Category: LHON

Generation and characterization of a human induced pluripotent stem cell line (SNUi001-A) harboring the MT-ND4 m.11778G>A mutation

Leber hereditary optic neuropathy (LHON) is a maternally inherited optic neuropathy caused by mutations in mitochondrial DNA. To facilitate disease modeling and the investigation of pathogenetic mechanisms, we generated an induced pluripotent stem cell (iPSC) line, SNUi001-A, derived from the peripheral blood mononuclear cells (PBMCs) of a patient carrying the m.11778G>A mutation in the MT-ND4 gene. The iPSCs were generated using non-integrating episomal vectors. These reprogrammed cells…

Mitochondrial genome microhomology-mediated editing by donor DNA delivery into mitochondria in human cells

Mutations in mitochondrial DNA (mtDNA) are associated with severe human diseases, lacking efficient therapies. Direct correction of mtDNA mutations may offer a cure for such diseases. We propose a novel strategy based on double-stranded DNA (dsDNA) oligonucleotide delivery into mitochondria and intrinsic microhomology-mediated end joining (MMEJ) for mtDNA editing. This strategy enables the introduction of multiple predefined nucleotide changes in mtDNA. For this, the presence of MMEJ activity in…

Mitochondrial complex I deficiency-associated diseases and models

Mitochondrial complex I is the first and largest enzyme of the mitochondrial respiratory chain and thus plays a crucial role in cellular energy metabolism. Defects in the mitochondrial respiratory chain, and in particular CI deficiency, are the primary cause of human mitochondrial associated diseases, which most often presents as severe neurometabolic disorders with fatal outcome. Up to this date the diagnosis and treatment of CI deficiency-associated diseases is challenging, only limited…

The “Triple-hit” pathogenic mechanism of Leber hereditary optic neuropathy

Leber hereditary optic neuropathy (LHON) is a classic mitochondrial disorder primarily affecting retinal ganglion cells and leading to irreversible visual loss. Although primary mitochondrial DNA (mtDNA) mutations, such as m.11778G>A, m.14484T>C, and m.3460G>A, provide the genetic basis of LHON, they do not fully explain its incomplete penetrance, male predominance, or clinical heterogeneity. Based on familial genetic analyses and functional studies, this review proposes a “triple hit”…

A case report of atypical optic neuritis

Optic neuritis is a severe blinding ocular disease, and identifying its etiology is crucial for selecting appropriate treatment strategies and evaluating patient prognosis. This paper reports the clinical data of a patient initially presenting with unilateral visual decline who was ultimately diagnosed with bilateral atypical optic neuritis. The patient was a 40-year-old male who presented with decreased vision in the left eye for 2 weeks. Fundus examination at admission revealed bilateral optic…

Progressive Visual Recovery in a Patient with Leber Hereditary Optic Neuropathy Harboring a Rare Heteroplasmic (MT-ND5):m.13042G>A, p(Ala236Thr) Variant with Low Mutant Load: A Case Report

CONCLUSION: In patients with a strong clinical suspicion of LHON, complete mitochondrial genome sequencing should be considered when initial testing, typically limited to the three primary mutations, is negative. Furthermore, the diagnosis of LHON should not be dismissed if “low” blood mutant loads are found, as important discrepancies of heteroplasmy levels between different tissues have been reported for variants located in the mitochondrial ND5 gene.

Leber hereditary optic neuropathy (LHON) in a 6-year-old boy with a transient spinal cord lesion

CONCLUSION: Since optic neuropathy and spinal cord involvement typically indicate demyelinating diseases, these should be prioritized in initial evaluation due to their frequency and need for early immunomodulatory treatment. However, spinal cord involvement can occur in mitochondrial diseases, as demonstrated in this case. The presence of a transient and asymptomatic spinal cord lesion in this patient expands the recognized spectrum of central nervous system involvement in LHON. Therefore,…