Purpose: To quantify relevant fundus autofluorescence (FAF) image features cross-sectionally and longitudinally in a large cohort of inherited retinal diseases (IRDs) patients. Design: Retrospective study of imaging data (55-degree blue-FAF on Heidelberg Spectralis) from patients. Participants: Patients with a clinical and molecularly confirmed diagnosis of IRD who have undergone FAF 55-degree imaging at Moorfields Eye Hospital (MEH) and the Royal Liverpool Hospital (RLH) between 2004 and 2019. Methods: Five FAF features of interest were defined: vessels, optic disc, perimacular ring of increased signal (ring), relative hypo-autofluorescence (hypo-AF) and hyper-autofluorescence (hyper-AF). Features were manually annotated by six graders in a subset of patients based on a defined grading protocol to produce segmentation masks to train an AI model, AIRDetect, which was then applied to the entire imaging dataset. Main Outcome Measures: Quantitative FAF imaging features including area in mm 2 and vessel metrics, were analysed cross-sectionally by gene and age, and longitudinally to determine rate of progression. AIRDetect feature segmentation and detection were validated with Dice score and precision/recall, respectively. Results: A total of 45,749 FAF images from 3,606 IRD patients from MEH covering 170 genes were automatically segmented using AIRDetect. Model-grader Dice scores for disc, hypo-AF, hyper-AF, ring and vessels were respectively 0.86, 0.72, 0.69, 0.68 and 0.65. The five genes with the largest hypo-AF areas were CHM , ABCC6 , ABCA4 , RDH12 , and RPE65 , with mean per-patient areas of 41.5, 30.0, 21.9, 21.4, and 15.1 mm 2 . The five genes with the largest hyper-AF areas were BEST1 , CDH23 , RDH12 , MYO7A , and NR2E3 , with mean areas of 0.49, 0.45, 0.44, 0.39, and 0.34 mm 2 respectively. The five genes with largest ring areas were CDH23 , NR2E3 , CRX , EYS and MYO7A, with mean areas of 3.63, 3.32, 2.84, 2.39, and 2.16 mm 2 . Vessel density was found to be highest in EFEMP1 , BEST1 , TIMP3 , RS1 , and PRPH2 (10.6%, 10.3%, 9.8%, 9.7%, 8.9%) and was lower in Retinitis Pigmentosa (RP) and Leber Congenital Amaurosis genes. Longitudinal analysis of decreasing ring area in four RP genes ( RPGR, USH2A, RHO, EYS ) found EYS to be the fastest progressor at -0.18 mm 2 /year. Conclusions: We have conducted the first large-scale cross-sectional and longitudinal quantitative analysis of FAF features across a diverse range of IRDs using a novel AI approach.
PURPOSE: To assess the impact of baseline data on psychophysical and morphological outcomes of subretinal voretigene neparvovec (VN) (Luxturna, Spark Therapeutics, Inc.) treatment. DESIGN: Single-center, retrospective, longitudinal, consecutive case series. PARTICIPANTS: Patients with RPE65-biallelic mutation-associated inherited retinal degeneration (RPE65-IRD) treated between February 2020 and March 2022 with VN and oral immunosuppression according to the manufacturer's recommendation by one surgeon (F.G.H.). METHODS: Retrospective analysis of surgical and clinical records, ancillary testing, and retinal imaging after VN therapy for RPE65-IRD. Descriptive statistics compared data at baseline up to 32 months post-treatment. MAIN OUTCOME MEASURES: Best-corrected visual acuity (BCVA), low-luminance VA (LLVA), Goldmann visual fields (GVFs), chromatic full-field stimulus threshold (FST) testing (FST), scotopic and photopic 2-color threshold perimetry (2CTP), and multimodal retinal imaging. RESULTS: Thirty eyes of 19 patients were analyzed (10 pediatric patients < 20 years; 20 adult patients > 20 years of age; overall range: 8-40 years) with a median follow-up of 15 months (range, 1-32). The fovea was completely or partially detached in 16 eyes, attached in 12 eyes, and not assessable in 2 eyes on intraoperative imaging. Median BCVA at baseline was better in the pediatric group (P < 0.05) and did not change significantly independent of age. Meaningful loss of BCVA (≥ 0.3 logarithm of the minimal angle of resolution [logMAR]) occurred in 5 of 18 adult eyes, and a meaningful gain (≥-0.3 logMAR) occurred in 2 of 18 adult and 2 of 8 pediatric eyes. The LLVA and scotopic 2CTP improved considerably in pediatric patients. Scotopic blue FST improved at all ages but more in pediatric patients (8/8 eyes gained ≥ 10 decibels [dB]; P < 0.05). In pediatric patients, median GVF improved by 20% for target V4e and by 50% for target III4e (target I4e not detected). Novel atrophy developed in 13 of 26 eyes at the site of the bleb or peripheral of vascular arcades. Improvements in FST did not correlate with development of chorioretinal atrophy at 12 months. Mean central retinal thickness was 165.87 µm (± 26.26) at baseline (30 eyes) and 157.69 µm (± 30.3) at 12 months (26 eyes). Eight adult patients were treated unilaterally. The untreated eyes did not show meaningful changes during follow-up. CONCLUSIONS: These data in a clinical setting show the effectiveness of VN therapy with stable median BCVA and mean retinal thickness and improvements of LLVA, FST, and 2CTP up to 32 months. Treatment effects were superior in the pediatric group. We observed new chorioretinal atrophy in 50% of the treated eyes. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Retina , Retinal Dystrophies , Adult , Humans , Child , Retrospective Studies , Retinal Dystrophies/diagnosis , Retinal Dystrophies/genetics , Retinal Dystrophies/therapy , Mutation , Atrophy
