Heterozygous mutations in the C-terminal domain of COPA underlie a complex autoinflammatory syndrome.

Mutations in the N-terminal WD40 domain of coatomer protein complex subunit α (COPA) cause a type I interferonopathy, typically characterized by alveolar hemorrhage, arthritis, and nephritis. We described 3 heterozygous mutations in the C-terminal domain (CTD) of COPA (p.C1013S, p.R1058C, and p.R1142X) in 6 children from 3 unrelated families with a similar syndrome of autoinflammation and autoimmunity. We showed that these CTD COPA mutations disrupt the integrity and the function of coat protein complex I (COPI). In COPAR1142X and COPAR1058C fibroblasts, we demonstrated that COPI dysfunction causes both an anterograde ER-to-Golgi and a retrograde Golgi-to-ER trafficking defect. The disturbed intracellular trafficking resulted in a cGAS/STING-dependent upregulation of the type I IFN signaling in patients and patient-derived cell lines, albeit through a distinct molecular mechanism in comparison with mutations in the WD40 domain of COPA. We showed that CTD COPA mutations induce an activation of ER stress and NF-κB signaling in patient-derived primary cell lines. These results demonstrate the importance of the integrity of the CTD of COPA for COPI function and homeostatic intracellular trafficking, essential to ER homeostasis. CTD COPA mutations result in disease by increased ER stress, disturbed intracellular transport, and increased proinflammatory signaling.

Unilateral Melanoma-Associated Retinopathy Case Report.

In this report, we present a case of unilateral melanoma-associated retinopathy in a 72-year-old woman. The patient's main symptoms were decreased vision and positive dysphotopsia. Unilateral electronegative electroretinogram (ERG) was suggestive for melanoma retinopathy. PET-CT discovered metastatic disease, 3 years after the initial melanoma. A prompt treatment with corticosteroids was started, followed by immunotherapy. The central and peripheral vision of the patient improved, and the ERG showed normalization of the responses. This case highlights the importance of early recognition and individualized treatment strategies for melanoma-associated retinopathy.

DNA extraction protocol impacts ocular surface microbiome profile.

Purpose: The aim of this study is to provide a reference frame to allow the comparison and interpretation of currently published studies on 16S ribosomal ribonucleic acid amplicon sequencing of ocular microbiome samples using different DNA extraction protocols. Alongside, the quantitative and qualitative yield and the reproducibility of different protocols has been assessed. Methods: Both eyes of 7 eligible volunteers were sampled. Five commercially available DNA extraction protocols were selected based on previous publications in the field of the ocular surface microbiome and 2 host DNA depletion protocols were added based on their reported effective host DNA depletion without significant reduction in bacterial DNA concentration. The V3-V4 region of the 16S rRNA gene was targeted using Illumina MiSeq sequencing. The DADA2 pipeline in R was used to perform the bio-informatic processing and taxonomical assignment was done using the SILVA v132 database. The Vegdist function was used to calculate Bray-Curtis distances and the Galaxy web application was used to identify potential metagenomic biomarkers via linear discriminant analysis Effect Size (LEfSe). The R package Decontam was applied to control for potential contaminants. Results: Samples analysed with PowerSoil, RNeasy and NucleoSpin had the highest DNA yield. The host DNA depletion kits showed a very low microbial DNA yield; and these samples were pooled per kit before sequencing. Despite pooling, 1 of both failed to construct a library.Looking at the beta-diversity, clear microbial compositional differences - dependent on the extraction protocol used - were observed and remained present after decontamination. Eighteen genera were consistently retrieved from the ocular surface of every volunteer by all non-pooled extraction kits and a comprehensive list of differentially abundant bacteria per extraction method was generated using LefSe analysis. Conclusion: High-quality papers have been published in the field of the ocular surface microbiome but consensus on the importance of the extraction protocol used are lacking. Potential contaminants and discriminative genera per extraction protocol used, were introduced and a reference frame was built to facilitate both the interpretation of currently published papers and to ease future choice - making based on the research question at hand.

Two siblings with Bosch-Boonstra-Schaaf optic atrophy syndrome due to parental gonadal mosaicism.

Bosch-Boonstra-Schaaf Optic Atrophy Syndrome (BBSOAS, OMIM 615722) is a rare autosomal dominant disorder characterized by intellectual disability, optic atrophy, cortical visual impairment, mild facial dysmorphism, hypotonia, hearing problems, attention deficit and a thin corpus callosum. The gene underlying this disorder is NR2F1 located on chromosome 5q15 which encodes for a nuclear receptor protein. Mutations and deletions have been identified in patients. Here we report on a brother and a sister carrying a pathogenic nonsense NR2F1 variant. The patients have a mild phenotype showing optic atrophy, mild intellectual disability, dysmorphic features and thin corpus callosum. This correlates with previously described milder phenotypes in patients with mutations in this domain. The variant was not identified in the parental genome indicating most likely a gonadal mosaicism. Gonadal mosaicism has not yet been reported in Bosch-Boonstra-Schaaf Optic Atrophy Syndrome.

