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We read with great interest the recent publication by Rocatcher and colleagues[1] entitled 'The top 10 most frequently involved genes in hereditary optic neuropathies in 2186 probands', reporting on the experience of a national diagnostic centre for hereditary optic neuropathies (HON) in France. This flexible approach enlarges the number of genes screened, compared with the fixed number of 87 genes included in the custom targeted gene panel reported by Rocatcher I et al i .[1] Therefore, we found pathogenic variants in 30 genes, of which 18 were in single families (8.4%), whereas in the French cohort, only 21 genes were found to carry pathogenic variants, with seven singleton cases (1.5%). This is currently the standard algorithm followed by I in silico i panel analysis, prioritizing variants in known HON genes, to eventually discover new disease genes. Thus, the top 10 genes are consolidated by the contribution of the Italian cohort, with I OPA1 i , I WFS1 i and I ACO2 i accounting for 76% of diagnosed HON, due to a nuclear gene defect. [Extracted from the article]

Purpose: Recent investigations suggested that unaffected carriers of Leber hereditary optic neuropathy (LHON) may show subclinical visual alterations. Structural changes have also been detected by optical coherence tomography (OCT), which revealed a temporal thickening of the retinal nerve fiber layer (RNFL). These changes may reflect compensatory effects such as mitochondria accumulation within the RNFL axons. This study aimed to investigate whether the RNFL of LHON carriers shows greater than expected thickness variations, which may reflect transient subclinical changes, over the course of years., Methods: Using Stratus OCT, the RNFL thickness was measured yearly from 2005 to 2008 in 24 Brazilian LHON carriers, all with homoplasmic 11778/ND4 mtDNA mutation. An Italian sample of 20 healthy subjects served as a control. Data were compared also to a previously published sample (n=59) of glaucomatous eyes., Results: The LHON carriers showed test-retest standard deviations that were larger than normal controls in the temporal (p=0.004), superior (p<0.0001), and inferior quadrants (p=0.019). Compared to the glaucoma cases, no statistical differences were observed., Conclusions: The RNFL thickness in LHON carriers, when measured at different time points, has higher variability than in normal subjects. Transitory RNFL swelling may be caused either by compensatory mechanisms (increased mitochondrial biogenesis) or by axonal stasis preceding decompensation of retinal ganglion cells. In both situations, these changes may represent the origin of the visual alterations previously detected in LHON carriers. Alternatively, increased variability of RNFL thickness may be influenced by the LHON microangiopathy, as retinal blood vessels contribute to the OCT RNFL thickness measurements.