Could internal limiting membrane peeling before Voretigen neparvovec-ryzl subretinal injection prevent focal chorioretinal atrophy?

Purpose: To report the effect of internal limiting membrane (ILM) peeling prior to Voretigen Neparvovec-ryzl (VN) subretinal injection on focal chorioretinal atrophy development in patients presenting with RPE65-mediated Leber congenital amaurosis (LCA). Design: Retrospective case series. Methods: Three patients who underwent bilateral subretinal VN injection for RPE65-mediated LCA were followed up for 18-24 months. ILM peeling was performed unilaterally in patients 1 and 2 and bilaterally in patient 3. Chorioretinal atrophy was identified on fundus biomicroscopy, non-mydriatic retinography and/or ultrawide field fundus imaging. Best corrected visual acuity (BCVA), spectral-domain optical coherence tomography (SD-OCT), visual fields, full-field stimulus threshold (FST) and visual functioning questionnaire score (NEI-VFQ-25) were reported. Outcome measures were changes in BCVA, visual fields, FST, NEI-VFQ-25, and chorioretinal atrophy location. Results: Chorioretinal atrophy at the injection site exclusively developed in eyes which did not undergo prior ILM peeling. In patient 3, bilateral pre-operative nummular chorioretinal alterations progressed toward epithelial atrophic patches in the mid and extreme retinal periphery 18 months after VN injection. BCVA and visual fields improved bilaterally. NEI_VFQ 25 remained stable in patient 1 and improved in patient 2 and 3. FST test improved bilaterally in patient 3. Conclusions: ILM peeling prior to VN injection seems to be a smoother and safer technique to administer VN treatment and may prevent secondary focal atrophy development at the injection site. However, another type of more extended chorioretinal atrophy might exist and could be related to LCA evolution or to incompletely understood adverse effect of VN product.

Improved performance and safety from Argus II retinal prosthesis post-approval study in France.

PURPOSE: To evaluate the post-approval long-term outcomes of the Argus II Retinal Prosthesis, with a specific focus on its functional visual benefit in patients' daily activities. METHODS: Eighteen patients with bare light perception due to end-stage retinitis pigmentosa were included in a French prospective, multicentre, single-arm study and followed for 2 years. Visual benefit in patients' daily activities was monitored through the use of the Functional Low-vision Observer Rated Assessment (FLORA), and the final score at 2 years was the primary effectiveness outcome. Standardized visual assessments were also performed. Device- or procedure-related adverse events were recorded. RESULTS: Seventeen subjects completed the study. Positive impacts of the Argus II system on functional vision and well-being were demonstrated for over 70% of subjects on the FLORA. Among the daily activities/tasks tested, finding doorways was one of the most statistically significantly improved tasks (p < 0.001), along with estimating the size of an obstacle (p < 0.001), visually locating a place setting on a dining table (p < 0.001) and visually locating people in a non-crowded setting (p < 0.001). Visual function was improved on most standardized tests. Only two device- or procedure-related serious adverse events were observed (one vitreous haemorrhage and one endophthalmitis, both resolved with treatment). No explantation was required. CONCLUSION: This first report of a completed post-approval study of Argus II with a two-year follow-up demonstrates the safety and effectiveness of the Argus II System in a real-world cohort of patients and further highlights its real functional benefit in implanted patients' daily activities.

Atypical Retinal Phenotype in a Patient With Alström Syndrome and Biallelic Novel Pathogenic Variants in ALMS1, Including a de novo Variation.

Alström syndrome (ALMS) is a rare autosomal recessive multi-organ syndrome considered to date as a ciliopathy and caused by variations in ALMS1. Phenotypic variability is well-documented, particularly for the systemic disease manifestations; however, early-onset progressive retinal degeneration affecting both cones and rods (cone-rod type) is universal, leading to blindness by the teenage years. Other features include cardiomyopathy, kidney dysfunction, sensorineural deafness, and childhood obesity associated with hyperinsulinemia and type 2 diabetes mellitus. Here, we present an unusual and delayed retinal dystrophy phenotype associated with ALMS in a 14-year-old female, with affected cone function and surprising complete preservation of rod function on serial electroretinograms (ERGs). High-throughput sequencing of the affected proband revealed compound heterozygosity with two novel nonsense variations in the ALMS1 gene, including one variant of de novo inheritance, an unusual finding in autosomal recessive diseases. To confirm the diagnosis in the context of an unusually mild phenotype and identification of novel variations, we demonstrated the biallelic status of the compound heterozygous variations (c.[286C > T];[1211C > G], p.[(Gln96*)];[(Ser404*)]). This unique case extends our knowledge of the phenotypic variability and the pathogenic variation spectrum in ALMS patients.

