MITOCHONDRIAL GENETIC DISEASES WITH OPHTHALMOLOGICAL MANIFESTATIONS: FROM MOLECULAR PATHOPHYSIOLOGY TO CLINICAL MANAGEMENT

Abstract

Mitochondrial genetic disorders are the most common group of inherited metabolic diseases, and the eye – a tissue of exceptionally high, heterogeneous energy demand – is affected in more than half of patients, often as the presenting feature. This review synthesises current understanding of the molecular pathophysiology, clinical spectrum, diagnosis, and therapeutic landscape of mitochondrial disease with ophthalmic involvement. We outline how the unique biology of mitochondrial DNA (mtDNA) – maternal inheritance, high mutability, heteroplasmy, and the threshold effect – together with the tissue-specific bioenergetic dependence of photoreceptors, retinal pigment epithelium, and retinal ganglion cells, explains the phenotypic heterogeneity of these conditions. Leber hereditary optic neuropathy is discussed as a paradigm of primary mtDNA complex I disease, alongside large scale deletion syndromes (chronic progressive external ophthalmoplegia, Kearns-Sayre syndrome, Pearson syndrome), multisystem syndromes with secondary ophthalmic involvement (MELAS, MERRF), and nuclear encoded disorders such as POLG-related disease and autosomal dominant optic atrophy. We review the diagnostic pathway, integrating clinical red flags, electrophysiology and imaging with dual-genome and long-read sequencing, and discuss current management – idebenone, supportive care, and genetic counselling around maternal mtDNA transmission. We summarise emerging strategies (allotopic and non-viral gene delivery, mitochondrially targeted nucleases, antioxidants, mitophagy modulation, mitochondrial transplantation, and stem cell approaches) and their limitations, and discuss unresolved challenges around diagnostic cost, variant interpretation, and reproductive counselling. Earlier, more systematic recognition of mitochondrial ophthalmic disease, supported by expanding genomic and therapeutic tools, is likely to reshape clinical outcomes for this historically underdiagnosed group of conditions.