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Background/aims Initially reported in a few patients with homozygous sickle cell disease (SCD), atrophic areas of the retina temporal from the macula are now known to be present in about 48% of eyes of adult patients with SS-SCD and in 35% of eyes of adult patients with SC-SCD. The aim of this study is to describe this paramacular atrophy in children affected with SCD. Methods In this retrospective series, spectral-domain optical coherence tomography images of 81 children with SCD, acquired with specific patterns including one evaluating the retina temporal to the macula, were reviewed, in order to look for retinal atrophy. Fundus examination status for SCD peripheral retinopathy was also reviewed. results Mean age was 12.0 years (SD: 3.56). The genotype distribution was: 64 HbSS (79%), 10 HbSC (12%) and 7 HbS/β0 thalassaemia (9%). Using a usual fovea-centred programme, retinal atrophy was found in 38% of eyes (52% of children). Using a specific temporal pattern, retinal atrophy was found in 53% of eyes (64% of children), with no significant difference in the prevalence between HbSS and HbSC genotype (p=0.92), and no effect of age (mean 12.3 years (SD=3.61) vs 11.9 (3.56), p=0.65). Peripheral retinopathy was found in 11% of children, with a significant relation between the HbSC genotype and the severity of the retinopathy (p=0.003). Conclusion Paramacular temporal atrophy occurs early in the course of SCD, which suggests distinct mechanisms from those of peripheral retinopathy. [ABSTRACT FROM AUTHOR]

Leber hereditary optic neuropathy (LHON) is a maternally inherited, bilateral, sequential optic neuropathy that usually affects young males. LHON arises from a defect in complex I of the oxidative phosphorylation chain that generates increased reactive oxygen species and causes a decline in cellular ATP production. There exists no cure at present for LHON. Asymptomatic LHON mutation carriers show signs of increased mitochondrial biogenesis that may compensate for the compromise in complex I activity. Partial recovery in LHON is associated with a wider optic disc diameter and a younger age at disease onset, which may allow for greater mitochondrial bioenergetic capacity. Rescuing a mitochondrial bioenergetic deficit soon after disease onset may improve the chances of recovery and reduce visual loss in the second eye. We here propose that a calorie-restricted ketogenic diet has the potential to enhance mitochondrial bioenergetic capacity and should be explored as a potential therapeutic option for treating LHON. [ABSTRACT FROM AUTHOR]

Bi-allelic mutations in I LRMDA i gene (leucine-rich melanocyte differentiation-associated protein or I C10orf11 i gene, chromosome 10 open reading frame 11 or leucine-rich differentiation-associated protein), located on chromosome 10q22, are associated with the newly described and very rare OCA7 subtype (MIM615179). OCA7 was first described in 8 members from the same family from Faroe Islands and in one patient from Lithuania.[2] While ocular symptoms predominate, patients presented with pale skin, scalp hair colors varied from pale blond to dark brown. Notably, four patients (from Turkey, Lithuania and our two patients) carry the same c.66dupC suggesting a founder effect in the east part of Europe and Asia. [Extracted from the article]

Congenital aniridia is a rare and severe panocular disease characterized by a complete or partial iris defect clinically detectable at birth. The most common form of aniridia occurring in around 90% of cases is caused by PAX6 haploinsufficiency. The phenotype includes ptosis, nystagmus, corneal limbal insufficiency, glaucoma, cataract, optic nerve, and foveal hypoplasia. Ataluren eye drops aim to restore ocular surface PAX6 haploinsufficiency in aniridia-related keratopathy (ARK). However, there are currently no available forms of the ophthalmic solution. The objective of this study was to assess the physicochemical and microbiological stability of ataluren 1% eye drop in preservative-free low-density polyethylene (LDPE) bottle with an innovative insert that maintains sterility after opening. Because ataluren is a strongly lipophilic compound, the formulation is complex and involves a strategy based on co-solvents in an aqueous phase or an oily formulation capable of totally dissolving the active ingredient. The visual aspect, ataluren quantification by a stability-indicating chromatographic method, and microbiological sterility were analyzed. The oily formulation in castor oil and DMSO (10%) better protects ataluren hydrolysis and oxidative degradation and permits its complete solubilization. Throughout the 60 days period, the oily solution in the LDPE bottle remained clear without any precipitation or color modification, and no drug loss and no microbial development were detected. The demonstrated physical and microbiological stability of ataluren 1% eye drop formulation at 22–25 °C might facilitate clinical research in aniridia. [ABSTRACT FROM AUTHOR]