PURPOSE: To analyze changes in demographic parameters and retreatment patterns over a 10-year period in a clinical routine setting of infants with retinopathy of prematurity (ROP) requiring treatment documented in the German Retina.net ROP registry. DESIGN: Multicenter, noninterventional, observational registry study recruiting patients treated for ROP. SUBJECTS: A total of 692 eyes of 353 infants treated for ROP were documented in the Retina.net ROP registry over a 10-year period between 2011 and 2020. These cases cover about 15% of all infants treated for ROP in Germany. METHODS: The Retina.net ROP registry was established in 2012 to jointly collect information on infants treated for ROP. The database collects information on demographic parameters (gestational age [GA], birth weight, neonatal comorbidities) as well as treatment parameters (type of treatment, weight and age at treatment, and stage of ROP). A total of 19 centers contributed to the analysis. This is the 10-year analysis of data from 2011 to 2020, in which we focus on changes over time regarding the respective parameters. MAIN OUTCOME MEASURES: Changes over time in demographic parameters and treatment patterns for ROP in Germany. RESULTS: The overall incidence of treatment requiring ROP was 3.5% of all infants screened for ROP at participating centers. Gestational age, weight at birth, and weight at treatment remained stable over the 10-year period, whereas postmenstrual and postnatal age at treatment increased moderately but statistically significantly over the years. The most prevalent ROP severity stage at treatment was stage 3+ in zone II (76.6% of all treated eyes). Treatment patterns changed considerably from predominantly laser treatments in 2011 (75% of all treated eyes) to predominantly ranibizumab treatments in 2020 (60.9% of all treated eyes). The overall retreatment rate was 15.6%. Retreatment rates differed between initial treatment modalities (14.1% after laser coagulation, 12% after bevacizumab and 24.5% after ranibizumab). Treatment-associated systemic or ophthalmic complications were rare. CONCLUSIONS: This data analysis represents one of the largest documented cohorts of infants treated for ROP. The data on demographic parameters and treatment patterns provide useful information for further improvement of ROP management. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Angiogenesis Inhibitors , Gestational Age , Registries , Retinopathy of Prematurity , Humans , Retinopathy of Prematurity/epidemiology , Retinopathy of Prematurity/diagnosis , Germany/epidemiology , Infant, Newborn , Male , Female , Angiogenesis Inhibitors/administration & dosage , Angiogenesis Inhibitors/therapeutic use , Laser Coagulation/methods , Incidence , Follow-Up Studies , Intravitreal Injections , Retrospective Studies , Infant
BACKGROUND: Inherited retinal diseases (IRDs) refer to a heterogeneous group of rare disorders that potentially lead to blindness. Emerging therapeutic options have led to a growing interest in IRDs; however, there are insufficient systematic studies on IRDs in Germany characterizing the demographics and management in clinical practice. OBJECTIVE: To characterize the care for IRD patients in Germany, to assess the applied diagnostics, the use of databases and the implementation of education in ophthalmic genetics. METHODS: The anonymous online survey (SoSci Survey GmbH) was sent to all German ophthalmology departments listed on the website of the German Ophthalmological Society and to three practices focusing on IRDs. RESULTS: The overall response rate was 44.8%. Almost all institutions (93.6%) reported seeing IRD patients, but university and non-university hospitals differed in the number of patients. Databases are used in 60% of universities but only in 5.9% of non-university hospitals. Regarding the number of patients with genetic diagnostics, 53% of the non-university and 12% of the university sites reported that 20% at most of their patients had received a molecular genetic diagnosis. The results of the IRD practices are comparable with the university hospitals. Patients with biallelic RPE65 mutations-associated IRD, potential candidates for treatment with voretigene neparvovec (Luxturna®), were followed in 9/25 participating university departments. CONCLUSION: This survey highlights the deficits in the management of IRD patients. In particular, we found a clear difference between university and non-university hospitals in the rate of patients with known molecular genetic results. Improvements should be initiated in the latter, especially because of existing and emerging therapeutic options.
