Update on gene therapies in pediatric ophthalmology.

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.

Intravitreal Glioma in a Boy Aged 7 Years.

This case report discusses a diagnosis of intravitreal glioma in a boy aged 7 years with neurofibromatosis type 1.

Long term follow-up after haematopoietic stem cell transplantation for mucopolysaccharidosis type I-H: a retrospective study of 51 patients.

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.

Function of the Retinal Pigment Epithelium in Patients With Neurofibromatosis Type 1.

Purpose: Retinal and choroidal abnormalities in neurofibromatosis type 1 (NF1) remain poorly studied. It has been reported, however, that the function of the retinal pigment epithelium (RPE) in NF1 was abnormal, with a supra-normal Arden ratio of the electro-oculogram (EOG). This study aims to evaluate the function of the RPE, using EOG, first in patients with NF1 compared to controls and second in patients with NF1 with choroidal abnormalities compared to patients with NF1 without choroidal abnormalities. Methods: This prospective case-control study included 20 patients with NF1 (10 patients with choroidal abnormalities and 10 patients without) and 10 healthy patients, matched for age. A complete ophthalmologic assessment with multimodal imaging, an EOG, and a full-field electroretinogram were performed for each included patient. The main outcome measured was the EOG light peak (LP)/dark trough (DT) ratio. Results: The LP/DT ratio was 3.02 ± 0.52 in patients with NF1 and 2.63 ± 0.31 in controls (P = 0.02). DT values were significantly lower in patients with NF1 than in controls (240 vs. 325 µV, P = 0.02), while light peak values were not significantly different (P = 0.26). No difference was found for peak latencies. No significant correlation between the surface and number of choroidal abnormalities and EOG parameters was demonstrated. Conclusions: This study confirms the dysfunction of the RPE in patients with NF1, involving a lower DT and a corresponding higher LP/DT ratio. We hypothesize that this pattern may be due to a dysregulation of the melanocytogenesis, inducing a disruption in Ca2+ ion flux and an abnormal polarization of the RPE.

The role of irinotecan-bevacizumab as rescue regimen in children with low-grade gliomas: a retrospective nationwide study in 72 patients.

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.

Optic Nerve Abnormalities in Morning Glory Disc Anomaly: An MRI Study.

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.

RETINAL VASCULAR ABNORMALITIES IN CHILDREN WITH NEUROFIBROMATOSIS TYPE 1.

PURPOSE: Retinal vascular abnormalities (RVAs) have been recently described in patients with neurofibromatosis Type 1 (NF1) as vascular tortuosity, best visible on infrared imaging. This study assessed clinical RVA's characteristics in a large series of children with NF1. METHODS: This retrospective observational study was conducted in children (0-18 years) with an NF1 diagnosis. Using near-infrared imaging, RVAs were classified according to the nature of vessels involvement and their degree of tortuosity. RESULTS: Retinal imaging from 140 children, with a median age of 8.8 years (1.5-18), was included; 52 patients (37.1%) (81 eyes) exhibited RVAs. These RVAs comprised 96% (50/52) of simple vascular tortuosity and 17% (9/52) of a corkscrew pattern. A corkscrew pattern involved only small veins, whereas simple vascular tortuosity could affect both arteries and veins. No statistically significant age correlation was observed, but evolution of RVAs from simple vascular tortuosity to corkscrew pattern was observed in 5 cases. CONCLUSION: Retinal vascular abnormalities occurred in 37.1% of children with NF1. These abnormalities may result from NF1 promoting localized tortuosity in both small arteries and veins, whereas only small second-order or tertiary-order venules evolve to a highly tortuous pattern.

Recent developments in the management of congenital cataract.

