital stationary night blindness (CSNB). Dark adaptometry has emerged as a sensitive biomarker capable of detecting functional deficits before structural changes are evident, making it a valuable tool for early diagnosis and monitoring disease progression. However, limitations such as age-related variability, patient compliance, and lack of standardization remain challenges to broader clinical adoption. Continued refinement of dark adaptometry protocols and instrumentation is essential to maximize its diagnostic potential in ophthalmic practice. Full article

Color vision is a critical aspect of human visual perception, yet traditional assessments often lack quantitative precision. The Rabin Cone Contrast Test and its successors offer objective, standardized measurements of cone-specific contrast sensitivity. These tests improve the detection and classification of color vision deficiencies and can facilitate the monitoring of color vision deficits in inherited retinal diseases, cone dystrophies, optic neuropathies, and brain injuries. Integrating quantitative color vision testing into clinical practice presents a more reliable, reproducible, and functionally relevant evaluation, highlighting its value in disease diagnosis, characterization, and management. Full article

O-mannosylation is a post-translational modification required for the proper function of various proteins and critical for development and growth. POMGNT1 encodes the enzyme O-linked-mannose β-1,2-N-acetylglucosaminyltransferase 1, which catalyzes the second step in the synthesis of α-dystroglycan O-mannosyl glycans. Among POMGNT1-related α-dystroglycanopathies, muscle–eye–brain (MEB) disease presents with congenital muscular dystrophy, structural brain abnormalities, and retinal dystrophy. Defects in protein O-mannosylation due to biallelic loss-of-function POMGNT1 mutations produce disturbances in assembling and organizing the basal membrane in the neuroretinal system, involving both the central and peripheral nervous systems. In the retina, POMGNT1 is expressed in photoreceptors and is localized near the photoreceptor cilium basal body, a structure critical for protein transport. Recent studies have reported an isolated degenerative ocular phenotype without any involvement of muscular or neuronal tissues. Here, we report on a family with three siblings affected by an apparently isolated clinically variable retinal disease and sharing biallelic inactivating POMGNT1 variants. Notably, the rod-cone dystrophy phenotype in the three siblings varied significantly in onset, presentation, and severity. These findings provide further evidence of the clinical variability associated with defective POMGNT1 function. Full article

Biallelic pathogenic variants in the CRB1 gene are associated with severe retinal dystrophies, including early onset severe retinal dystrophy/Leber congenital amaurosis (EOSRD/LCA), retinitis pigmentosa (RP), cone–rod dystrophy (CORD), and macular dystrophy (MD). Despite growing research, scant genotype–phenotype correlations have been established. Here, we present two cases involving individuals that presented with cystoid macular oedema and high intraocular pressure, which were later diagnosed as CRB1-MD, demonstrating a mild and stable phenotype. Two unrelated patients of African heritage were included, a 7-year-old female (case 1) and a 25-year-old female (case 2), both presenting with ocular hypertension and cystoid macular oedema. Case 2 had a history of bilateral plateau iris, treated with laser iridotomy. Baseline visual acuity for case 1 was 0.66 logMAR in the right eye and 0.54 logMAR in the left eye. For case 2, visual acuity was recorded as 0.30 logMAR in both eyes. Genetic testing confirmed a homozygous c.2506C>A p.(Pro836Thr) variant in the CRB1 gene in both cases. Longitudinal follow-up over seven years revealed stable visual acuity, improvement of cystoid macular oedema, and effective intraocular pressure control with topical ocular hypotensive therapy. This study establishes a novel genotype–phenotype correlation between the c.2506C>A p.(Pro836Thr) variant and MD, suggesting a mild, stable disease course in homozygous cases. The findings also highlight a potential association of this variant with elevated IOP, expanding the clinical spectrum of CRB1-related ocular conditions. Early genetic diagnosis and regular ophthalmic monitoring are essential to optimise management and identify therapeutic opportunities in patients with mild CRB1-related phenotypes. Full article

