Leber hereditary optic neuropathy (LHON; OMIM 535000) is characterized by subacute painless bilateral or sequential central vision loss in young adults [1]. While there are three major mutations of m.3460G>A, m.11778A> G, and m.14484T>C in LHON, more than 20 other mitochondrial DNA (mtDNA) mutations have been identified. Unlike these major mutations with relatively well-known clinical presentations, detailed information on the clinical manifestations of LHON with rare mutations is still lacking. Among the rare mutations, m.13051G>A mutation is characterized by variable clinical features including ophthalmoplegia, ptosis and Leigh syndrome in addition to LHON [2-4].

Herein, we found an Asian female patient with LHON carrying m.13051G>A mutation and report the detailed clinical features. The study was approved by the Institutional Review Board of Soonchunhyang University Hospital (No. SCHUH 2025-06-010). Written informed consent for publication of the research details and clinical images was obtained from the patient.

A 26-year-old woman was referred to our clinic for painless bilateral diminished visual acuities which started a month ago. She had no family history of visual impairment. She had taken lorazepam 0.5 mg (Loravan, Whan In Pharm) and flunitrazepam 0.5 mg (Razepam, Whan In Pharm) for 6 months due to depression. At her first visit, best-corrected visual acuities were 20 / 30 in the right eye and 20 / 25 in the left eye. She presented with cecocentral scotomas on Humphrey visual field testing and a mild red-green/blue-yellow defect with the Hardy-Rand-Ritter color vision test in both eyes. Fundus photography revealed mild optic disc hyperemia in both eyes, corresponding to increased peripapillary retinal nerve fiber layer (RNFL) on spectral-domain optical coherence tomography (Spectralis OCT, Heidelberg Engineering) (Fig. 1A-1C). Brain magnetic resonance imaging with angiography did not show any abnormal findings. After 1 month, her visual acuities had dropped rapidly to 20 / 630 in both eyes. Visual field defects had enlarged, and disc swelling had progressed (Fig. 1D-1F). Oral intake of idebenone was recommended at 900 mg per day. Four months later, her visual acuities had deteriorated to counting finger in the right eye and 20 / 630 in the left eye (Fig. 1G-1I).

Blood tests including m.3460G>A, m.11778A>G, and m.14484T>C LHON mutation, antibodies to aquaporin-4 (AQP4-IgG), myelin oligodendrocyte glycoprotein (MOG-IgG) were negative. Entire mitochondrial genome sequencing revealed a heteroplasmic mutation (level of 81.7%) of m.13051 G>A (MT-ND5:c.715G>A:p.(Gly239Ser). The detailed sequencing method was described as below. DNA was extracted from peripheral blood samples using a Chemagic 360 instrument (Perkin Elmer). The entire mitochondrial genome was amplified in two overlapping fragments with sizes of 9.3 and 7.6 kb. The primer sets for long-range polymerase chain reaction (PCR) were as follows: F-5′-AACCAAACCCCAAAGACACC-3′ and R-5′-GCCAATAATGACGTGAAGTCC-3′ for the 9.3 kb-sized fragment I, and F-5′-TCCCACTCCTAAACACATCC-3′ and R-5′-TTTATGGGGTGATGTGAGCC-3′ for the 7.6 kb-sized fragment II. Long-range PCR was performed using LA Taq polymerase (Takara). The library was prepared following the manufacturer’s protocol. Briefly, equimolar amounts of PCR products were pooled for each patient and were sheared to yield smaller fragments of 300 to 500 base pairs. Then, barcoded adaptors were ligated to each fragment with DNA ligase. Adaptor-modified fragments were amplified clonally by emulsion PCR. Sequencing reactions were performed with MiSeq (Illumina Inc).

This extremely rare mtDNA mutation has been previously described in three published reports [2-4]. Howell et al. [2] reported 63 Dutch pedigrees with LHON, among them two affected brothers and their maternal aunt carried a mutation at nucleotide 13051. Dombi et al. [3] described two families and one singleton case with lactic acidosis, Leigh syndrome and Leigh-like phenotype. Smirnov et al. [4] reported a 5-year-old boy with subacute onset exotropia, bilateral ptosis, bilateral temporal optic disc pallor and ataxic gait/limb tremor, together with his sibling (12-year-old boy) who had acute bilateral LHON, and their mother with bilateral ophthalmoplegia and ptosis starting from 7 years old. Combining our case with the three previously published reports, the m.13051 G>A mt DNA mutation may manifest as a typical LHON, LHON associated with ophthalmoplegia or ptosis like mitochondrial cytopathies, or a complicated early-onset Leigh-like neurodegenerative phenotype.

The most common mutations that cause isolated LHON are located in mitochondrial complex 1 which is the largest multi-subunit of the respiratory chain (e.g., 3460G>A in ND1, 11778A>G in ND4, 14484T>C in ND6). ND5 mutation often occurs in conjunction with other neurodegenerative disorders like mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) or Leigh syndrome, rather than causing isolated LHON. A possible explanation would be that ND5 subunit has stringent evolutionary conservation, and significantly affects the normal function of complex I and respiratory chain activity. Our case manifested solely as adult-onset LHON without other neurologic or systemic abnormalities. The heteroplasmic mutation may influence the clinical manifestations and the risk of maternal transmission of mtDNA defects. There has been an experimental report that treatment of idebenone to m.13051 G>A patient cell lines attenuated the increase in mitophagy [3]; however, no notable clinical effects were observed in our case despite initiating treatment rapidly.

This is the first case with mtDNA m.13501 G>A mutation reported in a Korean patient. This mutation was absent from a large Chinese cohort of LHON patients, and only one case from Japan has been reported in 2024 [5]. Although the prevalence of major mutations among Korean LHON patients is reported to be 93% to 99%, the diagnosis in the present case could not be confirmed by major mutation testing alone. However, given the characteristic clinical features of LHON observed in this patient, we believe that a thorough analysis of the entire mitochondrial genome should be performed in strongly suspected cases.