Congenital cataract is a rare eye disease, one of the leading treatable causes of low vision in children worldwide. Hereditary cataracts can be divided in syndromic and non-syndromic cataracts. Early diagnosis in congenital cataracts is key to reach good visual function. Current surgical techniques, that combine microincision cataract extraction and primary intraocular lens (IOL) implantation, have improved childhood cataract outcome. Complications include posterior capsule opacification (PCO), aphakic or pseudophakic glaucoma, uveitis, pupil displacement and IOL decentration. A recent study using a modified Delphi approach identified areas of consensus and disagreement in the management of pediatric cataract. A consensus or near consensus was achieved for 79% of the questions, however 21% of the questions remained controversial, as for IOL implantation strategy. Congenital cataracts show a highly variable phenotype and genotype, and can be related to different mutations, genetic variance, and other risk factors. Congenital cataracts can be associated with other ocular developmental abnormalities, including microphthalmia, microcornea, or aniridia and with systemic findings. Next-generation sequencing (NGS) and forthcoming new ultra-high-throughput sequencing represent excellent tools to investigate the genetic causes of congenital cataracts. A better recognition of different clinical presentations and underlying etiologies of congenital cataracts may lead to the development of new approaches to improve visual outcome after cataract surgery and promote early detection of systemic associated syndromes.

Extraocular muscle positions in anterior plagiocephaly: V-pattern strabismus explained using geometric mophometrics.

INTRODUCTION: Ophthalmological involvement in anterior plagiocephaly (AP) due to unicoronal synostosis (UCS) raises management challenges. Two abnormalities of the extraocular muscles (EOM) are commonly reported in UCS without objective quantification: (1) excyclorotation of the eye and (2) malposition of the trochlea of the superior oblique muscle. Here we aimed to assess the positions of the EOM in AP, using geometric morphometrics based on MRI data. MATERIALS AND METHODS: Patient files were listed using Dr WareHouse, a dedicated big data search engine. We included all patients with AP managed between 2013 and 2018, with an available digital preoperative MRI. MRIs from age-matched controls without craniofacial conditions were also included. We defined 13 orbital and skull base landmarks in order to model the 3D position of the EOM. Cephalometric analyses and geometric morphometrics with Procrustes superimposition and principal component analysis were used with the aim of defining specific EOM anomalies in UCS. RESULTS: We included 15 preoperative and 7 postoperative MRIs from patients with UCS and 24 MRIs from age-matched controls. Cephalometric analyses, Procrustes superimposition and distance computations showed a significant shape difference for the position of the trochlea of the superior oblique muscle and an excyclorotation of the EOM. CONCLUSIONS: Our results confirm that UCS-associated anomalies of the superior oblique muscle function are associated with malposition of its trochlea in the roof of the orbit. This clinical anomaly supports the importance of MRI imaging in the surgical management of strabismus in patients with UCS.

Corpus callosum metrics predict severity of visuospatial and neuromotor dysfunctions in ARID1B mutations with Coffin-Siris syndrome.

ARID1B mutations in Coffin-Siris syndrome are a cause of intellectual disability (0.5-1%), with various degrees of autism and agenesis of the corpus callosum (10%). Little is known regarding the cognitive and motor consequences of ARID1B mutations in humans and no link has been made between corpus callosum anomalies and visuospatial and neuromotor dysfunctions. We have investigated the visuospatial and neuromotor phenotype in eight patients with ARID1B mutations. A paramedian sagittal section of the brain MRI was selected, and corpus callosum was measured in anteroposterior length, genu and trunk width. Spearman's rank order coefficients were used to explore correlations between visuospatial and social cognitive variables and dimensions of the corpus callosum. A significant correlation between genu width size and visual cognition was observed. Retrocerebellar cysts were associated with corpus callosum anomalies. Here, we show that corpus callosum anomalies caused in ARID1B mutations may be predictive of the visuospatial and motor phenotype in Coffin-Siris syndrome.

The therapeutic potential of a calorie-restricted ketogenic diet for the management of Leber hereditary optic neuropathy.

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.

Spontaneous consecutive esotropia.

PURPOSE: Although less frequent than consecutive exotropia, consecutive esotropia is a well-known type of strabismus when it follows the surgical correction of an exotropia. Spontaneous conversion from initial constant, large-angle exotropia beyond the age of 3 months to esotropia or orthophoria, however, is not common. We describe a series of infants who presented a spontaneous evolution from a large-angle infantile exotropia to either an orthophoria or a spontaneously consecutive esotropia. METHODS: Cases of infants examined in the pediatric neuro-ophthalmology clinic of a tertiary ophthalmology department between 2009 and 2015, and having presented an early large-angle exotropia that spontaneously converted into an esotropia or orthophoria-i.e., without any previous surgery or botulinum toxin injection-were studied. RESULTS: Ten cases (6 M:4 F) were followed up. Median age at first exotropia assessment was 3.88 months (SD = 6.35). Median age at spontaneous conversion to esotropia or orthophoria was 7.23 months (SD = 14.73). Six patients suffered from severe neurologic or metabolic diseases, three had neonatal respiratory distress syndrome, and one was healthy. CONCLUSION: Spontaneous conversion from initial large-angle exotropia to esotropia or orthophoria can be encountered. The cerebral maturation of visual structures probably accounts for this uncommon strabismus sequence.

