srjcmsSRJCMSSRJCMS2788-8851https://doi.org/10.47310/srjcms.2021.v01i01.008The M.3460G>A Variant Impairs Mitochondrial Functions and Can Present as a Multiorgan PhenotypeJosefFinstererWith interest we read the article by Zhang et al. about molecular, functional, and genetic investigations in 42 Han Chinese patients with Leber’s hereditary optic neuropathy (LHON) due to the primary LHON mutation m.3460G>A in MT-ND1 [1]. It was found that the variant impairs assembly of complex-I, reduces ATP production, decreases the mitochondrial membrane potential, increases ROS production in mutant cybrids, mediates apoptosis, and impairs mitophagy [1].  The study is appealing but has several limitations which raise the following comments and concerns. Though LHON is commonly a disorder affecting retinal ganglion cells (RGCs) and the optic nerve [2], there is increasing evidence that any of the primary LHON mutations can also manifest in tissues other than the RGCs (LHON plus). Patients with LHON plus may additionally manifest with central nervous system (CNS) disease (dystonia, myoclonic epilepsy, temporal lobe epilepsy, leukoencephalopathy mimicking multiple sclerosis, psychomotor regression, posterior reversible encephalopathy syndrome (PRES), migraine with or without aura, chorea, cerebellar ataxia, dementia, or spinal cord problems), otologic disease (hypoacusis or hearing loss), endocrinological abnormalities (diabetes, pituitary adenoma, Hashimoto hypothyroidism, or hyperthyroidism), cardiac disease (dilated cardiomyopathy, ventricular arrhythmias, left ventricular hypertrabeculation, syncope, palpitations, angina, exertional dyspnoea, sudden cardiac death), vascular disease (aortic stiffness), bone marrow disease (anemia, fibrous dysplasia), kidney disease (renal failure), or peripheral nervous system (PNS)  disease (neuropathy, myopathy) [3]. In the eyes LHON patients may develop glaucoma or cataract in addition to RGC impairment [3]. Since these additional manifestations may be subclinical particular in the early stages of the disease, treating physicians have to actively look for them by prospective investigations. Since these manifestations can develop with progression of the disease, these investigations have to be regularly repeated during follow-up. The standard treatment of LHON is idebenone (900mg/d) [4]. Idebenone has anti-oxidative capacities and is usually given at onset of the disease. Since idebenone may modify the phenotype and mitochondrial functions, we should be told how many of the 42 included patients were regularly taking idebenone and how many of them benefited from the drug. It should be additionally mentioned which other drugs the 42 included patients were regularly taking. Though LHON mutations usually occur in the homoplasmic state [2], there are cases with heteroplasmic LHON mutations [5]. Since heteroplasmy rates not only influence the phenotypic expression but are crucial for genetic counselling [6], it is crucial that heteroplasmy rates of the m.3460G>A are presented.  Overall, the study is appealing as it documents functional mitochondrial impairment in m.3460G>A carriers but has some limitations which should be addressed before drawing final conclusions.