Congenital PAX6 -aniridia, initially characterized by the absence of the iris, has progressively been shown to be associated with other developmental ocular abnormalities and systemic features making congenital aniridia a complex syndromic disorder rather than a simple isolated disease of the iris. Moreover, foveal hypoplasia is now recognized as a more frequent feature than complete iris hypoplasia and a major visual prognosis determinant, reversing the classical clinical picture of this disease. Conversely, iris malformation is also a feature of various anterior segment dysgenesis disorders caused by PAX6 -related developmental genes, adding a level of genetic complexity for accurate molecular diagnosis of aniridia. Therefore, the clinical recognition and differential genetic diagnosis of PAX6 -related aniridia has been revealed to be much more challenging than initially thought, and still remains under-investigated. Here, we update specific clinical features of aniridia, with emphasis on their genotype correlations, as well as provide new knowledge regarding the PAX6 gene and its mutational spectrum, and highlight the beneficial utility of clinically implementing targeted Next-Generation Sequencing combined with Whole-Genome Sequencing to increase the genetic diagnostic yield of aniridia. We also present new molecular mechanisms underlying aniridia and aniridia-like phenotypes. Finally, we discuss the appropriate medical and surgical management of aniridic eyes, as well as innovative therapeutic options. Altogether, these combined clinical-genetic approaches will help to accelerate time to diagnosis, provide better determination of the disease prognosis and management, and confirm eligibility for future clinical trials or genetic-specific therapies. • Severe foveal hypoplasia is more common than complete absence of the iris in PAX6- related aniridia. • Association of congenital aniridia and cartwheel cataracts is highly indicative of a PAX6 gene defect • 11p13 microdeletions restricted to the PAX6 3′ downstream region are associated with a milder retinal and corneal phenotypes • Targeted Next-Generation Sequencing combined with Whole-Genome Sequencing make it possible to increase the diagnostic yield of congenital aniridia • New molecules are emerging to treat corneal opacification in aniridia-associated keratopathy [ABSTRACT FROM AUTHOR]

Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) are serious and rare diseases, most often drug-induced, and their incidence has been estimated at 6 cases/million/year in France. SJS and TEN belong to the same spectrum of disease known as epidermal necrolysis (EN). They are characterized by more or less extensive epidermal detachment, associated with mucous membrane involvement, and may be complicated during the acute phase by fatal multiorgan failure. SJS and TEN can lead to severe ophthalmologic sequelae. There are no recommendations for ocular management during the chronic phase. We conducted a national audit of current practice in the 11 sites of the French reference center for toxic bullous dermatoses and a review of the literature to establish therapeutic consensus guidelines. Ophthalmologists and dermatologists from the French reference center for epidermal necrolysis were asked to complete a questionnaire on management practices in the chronic phase of SJS/TEN. The survey focused on the presence of a referent ophthalmologist at the center, the use of local treatments (artificial tears, corticosteroid eye drops, antibiotic-corticosteroids, antiseptics, vitamin A ointment (VA), cyclosporine, tacrolimus), the management of trichiatic eyelashes, meibomian dysfunction, symblepharons, and corneal neovascularization, as well as the contactologic solutions implemented. Eleven ophthalmologists and 9 dermatologists from 9 of the 11 centers responded to the questionnaire. Based on questionnaire results, 10/11 ophthalmologists systematically prescribed preservative-free artificial tears, and 11/11 administered VA. Antiseptic or antibiotic eye drops or antibiotic-corticosteroid eye drops were recommended as needed by 8/11 and 7/11 ophthalmologists, respectively. In case of chronic inflammation, topical cyclosporine was consistently proposed by 11/11 ophthalmologists. The removal of trichiatic eyelashes was mainly performed by 10/11 ophthalmologists. Patients were referred to a reference center for fitting of scleral lenses (10/10,100%). Based on this practice audit and literature review, we propose an evaluation form to facilitate ophthalmic data collection in the chronic phase of EN and we also propose an algorithm for the ophthalmologic management of ocular sequelae. [ABSTRACT FROM AUTHOR]

