Genotypic and phenotypic characterisation of RP2- and RPGR-associated X-linked inherited retinal dystrophy, including female manifestations.

BACKGROUND: With the promise of gene replacement therapy, eligible males and females with X-linked inherited retinal dystrophy (XL-IRD) should be identified. METHODS: Retrospective observational cohort study to establish the phenotypic and genotypic spectrum of XL-IRD within New Zealand (NZ). Thirty-two probands, including 9 females, with molecularly proven XL-IRD due to RP2 or RPGR mutations, and 72 family members, of which 43 were affected, were identified from the NZ IRD Database. Comprehensive ophthalmic phenotyping, familial cosegregation, genotyping, and bioinformatics were undertaken. Main outcome measures were: RP2 and RPGR pathogenic variant spectrum, phenotype in males and females (symptoms, age of onset, visual acuity, refraction, electrophysiology, autofluorescence, retinal appearance), and genotype-phenotype correlation. RESULTS: For 32 families, 26 unique pathogenic variants were identified; in RP2 (n = 6, 21.9% of all families), RPGR exons 1-14 (n = 10, 43.75%), and RPGR-ORF15 (n = 10, 34.3%). Three RP2 and 8 RPGR exons 1-14 variants are novel, rare, and cosegregate. Thirty-one percent of carrier females were significantly affected, with 18.5% of families initially classified as autosomal dominant. Of five Polynesian families, 80% had novel disease-causing variants. One Maori family showed keratoconus segregating with an ORF15 variant. CONCLUSIONS: Significant disease was present in 31% of genetically proven female carriers, often leading to an erroneous presumption of the inheritance pattern. Pathogenic variants in 44% of the families were in exon 1-14 of RPGR, more frequent than usually described, which may inform the gene testing algorithm. Proving cosegregation in families for novel variants and identifying affected females and males translates to optimised clinical care and potential for gene therapy.

High Polygenic Risk Is Associated with Earlier Trabeculectomy in Patients with Primary Open-Angle Glaucoma.

PURPOSE: To evaluate the association between a polygenic risk score (PRS) for primary open-angle glaucoma (POAG) and the age at the first trabeculectomy and the need for bilateral trabeculectomy. DESIGN: Retrospective observational cohort study. PARTICIPANTS: Nine hundred and three genotyped participants with POAG from the Australian and New Zealand Registry of Advanced Glaucoma. METHODS: The ocular surgical history of these participants was reviewed and the following parameters were recorded: age at diagnosis, age at trabeculectomy, and lateraly of trabeculectomy. Multivariate linear regression analyses correlated glaucoma PRSs with age at trabeculectomy, and laterality of trabeculectomy. For descriptive purposes, the participants were stratified into the top decile, intermediate group (10th-89th percentile), and bottom decile. MAIN OUTCOME MEASURES: Age at trabeculectomy, and laterality of trabeculectomy. RESULTS: Higher PRS was associated with younger age at the first trabeculectomy (ß, -1.94 years/standard deviation; 95% confidence interval [CI], - 0.41 to -3.47; P = 0.014). Participants in the top decile underwent their first trabeculectomy approximately 7 years earlier than participants in the lowest decile (mean difference, -7.04 years; 95% CI, 2.82-11.26). Participants in the top decile were 1.41-fold more likely to require bilateral trabeculectomy than participants in the bottom decile (odds ratio, 1.41; 95% CI, 1.06-1.91; P = 0.021). CONCLUSIONS: This report identified clinically relevant correlations between glaucoma PRS and the need for surgical intervention in patients with glaucoma. Further work is required to investigate the association between PRS and other clinical end points such as treatment initiation.

RNA Sequencing of Lens Capsular Epithelium Implicates Novel Pathways in Pseudoexfoliation Syndrome.