Background: Usher syndrome (USH), the most common cause of combined deaf-blindness, is a genetically and phenotypically heterogeneous disorder characterized by congenital hearing impairment and progressive vision loss due to rod-cone dystrophy. Although the original classification in three subtypes (USH I, USH II, and USH III) is still valid, recent findings have changed and widened perspectives in its classification, genotype–phenotype correlations, and management strategies: Objective: This study aims to provide new insights into the classification of Usher syndrome, explore the genotype-phenotype correlations, and review current and emerging management strategies. Methods: A comprehensive literature review has been conducted, incorporating data from clinical studies, genetic databases, and patient registries. Results: Recent studies have led to the identification of several novel pathogenic variants in the USH genes, leading to refined subclassifications of Usher syndrome. Interactions between different genes being part of the network of this ciliopathy have been investigated and new mechanisms unveiled. Significant correlations were found between certain genotypes and the presentation of both auditory and visual phenotypes. For instance, pathogenic variants in the MYO7A gene (USH1B) were generally associated with more severe hearing impairment and earlier onset of retinal dystrophy, if compared to other USH genes-related forms. Other genes, such as USH1G, traditionally considered as causing a specific subtype, can display phenotypic heterogeneity in some patients. Conclusions: This review provides insights into a better understanding of Usher syndrome that considers recent findings regarding its genetic causes and clinical features. Precise genotype–phenotype correlations can lead to better genetic counselling, more precise characterization of the natural history of the condition, and a personalized and effective management approach. Recent progress has been made in research into gene-specific therapies that appear promising for improving the quality of life for individuals affected by Usher syndrome. Full article

Goldmann–Favre syndrome (GFS) is a rare vitreoretinal degenerative disorder caused by mutations in the NR2E3 gene located on the short arm of chromosome 15. This condition, inherited in an autosomal recessive manner, was first described by Favre in two siblings, with Ricci later confirming its hereditary pattern. In GFS, rod photoreceptors are essentially replaced by S-cone photoreceptors. Enhanced S-Cone Syndrome (ESCS) and Goldmann–Favre syndrome are two distinct entities within the spectrum of retinal degenerative diseases, both caused by mutations in the NR2E3 gene. Despite sharing a common genetic basis, these conditions exhibit significantly different clinical phenotypes. ESCS is characterized by an excessive number of S-cones (blue-sensitive cones) with degeneration of rods and L-/M-cones, leading to increased sensitivity to blue light and early-onset night blindness. In contrast, GFS is considered a more severe form of ESCS, involving additional features such as retinal schisis, vitreous degeneration, and more pronounced visual impairment. GFS typically manifests in the first decade of life as night blindness (nyctalopia) and progressive visual acuity impairment. The clinical features include degenerative vitreous changes such as liquefaction, strands, and bands, along with macular and peripheral retinoschisis, posterior subcapsular cataract, atypical pigmentary dystrophy, and markedly abnormal or nondetectable electroretinograms (ERGs). Although peripheral retinoschisis is more common in GFS, central retinoschisis may also occur. Despite the consistent genetic basis, the phenotype of GFS can vary significantly among individuals. The differential diagnosis should consider diseases within the retinal degenerative spectrum, including retinitis pigmentosa, congenital retinoschisis, and secondary pigmentary retinopathy. Full article

Background: A cross-sectional study was conducted at Moorfields Eye Hospital, UK, involving patients with CRB1-associated retinopathies: macular dystrophy (MD), cone-rod dystrophy (CORD), and early-onset severe retinal dystrophy/Leber congenital amaurosis (EOSRD/LCA). The study aimed to evaluate CRB1-associated retinopathies using microperimetry (macular integrity assessment (S-MAIA) fast protocol) and spectral domain optical coherence tomography (SD-OCT). Methods: Data quality and participant attrition were assessed in 18 patients (10 MD, 5 EOSRD/LCA, 3 CORD), aged 10–52 years, with a median best corrected visual acuity (BCVA) of 0.41 logMAR. Results: Microperimetry and SD-OCT data were obtained from 14 and 18 patients, respectively, but eccentric fixation hindered structure-function analysis. All participants showed overall abnormal sensitivity on the S-MAIA fast protocol. Parafoveal volume was significantly increased, while foveal thickness and volume were reduced compared to normative data (p < 0.01). Conclusions: This study highlights the challenges of participant attrition and the need for alternative functional metrics to complement traditional evaluations. It also reinforces previous findings of abnormal retinal architecture in CRB1-associated retinopathies, providing further insights into S-MAIA and SD-OCT assessments for this patient population. Full article

Near-infrared autofluorescence (NIA) is a non-invasive retinal imaging technique used to examine the retinal pigment epithelium (RPE) based on the autofluorescence of melanin. Melanin has several functions within RPE cells. It serves as a protective antioxidative factor and is involved in the phagocytosis of photoreceptor outer segments. Disorders affecting the photoreceptor–RPE complex result in alterations of RPE cells which are detectable by alterations of NIA. NIA allows us to detect early alterations in various chorioretinal disorders, frequently before they are ophthalmoscopically visible and often prior to alterations in lipofuscin-associated fundus autofluorescence (FAF) or optical coherence tomography (OCT). Although NIA and FAF relate to disorders affecting the RPE, the findings for both imaging methods differ and the area involved has been demonstrated to be larger in NIA compared to FAF in several disorders, especially inherited retinal dystrophies (IRDs), indicating that NIA detects earlier alterations compared to FAF. Foveal alterations can be much more easily detected using NIA compared to FAF. A reduced subfoveal NIA intensity is the earliest sign of autosomal dominant Best disease, when FAF and OCT are still normal. In other IRDs, a preserved subfoveal NIA intensity is associated with good visual acuity. So far, the current knowledge on NIA in IRD has been presented in multiple separate publications but has not been summarized in an overview. This review presents the current knowledge on NIA in IRD and demonstrates NIA biomarkers. Full article

