LHON is characterized by mitochondrial deoxyribonucleic acid (mtDNA) point mutations that lead to retinal ganglion cell degeneration and acute, progressive visual loss. In rare instances, referred to as LHON plus, additional systemic manifestations might occur, including peripheral neuropathy, ataxia, myopathy, or cardiac arrhythmias.We report a male patient who first experienced mild visual impairment at 12 years of age. After two decades, his vision deteriorated over several months, resulting in the complete loss of reading ability. At age 45, he developed gait ataxia, lower limb paresthesia, foot pain, and left palm muscle atrophy. After extensive examinations, mtDNA sequencing detected two mitochondrial mutations, while electroneurography confirmed chronic sensorimotor axonal polyneuropathy. Based on these findings, a diagnosis of LHON plus was established.Genetic analysis identified the m.8836A>G mutation, which has been reported in sporadic cases of LHON. Moreover, another mutation, m.9957T>C, typically linked to recurrent focal neurological deficits, seizures, headaches, and myopathy (MELAS syndrome), was also detected. The coexistence of these mitochondrial mutations has not been previously documented. The combination of this unique genotype and peripheral nerve involvement represents an atypical case of LHON.The coexistence of two mtDNA mutations might synergistically worsen mitochondrial dysfunction, broadening the phenotype from isolated optic neuropathy to systemic LHON plus. Comprehensive mtDNA sequencing should be performed in patients with an atypical clinical course.Our patient was treated with idebenone, vitamin E, alpha-lipoic acid, and creatine monohydrate for mitochondrial and neuroprotective support, alongside pregabalin and ongoing rehabilitation. Neuromuscular symptoms showed notable recovery, though visual improvement was temporary. Some studies report reversal of visual loss in patients treated during the acute stage, mainly in those harboring the more prevalent m.14484T>C mutation. These findings underline the potential role of genotype in determining therapeutic response.LHON plus is often misdiagnosed and mismanaged due to its low prevalence in the population (<1:1 000 000). Despite limited treatment options, early diagnosis and prompt mitochondrial-targeted therapy might slow disease progression or partially restore function. Long-term multidisciplinary management is vital to preserve quality of life.