Purpose: Pseudoexfoliation syndrome (PEX) is a common systemic disease that results in severe and often irreversible vision loss. Despite considerable research effort, PEX remains incompletely understood. This study sought to perform the first RNAseq study in elucidate the pathophysiology of PEX, and contribute a publicly available transcriptomic data resource for future research. Methods: Human ocular lens capsular epithelium samples were collected from 25 patients with PEX and 39 non-PEX controls undergoing cataract surgery. RNA extracted from these specimens was subjected to polyadenylated (mRNA) selection and deep bulk RNA sequencing. Differential expression analysis investigated protein-coding gene transcripts. Exploratory analyses used pathway analysis tools, and curated class- and disease-specific gene sets. Results: Differential expression analysis demonstrated that 2882 genes were differentially expressed according to PEX status. Genes associated with viral gene expression pathways were among the most upregulated, alongside genes encoding ribosomal and mitochondrial respiratory transport chain proteins. Cell adhesion protein transcripts including type 4 collagen subunits were downregulated. Conclusions: This comparative transcriptomic dataset highlights novel and previously recognized pathogenic pathways in PEX and provides the first comprehensive transcriptomic resource, adding an additional layer to build further understanding of PEX pathophysiology.

Complications of Limbal Stay Sutures in Strabismus Surgery.

Introduction: The use of limbal stay sutures is a well-established and frequently used technique to assist in intraoperative globe manipulation. As they are removed at the termination of the surgical procedure, they are presumed to be innocuous and not associated with significant postoperative complications.Methods: We describe two cases presenting to the same tertiary care center for the management of their complications post strabismus surgery, the causative factor in both cases being the stay sutures used during the surgical procedure. The clinical details of each case are discussed, followed by a literature review.Cases: Case 1 showed evidence of epithelial ingrowth into the cornea from the stay suture site. This case, previously reported by the senior author, is now described over an eight-year period, along with clinical photographs. Case 2 developed microbial keratitis and postoperative endophthalmitis with the locus at the stay suture site.Discussion: Complications of stay suture are rare but can occur, with potentially blinding sequelae. It is important to be aware of these risks and consider alternate methods of globe traction during strabismus surgery.

Association of Monogenic and Polygenic Risk With the Prevalence of Open-Angle Glaucoma.

IMPORTANCE: Early diagnosis of open-angle glaucoma can lead to vision-saving treatment, and genetic variation is an increasingly powerful indicator in disease risk stratification. OBJECTIVE: To compare polygenic and monogenic variants in risk of glaucoma. DESIGN, SETTING, AND PARTICIPANTS: Clinical and genetic data were obtained for 2507 individuals from the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG) and 411 337 individuals in cross-sectional cohort studies including individuals of European ancestry in the UK Biobank. Recruitment to the UK Biobank occurred between 2006 and 2010, and data analysis occurred between September 2019 and August 2020. MAIN OUTCOMES AND MEASURES: Association of monogenic and polygenic variants with glaucoma risk. RESULTS: Individuals at high polygenic risk, defined as those in the top 5% of an unselected population, had a glaucoma risk (odds ratio [OR], 2.77; 95% CI, 2.58-2.98) comparable with the risk among individuals heterozygous for the MYOC p.Gln368Ter variant (OR 4.19; 95% CI, 3.25-5.31), which is the most common single-gene variant known to cause primary open-angle glaucoma. High polygenic risk was more than 6 times more common than MYOC p.Gln368Ter heterozygosity in ANZRAG (15.7% vs 2.6%) and more than 15 times more common in the general population (5.0% vs 0.32%). Within ANZRAG, high polygenic risk was associated with a mean (SD) age at glaucoma diagnosis that did not differ from the age at glaucoma diagnosis among individuals heterozygous for MYOC p.Gln368Ter (57.2 [14.2] vs 54.8 [13.6] years; P > .99). CONCLUSIONS AND RELEVANCE: Monogenic and high polygenic risk were each associated with a more than 2.5-fold increased odds of developing glaucoma and an equivalent mean age at glaucoma diagnosis, with high polygenic risk more than 15 times more common in the general population.

Microcornea and bilateral ectopia lentis in an infant: unusual severe ocular presentation of neonatal Marfan syndrome.

We present an unusual case of microcornea, bilateral spontaneous dislocation of lenses, and anomalous optic disks in a 7-week-old girl in whom a systemic diagnosis of Marfan syndrome had not yet been confirmed at presentation. The causes and differential diagnoses of this condition are discussed, and the literature on ocular manifestations of neonatal Marfan syndrome is reviewed.

Comparison of optic disk features in preterm and term infants.