Genetic Therapy , Retinal Diseases , Humans , Universities , Genetic Therapy/methods , Retinal Diseases/diagnosis , Vision, Ocular , Germany/epidemiology
BACKGROUND/AIMS: To describe the patterns of pre-operative aberrant regeneration and motility outcomes reported in an international registry of patients with 3rd-nerve palsy treated with nasal transposition of the split lateral rectus muscle (NTSLR). METHODS: This cross-sectional study used data from an international, multicentre registry of patients with 3rd-nerve palsy treated with NTSLR. Patients with aberrant regeneration were identified, and patterns of innervation described. Demographics and postoperative success defined as horizontal alignment ≤15 PD were compared based on the presence, and type, of aberrant regeneration using Wilcoxon rank sum and Fisher's exact tests. RESULTS: Aberrant regeneration was reported in 16% (21/129) of patients. Age at diagnosis, sex, and aetiology of palsy were not significantly associated with aberrant regeneration. Abnormal movements were triggered by adduction in 52% (11/21), infraduction in 23% (5/21), and supraduction in 23% (5/21) of cases. Presentation patterns involved rectus muscle innervation in 29% (6/21) and levator muscle innervation in 71% (15/21) of cases. Although patients with aberrant regeneration had similar probability of success in comparison to those without following NTLSR (76% vs. 69%, p = 0.5), those with abnormal innervation of a rectus muscle had a lower success rate than those with abnormal innervation of the levator palpebrae superioris muscle (17% vs. 93%; p = 0.002). CONCLUSION: Successful treatment of a 3rd nerve palsy with NTSLR was not influenced by aberrant regeneration involving the levator muscle. Alternative surgical interventions should be considered when aberrant regeneration alters rectus muscle function given its adverse impact on motor outcomes with NTSLR.
The accurate localization of facial landmarks is essential for several tasks, including face recognition, head pose estimation, facial region extraction, and emotion detection. Although the number of required landmarks is task-specific, models are typically trained on all available landmarks in the datasets, limiting efficiency. Furthermore, model performance is strongly influenced by scale-dependent local appearance information around landmarks and the global shape information generated by them. To account for this, we propose a lightweight hybrid model for facial landmark detection designed specifically for pupil region extraction. Our design combines a convolutional neural network (CNN) with a Markov random field (MRF)-like process trained on only 17 carefully selected landmarks. The advantage of our model is the ability to run different image scales on the same convolutional layers, resulting in a significant reduction in model size. In addition, we employ an approximation of the MRF that is run on a subset of landmarks to validate the spatial consistency of the generated shape. This validation process is performed against a learned conditional distribution, expressing the location of one landmark relative to its neighbor. Experimental results on popular facial landmark localization datasets such as 300 w, WFLW, and HELEN demonstrate the accuracy of our proposed model. Furthermore, our model achieves state-of-the-art performance on a well-defined robustness metric. In conclusion, the results demonstrate the ability of our lightweight model to filter out spatially inconsistent predictions, even with significantly fewer training landmarks.