Inherited epidermolysis bullosa (EB) is a group of genetic rare diseases associated with skin fragility, which leads to the formation of blisters, erosions, and scars on the skin and mucous membranes. Epidermolysis bullosa includes four main types and some several clinical subtypes including EB simplex, junctional EB, dystrophic EB, and Kindler's EB. Ocular involvement ranged from 51 to 68% in EB and can cause irreversible damages if not properly managed. Corneal erosions are the most common finding among series, including our cohort. We review here clinical and pathological features of ocular involvement in EB and the main keys for management, with a focus on recent innovative therapies. [ABSTRACT FROM AUTHOR]

We describe two sporadic and two familial cases with loss-of-function variants in PRPS1, which is located on the X chromosome and encodes phosphoribosyl pyrophosphate synthetase 1 (PRS-1). We illustrate the clinical variability associated with decreased PRS-1 activity, ranging from mild isolated hearing loss to severe encephalopathy. One of the variants we identified has already been reported with a phenotype similar to our patient's, whereas the other three were unknown. The clinical and biochemical information we provide will hopefully contribute to gain insight into the correlation between genotype and phenotype of this rare condition, both in females and in males. Moreover, our observation of a new family in which hemizygous males display hearing loss without any neurological or ophthalmological symptoms prompts us to suggest analysing PRPS1 in cases of isolated hearing loss. Eventually, PRPS1 variants should be considered as a differential diagnosis of mitochondrial disorders. [ABSTRACT FROM AUTHOR]

Rare eye diseases encompass a broad spectrum of genetic anomalies with or without additional extraocular manifestations. Genetic eye disorders in pediatric patients often lead to severe visual impairments. Therefore, a challenge of gene therapy is to provide better vision to these affected children. In recent years, inherited retinal diseases, inherited optic neuropathies, and corneal dystrophies have dominated discussions to establish gene and cell replacement therapies for these diseases. Gene therapy involves the transfer of genetic material to remove, replace, repair, or introduce a gene, or to overexpress a protein, whose activity would have a therapeutic impact. For the majority of anterior segment diseases, these studies are still emerging at a preclinical stage; however, for inherited retinal disorders, translation has been reached, leading to the introduction of the first gene therapies into clinical practice. In the past decade, the first gene therapy for biallelic RPE65-mediated inherited retinal dystrophy has been developed and the FDA and EMA both approved ocular gene therapy. Other promising approaches by intravitreal injection have been investigated such as in CEP290-Leber congenital amaurosis. Various techniques of gene therapies include gene supplementation, CRISPR-based genome editing, as well as RNA modulation and optogenetics. Optogenetic therapies deliver light-activated ion channels to surviving retinal cell types in order to restore photosensitivity. Beyond retinal function, ataluren, a nonsense mutation suppression therapy, enables ribosomal read-through of mRNA containing premature termination codons, resulting in the production of a full-length protein. An ophthalmic formulation was recently evaluated with the aim of repairing corneal damage, pending new clinical studies. However, various congenital disorders exhibit severe developmental defects or cell loss at birth, limiting the potential for viral gene therapy. Therefore mutation-independent strategies seem promising for maintaining the survival of photoreceptors or for restoring visual function. Restoring vision in children with gene therapy continues to be a challenge in ophthalmology. © 2023 Published by Elsevier Masson SAS on behalf of French Society of Pediatrics., (Copyright © 2023 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.)

