網膜色素変性症

Biallelic variants in the RDH11 gene, a retinol dehydrogenase involved in the visual cycle and systemic retinoid homeostasis, were initially implicated in a rare condition characterized by retinal dystrophy, early-onset cataract, neurodevelopmental anomalies and myopathy, through single-family reports, with this association more recently being confirmed in a larger study. Here, we further establish the pathogenic role of RDH11 by presenting a large multi-center cohort, comprising eight individuals from seven unrelated families. Comprehensive genetic analysis identified homozygous variants in all affected subjects, including two novel variants, strongly supporting loss-of-function as the primary disease mechanism. Detailed clinical phenotyping defined a consistent and severe multisystem disorder. Ophthalmologically, the hallmark features include bilateral congenital or early-childhood cataracts requiring surgical intervention, accompanied by retinitis pigmentosa (RP). In terms of extra-ocular involvement, the cohort exhibited a high prevalence of neurodevelopmental delay, including intellectual disability, autistic spectrum disorder and learning difficulties. These features were frequently accompanied by congenital microcephaly, intrauterine and postnatal growth restriction, facial dysmorphisms, and dental anomalies. By significantly expanding both the mutational and phenotypic spectrum of RDH11-related disease, our findings provide independent replication of this gene-disease association and definitively support RDH11 as a bona fide syndromic RP gene.

OBJECTIVE: Maintaining a drivers' licence is an important patient-reported outcome. Conditions resulting in peripheral vision loss such as inherited retinal disorders (IRDs) can result in loss of licence due to an inadequate horizontal visual field (VF) extent. There are currently no international visual standards for licensing and current testing protocols outlined in licensing guidelines and conducted in out-patient clinics may not adequately reflect or predict on-road driving performance. The present study undertakes a scoping review of the VF of individuals with an IRD and their driving status and/or performance. It aims to determine the proportion of individuals who either meet the VF licensing requirements or pass a driving test and the impact of VF extent. METHODS AND ANALYSIS: 193 publications from online databases and other sources were identified, of which three publications met the inclusion criteria for the review. Publications were from two countries and included studies which measured driving performance based on collision records and driving simulator performance. RESULTS: Only level 4 evidence was available on the topic, including two case-control studies and one cross-sectional study. CONCLUSION: One study reported 36% of retinitis pigmentosa patients met the VF licencing requirements. There was inconclusive evidence regarding the impact of VF extent on driving performance, with one study finding that VF extent was predictive of driving performance, and other findings did not correlate.

INTRODUCTION: We report a unique clinical presentation of a patient with undiagnosed neurologic symptoms in the setting of retinitis pigmentosa (RP) with Coats-like reaction and FLVCR1 variant, expanding the presentation of FLVCR1 variants. CASE PRESENTATION: A 31-year-old Caucasian female with RP with Coats-like reaction initially presented to our clinic in August 2021 with worsening vision. Genetic testing identified the patient as heterozygous for FLVCR1 c.1092 + 5G>A and FLVCR1 c.1058C>T, p.(Thr353Met). The patient notably had a long-standing history of nyctalopia as well as complex neurologic symptoms without diagnosis. Neurologic presentation over 6 years included migraine headaches, decreased extremity strength, seizure-like episodes, and urinary incontinence. Progressive leg weakness and spasms eventually impaired weight bearing and ambulation. On presentation to the clinic again in February 2025, she reported progressive central vision loss, ocular pain OD, and persistent instability in her legs. OCT revealed cystoid macular edema, attenuated retinal vessels, and a large lipid exudation in the fovea OD. The patient was initiated on anti-VEGF therapy in February. Follow-up OCT 1 month later revealed a reduction in lipid exudation. CONCLUSION: This case underscores the importance of considering an underlying FLVCR1 variant in patients with retinitis pigmentosa and atypical neurologic symptoms. Despite prior genetic testing, this patient's neurologic findings remained undiagnosed, highlighting the need for greater clinical awareness of neuro-ophthalmic manifestations of rare genetic disorders. Anti-VEGF therapy appears effective in reducing lipid exudation in Coats-like retinopathy.

The gut microbiota crucial role in maintaining host metabolism, immune homeostasis, intestinal integrity, and mitochondrial function. Emerging evidence suggests that dysregulation of the microbiota-mitochondria axis represents one of the key mechanisms linking gut dysbiosis to the development of neurodegenerative and ocular diseases. The dysbiosis causes disruptions in mitochondrial physiology due to lower levels of short-chain fatty acids, increased intestinal permeability, endotoxemia, oxidative stress, and inflammation. These mechanisms contribute to the pathogenesis of Alzheimer's disease, Parkinson's disease, age-related macular degeneration, diabetic retinopathy, retinitis pigmentosa, and central serous chorioretinopathy. Environmental factors such as unhealthy dietary patterns, excessive antibiotic use, and prolonged exposure to artificial blue light may exacerbate dysbiosis and further disrupt mitochondrial homeostasis, thereby contributing to disease progression. We also elaborated the emerging therapeutic strategies targeting both the gut microbiota and mitochondrial function, including next-generation probiotics, postbiotics, dietary interventions, mitochondria-targeted antioxidants, NAD+ precursors, and precision medicine approaches. Collectively, current evidence represents the microbiota-mitochondria axis as a one of the promising mechanistic and therapeutic targets for neurodegenerative and ocular diseases. However, most therapeutic evidence discussed in this review is derived from preclinical studies, with relatively limited clinical validation. Future well-designed longitudinal studies and randomized clinical trials are essential to establish efficacy, safety, and translational applicability in humans.

INTRODUCTION: N6-methyladenosine (m6A) RNA modification is essential for retinal homeostasis. Pathogenic mutations in U6 snRNA have recently been identified in families with retinitis pigmentosa (RP), underscoring the importance of precise RNA processing in photoreceptor survival. METTL16 installs m6A at A43 of U6 snRNA, but its retinal role remains unknown. OBJECTIVES: To define the role of METTL16 in photoreceptor maintenance and determine how its deficiency contributes to retinal degeneration. METHODS: We generated rod-specificMettl16knockout (RKO) mice. Visual function was comprehensively evaluated by electroretinography, light-dark box test, and optomotor response. Retinal morphology was examined using immunohistochemical staining. Multi-omics profiling (RNA-seq, proteomics, MeRIP-seq) systematically identified differentially expressed genes and downstream targets. Translational efficiency was assessed through SUnSET assay and polysome profiling. RESULTS: RKO mice exhibited progressive visual impairment, photoreceptor degeneration, and synaptic defects. Mechanistically, METTL16 deficiency disrupted multiple layers of RNA regulation. In the nucleus, loss of U6 snRNA A43 m6A modification impaired 5' splice-site selection, causing aberrant exon skipping in RP-associated genes, including Tulp1 and Pde6g, before overt degeneration. METTL16 deficiency also altered m6A-associated regulation of selected transcripts, including Tor1b and Nlgn2. In the cytoplasm, METTL16 associated with translation-related factors, and its loss was accompanied by reduced global translation efficiency and decreased levels of several phototransduction proteins. CONCLUSION: These findings identify METTL16 as a regulator of photoreceptor integrity through U6 snRNA modification and m6A-associated transcript regulation, with additional evidence supporting a potential role in translational control. They provide a mechanistic link between RNA dysregulation and retinal degeneration.