Rare genetic variants in leber hereditary optic neuropathy: molecular mechanisms, diagnosis, and emerging therapies

Hereditary optic neuropathies, such as Leber’s hereditary optic neuropathy (LHON), remain a focus of active research. Diagnostic challenges and severe clinical consequences often result in atypical presentations, creating significant obstacles for neuro-ophthalmology. The field has garnered increased attention due to advances in molecular biology and genetic engineering. Pathogenic variants in mitochondrial DNA (mtDNA) and nuclear DNA disrupt oxidative phosphorylation, reduce adenosine triphosphate production, and increase reactive oxygen species generation, to which retinal ganglion cells are particularly vulnerable. Rare genetic variants have been identified in LHON and related mitochondrial disorders, including mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes and Leigh syndrome. Phenotypic heterogeneity, variable heteroplasmy levels, and limited sensitivity of targeted genetic testing complicate the detection and interpretation of rare variants. As a result, comprehensive next-generation sequencing is increasingly necessary for accurate molecular diagnosis and timely treatment initiation. Recent therapeutic interventions include genotype-specific approaches, such as adeno-associated virus serotype 2-mediated allotopic expression, and genotype-independent therapies, such as idebenone. Diagnostic standards for mitochondrial optic neuropathies have shifted from focusing solely on the three primary pathogenic mtDNA variants to a broader molecular diagnostic framework. Future research should prioritize mtDNA sequencing in cases with inconclusive diagnoses using conventional methods, incorporate mitochondrial and nuclear genomics, and leverage artificial intelligence-based approaches. Accurate identification and classification of rare variants, together with a deeper understanding of their phenotypic consequences, will facilitate the development of individualized therapeutic strategies to prevent further visual decline. This review outlines potential directions for multifaceted treatment strategies in patients with rare LHON-associated variants and critically evaluates current evidence regarding the clinical significance of rare mitochondrial and nuclear genetic variants in LHON and related mitochondrial optic neuropathies.