BACKGROUND: Retinopathy of prematurity (ROP) is one of the most common causes of childhood blindness in Germany and worldwide and adequate screening is essential. The telemedical approach with objective documentation of retinal findings opens up the possibility of reliably diagnosing all ROP stages independent of the examiner, if a team of ophthalmologists specialized in ROP evaluates the images. OBJECTIVE: A 10-year comparison of ROP screening at two level1 neonatal intensive care units (NICU): university and on-site vs. non-university and telemedical. MATERIAL AND METHODS: Retrospective analysis of screened premature infants by gestational age (GA), birth weight (BW), sex, multiple births, time of ROP occurrence, treatment needs and time as well as examination frequency. RESULTS: From 2009 to 2019, we screened 1191 infants of whom 29 had been screened before by an external clinic. The internal 1162 infants were screened on-site with 3713 retinal examinations. We diagnosed 34% with ROP and treated 5.4% (3.7% in Giessen, 7.2% in Siegen). Mean GA was 28.9 weeks (±â¯2.5 weeks); mean BW 1155â¯g (±â¯417.5â¯g). The number of ROP diagnoses increased by 227.3% in Giessen and by 111.1% in Siegen due to the increasing number of premature births in neonatal care. CONCLUSION: Comparative analysis confirmed nationally and internationally increasing ROP screening and children with acute ROP. Telemedical screening was equivalent to on-site screening and safe. Both screening methods identified infants requiring treatment on time. No child with GA >â¯29 weeks required treatment, analogous to Swedish ROP registry results; however, in the German ROP registry some premature babies with GA ≥â¯30 weeks required treatment.
Intensive Care Units, Neonatal , Retinopathy of Prematurity , Infant, Newborn , Infant , Humans , Retinopathy of Prematurity/diagnosis , Retrospective Studies , Infant, Premature , Birth Weight
INTRODUCTION: The aim of this study was to evaluate the current management of RPE65 biallelic mutation-associated inherited retinal degeneration (RPE65-IRD) in Europe since market authorization of voretigene neparvovec (VN, LuxturnaTM) in 2018. By July 2022, over 200 patients have been treated outside the USA, of whom about 90% in Europe. We conducted among all centers of the European Vision Institute Clinical Research Network (
Quality of Life , Retinal Degeneration , Humans , Child, Preschool , Child , Adolescent , Young Adult , Adult , Middle Aged , Follow-Up Studies , Retinal Degeneration/genetics , Retinal Degeneration/therapy , Research Design , Europe , Mutation
INTRODUCTION: An increasing number of gene-specific therapies are being developed for inherited retinal degenerations (IRDs). Identification of well-characterized patients is an emerging need. We conducted the second multinational survey among the
Retinal Degeneration , Adult , Humans , Retinal Degeneration/diagnosis , Retinal Degeneration/genetics , Retinal Degeneration/therapy , Follow-Up Studies , Vision Tests , Research Design , Europe
BACKGROUND/AIMS: To determine success rate and complications associated with nasal transposition of the split lateral rectus muscle (NTSLR) for treating strabismus from 3rd-nerve palsy. METHODS: An international, multicentre, registry of patients with unilateral 3rd-nerve palsy treated with NTSLR was created. Patients with concurrent surgery on the contralateral eye were excluded. Primary outcome was horizontal alignment within 15 prism dioptres (PD) of orthotropia. Incidence of technical difficulties and vision-threatening complications by 6 months post-procedure were reported. RESULTS: Ninety-eight patients met inclusion criteria. Median age was 33.5 years (IQR 10.75-46). Aetiologies included congenital (31%), neoplastic (16%) and traumatic (15%). Twenty-five per cent of patients had prior ipsilateral strabismus surgery. Median exotropia decreased from 70PD preoperatively (IQR 50-90) to 1PD postoperatively (IQR 0-15.5), with a success rate of 69%. Performing concurrent superior oblique muscle tenotomy (SOT) was independently associated with success (p=0.001). Technical challenges occurred in 30% of cases, independently associated with a history of ipsilateral strabismus surgery (p=0.01). Eleven per cent of patients had vision-threatening complications, independently associated with more posterior placement of the split lateral rectus (LR) muscle (p<0.001), and most commonly transient serous choroidal effusion. Surgical placement of the split LR muscle within 4.25 mm of the medial rectus (MR) muscle insertion reduced this risk. CONCLUSION: NTSLR significantly improved primary position alignment altered by 3rd-nerve palsy. Concurrent SOT and placement of the split LR muscle ≤4.25 mm posterior to the MR muscle insertion optimised outcomes. NTSLR proved technically challenging when prior ipsilateral strabismus surgery had been performed.