Proteasome subunit PSMC3 variants cause neurosensory syndrome combining deafness and cataract due to proteotoxic stress.

The ubiquitin-proteasome system degrades ubiquitin-modified proteins to maintain protein homeostasis and to control signalling. Whole-genome sequencing of patients with severe deafness and early-onset cataracts as part of a neurological, sensorial and cutaneous novel syndrome identified a unique deep intronic homozygous variant in the PSMC3 gene, encoding the proteasome ATPase subunit Rpt5, which lead to the transcription of a cryptic exon. The proteasome content and activity in patient's fibroblasts was however unaffected. Nevertheless, patient's cells exhibited impaired protein homeostasis characterized by accumulation of ubiquitinated proteins suggesting severe proteotoxic stress. Indeed, the TCF11/Nrf1 transcriptional pathway allowing proteasome recovery after proteasome inhibition is permanently activated in the patient's fibroblasts. Upon chemical proteasome inhibition, this pathway was however impaired in patient's cells, which were unable to compensate for proteotoxic stress although a higher proteasome content and activity. Zebrafish modelling for knockout in PSMC3 remarkably reproduced the human phenotype with inner ear development anomalies as well as cataracts, suggesting that Rpt5 plays a major role in inner ear, lens and central nervous system development.

Novel IQCE variations confirm its role in postaxial polydactyly and cause ciliary defect phenotype in zebrafish.

Polydactyly is one of the most frequent inherited defects of the limbs characterized by supernumerary digits and high-genetic heterogeneity. Among the many genes involved, either in isolated or syndromic forms, eight have been implicated in postaxial polydactyly (PAP). Among those, IQCE has been recently identified in a single consanguineous family. Using whole-exome sequencing in patients with uncharacterized ciliopathies, including PAP, we identified three families with biallelic pathogenic variations in IQCE. Interestingly, the c.895_904del (p.Val301Serfs*8) was found in all families without sharing a common haplotype, suggesting a recurrent mechanism. Moreover, in two families, the systemic phenotype could be explained by additional pathogenic variants in known genes (TULP1, ATP6V1B1). RNA expression analysis on patients' fibroblasts confirms that the dysfunction of IQCE leads to the dysregulation of genes associated with the hedgehog-signaling pathway, and zebrafish experiments demonstrate a full spectrum of phenotypes linked to defective cilia: Body curvature, kidney cysts, left-right asymmetry, misdirected cilia in the pronephric duct, and retinal defects. In conclusion, we identified three additional families confirming IQCE as a nonsyndromic PAP gene. Our data emphasize the importance of taking into account the complete set of variations of each individual, as each clinical presentation could finally be explained by multiple genes.

Adapted Surgical Procedure for Argus II Retinal Implantation: Feasibility, Safety, Efficiency, and Postoperative Anatomic Findings.