Usefulness of cocaine drops in investigating infant anisocoria.

INTRODUCTION: Whereas apraclonidine has eclipsed cocaine test in the exploration of unilateral miosis in adults, its use in infants is avoided because of the risk of central nervous system depression. This chart review evaluates the usefulness of cocaine drops in infants. METHODS: Infants under the age of one referred for unilateral miosis between November 1, 2009 and November 1, 2015, were reviewed. Patients underwent the following protocol: (1) in case of isolated miosis, cocaine test was performed. If the miotic pupil did not dilate, imaging was performed. Dilation in both eyes led to simple clinical follow-up. (2) In case of miosis associated with ptosis or iris heterochromia, imaging of the brain, neck and chest was directly performed. RESULTS: Twenty-six children were included. Twenty-two presented an isolated miosis; three had ipsilateral ptosis, and one had no pupillary light reflex in the miotic eye. Cocaine tests performed in the 22 patients led to imaging in four, which was always normal. No side effect of the test was noticed. Imaging found one neuroblastoma and one intraorbital hemolymphangioma in two patients presenting miosis plus another sign. Imaging was avoided for 18 patients thanks to negative cocaine test. DISCUSSION: Urgent imaging is mandatory in infants presenting with miosis associated with other localizing sign on the sympathetic nerve pathway (Horner syndrome). Since the uselessness of complementary investigations in isolated infantile miosis cannot be proven so far, cocaine test remains the gold standard, as it is safe, cheaper and less stressful than systematic imaging.

Relevance of Identifying JAG1 Mutations in Patients With Isolated Posterior Embryotoxon.

PURPOSE: Although posterior embryotoxon (PE) has a high incidence in the general population, clinicians should exclude any sign of glaucoma in its presence. This anatomic abnormality is often referred to as "isolated" when the intraocular pressure is normal. Nevertheless, it may be the only sign of Alagille syndrome (AS) that can be clinically heterogenous, as presented here. This possibility must be known, to look for involvement of other organs, and in case of suspicion, mutation of the JAG1 gene must be considered. METHODS: In this case series, we present the observation of a family with 3 individuals from 3 generations, in whom PE was a marker of AS. RESULTS: PE were observed in these 3 patients and considered as "isolated" as the intraocular pressure was normal. The 2 elder patients were also followed for atypical retinal dystrophy with speckling of the retinal pigment and optic disc drusen. AS syndrome was suspected when mild liver dysfunction was detected in the youngest girl. The detection of JAG1 mutation confirmed this diagnosis. CONCLUSIONS: As AS can be clinically heterogenous, it must be considered in case of isolated PE. Involvement of other organs must be looked for to search for mutation of the JAG1 gene in relevant cases.

Transient Retinal Dysfunctions after Acute Cannabis Use.

Although cannabis is very widespread worldwide, the impact of cannabis on visual function remains poorly understood. This is partly due to numerous difficulties met in developing clinical studies in cannabis users. Here, we report the first documented case of neuroretinal dysfunction after acute cannabis smoking. This observation was favored by the need of an annual ophthalmic evaluation in the context of a chloroquine intake for a systemic lupus erythematosus in a 47-year-old heavy cannabis user. A complete ophthalmic evaluation including visual acuity tests, intraocular pressure, fundoscopic examination, automated 10° central visual field, full-field electroretinogram (ERG) and multifocal ERG was performed twice - 30 min and 5 h after cannabis smoking. A strong decrease (up to 48%) in the a-wave amplitude of the full-field ERG was measured 30 min after cannabis smoking for all scotopic responses compared with the responses 5 h after smoking. Other tests showed reproducible results between the 2 series of measurements. This clinical case suggests that acute inhalation of cannabis affects the photoreceptors functioning. This rare situation suggests further investigations are required on the impact of cannabis on retinal processing, especially since cannabis has been incriminated in car injuries.