Exotropia , Oculomotor Nerve Diseases , Strabismus , Humans , Adult , Oculomotor Muscles/surgery , Oculomotor Nerve Diseases/etiology , Oculomotor Nerve Diseases/surgery , Strabismus/etiology , Strabismus/surgery , Exotropia/surgery , Paralysis/complications , Paralysis/surgery , Ophthalmologic Surgical Procedures/methods , Retrospective Studies , Treatment Outcome , Vision, Binocular
OBJECTIVE: To quantify changes in ductions following nasal transposition of the split lateral rectus muscle (NTSLR) for treating third nerve palsy. DESIGN: Retrospective cohort study. PARTICIPANTS: A single eye from each patient with third nerve palsy treated with NTSLR with ocular motility measurements. METHODS: Observation of changes in pre- and postoperative ductions. Outcome measures including patient demographic and surgical factors associated with the ability to adduct beyond the midline after NTSLR were evaluated using multivariable logistic regression. RESULTS: A total of 116 patients met the inclusion criteria for this study. The NTSLR significantly decreased abduction (median of 0 limitation [interquartile range (IQR), 0-0] prior to surgery to -4 [IQR, -4 to -3] after NTSLR; p < 0.001), with a corresponding improvement in adduction (median, -5 [IQR, -5 to -4] prior to surgery to -4 [IQR, -4 to -3] after NTSLR; p < 0.001). There was no change in median supraduction or infraduction after NTSLR (p > 0.05). The ability to adduct beyond the midline after NTSLR was demonstrated in 42% of patients. Although not statistically significant, a trend toward a postoperative ability to adduct beyond the midline was seen in patients who had concurrent superior oblique muscle tenotomy (odds ratio [OR]â¯=â¯5.08; 95% CI, 0.91-40.9) or who were designated with partial rather than complete third nerve palsy (ORâ¯=â¯2.29; 95% CI, 0.82-6.70). CONCLUSIONS: NTSLR improves the horizontal midline positioning of eyes with third nerve palsy. Most eyes lose the ability to abduct, but some regain a modest ability to adduct while vertical ductions remain unchanged.
Oculomotor Nerve Diseases , Strabismus , Humans , Oculomotor Muscles/surgery , Retrospective Studies , Eye Movements , Nose , Oculomotor Nerve Diseases/diagnosis , Oculomotor Nerve Diseases/etiology , Oculomotor Nerve Diseases/surgery , Ophthalmologic Surgical Procedures , Strabismus/surgery
AIMS: The aim of the study was to evaluate the feasibility of ultra-widefield (UWF) imaging to identify ocular pathologies amongst in- and out-patients in a tertiary university hospital. METHODS: We followed a prospective double-blinded multicenter clinical study. In total, 634 patients from a university hospital with pulmonary, cardiovascular, and endocrine diseases were examined by two teams by conventional slit-lamp biomicroscopy (CBM). UWF images with Optos Tx200 were taken and subsequently graded independently by two retina specialists and graders from two reading centers for the presence of pre-defined pathologies. Interrater reliability was calculated using Fleiss statistical software. An independent, trained and certified ophthalmologist with retinal subspecialty (BL) classified all UWF images with retinal hemorrhages by severity and interrater agreement. RESULTS: Complete data were available for 502 patients. The Moorfields Eye Hospital Reading Center, London, UK (RM), reported the highest number of cases with retinal pathologies (378), and the Reading Center GRADE Bonn, Germany (RB), did so for cases with optic disc cupping (466). Two retinal consultants (R1 and R2) from the Department of Ophthalmology, University Hospital Giessen and Marburg GmbH, Campus Giessen, Germany, noted optic disc pathologies. R1 reported 151 cases with optic disc pallor, while R2 reported only 39 disc pathologies. Both for clinical and for image readers, the early changes had equally low interrater reliability. The presence of at least 3 retinal hemorrhages had the highest interrater reliability (0.59). CONCLUSIONS: UWF imaging is convenient to identify overt retinal pathologies in patients at risk of ocular complications of their systemic disease who are attending hospital clinics. Imaging the eye allows for remote retinal assessment and for placing the patient into the appropriate clinical pathway for ophthalmology. PRECIS: UWF-imaging in a population of in- and out-patients at a university hospital who are at risk of retinal complications is effective to detect overt retinal pathologies and allows for tele-ophthalmology approaches to be enabled for placing the patients into the appropriate clinical pathways.