PURPOSE: To evaluate the feasibility, safety, and efficiency of an adapted surgical procedure used for postmarket Argus II implantations, so as to lower risks of postoperative hypotony or conjunctivoscleral erosion, and to describe the observed anatomic characteristics of the positioning of the implanted array. DESIGN: Single-arm prospective multicenter clinical trial. PARTICIPANTS: Eighteen consecutive patients with end-stage retinitis pigmentosa. METHODS: To protect the site of insertion of the cable of the device, a scleral flap was systematically added to the standardized implantation procedure. It was associated with temporalis fascia autograft, so as to cover the episcleral-fixed electronics case. Intraoperative and postoperative data at day 1, weeks 1 and 2, and months 1, 3, and 6 were collected. Postoperative distance between electrode-array and retina was measured on spectral-domain optical coherence tomography images. Position of the array was evaluated on fundus images between months 1 and 6. MAIN OUTCOME MEASURES: Feasibility of the modified surgical technique (time constraints, intraoperative complications), variations of intraocular pressure over time, postoperative ocular findings and adverse events, postoperative distance between the array and the retina, and rotation of the array between months 1 and 6 after implantation. RESULTS: The adapted surgical technique was performed easily without associated specific complications. No cases of chronic hypotony or conjunctivoscleral erosion were reported. One serious device/procedure-related adverse event was recorded (sterile posterior uveitis), which resolved after vitrectomy. Postoperative distance between array and retina was variable: full apposition was achieved in 4 patients (22.22%), partial apposition observed in 9 patients (50.00%), and absence of strict apposition noted in 5 patients (27.78%, 4 of whom had posterior staphyloma). A statistically significant slight rotation of the array was observed between months 1 and 6 (P < 0.0001), occurring downwardly in 68.75% of cases. CONCLUSIONS: The combined use of scleral flap and temporalis fascia autograft was easily achieved and effective in preventing hypotony and conjunctival erosion in our study. Postoperative distance between semirigid array and retinal surface was variable, and increased in the case of preoperative staphyloma. A slight rotation of the device occurred over time. Further studies based on larger samples are needed to confirm our findings and determine their functional consequences.

Predominantly Cone-System Dysfunction as Rare Form of Retinal Degeneration in Patients With Molecularly Confirmed Bardet-Biedl Syndrome.

PURPOSE: To describe a series of patients with Bardet-Biedl syndrome (BBS) and predominantly retinal cone dysfunction, a previously only rarely reported association. DESIGN: Retrospective observational case series. METHODS: Seven patients with clinically proven Bardet-Biedl syndrome had undergone detailed ocular phenotyping, which included fundus examination, Goldmann visual fields, fundus autofluorescence imaging (FAF), optical coherence tomography (OCT), and electroretinography (ERG). Mutational screening in the BBS genes was performed either by direct Sanger sequencing or targeted next-generation sequencing. RESULTS: All 7 patients had proven BBS mutations; 1 had a cone dystrophy phenotype on ERG and 6 had a cone-rod pattern of dysfunction. Macular atrophy was present in all patients, usually with central hypofluorescence surrounded by a continuous hyperfluorescent ring on fundus autofluorescence imaging. OCT confirmed loss of outer retinal structure within the atrophic areas. No clear genotype-phenotype relationship was evident. CONCLUSIONS: Patients with Bardet-Biedl syndrome usually develop early-onset retinitis pigmentosa. In contrast, the patients described herein, with molecularly confirmed Bardet-Biedl syndrome, developed early cone dysfunction, including the first reported case of a cone dystrophy phenotype associated with the disorder. The findings significantly expand the phenotype associated with Bardet-Biedl syndrome.

MSX2 Gene Duplication in a Patient with Eye Development Defects.

BACKGROUND: MSX2 mutations are a very rare cause of craniosynostosis. Gain-of-function mutations may lead to the Boston-type craniosynostosis with limb defects and refraction errors, whereas loss-of-function mutations causes primary osseous defects such as enlarged parietal foramina. MATERIALS AND METHODS: Herein we report the case of a child with bicoronal synostosis and cutaneous syndactylies, who presented iridal and chorioretinal colobomas. Due to the craniofacial features that were prominent in the clinical picture, the genes involved in craniosynostosis were explored. RESULTS: The patient disclosed an intragenic duplication of the entire MSX2 gene whereas no mutation was identified in any major genes known to be involved in craniosynostosis. CONCLUSION: This is the first report of an eye development defect due to an increase in the MSX2 copy number in a human being. The implication of this gene in eye development has already been shown in several animal models. Indeed, overexpression of the Msx2 gene in a mouse model resulted also in optic nerve aplasia and microphthalmia. This report expands the phenotypic spectrum of the MSX2 mutations impacting early ocular development knowledge.