The Effect of Topical Anesthetics on 16S Ribosomal Ribonucleic Acid Amplicon Sequencing Results in Ocular Surface Microbiome Research.

PURPOSE: To clarify the short-term effect of topical anesthetics on 16S ribosomal ribonucleic acid amplicon sequencing results in ocular surface microbiome research. METHODS: Both eyes of 24 eligible volunteers undergoing general anesthesia were sampled. Before sampling, a drop of artificial tears or a drop of topical anesthetic was applied in a randomized way. By using artificial tears as a control, we assured blinding of the executer and took a potential diluting effect into account. Bacterial DNA was extracted using the QIAGEN RNeasy PowerMicrobiome Kit with specific adaptations. Amplified DNA was sequenced with the Illumina MiSeq sequencing platform. RESULTS: Four sample pairs were excluded due to low yield of bacterial DNA. In the remaining 20 sample pairs, no differences were observed with topical anesthetics at the levels of amplicon sequence variants (ASVs), phylum, genera, or alpha and beta diversity. Weighted UniFrac distance confirmed that the intraindividual distance between the right and left eye was smaller than the effect of the topical anesthetic. Interestingly, however, we identified Cutibacterium as a potential discriminative biomarker for topical anesthetic use. Overall, a significantly higher number of observed reads were assigned to genera with Gram-positive characteristics. CONCLUSIONS: Based on our targeted, double-blinded, within-subject study, topical anesthetics do not affect the overall sequencing results but display a specific effect on Cutibacterium. When comparing research results, the impact of topical anesthetics on prevalence and abundance of Cutibacterium should be considered. TRANSLATIONAL RELEVANCE: Understanding and standardization of sampling techniques are indispensable to properly execute clinical microbiome research.

Association between near viewing and acute acquired esotropia in children during tablet and smartphone use.

We investigated a possible association between the acute onset of esotropia and tablet or smartphone use in children. We characterized the clinical aspects of esotropia associated with tablet or smartphone use. The medical records of 10 children aged between 5 and 15 years old with presumably tablet or smartphone associated esotropia were reviewed regarding orthoptic examination and cycloplegic refraction. Legal guardians of the children were asked to fill in a questionnaire regarding tablet and smartphone use of their child. This questionnaire was also conducted in a control group of age-matched children. The results of this questionnaire were compared to search for possible determinants of tablet or smartphone associated esotropia. All 10 patients presented with a comitant esotropia ranging from 8 to 45 prism diopters with no significant difference between near and far. The mean age of onset was 9.8 years. Cycloplegic refraction showed a mild hyperopia in eight patients, a mild myopia in one patient and emmetropia in the other patient. All patients had near full refractive correction at the onset of esotropia. Diplopia was reduced after visual hygiene recommendations, however in six patients, strabismus surgery was needed. The working distance was significantly shorter in the 10 cases compared to the controls. In children with acute acquired esotropia, we found a statistically significant association with a smaller working distance during tablet or smartphone use compared to age-matched controls. We hypothesize that intensive near viewing can be a precipitating factor in this type of esotropia.

Management of Childhood Glaucoma Following Cataract Surgery.

Glaucoma remains a frequent serious complication following cataract surgery in children. The optimal approach to management for 'glaucoma following cataract surgery' (GFCS), one of the paediatric glaucoma subtypes, is an ongoing debate. This review evaluates the various management options available and aims to propose a clinical management strategy for GFCS cases. A literature search was conducted in four large databases (Cochrane, PubMed, Embase, and Web of Science), from 1995 up to December 2021. Thirty-nine studies-presenting (1) eyes with GFCS; a disease entity as defined by the Childhood Glaucoma Research Network Classification, (2) data on treatment outcomes, and (3) follow-up data of at least 6 months-were included. Included papers report on GFCS treated with angle surgery, trabeculectomy, glaucoma drainage device implantation (GDD), and cyclodestructive procedures. Medical therapy is the first-line treatment in GFCS, possibly to bridge time to surgery. Multiple surgical procedures are often required to adequately control GFCS. Angle surgery (360 degree) may be considered before proceeding to GDD implantation, since this technique offers good results and is less invasive. Literature suggests that GDD implantation gives the best chance for long-term IOP control in childhood GFCS and some studies put this technique forward as a good choice for primary surgery. Cyclodestruction seems to be effective in some cases with uncontrolled IOP. Trabeculectomy should be avoided, especially in children under the age of one year and children that are left aphakic. The authors provide a flowchart to guide the management of individual GFCS cases.