Inherited retinal dystrophies (IRDs) are a common cause of blindness or severe visual impairment in children and may occur with or without systemic associations. The aim of the present study is to describe the phenotypic and genotypic spectrum of IRDs in a pediatric patient cohort in Retrospective single-center cross-sectional analysis. Presenting symptoms, clinical phenotype, and molecular genetic diagnosis were assessed in 309 pediatric patients with suspected IRD. Patients were grouped by age at genetic diagnosis (preschool: 0–6 years, n = 127; schoolchildren: 7–17 years, n = 182). Preschool children most frequently presented with nystagmus (34.5% isolated, 16.4% syndromic), no visual interest (20.9%; 14.5%), or nyctalopia (22.4%; 3.6%; p < 0.05); schoolchildren most frequently presented with declining visual acuity (31% isolated, 21.1% syndromic), nyctalopia (10.6%; 13.5%), or high myopia (5.3%; 13.2%). Pathogenic variants were identified in 96 different genes (n = 69 preschool, n = 73 schoolchildren). In the preschool group, 57.4% had isolated and 42.6% had syndromic IRDs, compared to 70.9% and 29.1% in schoolchildren. In the preschool group, 32.4% of the isolated IRDs were related to forms of Leber’s congenital amaurosis (most frequent were RPE65 (11%) and CEP290 (8.2%)), 31.5% were related to stationary IRDs, 15.1% were related to macular dystrophies (ABCA4, BEST1, PRPH2, PROM1), and 8.2% to rod–cone dystrophies (RPGR, RPB3, RP2, PDE6A). All rod–cone dystrophies (RCDs) were subjectively asymptomatic at the time of genetic diagnosis. At schoolage, 41% were attributed to cone-dominated disease (34% ABCA4), 10.3% to BEST1, and 10.3% to RCDs (RP2, PRPF3, RPGR; IMPG2, PDE6B, CNGA1, MFRP, RP1). Ciliopathies were the most common syndromic IRDs (preschool 37%; schoolchildren 45.1%), with variants in USH2A, CEP290 (5.6% each), CDH23, BBS1, and BBS10 (3.7% each) being the most frequent in preschoolers, and USH2A (11.7%), BBS10 (7.8%), CEP290, CDHR23, CLRN1, and ICQB1 (3.9% each) being the most frequent in syndromic schoolkids. Vitreoretinal syndromic IRDs accounted for 29.6% (preschool: COL2A1, COL11A1, NDP (5.6% each)) and 23.5% (schoolage: COL2A1, KIF11 (9.8% each)), metabolic IRDs for 9.4% (OAT, HADHA, MMACHD, PMM2) and 3.9% (OAT, HADHA), mitochondriopathies for 3.7% and 7.8%, and syndromic albinism accounted for 5.6% and 3.9%, respectively. In conclusion we show here that the genotypic spectrum of IRDs and its quantitative distribution not only differs between children and adults but also between children of different age groups, with an almost equal proportion of syndromic and non-syndromic IRDs in early childhood. Ophthalmic screening visits at the preschool and school ages may aid even presymptomatic diagnosis and treatment of potential sight and life-threatening systemic sequelae. Full article

Bardet–Biedl syndrome (BBS) is a genetic disease caused by mutations of the BBS genes that encode proteins involved in cilia functioning. It can present with major and/or minor clinical manifestations, such as rod–cone dystrophy, polydactyly, obesity, speech delay, anosmia, congenital heart disease and genital and renal abnormalities. Diagnosis of this rare disease is based on clinical criteria and can be confirmed with molecular genetic testing. Although BBS is a ciliopathy, nasal polyposis has never before been reported in patients with this condition. This article presents the case of a 12-year-old male patient admitted with symptoms of retinopathy, development delay, anosmia, bifid epiglottis and recurrent nasal polyposis. After several clinical, imaging and genetic examinations, the patient was diagnosed with BBS. His nasal symptoms were treated with functional endoscopic sinus surgery and long-term antibiotic therapy, whereas courses of topical antibiotics as well as topical and systemic corticosteroids had no effect. As a conclusion, it is a rare case that presents new clinical manifestations (nasal polyps) that can be related to BBS and possible effective treatments. Full article