Many Factors Determine Phenotypic Heterogeneity in LHON [Letter]
No abstract
Sterile inflammation in LHON: mitochondrial stress, innate immune signaling, and implications for AAV gene therapy
Leber hereditary optic neuropathy (LHON) is a mitochondrial disease caused primarily by pathogenic mitochondrial DNA (mtDNA) variants that impair respiratory chain complex I function. Although bioenergetic failure, oxidative stress, and retinal ganglion cell degeneration are central features of disease pathogenesis, these mechanisms do not fully explain the incomplete penetrance, male predominance, and marked clinical heterogeneity observed in LHON. Emerging evidence suggests that mitochondrial…
Functional and structural analysis in relation to age at onset of Leber hereditary optic neuropathy: a Swedish cohort
CONCLUSIONS: LHON onset before 15 years of age is associated with better preserved retinal structure and visual function in the chronic stage.
When rare diseases do not appear as a single entity
CONCLUSIONS: In this patient, mitochondrial dysfunction from PPA may have precipitated the clinical expression of LHON, a condition with incomplete penetrance. This exceptional coexistence highlights that rare diseases may overlap and that unexplained multisystem findings warrant comprehensive metabolic and genetic evaluation.
Allotopic Expression of ND6 Restores Vision in a Mitochondrial Disease Model
Mutations in mitochondrial DNA (mtDNA) cause various mitochondrial diseases that are currently incurable. Allotopic expression of nuclear-recoded mitochondrial genes represents a promising therapeutic strategy, given its demonstrated capacity to restore mitochondrial function in human cell models harboring mtDNA mutations. However, the in vivo evaluation of allotopic gene therapy has been hindered by optimization challenges and the lack of appropriate animal models. Here, we overcome these…
Mitochondrial diabetes mellitus: real world insights from the GENOMIT registry-a multinational, longitudinal cohort study
BACKGROUND: Diabetes mellitus is a common but incompletely characterised manifestation of mitochondrial diseases (MD). Data on risk factors, clinical course, and treatment recommendations are lacking.
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…