Background: Around one in forty patients are diagnosed with optic disc drusen (ODD) during their lifetime. Complications of these acellular deposits range from asymptomatic visual field deficits to artery occlusion and subsequent cecity. Still, the pathogenesis of their emergence remains controversial. In particular, it was suggested 50 years ago that a narrow disc and scleral canal is one factor leading to axoplasmic flow disturbance, which induces ODD formation. However, this hypothesis is still debated today. To evaluate the basis of this theory, we will conduct a systematic review and meta-analysis of studies evaluating the scleral canal size in patients with ODD and in healthy subjects., Methods: We will search MEDLINE via PubMed, Cochrane, and EMBASE electronic databases to identify articles published before November 29, 2022 that measure the scleral canal size in patients with ODD and in healthy subjects. In addition, grey literature will be searched. The meta-analysis will include studies that include patients with a clinical or imaging diagnosis of ODD and healthy subjects. Additionally, we will perform a subgroup analysis to compare patients with buried ODD and patients with visible ODD. Extracted data from included studies will be presented descriptively, and effect sizes will be computed based on the recommendations from the Cochrane Collaboration handbook., Discussion: The hypothesis that a narrow scleral canal is a risk factor of ODD has long been debated and this systematic review and meta-analysis should disentangle the different views. Understanding the underlying factors driving the development of ODD should help us focus on patients at risk and develop strategies to prevent advanced stages of the disease in these patients. Besides, focusing on patients with small scleral canals should help us derive associated factors and provide a better understanding of the pathology., Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022375110., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author DB-G declared that they were an editorial board member of Frontiers at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Vienne-Jumeau, Brémond-Gignac and Robert.)

Purpose: This study aims to characterize foveal vasculature assessed by optical coherence tomography angiography (OCT-A) in congenital aniridia which is hallmarked by foveal hypoplasia (FH)., Design: Cross-sectional case-control analysis., Methods: At the National Referral Center for congenital aniridia, patients with confirmed PAX6-related aniridia and FH diagnosed on spectral-domain OCT (SD-OCT) with available OCT-A and matched control subjects were included. OCT-A was performed in patients with aniridia and control subjects. Foveal avascular zone (FAZ) and vessel density (VD) were collected. VD in the foveal and parafoveal areas at the level of the superficial and deep capillary plexi (SCP and DCP, respectively) were compared between the 2 groups. In patients with congenital aniridia, correlation between VD and the grading of FH was assessed., Results: Among 230 patients with confirmed PAX6-related aniridia, high-quality macular B-scans and OCT-A were available in 10 patients. On the foveal area, mean VD was higher in aniridia patients (41.10%, n = 10) than in control subjects (22.65%, n = 10) at the level of the SCP and the DCP (P = .0020 and P = .0273, respectively). On the parafoveal area, mean VD was lower in patients with aniridia (42.34%, n = 10) than in healthy subjects (49.24%, n = 10) at the level of both plexi (P = .0098 and P = .0371, respectively). In patients with congenital aniridia, a positive correlation was found between the grading of FH and the foveal VD at the SCP (r = 0.77, P = .0106)., Conclusions: Vasculature is altered in PAX6-related congenital aniridia, higher in foveal and lower in parafoveal areas, especially when FH is severe, which is consistent with the concept that the absence of retinal blood vessels is essential for foveal pit development., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Mucopolysaccharidosis type I-H (MPS I-H) is a rare lysosomal storage disorder caused by α-L-Iduronidase deficiency. Early haematopoietic stem cell transplantation (HSCT) is the sole available therapeutic option to preserve neurocognitive functions. We report long-term follow-up (median 9 years, interquartile range 8-16.5) for 51 MPS I-H patients who underwent HSCT between 1986 and 2018 in France. 4 patients died from complications of HSCT and one from disease progression. Complete chimerism and normal α-L-Iduronidase activity were obtained in 84% and 71% of patients respectively. No difference of outcomes was observed between bone marrow and cord blood stem cell sources. All patients acquired independent walking and 91% and 78% acquired intelligible language or reading and writing. Intelligence Quotient evaluation (n = 23) showed that 69% had IQ ≥ 70 at last follow-up. 58% of patients had normal or remedial schooling and 62% of the 13 adults had good socio-professional insertion. Skeletal dysplasia as well as vision and hearing impairments progressed despite HSCT, with significant disability. These results provide a long-term assessment of HSCT efficacy in MPS I-H and could be useful in the evaluation of novel promising treatments such as gene therapy., (© 2022. The Author(s).)

