Leber’s hereditary optic neuropathy (LHON) is the most frequent mitochondrial disease and was the first to be genetically defined by a point mutation in mitochondrial DNA (mtDNA). A molecular diagnosis is achieved in up to 95% of cases, the vast majority of which are accounted for by 3 mutations within mitochondrial complex I subunit–encoding genes in the mtDNA (mtLHON). Here, we resolve the enigma of LHON in the absence of pathogenic mtDNA mutations. We describe biallelic mutations in a nuclear encoded gene, DNAJC30 , in 33 unsolved patients from 29 families and establish an autosomal recessive mode of inheritance for LHON (arLHON), which to date has been a prime example of a maternally inherited disorder. Remarkably, all hallmarks of mtLHON were recapitulated, including incomplete penetrance, male predominance, and significant idebenone responsivity. Moreover, by tracking protein turnover in patient-derived cell lines and a DNAJC30 -knockout cellular model, we measured reduced turnover of specific complex I N-module subunits and a resultant impairment of complex I function. These results demonstrate that DNAJC30 is a chaperone protein needed for the efficient exchange of complex I subunits exposed to reactive oxygen species and integral to a mitochondrial complex I repair mechanism, thereby providing the first example to our knowledge of a disease resulting from impaired exchange of assembled respiratory chain subunits.

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Leber's hereditary optic neuropathy (LHON) refers to a group of mitochondrial diseases and is characterized by defects of the mitochondrial electron transport chain and decreased level of oxidative phosphorylation. The list of LHON primary mtDNA mutations is regularly updated. In this study, we describe the homoplasmic nucleotide substitution m.3472T>C in the MT-ND1 (NADH-ubiquinone oxidoreductase chain 1) gene and specific changes in cell metabolism in a patient with LHON and his asymptomatic sister. To confirm the presence of mutation-related mitochondrial dysfunction, respiration of skin fibroblasts and platelets from the patient and his sister was studied, as well as the mitochondrial potential and production of reactive oxygen species in the skin fibroblasts. In addition, based on characteristics of the toxic effect of paraquat, a new approach was developed for detecting the functional activity of complex I of the mitochondrial respiratory chain.

Aim. To study the features of the clinical symptoms of toxic optic neuropathy. Methods. 21 patients (42 eyes) with toxic optic neuropathy were examined with the use of standard ophthalmic exam, computer visual field test, spectral optical coherence tomography of the retina and optic nerve. Results. Toxic optic neuropathies were caused by the acute (4 patients) or chronic (10 patients) alcohol intake, drug abuse (6 patients) and medications (ethambutol, 1 patient). In all patients bilateral visual deterioration with central scotomas with various levels of light sensitivity reduction and prominent dyschromatopsia was revealed. The features of structural changes were reveled in patients with toxic optic neuropathy: the primary thinning of the retinal inner layers with further peripapillary retinal nerve fiber layer thickness loss. Severity of the structural changes ranged from the predominant damage of the retinal inner layers and minor decrease in the temporal peripapillary sector thickness to profound atrophy of the ganglion cell complex and optic nerve. In acute and chronic alcohol abuse after the treatment and complete alcohol cessation 43% of patients noted recovered visual function. Conclusion. Severity of the symptoms of toxic optic neuropathy, intensity and the rate of atrophy development, and prognosis depend on the nature of the toxin, its dose and exposure time, genetic features in each case; such algorithm of the changes is probably connected to the pathogenesis based on mitochondrial dysfunction.

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