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Purpose: RTN4IP1 biallelic mutations cause a recessive optic atrophy, sometimes associated to more severe neurological syndromes, but so far, no retinal phenotype has been reported in RTN4IP1 patients, justifying their reappraisal., Methods: Seven patients from four families carrying biallelic RTN4IP1 variants were retrospectively reviewed, with emphasis on their age of onset, visual acuity, multimodal imaging including color and autofluorescence frames, spectral-domain optical coherence tomography with RNFL and macular analyses., Results: Seven patients from four RTN4IP1 families developed in their first decade of life a bilateral recessive optic atrophy with severe central visual loss, and primary nystagmus developed in 5 of 7 patients. Six patients were legally blind. In a second stage, the seven individuals developed a rod-cone dystrophy, sparing the macular zone and the far periphery. This retinal damage was identified by 55° field fundus autofluorescence frames and also by spectral-domain optical coherence tomography scans of the temporal part of the macular zone in five of the seven patients. Full-field electroretinography measurements disclosed reduced b-wave amplitude of the rod responses in all patients but two. Family 4 with the p.R103H and c.601A > T (p.K201*) truncating mutation had further combined neurological signs with cerebellar ataxia, seizures, and intellectual disability., Conclusion: RTN4IP1 recessive optic atrophy is systematically associated to a rod-cone dystrophy, which suggests that both the retinal ganglion cells and the rods are affected as a result of a deficit in the mitochondrial respiratory chain. Thus, systematic widefield autofluorescence frames and temporal macular scans are recommended for the evaluation of patients with optic neuropathies., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Opthalmic Communications Society, Inc.)

Variants of the TTLL5 gene, which encodes tubulin tyrosine ligase-like family member five, are a rare cause of cone dystrophy (COD) or cone-rod dystrophy (CORD). To date, only a few TTLL5 patients have been clinically and genetically described. In this study, we report five patients harbouring biallelic variants of TTLL5. Four adult patients presented either COD or CORD with onset in the late teenage years. The youngest patient had a phenotype of early onset severe retinal dystrophy (EOSRD). Genetic analysis was performed by targeted next generation sequencing of gene panels and assessment of copy number variants (CNV). We identified eight variants, of which six were novel, including two large multiexon deletions in patients with COD or CORD, while the EOSRD patient harboured the novel homozygous p.(Trp640*) variant and three distinct USH2A variants, which might explain the observed rod involvement. Our study highlights the role of TTLL5 in COD/CORD and the importance of large deletions. These findings suggest that COD or CORD patients lacking variants in known genes may harbour CNVs to be discovered in TTLL5, previously undetected by classical sequencing methods. In addition, variable phenotypes in TTLL5 -associated patients might be due to the presence of additional gene defects.

Autosomal-recessive optic neuropathies are rare blinding conditions related to retinal ganglion cell (RGC) and optic-nerve degeneration, for which only mutations in TMEM126A and ACO2 are known. In four families with early-onset recessive optic neuropathy, we identified mutations in RTN4IP1, which encodes a mitochondrial ubiquinol oxydo-reductase. RTN4IP1 is a partner of RTN4 (also known as NOGO), and its ortholog Rad8 in C. elegans is involved in UV light response. Analysis of fibroblasts from affected individuals with a RTN4IP1 mutation showed loss of the altered protein, a deficit of mitochondrial respiratory complex I and IV activities, and increased susceptibility to UV light. Silencing of RTN4IP1 altered the number and morphogenesis of mouse RGC dendrites in vitro and the eye size, neuro-retinal development, and swimming behavior in zebrafish in vivo. Altogether, these data point to a pathophysiological mechanism responsible for RGC early degeneration and optic neuropathy and linking RTN4IP1 functions to mitochondrial physiology, response to UV light, and dendrite growth during eye maturation., (Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Importance: Retinitis punctata albescens (RPA) is an autosomal recessive form of retinitis pigmentosa characterized by white dotlike deposits in the fundus, in most cases caused by mutations in RLBP1., Objective: To study disease progression and visual function in RPA., Design: We performed clinical and molecular investigations in patients with RPA at various ages, from November 5, 2003, through June 20, 2012, with no planned patient follow-up., Setting: The National Reference Center for Genetic Sensory Diseases (Montpellier)., Participants: Eleven patients with RPA (mean age, 24 [range, 3-39] years) from 7 families and 11 control subjects undergoing evaluation., Exposure: Optical coherence tomography measurements., Main Outcomes and Measures: Screening for mutations by polymerase chain reaction sequencing of the 9 RLBP1 exons. Patients underwent standard ophthalmic examination, fundus imaging, autofluorescence testing, Goldmann visual field measurement, optical coherence tomography, adaptive optics-based infrared fundus ophthalmoscopy, dark adaptometry, and electroretinography., Results: We found 2 novel RLBP1 mutations (p.Tyr111X and p.Arg9Cys), and 8 patients from Morocco were homozygous for the recurrent 7.36-kilobase RLBP1 deletion of exons 7 through 9. All patients had night blindness (before age 6 years in 10). The dotlike deposits were generally dense but could be rare, appearing in adaptive optics as elongated structures with variable orientation and no foveal involvement. We found no specific refractive error, and visual acuity varied widely from normal (1.2) to counting fingers. Variable degrees of visual field impairment were present, and all patients had severely decreased electroretinographic responses with predominant rod impairment. No correlation between visual acuity (P = .27) or visual field and age (P = .08) was present. On optical coherence tomography, the mean (SD) central foveal (122 [23] vs 187 [30] µm in controls) and foveal (147 [19] vs 217 [17] µm) thicknesses were significantly (P < .01) decreased, independently of age, whereas the retinal thickness at the 3- and 6-mm rings around the fovea progressively decreased with age. Mean (SD) cone number was normal in 1 patient aged 13 years (21,000/mm² [2000/mm²]) but dropped to 10,500/mm² (5244/mm²), 8667/mm² (2944/mm²), and 5833/mm² (983/mm²) in 3 other patients aged 39, 32, and 29 years, respectively., Conclusions and Relevance: Patients with RPA show variable degrees of foveal cone death, even at an early stage. This finding has implications for future treatment.

Mutations in genes encoding components of the mitochondrial DNA (mtDNA) replication machinery cause mtDNA depletion syndromes (MDSs), which associate ocular features with severe neurological syndromes. Here, we identified heterozygous missense mutations in single-strand binding protein 1 (SSBP1) in 5 unrelated families, leading to the R38Q and R107Q amino acid changes in the mitochondrial single-stranded DNA-binding protein, a crucial protein involved in mtDNA replication. All affected individuals presented optic atrophy, associated with foveopathy in half of the cases. To uncover the structural features underlying SSBP1 mutations, we determined a revised SSBP1 crystal structure. Structural analysis suggested that both mutations affect dimer interactions and presumably distort the DNA-binding region. Using patient fibroblasts, we validated that the R38Q variant destabilizes SSBP1 dimer/tetramer formation, affects mtDNA replication, and induces mtDNA depletion. Our study showing that mutations in SSBP1 cause a form of dominant optic atrophy frequently accompanied with foveopathy brings insights into mtDNA maintenance disorders. [ABSTRACT FROM AUTHOR]