Genetic architecture and inheritance patterns of Leber hereditary optic neuropathy among 419 Chinese pedigrees carrying the ND4 11778G>A mutation
Leber’s hereditary optic neuropathy (LHON) is a mitochondrial disease mainly driven by the m.11778G>A mutation, and its incomplete penetrance and diverse inheritance patterns remain unclear. This study integrates clinical and genetic analyses of 419 Han Chinese pedigrees carrying this mutation, covering 5262 matrilineal relatives. Distinct phenotypic heterogeneity emerges, including sporadic, maternal and complex transmission patterns; 209 pedigrees contain only single affected individuals,…
2000-2025: Emerging therapies in primary mitochondrial disease: A structured review, horizon scan, and roadmap for the future
Primary mitochondrial diseases (PMD) are ultra-rare, genetically diverse disorders that impair cellular energy metabolism and typically present with multisystemic symptoms. Over the past decades, the therapeutic landscape of PMD has evolved substantially. Early trials of non-specific antioxidant and metabolic therapies produced largely negative or mixed results, providing important methodological lessons for the field. More recent studies have adopted improved outcome measures, natural…
Novel Variants in Mitochondrial Ribosomal RNA Genes MT-RNR1 and MT-RNR2 Identified in Hereditary Optic Neuropathy Initially Presenting as Normal Tension Glaucoma: A Case Report
CONCLUSION: Neither MT-RNR1 and MT-RNR2 variants could be definitively linked to the hereditary optic neuropathy in this patient, and they are best regarded as findings of uncertain significance. This case highlights a diagnostic pitfall as non-glaucomatous optic disc pallor can be mistaken for normal tension glaucoma and underscores the diagnostic value of whole mtDNA sequencing when primary LHON screening is negative.
Systemic comorbidities before and after onset in Leber hereditary optic neuropathy: a descriptive study
Introduction: lthough Leber hereditary optic neuropathy (LHON) is primarily an optic neuropathy, systemic comorbidities across the disease timeline have not been systematically described. We aimed to describe systemic comorbidities documented before and after LHON onset.Methods: We retrospectively reviewed medical records of 187 genetically confirmed patients with LHON (m.11778G>A, m.14484T>C, or m.3460G>A) seen at a single center between January 1990 and March 2025. Systemic comorbidities were…
Late-onset Leber Hereditary Optic Neuropathy: disease triggers and prognostic factors in a large Italian cohort
CONCLUSIONS: Late-onset LHON represents a clinically relevant subset in which environmental and hormonal factors may contribute to disease conversion. In this retrospective cohort, high-dose idebenone treatment was associated with a higher probability of visual recovery, particularly among patients with a J or T haplogroup background. These exploratory findings should be considered hypothesis-generating and warrant confirmation in prospective studies.
Leber’s hereditary optic nerve atrophy
This review is devoted to Leber’s hereditary optic neuropathy (LHON), a rare maternally inherited ophthalmic disorder presenting as optic nerve atrophy and associated with an unfavorable prognosis. LHON is the most common primary mitochondrial DNA disorder, and most patients (more than 90% of cases) carry one of three point mutations. The 11778G>A mutation in the MT-ND4 gene is the most common worldwide and causes the most severe variant of the disease. LHON typically manifests as bilateral,…
Disease-mutations perturb proton transfer reactions in respiratory complex I
Respiratory Complex I powers oxidative phosphorylation by a long-range proton-coupled electron transfer (PCET) reaction, with mutations linked to more than half of all human mitochondrial disorders. Yet, the molecular principles underlying the functional impairment remain difficult to test, as most mutations impede both the proton pumping and oxidoreductase activities due to the tightly coupled PCET process. Here, we probe how key disease mutations in the terminal ND5 subunit (NuoL/Nqo12),…
Reframing spaceflight-associated neuro-ocular syndrome as spaceflight-associated optic neuropathy (SAON): Transcriptomic in-vivo analysis reveals mitochondrial retinal ganglion cell injury during spaceflight
Spaceflight-Associated Neuro-Ocular Syndrome (SANS) has remained poorly understood throughout the history of human spaceflight despite being classified as the largest physiologic barrier that astronauts face. Existing mechanistic explanations of SANS are limited in accounting for its tissue specificity, interindividual heterogeneity, and persistence beyond return to Earth, which has left countermeasure development without a coherent biological target. Through integration of tissue-resolved…
Acute-phase characteristics of RNFL thickness in older patients with Leber hereditary optic neuropathy: a single-center retrospective OCT study
CONCLUSION: Acute-phase RNFL thickening may be less prominent with increasing age in m.11778G > A LHON, particularly in patients aged ≥ 50 years. LHON should not be excluded solely because RNFL thickening is inconspicuous in older-onset cases.
Progressive mitochondrial and autophagic dysfunction during RGC development driven by a LHON-associated mitochondrial tRNA(Thr) mutation
Leber’s hereditary optic neuropathy (LHON) is a genetically inherited disease of the eye triggered by mtDNA mutations, leading to degeneration of RGCs. We previously reported that the mitochondrial tRNA^(Thr) (MT-TT) 15927G > A homoplasmic mutation disrupted the base pairing (28C-42G) conserved in the anticodon stem of tRNA^(Thr), impairing t⁶A modification, aminoacylation, and steady-state tRNA^(Thr) levels, ultimately resulting in mitochondrial dysfunction. However, the absence of suitable…