Andrea L. Vincent

Introduction: Cystic maculopathy (CM) occurs in 10-50% of inherited rod-cone retinal degenerations (RCD), with carbonic anhydrase inhibitors reported to show improvement, but rebound may occur. Alternate day treatment with topical Brinzolamide may alleviate this effect. We assessed treatment response in alternate day vs continuous day dosing.Methods: A retrospective chart review of patients with RCD undertaken, identifying those with CM, recording treatment regimen, vision, and OCT parameters. Outcomes were visual acuity (VA) improvement ≥3 letters significant, OCT reduction of mean cyst size (CMT) ≥11% significant, and macular volume (MV).Results: Of 260 patients identified, 66 (25.3%) had CM; complete data were available for 22 patients (41 eyes) in Group 1 (alternate day) and 12 patients (22 eyes) in Group 2 (continuous). In group 1, VA improved in 29% patients, with significant CMT mean reduction of 16 μm (80% eyes). Group 2 VA improved in 13.6% patients, with significant CMT mean reduction of 34 μm (77% eyes). No statistical difference between groups was found with VA or MV. Mean CMT reduction was significant in Group 2, 21 μm (p-value 0.034) and VA improvement was better with alternate day treat- ment.Discussion: This study suggests both treatment regimens have similar functional outcomes, enabling a tailored and patient-centric approach to dosing.

1. Inherited maculopathies constitute a genetically heterogeneous group of disorders, with more than 32 genes implicated to date (1). These conditions may be transmitted through autosomal dominant,...

Heterozygous FOXL2 (non-)coding sequence and structural variants (SVs) lead to blepharophimosis, ptosis and epicanthus inversus syndrome (BPES), a rare, autosomal dominant developmental disorder characterized by a completely penetrant eyelid malformation and incompletely penetrant primary ovarian insufficiency (POI). We collected variants from our in-house database, generated via clinical genetic testing and downstream research testing in the Center for Medical Genetics Ghent, Belgium (2001-2024), and via literature and other resources in the same period. All retrieved variants were categorized using ACMG/AMP classifications to increase the knowledge of pathogenicity. We collected 413 unique genetic defects of the FOXL2 region, including 76 novel variants, in 864 index patients. Of these, 87% of patients were identified with a coding FOXL2 sequence variant. The polyalanine tract is a known mutational hotspot of FOXL2 , illustrated here by the high percentage of pathogenic polyalanine expansions (24%). Furthermore, the molecular spectrum in typical BPES index patients is characterized by 8% coding deletions and 3% deletions located up- and downstream of FOXL2 . The remaining 2% carry translocations along with chromosomal rearrangements of 3q23. This uniform and structured reclassification, incorporating the largest dataset of variants implicated in FOXL2 -associated disease so far, will improve both the diagnosis as well as genetic counselling for individuals with BPES.

Small nuclear RNAs (snRNAs) combine with specific proteins to generate small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome. U4 snRNA forms a duplex with U6 and, together with U5, contributes to the tri-snRNP spliceosomal complex. Variants in RNU4-2, which encodes U4, have recently been implicated in neurodevelopmental disorders. Here we show that heterozygous inherited and de novo variants in RNU4-2 and in four RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8 and RNU6-9), which encode U6, recur in individuals with nonsyndromic retinitis pigmentosa (RP), a genetic disorder causing progressive blindness. These variants cluster within the three-way junction of the U4/U6 duplex, a site that interacts with tri-snRNP splicing factors also known to cause RP (PRPF3, PRPF8, PRPF31), and seem to affect snRNP biogenesis. Based on our cohort, deleterious variants in RNU4-2 and RNU6 paralogs may explain up to ~1.4% of otherwise undiagnosed RP cases. This study highlights the contribution of noncoding RNA genes to Mendelian disease and reveals pleiotropy in RNU4-2, where distinct variants underlie neurodevelopmental disorder and retinal degeneration.

Wolfram-like syndrome leads to retinal ganglion cell degeneration and vision loss. Wolfram-like syndrome is primarily caused by variants in the WFS1 gene, which encodes an endoplasmic reticulum resident transmembrane protein, Wolframin. To date, the disease mechanism remains unclear, and no therapies are available. Here, we generated a mouse model carrying the pathogenic WFS1 ^E864K allele that recapitulated key features of human Wolfram-like syndrome, including bilateral optic atrophy, retinal nerve fiber thinning and lamination of the outer plexiform layer. We demonstrated, using the Wfs1 ^E864K mouse model, that alteration of the protein leads to impairments of retinal ganglion cell function, associated with a thinning of the inner retina layer and nerve fibers. These alterations are associated with myelin disorganization, axonal death, mitochondrial alterations in the axons, and impairment of endoplasmic reticulum-mitochondria communication in the soma. Our data showed that primary deficits are localized in the optic nerve before progressing towards the retinal ganglion cell soma. RNAseq analysis identified several altered signaling pathways such as in lipid metabolism, glia activation response, metabolic stress, organelle transport and quality control. These findings highlighted the critical role of Wolframin in optic nerve mitochondrial physiology, providing us with a pertinent model to develop novel innovative therapeutic strategies.