Retina , Retinal Hemorrhage , Humans , Prospective Studies , Tertiary Healthcare , Reproducibility of Results , Retinal Hemorrhage/pathology , Feasibility Studies , Retina/diagnostic imaging , Retina/pathology , Hospitals , Fluorescein Angiography/methods
PURPOSE: To determine the success rate and complications associated with nasal transposition of the split lateral rectus muscle (NTSLR) for treating bilateral 3rd-nerve palsy. DESIGN: Retrospective, interventional case series. METHODS: An international, multicenter registry was used for the study. The study population was all patients with bilateral 3rd-nerve palsy treated with NTSLR. Sensorimotor evaluations were conducted before and 6 months after unilateral or bilateral NTSLR. Outcome measures were postoperative horizontal alignment ≤15 prism diopters (PD), intraoperative technical difficulties, and vision-threatening complications. The association of patient demographics and surgical technique with each outcome was analyzed using multivariable logistic regression. RESULTS: A total of 34 patients were included, with a median age of 46 years (interquartile range [IQR] = 25-54 years) at surgery. The most common etiologies were ischemic (29%), neoplastic (15%), and congenital (12%). NTSLR performed unilaterally with alternative surgery on the opposite eye (65%) resulted in a median postoperative exotropia of 18 PD (IQR = 7-35 PD), and when performed bilaterally (35%) resulted in postoperative exotropia of 14 PD (IQR = 5-35 PD). Success was achieved in 50% of cases, intraoperative technical difficulties were reported in 18%, and vision-threatening complications occurred in 21%. Attachment of the lateral rectus muscle ≥10 mm posterior to the medial rectus insertion was associated with increased vision-threatening complications (odds ratio = 9.0; 95% CI = 1.3-99). CONCLUSIONS: NTSLR can address the large-angle exotropia associated with bilateral 3rd-nerve palsy. Surgeons should be aware that posterior placement of the lateral rectus muscle may increase the risk of vision-threatening complications, particularly serous choroidal effusion.
Exotropia , Strabismus , Adult , Exotropia/surgery , Follow-Up Studies , Humans , Middle Aged , Oculomotor Muscles/surgery , Ophthalmologic Surgical Procedures/methods , Paralysis/surgery , Retrospective Studies , Strabismus/etiology , Strabismus/surgery , Treatment Outcome , Vision, Binocular/physiology
Blue cone monochromacy (BCM) is an X-linked retinal disorder characterized by low vision, photoaversion, and poor color discrimination. BCM is due to the lack of long-wavelength-sensitive and middle-wavelength-sensitive cone photoreceptor function and caused by mutations in the OPN1LW/OPN1MW gene cluster on Xq28. Here, we investigated the prevalence and the landscape of submicroscopic structural variants (SVs) at single-base resolution in BCM patients. We found that about one-third (n = 73) of the 213 molecularly confirmed BCM families carry an SV, most commonly deletions restricted to the OPN1LW/OPN1MW gene cluster. The structure and precise breakpoints of the SVs were resolved in all but one of the 73 families. Twenty-two families-all from the United States-showed the same SV, and we confirmed a common ancestry of this mutation. In total, 42 distinct SVs were identified, including 40 previously unreported SVs, thereby quadrupling the number of precisely mapped SVs underlying BCM. Notably, there was no "region of overlap" among these SVs. However, 90% of SVs encompass the upstream locus control region, an essential enhancer element. Its minimal functional extent based on deletion mapping in patients was refined to 358 bp. Breakpoint analyses suggest diverse mechanisms underlying SV formation as well as in one case the gene conversion-based exchange of a 142-bp deletion between opsin genes. Using parsimonious assumptions, we reconstructed the composition and copy number of the OPN1LW/OPN1MW gene cluster prior to the mutation event and found evidence that large gene arrays may be predisposed to the occurrence of SVs at this locus.
