Inherited optic neuropathies include complex phenotypes, mostly driven by mitochondrial dysfunction. We report an optic atrophy spectrum disorder, including retinal macular dystrophy and kidney insufficiency leading to transplantation, associated with mitochondrial DNA (mtDNA) depletion without accumulation of multiple deletions. By whole-exome sequencing, we identified mutations affecting the mitochondrial single strand binding protein (SSBP1) in four families with dominant and one with recessive inheritance. We show that SSBP1 mutations in patient-derived fibroblasts variably affect its amount and alter multimer formation, but not the binding to ssDNA. SSBP1 mutations impaired mtDNA, nucleoids and 7S-DNA amounts as well as mtDNA replication, impacting replisome machinery. The variable mtDNA depletion in cells reflected in severity of mitochondrial dysfunction, including respiratory efficiency, OXPHOS subunits and complexes amount and assembly. mtDNA depletion and cytochrome c oxidase-negative cells were found ex-vivo in biopsies of affected tissues, like kidney and skeletal muscle. Reduced efficiency of mtDNA replication was also reproduced in vitro, confirming the pathogenic mechanism. Furthermore, ssbp1 suppression in zebrafish induced signs of nephropathy and reduced optic nerve size, the latter phenotype complemented by wild-type mRNA but not by SSBP1 mutant transcripts. This previously unrecognized disease of mtDNA maintenance implicates SSBP1 mutations as cause of human pathology.

To determine the reproducibility of spectral-domain optical coherence tomography (OCT) measurements of peripapillary retinal nerve fiber layer (RNFL) and macular retinal thickness of the central 20-degree area of the posterior pole in adult and pediatric glaucoma and normal subjects. Prospective. Normal, glaucoma suspect and glaucoma eyes of adult and pediatric subjects were recruited. Spectralis OCT scans were obtained 3 times on the same day (intravisit) and 4 weeks later (intervisit). Six individual sectors, average RNFL, and macular retinal thickness using an 8×8 mm grid centered on the foveal pit were measured for all the eyes. The central 16 square areas centered on the foveal pit were called the central macular area and the surrounding 48 square areas were called the perimacular area. Intraclass correlation coefficient, coefficient of variation (COV), and test-retest variability were calculated. Included were 51 adult eyes and 25 pediatric eyes. The intravisit and intervisit intraclass correlation coefficient for the central macular, perimacula, and average RNFL was very good (>0.8) for all adult and pediatric normal and glaucomatous eyes. The mean COVs of normal and glaucomatous eyes were higher for average RNFL (1.5 ± 1.5% adults, 1.0 ± 0.9% pediatric) compared to the central macula (0.56 ± 0.54% adults, 0.68 ± 0.64% pediatric) and perimacular thickness (0.64 ± 0.51% adults, 0.57 ± 0.42% pediatric) (1-way analysis of variance, P0.05). No intervisit reproducibility analysis was available for pediatric glaucoma eyes. The reproducibility of Spectralis spectral-domain-OCT were very good for both RNFL and macular thickness measurements in glaucoma/glaucoma suspect eyes of adult and pediatric subjects.