Mitochondrial-Immune Overlap in Leber Hereditary Optic Neuropathy: A Case Report and Lessons Learned
Background and Clinical Significance: Leber hereditary optic neuropathy (LHON) is a mitochondrial disorder characterized by acute or subacute bilateral central vision loss, typically in young males. Multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) are immune-mediated demyelinating diseases that may present with optic neuritis and myelitis. Although distinct in etiology, recent evidence suggests that mitochondrial dysfunction and neuroinflammation can overlap, giving…
Optic Atrophy Predominant WFS1 Disorder-A Case-Control Study
CONCLUSIONS: Our cohort of patients with WS1 showed uncharacteristically mild vision loss and minimal syndromic features, suggesting that a milder alternative phenotype with WFS1 mutations is possible in contrast to the traditional DIDMOAD syndrome. Compared with other OA syndromes, these patients with WS1 showed significant associations with arcuate visual field defects and trends toward superior/inferior peripapillary RNFL thinning. This suggests that relative preservation of papillomacular…
Serum neuronal, glial and mitochondrial markers in autosomal dominant optic atrophy and Leber hereditary optic neuropathy
Leber hereditary optic neuropathy (LHON) and autosomal-dominant optic atrophy (ADOA) are the two most prevailing primary mitochondrial optic neuropathies. Both diseases preferentially affect the smallest retinal ganglion cells (GCs) of the papillomacular bundle, causing central visual loss in young patients. Although ADOA and LHON show striking similarities, including the convergence of underlying pathologic mitochondrial mechanisms, they differ clinically. The major distinction lies in the…
Trans-generational maintenance of mitochondrial DNA integrity in oocytes during early folliculogenesis
Mutations in mitochondrial DNA (mtDNA) can lead to mitochondrial and cellular dysfunction. However, recent studies suggest that purifying selection acts against mutant mtDNAs during transgenerational transmission. We investigated the mtDNA dynamics during ovarian follicle development. Using base-editing, we generated mice harboring a 3177 G > A mutation corresponding to the human Leber hereditary optic neuropathy (LHON)-related mtDNA mutation and confirmed a transgenerational reduction of the…
Advanced therapies for inherited optic neuropathies
Inherited optic neuropathies (IONs), such as Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (ADOA), typically lead to irreversible severe vision loss due to mitochondrial dysfunction causing retinal ganglion cell degeneration. Although current treatment options are limited, substantial progress has been made recently in our understanding of the molecular genetic pathways that lead to retinal ganglion cell loss. Clinical trials for LHON have demonstrated the…
Preclinical Assessment of Mitochondrial-Targeted ND4 Gene Therapy for Leber Hereditary Optic Neuropathy
CONCLUSIONS: Intravitreal delivery of MTSAAV/hND4 in rodents resulted in favorable biodistribution, with vector DNA largely confined to the injected eye and minimal systemic exposure. No vector-related adverse effects were observed based on functional, anatomic, and histopathological assessments, supporting the ocular safety of this gene therapy strategy. These findings provide preclinical evidence supporting the advancement of MTSAAV-mediated ND4 gene therapy toward clinical trials for LHON.
Metformin promotes mitochondrial integrity through AMPK-signaling in Leber’s hereditary optic neuropathy
Leber’s hereditary optic neuropathy (LHON) is a maternally inherited disorder caused by mitochondrial DNA mutations in complex I of the respiratory chain, leading to impaired ATP production, mitochondrial fragmentation, and oxidative stress that contribute to vision loss. This study investigated the potential repurposing of metformin, a widely used antidiabetic drug, in fibroblasts from LHON patients carrying the m.11778G>A mutation. Fibroblasts from LHON patients and healthy individuals were…
In vivo mitochondrial base editing restores genotype and visual function in a mouse model of LHON
Leber hereditary optic neuropathy (LHON), a maternally inherited mitochondrial disorder, results from point mutations in mitochondrial DNA (mtDNA), primarily affecting the MT-ND4 gene. To date, no animal model harboring authentic LHON mutations has been available, limiting therapeutic development. However, when we attempted to generate such models using mitochondrial base editors, we found that activity-enhanced DddA11-based cytosine base editors (DdCBEs) induce off-target mtDNA mutations and…
Pathogenic mechanisms of Leber hereditary optic neuropathy caused by m.3472T>C mutation
CONCLUSIONS: The m.3472T>C mutation contributes to the pathogenesis of LHON by disrupting the structural stability of the ND1 subunit in complex Ⅰ, leading to mitochondrial dysfunction.
The Pedigree Study of Leber’s Hereditary Optic Neuropathy in Korean Population
CONCLUSIONS: This study expands previous research by offering new information on the penetrance of LHON in the Korean population through pedigree analysis.