Color Vision Defects , Rod Opsins , Color Vision Defects/genetics , Gene Deletion , Humans , Multigene Family/genetics , Retinal Cone Photoreceptor Cells , Rod Opsins/genetics
Achromatopsia (ACHM) is a congenital cone photoreceptor disorder characterized by impaired color discrimination, low visual acuity, photosensitivity, and nystagmus. To date, six genes have been associated with ACHM (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, and ATF6), the majority of these being implicated in the cone phototransduction cascade. CNGA3 encodes the CNGA3 subunit of the cyclic nucleotide-gated ion channel in cone photoreceptors and is one of the major disease-associated genes for ACHM. Herein, we provide a comprehensive overview of the CNGA3 variant spectrum in a cohort of 1060 genetically confirmed ACHM patients, 385 (36.3%) of these carrying "likely disease-causing" variants in CNGA3. Compiling our own genetic data with those reported in the literature and in public databases, we further extend the CNGA3 variant spectrum to a total of 316 variants, 244 of which we interpreted as "likely disease-causing" according to ACMG/AMP criteria. We report 48 novel "likely disease-causing" variants, 24 of which are missense substitutions underlining the predominant role of this mutation class in the CNGA3 variant spectrum. In addition, we provide extensive in silico analyses and summarize reported functional data of previously analyzed missense, nonsense and splicing variants to further advance the pathogenicity assessment of the identified variants.
Color Vision Defects , Cyclic Nucleotide-Gated Cation Channels , Color Vision Defects/genetics , Cyclic Nucleotide-Gated Cation Channels/genetics , Humans , Mutation , Retinal Cone Photoreceptor Cells
Retinopathy of prematurity (ROP) is a leading cause of preventable childhood blindness. This proliferative retinal vascular disease affects only prematurely born infants. Major risk factors include low gestational age and prolonged postnatal oxygen supplementation. ROP screening allows for timely identification of treatment-requiring infants and thus significantly reduces the risk of severe visual impairment and blindness from ROP. Current treatment options comprise retinal laser coagulation and intravitreal anti-vascular endothelial growth factor (VEGF) therapy. We provide a review of scientific data and current treatment recommendations, with special attention to the updated German guideline on ROP screening, the statement of the German ophthalmological societies on anti-VEGF therapy of ROP, and the new third edition of the International Classification of Retinopathy of Prematurity (ICROP3).
Retinopathy of Prematurity , Child , Gestational Age , Humans , Infant , Infant, Newborn , Intravitreal Injections , Laser Coagulation , Retinopathy of Prematurity/diagnosis , Retinopathy of Prematurity/therapy , Vascular Endothelial Growth Factor A
PURPOSE: The International Classification of Retinopathy of Prematurity is a consensus statement that creates a standard nomenclature for classification of retinopathy of prematurity (ROP). It was initially published in 1984, expanded in 1987, and revisited in 2005. This article presents a third revision, the International Classification of Retinopathy of Prematurity, Third Edition (ICROP3), which is now required because of challenges such as: (1) concerns about subjectivity in critical elements of disease classification; (2) innovations in ophthalmic imaging; (3) novel pharmacologic therapies (e.g., anti-vascular endothelial growth factor agents) with unique regression and reactivation features after treatment compared with ablative therapies; and (4) recognition that patterns of ROP in some regions of the world do not fit neatly into the current classification system. DESIGN: Review of evidence-based literature, along with expert consensus opinion. PARTICIPANTS: International ROP expert committee assembled in March 2019 representing 17 countries and comprising 14 pediatric ophthalmologists and 20 retinal specialists, as well as 12 women and 22 men. METHODS: The committee was initially divided into 3 subcommittees-acute phase, regression or reactivation, and imaging-each of which used iterative videoconferences and an online message board to identify key challenges and approaches. Subsequently, the entire committee used iterative videoconferences, 2 in-person multiday meetings, and an online message board to develop consensus on classification. MAIN OUTCOME MEASURES: Consensus statement. RESULTS: The ICROP3 retains current definitions such as zone (location of disease), stage (appearance of disease at the avascular-vascular junction), and circumferential extent of disease. Major updates in the ICROP3 include refined classification metrics (e.g., posterior zone II, notch, subcategorization of stage 5, and recognition that a continuous spectrum of vascular abnormality exists from normal to plus disease). Updates also include the definition of aggressive ROP to replace aggressive-posterior ROP because of increasing recognition that aggressive disease may occur in larger preterm infants and beyond the posterior retina, particularly in regions of the world with limited resources. ROP regression and reactivation are described in detail, with additional description of long-term sequelae. CONCLUSIONS: These principles may improve the quality and standardization of ROP care worldwide and may provide a foundation to improve research and clinical care.