Extraocular muscle hypoplasia associated with Axenfeld-Rieger syndrome.

We describe a four-year-old girl with bilateral severe iris hypoplasia and secondary ocular hypertension. Genetic testing revealed a de novo deletion in the FOXC1 gene, establishing the diagnosis of Axenfeld-Rieger syndrome (ARS). The girl developed a gradually increasing exotropia, up to 95 prism diopters by the age of 3 years wherefore strabismus surgery was performed. Intra-operatively, only very rudimentary developed medial and lateral rectus muscles were found. This is the first observation of pronounced hypoplasia of both medial and lateral rectus muscles associated with ARS.

Two Cases Presenting With Unilateral Adduction Deficit Associated With Human Adenosine Deaminase 2 Deficiency.

Deficiency of human adenosine deaminase 2 (DADA2) is an auto-inflammatory inborn error of immunity caused by biallelic deleterious mutations in the gene encoding ADA2. The purpose of this article is to raise awareness among ophthalmologists and pediatricians to consider DADA2 as a possible diagnosis for patients with acute onset of diplopia. The authors describe two pediatric patients who presented with double vision due to uni-lateral adduction deficit, and discuss the importance of recognizing this clinically as an ophthalmologist. If a child presents with a sudden eye movement abnormality, ophthalmologists must be aware of the possibility of an ischemic insult due to an underlying genetic disorder (eg, DADA2), especially in patients with a positive familial history or associated clinical signs such as a personal history of characteristic skin lesions or paresis of other cranial nerves. Given the multi-organ involvement in this disorder, a multi-disciplinary approach is crucial to have a timely diagnosis and to treat this rare disorder appropriately. [J Pediatr Ophthalmol Strabismus. 2021;58(4):e22-e26.].

Subconjunctival Hemorrhage in a Child with the Blue Rubber Bleb Nevus Syndrome on Treatment with Oral Propranolol.

Blue rubber bleb nevus syndrome (BRBNS) is a rare syndrome characterized by venous malformations of mostly skin and gastrointestinal tract. Patients present with multiple venous malformations in various organs including liver, spleen, heart, eye, and central nervous system. Few ophthalmological cases have been published in literature and at present, there are no clear guidelines on the treatment of eye hemorrhages associated with the BRBNS. We report a 3-year-old boy with the BRBNS who developed a spontaneous progressive enlarging subconjunctival hemorrhage in the left eye despite being treated with oral propranolol. The subconjunctival hemorrhage was caused by an underlying conjunctival vascular malformation. With topical treatment with timolol maleate 0.5% once a day in the affected eye, the lesion regressed completely after 4 months. This child represents the first case of the BRBNS associated with a subconjunctival progressive bleeding necessitating topical treatment despite oral propranolol effectively controlling the cutaneous lesions. We recommend ophthalmic screening of patients with BRBNS in early childhood. For patients with BRBNS-related subconjunctival vascular lesions with subsequent hemorrhage, treatment with a topical ß-blocker may be an efficient and harmless treatment option.

Two siblings with Heimler syndrome caused by PEX1 variants: follow-up of ophthalmologic findings.

BACKGROUND: Heimler syndrome (OMIM number #234580 and #616617) is a rare condition comprising sensorineural hearing loss (SNHL), nail abnormalities and amelogenesis imperfecta. In addition, patients with this syndrome can have retinal dystrophies. Heimler syndrome is caused by bi-allelic pathogenic variants in the PEX1 or PEX6 gene. Only few patients with this syndrome have been reported. We hereby describe two siblings with genetically confirmed Heimler syndrome and provide imaging of the ocular phenotype. MATERIALS AND METHODS: The medical records of the siblings were reviewed retrospectively. RESULTS: Both brother and sister were diagnosed with SNHL and amelogenesis imperfecta of the permanent teeth; one of the affected siblings also had nail abnormalities. Both patients presented to the ophthalmology department with suboptimal visual acuity, fundus abnormalities and intraretinal cystoid spaces. Full-field electroretinogram revealed a cone-rod dysfunction. A genetic analysis revealed a homozygous likely pathogenic variant c.3077 T > C (p.Leu1026Pro) in the PEX1 gene in both siblings. The parents are heterozygous carriers of the variant. CONCLUSION: We recommend performing regular ophthalmic examination in patients with Heimler syndrome since the ophthalmic manifestations can manifest later in life. Our patients presented with cone-rod dystrophy and intraretinal cystoid spaces. Review of the literature shows that the ocular phenotype can be very variable in patients with Heimler syndrome.