Ciliopathies are associated with a range of phenotypes including retinal degeneration and skeletal abnormalities. We present a retrospective study of 49 patients with variants in Cilia and Flagella Associated Protein 410 (CFAP410) from multiple ophthalmic centers across the world. Common clinical features included early-onset reduced visual acuity, photophobia, and delayed light-to-dark adaptation. A cone-rod dystrophy pattern was observed roughly two times more commonly than rod-cone dystrophy. A minority of patients (22.4%) presented with skeletal abnormalities consistent with axial spondylometaphyseal dysplasia (SMDAX). Patients with the most severe ophthalmic and skeletal phenotypes had disease-associated variants within conserved leucine-rich regions of CFAP410, and the structural effects of these variants were modelled using ChimeraX. This report furthers our understanding of CFAP410-associated clinical phenotypes such as retinal dystrophy and skeletal dysplasia.

Corneal dystrophies are a group of predominantly rare inherited disorders. They are by definition bilateral, relatively symmetrical, and without systemic involvement, affecting corneal transparency and/or refraction. Traditional classification of corneal dystrophies is based on slit‐lamp appearance, affected corneal layer and histological features. Molecular genetics has provided ultimate proof for the existence of distinct corneal dystrophies and discarded duplicates in their terminology. Currently, there are at least 16 genes with identified pathogenic variants implicated in corneal dystrophies. Herein, we summarise contemporary knowledge on genotype–phenotype correlations of corneal dystrophies, including a critical review of some reported variants, along with the understanding of the underlying pathogenic dystrophic process; essential knowledge for the development of targeted therapies.

Purpose: To design and build a new disease registry to track the natural history and outcomes of approved gene therapy in patients with inherited retinal diseases. Methods: A core committee of six members was convened to oversee the construction of the Fight Inherited Retinal Blindness! module. A further 11 experts formed a steering committee, which discussed disease classification and variables to form minimum datasets using a consensus approach. Results: The web-based Fight Inherited Retinal Blindness! registry records baseline demographic, clinical, and genetic data together with follow-up data. The Human Phenotype Ontology and Monarch Disease Ontology nomenclature were incorporated within the Fight Inherited Retinal Blindness! architecture to standardize nomenclature. The registry software assigns individual diagnoses to one of seven broad phenotypic groups, with minimum datasets dependent on the broad phenotypic group. In addition, minimum datasets were agreed on for patients undergoing approved gene therapy with voretigene neparvovec (Luxturna). New patient entries can be completed in 5 minutes, and follow-up data can be entered in 2 minutes. Conclusion: Fight Inherited Retinal Blindness! is an organized, web-based system that uses observational study methods to collect uniform data from patients with inherited retinal disease to track natural history and (uniquely) treatment outcomes. It is free to users who have control over their data.

Wolfram syndrome due to bi-allelic variants in WFS1 and mono-allelic Wolfram-like syndrome have variable ocular and syndromic associations. In this report, eight patients are described. A retrospective observational case series with detailed ophthalmic and systemic phenotyping, optical coherence tomography (OCT), and neuroimaging. Molecular investigations included gene panel and targeted Sanger sequencing. Eight patients (six female, two male) from six families were diagnosed with optic atrophy at a mean age of 15.5 ± 6.2 years (range 8-23) with mean follow-up of 3.2 ± 3.4 years (range 1.5-12.1). Three were asymptomatic. Mean presenting visual acuity was 0.31 ± 0.26 logMAR (Snellen equivalent 20/40). Diabetes mellitus was present in five patients (detected after screening in one), sensorineural hearing loss in five and diabetes insipidus in one. Other systemic features included psychiatric disorders in four patients and bladder dysfunction in three patients. OCT demonstrated marked nerve fiber layer loss in all patients. In dominant disease, macular OCT demonstrated a linear splitting abnormality of the outer plexiform layer (OPL) not found in recessive disease. Three novel variants in WFS1 were identified. After identification of the p.Val606Gly variant in three Māori patients including one with cone-rod retinal dystrophy, a reference database of 80 Māori/Pasifika patients with retinal dystrophy/optic atrophy was interrogated. This identified the variant in 10 patients with disease attributed to other genes. In Wolfram syndrome, systemic features are variable. Pathognomonic OPL lamination is associated with dominant disease. Early recognition of potentially syndromic optic atrophy allows prompt diagnosis of unrecognized diabetes mellitus.