Retina/diagnostic imaging , Retinopathy of Prematurity/classification , Diagnostic Imaging , Disease Progression , Gestational Age , Humans , Infant, Newborn , Retinopathy of Prematurity/diagnosis
Infantile nystagmus syndrome (INS) denominates early-onset, involuntary oscillatory eye movements with different etiologies. Nystagmus is also one of the symptoms in oculocutaneus albinism (OCA), a heterogeneous disease mainly caused by defects in melanin synthesis or melanosome biogenesis. Dopachrome tautomerase (DCT, also called TYRP2) together with tyrosinase (TYR) and tyrosin-related protein 1 (TYRP1) is one of the key enzymes in melanin synthesis. Although DCT´s role in pigmentation has been proven in different species, until now only mutations in TYR and TYRP1 have been found in patients with OCA. Detailed ophthalmological and orthoptic investigations identified a consanguineous family with two individuals with isolated infantile nystagmus and one family member with subtle signs of albinism. By whole-exome sequencing and segregation analysis, we identified the missense mutation c.176G > T (p.Gly59Val) in DCT in a homozygous state in all three affected family members. We show that this mutation results in incomplete protein maturation and targeting in vitro compatible with a partial or total loss of function. Subsequent screening of a cohort of patients with OCA (n = 85) and INS (n = 25) revealed two heterozygous truncating mutations, namely c.876C > A (p.Tyr292*) and c.1407G > A (p.Trp469*), in an independent patient with OCA. Taken together, our data suggest that mutations in DCT can cause a phenotypic spectrum ranging from isolated infantile nystagmus to oculocutaneous albinism.
Albinism, Oculocutaneous/genetics , Intramolecular Oxidoreductases/genetics , Melanins/biosynthesis , Mutation, Missense , Nystagmus, Congenital/genetics , Adolescent , Albinism, Oculocutaneous/diagnosis , Albinism, Oculocutaneous/enzymology , Albinism, Oculocutaneous/pathology , Base Sequence , Calnexin/genetics , Calnexin/metabolism , Child , Cohort Studies , Consanguinity , Female , Gene Expression Regulation , HEK293 Cells , Homozygote , Humans , Intramolecular Oxidoreductases/deficiency , Male , Melanins/genetics , Membrane Glycoproteins/genetics , Membrane Glycoproteins/metabolism , Monophenol Monooxygenase/genetics , Monophenol Monooxygenase/metabolism , Nystagmus, Congenital/diagnosis , Nystagmus, Congenital/enzymology , Nystagmus, Congenital/pathology , Oxidoreductases/genetics , Oxidoreductases/metabolism , Pedigree , Exome Sequencing , Young Adult
BACKGROUND: Due to improvements in neonatal care of premature infants and the development of novel treatment options for retinopathy of prematurity (ROP), the requirements for screening for ROP have changed since publication of the last version of the German ROP screening guideline in 2008. Based on results of recent studies, the guideline has been extensively revised in 2020 and published in an updated version. OBJECTIVE: This article summarizes the most important changes in the new guideline. RESULTS: The age limit for screening inclusion was lowered to a gestational age of below 31 weeks for infants without additional risk factors. The minimum duration of oxygen supplementation necessitating screening inclusion in preterm infants was increased to more than 5 days. Treatment for ROP in zone II can now be given at any stage 3 with plus disease, regardless of the number of clock hours affected. Criteria for the frequency and duration have been defined for follow-up examinations after anti-vascular endothelial growth factor (VEGF) treatment. The binding document for these and other new recommendations is the guideline itself. CONCLUSION: The guideline recommendations enable a reliable identification of infants at risk for ROP for screening inclusion and a timely detection of advanced disease stages for treatment initiation, thus preventing blindness from ROP.
Retinopathy of Prematurity , Angiogenesis Inhibitors/therapeutic use , Bevacizumab/therapeutic use , Humans , Infant , Infant, Newborn , Infant, Premature , Intravitreal Injections , Laser Coagulation , Retinopathy of Prematurity/diagnosis , Retinopathy of Prematurity/epidemiology , Vascular Endothelial Growth Factor A