When LHON Mimics Demyelination: Area Postrema Syndrome in Biallelic DNAJC30 Variants
Introduction: Biallelic pathogenic variants in DNAJC30 cause an autosomal recessive form of Leber hereditary optic neuropathy (LHONAR1), traditionally considered a mitochondrially transmitted disorder. The phenotypic spectrum of diseases linked to DNAJC30 includes isolated optic neuropathy, Leigh syndrome spectrum (LSS), and atypical LHON-plus. Case description: Here, we report a 13-year-old boy presenting symptoms of area postrema syndrome (APS), with recurrent vomiting, vertigo, nystagmus, and…
Late-Onset Leber Hereditary Optic Neuropathy: A Report of a Case and Review of the Literature
Leber hereditary optic neuropathy (LHON) constitutes a mitochondrial disorder characterized by subacute, bilateral central vision impairment, secondary to mitochondrial DNA (mtDNA) mutations. These mutations compromise Complex I, subsequently precipitating the degeneration of retinal ganglion cells (RGCs). While traditionally manifesting in young males, contemporary literature has documented a small number of cases of late-onset presentation. Numerous studies have suggested the existence of a…
Archetypal Visual Field Analysis of Patients With Chronic Leber Hereditary Optic Neuropathy in Relation to Visual Recovery
CONCLUSIONS: AA is a robust method for categorizing and quantifying VF damage in patients with chronic LHON, providing novel insights into the complexity of the disease. The findings suggest that the recovery of VA and VF damage are not transposable, although not entirely independent either, and that both parameters should be considered in the comprehensive assessment of functional recovery in LHON.
Health-related quality of life and tobacco and alcohol consumption in Leber hereditary optic neuropathy in Sweden
CONCLUSIONS: The HRQoL was similar among the Swedish LHON cohort compared to HC references. Swedish LHON cohort showed a higher prevalence of smoking. Snus usage, and harmful or hazardous alcohol consumption were higher among LHON affected individuals.
Diagnostic Yield and Clinical Impact of Comprehensive WES/WGS Testing Beyond Common Genetic Causes in Hereditary Optic Atrophy
Hereditary optic atrophy is characterized by degeneration of retinal ganglion cells and may result from a wide range of genetic etiologies. While pathogenic variants in OPA1 and primary mitochondrial variants causing Leber hereditary optic neuropathy (LHON) account for a substantial proportion of cases, many patients remain genetically unsolved. We evaluated the diagnostic yield and clinical impact of comprehensive whole exome/genome sequencing (WES/WGS)-based virtual panel testing in 62…
Analysis of genetic risk factors for Leber hereditary optic neuropathy in the Polish population
Leber hereditary optic neuropathy (LHON) is primarily caused by pathogenic mitochondrial DNA (mtDNA) variants, most commonly the m.11778G>A variant in the MT-ND4 gene. The presence of this variant alone is insufficient to trigger disease symptoms, of which vision loss is the hallmark. Given the incomplete penetrance and inter-population variability in modifying factors, this study aimed to investigate two previously proposed genetic risk factors for LHON in the Polish population. Using…
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…
Interpreting relative afferent pupillary defect in Leber hereditary optic neuropathy using interocular visual acuity difference
CONCLUSIONS: In LHON, RAPD is largely driven by interocular acuity asymmetry. Quantitative |ΔBCVA| thresholds can support interpretation of RAPD without prematurely excluding LHON and may help plan diagnostic work-up and follow-up while confirmatory testing is pending.
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…