Background: The morning glory disc anomaly (MGDA) is a rare congenital malformation of the optic disc. The association with a significant enlargement of the optic nerve has been recently reported in a few cases, raising the question of potentially associated optic nerve gliomas. The objective was to report the anatomy of optic nerves on MRI in patients with MGDA., Methods: In this retrospective single-center study, files of patients with a clinical diagnosis of MGDA were identified through a rare disease database (CEMARA) and included. We reviewed every cerebral and orbital MRI available, performed between 2008 and 2018. Anatomy of the optic nerve from the optic disc to the chiasm was evaluated on MRI., Results: Nine patients were included. All presented unilateral MGDA. Age at first MRI was 0.6-62 years, median = 3.8 years. MRI showed posterior protrusion of the globe (staphyloma) centered by the optic disc in all cases (100%). Ipsilateral optic nerve abnormalities were found in all cases (100%). The optic nerve was found thinner than the contralateral one in its intraorbital, intracanalar, and intracranial portions in 1 case (11%); in 8 cases (89%), the thickness of the optic nerve was irregular and varied along its pathway: thick, normal, and/or thin. When gadolinium injection had been performed (3 cases), none exhibited gadolinium enhancement. When serial MRI scanning was available (4 cases), there was no evolution of the abnormalities., Conclusion: In patients with MGDA, optic nerve and chiasm abnormalities are the rule, with most often a unique pattern of irregular optic nerve thickness-hypertrophy and hypoplasia-from the orbit to the chiasm. Such pattern should be recognized and points to a developmental abnormality, rather than an optic nerve glioma., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by North American Neuro-Ophthalmology Society.)

Introduction: At least half of children with low-grade glioma (LGG) treated with first line chemotherapy experience a relapse/progression and may therefore need a second-line chemotherapy. Irinotecan-bevacizumab has been recommended in this setting in France after encouraging results of pilot studies. We performed a retrospective analysis to define the efficacy, toxicity and predictors for response to the combination on a larger cohort., Methods: We reviewed the files from children < 19 years of age with progressive or refractory LGG treated between 2009 and 2016 in 7 French centers with this combination., Results: 72 patients (median age 7.8 years [range 1-19]) received a median of 16 courses (range 3-30). The median duration of treatment was 9 months (range 1.4-16.2). 96% of patients experienced at least disease stabilization. The 6-month and 2-year progression-free survivals (PFS) were 91.7% [IC 95% 85.5-98.3] and 38.2% [IC 95% 28.2-51.8] respectively. No progression occurred after treatment in 18 patients with a median follow-up of 35.6 months (range 7.6-75.9 months). Younger patients had a worse PFS (p = 0.005). Prior chemoresistance, NF1 status, duration of treatment, histopathology or radiologic response did not predict response. The most frequent toxicities related to bevacizumab included grades 1-2 proteinuria in 21, epistaxis in 10, fatigue in 12 and hypertension in 8 while gastro-intestinal toxicity was the most frequent side effect related to irinotecan., Conclusions: Bevacizumab-irinotecan has the potential of disease control clinically and radiographically in children with recurrent LGG whatever their previous characteristics; in many cases however these responses are not sustained, especially in younger children., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The analysis of the Nystagmus waveforms from eye-tracking records is crucial for the clinical interpretation of this pathological movement. A major issue to automatize this analysis is the presence of natural eye movements and eye blink artefacts that are mixed with the signal of interest. We propose a method based on Convolutional Dictionary Learning that is able to automatically highlight the Nystagmus waveforms, separating the natural motion from the pathological movements. We show on simulated signals that our method can indeed improve the pattern recovery rate and provide clinical examples to illustrate how this algorithm performs.

The oculomotor deficits associated with Huntington's Disease (HD) are one of the earliest signs of disease onset. They include a marked delay in executing voluntary saccades and a difficulty inhibiting saccades to task-irrelevant stimuli. In addition, HD patients develop a deficit in task-switching, which can be demonstrated by the continued adherence to a rule after it has been recently changed. These deficits are likely to be the result of a progressive neural degeneration of the fronto-striatal system, which is a distinguishing feature of HD neuropathology. It is predicted that as the disease progresses the magnitude of these specific deficits should increase. We tested a cohort of early HD patients and presymptomatic HD gene carriers on a series of oculomotor tasks designed to measure saccade initiation, inhibition and rule switch cost. Saccadic latencies and error rates in early HD patients were found to be systematically higher than controls. Presymptomatic HD subjects showed small increases in saccadic latencies and error rates that were in proportion to the predicted age of disease onset. These results suggest that saccadometry and a cognitively demanding oculomotor task may be useful as an indicator of function in HD.