Insights into multiple sclerosis-associated uveitis: a scoping review.

PURPOSE: This paper is a scoping review of research on multiple sclerosis (MS)-associated uveitis to determine its epidemiology, pathophysiology, clinical features and treatment. METHODS: A comprehensive search of the medical databases MEDLINE (PubMed), EMBASE, Web of Science and Cochrane was carried out on 25 November 2019, to identify papers published between 1980 and 2019 that focus on patients with MS-associated uveitis. RESULTS: Based on large cohort studies (n ≥ 1000), the prevalence of uveitis in patients with MS is estimated to be 0.53-1.34% (mean = 0.83%), and MS is diagnosed in 0.52-3.20% (mean = 1.30%) of patients with uveitis. The condition is most frequent among middle-aged women. Patients usually complain of floaters and/or blurred vision, with bilateral intermediate uveitis (with retinal vasculitis) as the most frequent ophthalmological finding. Both MS and intermediate uveitis are associated with HLA-DRB1*15:01 and IL-2RA gene polymorphism rs2104286 A > G, suggesting a common genetic background. T cells, and possibly B cells, play an important role in both autoimmune disorders. Multiple sclerosis (MS)-related uveitis is classically treated as non-infectious uveitis, with corticosteroids as the first treatment step. Other treatments include immunosuppressants, cryotherapy, laser photocoagulation and vitrectomy. These treatment options have a limited, if any, effect on the course of MS and can be complicated by side-effects. As treatment strategies for MS have increased in the last decade, it would be interesting to evaluate the efficacy of these new treatments during the course of uveitis. Moreover, the correlation between retinal periphlebitis and MS could be established more accurately with the recently developed techniques of wide-field fluorescein angiography in a large cohort of MS patients. CONCLUSION: MS-associated uveitis is a rare, highly discussed pathology about which much is still unknown. Large epidemiological studies and extrapolation of new MS treatments to this condition are warranted.

Current knowledge on the human eye microbiome: a systematic review of available amplicon and metagenomic sequencing data.

Insights in the ocular surface microbiome are still at an early stage and many more questions remain unanswered compared with other human-associated microbial communities. The current knowledge on the human microbiome changed our viewpoint on bacteria and human health and significantly enhanced our understanding of human pathophysiology. Also in ocular medicine, microbiome research might impact treatment. Here, we summarize the current knowledge on ocular microbiome research with a particular focus on potential confounding factors and their effects on microbiome composition. Moreover, we present the ocular surface core microbiome based on current available data and defined it as genera present in almost half of the published control cohorts with a relative abundance of at least 1%.

Acute bilateral serous retinal detachments with spontaneous resolution in a 6-year-old boy.

A healthy 6-year-old boy presented with acute bilateral vision loss, multiple serous retinal detachments between the vascular arcades and a thickened choroid. Spontaneous resolution occurred over several weeks. We hypothesize that the clinical constellation in our patient is suggestive of acute exudative polymorphous vitelliform maculopathy (AEPVM) or might be an atypical presentation of Vogt-Koyanagi-Harada (VKH) disease. We propose that it was caused by an autoimmune-mediated activation of inflammatory cells at the level of the choroid, induced by an unknown trigger.

A Retrospective Case Series of Uveal Effusion Syndrome.

PURPOSE: This study aimed to describe the clinical findings and management of eyes affected by uveal effusion syndrome. METHODS: We retrospectively evaluated the charts of 13 eyes of 8 consecutive patients diagnosed with uveal effusion syndrome attending the Ophthalmology Unit of the University Hospitals Leuven, Belgium, between 2007 and 2018. The presenting features, investigations, management, and outcomes were analyzed for each case. RESULTS: Cataract surgery was the predisposing factor for uveal effusion in 6 eyes, 2 bilateral uveal effusions (4 eyes) were considered to be medication-induced, and in 3 eyes, the uveal effusion was described as idiopathic. Fundus examination of 5 of 13 eyes showed bullous choroidal detachment, treated with pars plana vitrectomy with superotemporal sclerectomy or transscleral punction. Fundoscopy showed uveal effusion without serous retinal detachment in 3 eyes. Serous retinal detachment accompanied by uveal swelling was observed in 3 eyes and the 2 remaining eyes presented with uveal swelling only. The 8 nonbullous choroidal detachments were treated in a conservative way. A rapid resolution of subretinal fluid and uveal effusion was observed in all cases. CONCLUSIONS: A conservative approach with acetazolamide treatment or just observation was used in our case series in choroidal detachment without substantial visual loss if, over time, slow improvement was documented. However, further studies are needed to verify the effectiveness of the reported therapy.