PURPOSE: To compare the optic disk features of preterm and term infants. METHODS: Digital fundus images of preterm infants were compared with those of infants born at term, imaged within 1 week of birth. The optic disk horizontal diameter to vertical diameter ratio, the disk-macula to disk-diameter ratio, and the presence or absence of double ring sign was noted. RESULTS: Images of 649 infants (324 preterm and 325 term) were analyzed. Of the preterm infants, 129 (40%) had a double ring sign, compared to 4% in term infants. The double ring was seen more frequently in infants of European descent and was more common with younger gestational age. The mean horizontal to vertical disk diameter in preterm infants on first examination was 0.75 ± 0.063, increasing to 0.80 ± 0.069 at final examination. Term infants had a horizontal to vertical disk diameter ratio of 0.79 ± 0.064. At final examination, the ratio of disk-to-macula distance to the horizontal disk diameter was 3.9 in preterm infants and 3.7 for term infants. CONCLUSIONS: In our study population preterm infants often had a double ring sign around the optic disk in the absence of optic nerve hypoplasia. Preterm disks tend to be more vertically oval, which becomes less oval closer to term. The mean disk-to-macula to disk-diameter ratio among normal preterm infants was higher than previously reported.

A rare variant of ankyloblepharon filiforme adnatum associated with skin hypopigmentation: A case report from South India.

We report ankyloblepharon filiforme adnatum (AFA) along with associated skin lesions in a 7-day-old child from South India. It could be a variant of the well described ankyloblepharon-ectodermal defects-cleft lip and palate syndrome also called Hay-Wells syndrome wherein AFA, skin lesions, and clefting are characteristic. The ocular features, genetic inheritance, and possible systemic associations, along with the options for management, are discussed. The need for awareness among ophthalmologists of its systemic associations is discussed to ensure that proper multidisciplinary care is offered to the individuals affected by this rare disorder. This article also highlights the unusual hypopigmented skin lesions found in this infant, which has been scantily reported in the literature, as a possible variation in patients of Indian ethnicity.

Ocular myiasis in a glioma: a case report.

BACKGROUND: Ocular myiasis though rare, is usually found in association with basal cell carcinoma. It is rarer still in tumors other than basal cell carcinoma. We report a case of ocular myiasis in a glioma which is hitherto unreported to the best of our knowledge. CASE: A 50 year old male presented with bleeding and maggots emanating from a tumourous outgrowth which had replaced his right eye. He complained of swelling and pain in his right eye for the last 2 years. Manual removal of maggots was carried out following which he underwent total excision of the mass and local debridement. Biopsy of the mass was consistent with astrocytoma. CONCLUSION: Myiasis though rare should be suspected in long standing neglected lesions with suggestive history. Infection, ischemic necrosis and malignancy coupled with overcrowding, poor living conditions, presence of excessive arthropods in the locality and low levels of hygiene drastically increase the risk of myiasis.

Incidence and risk factor evaluation of exposure keratopathy in critically ill patients: a cohort study.

PURPOSE: Recent emphasis on eye care in intensive care unit (ICU) patients has translated to eye assessment being part of routine care. In this setting, we determined the incidence, risk factors, and resolution time of exposure keratopathy. METHODS: In this prospective cohort study, 301 patients were examined within 24 hours of ICU admission and subsequently daily by an ophthalmologist till death or discharge. Eyelid position, conjunctival and corneal changes, treatment, and outcome data were collected. RESULTS: Admission diagnoses included febrile illnesses (35.2%) and respiratory failure (32.6%); 84.1% were ventilated. Forty-nine patients had exposure keratopathy (bilateral = 35, unilateral = 14) at admission; 35 patients developed new onset keratopathy (incidence 13.2%) 4.6 ± 2.6 days after ICU admission. In 67 patients, keratopathy was mild (punctate epithelial erosions). Macroepithelial defects (n = 9), stromal whitening with epithelial defect (n = 3), and stromal scar (n = 3) were infrequent. None developed microbial keratitis. On multivariate logistic regression analysis, eyelid position (odds ratio, 2.93; 95% confidence interval, 1.37-6.25), and ventilation duration (odds ratio, 1.11; 95% confidence interval, 1.04-1.19) were strongly associated with the development of keratopathy after ICU admission. Keratopathy resolved in 3.6 ± 4.5 days. CONCLUSIONS: Severe exposure keratopathy is infrequent in a protocolized ICU setting. Eyelid position and duration of ventilation are associated with exposure keratopathy.