レーベル遺伝性視神経症

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 subacute visual deterioration with central scotoma. Ophthalmological examination revealed bilateral papilledema with telangiectatic vessels, while visual evoked potentials demonstrated severe bilateral optic pathway dysfunction. Brain magnetic resonance imaging (MRI) showed T2/FLAIR hyperintense lesions involving the area postrema and enhancement of the optic nerves, strongly suggesting seronegative neuromyelitis optica spectrum disorder (NMOSD). Extensive immunological and cerebrospinal fluid studies, including anti-aquaporin-4 (AQP4) and anti-MOG antibodies, were negative. High-dose corticosteroids and intravenous immunoglobulins resulted in only transient and incomplete improvement, followed by further visual decline. Additionally, laboratory tests detected elevated lactate plasma levels. Hence, whole-exome sequencing was performed, which identified a homozygous pathogenic DNAJC30 c.152A>G, p.(Tyr51Cys) variant, associated with LHONAR1. After initiation of idebenone therapy, the patient showed significant improvement in visual function, normalization of lactate levels, and complete resolution of the brainstem lesions on follow-up MRI. Conclusions: This case further expands the neuro-ophthalmic spectrum associated with DNAJC30 variants and suggests that DNAJC30-related disease may closely mimic seronegative NMOSD. We highlight that early genetic diagnosis is essential, as recognition of this mitochondrial etiology enables targeted therapy and may substantially improve clinical outcomes.

Mitochondrial diseases have traditionally been viewed as energy deficiencies, but current evidence positions mitochondria as central regulators of multiple cell death pathways. This review systematically analyzes the molecular mechanisms of apoptosis and ferroptosis in the context of both primary mitochondrial diseases-caused by mutations in mtDNA or nuclear DNA directly affecting oxidative phosphorylation-and secondary mitochondrial dysfunction associated with broader pathological conditions. Apoptosis is an energy-dependent process characterized by mitochondrial outer membrane permeabilization, cytochrome c release, and caspase cascade activation, whereas ferroptosis involves iron-dependent lipid peroxidation, glutathione depletion, and inactivation of glutathione peroxidase 4 (GPX4), leading to accumulation of oxidized phospholipids predominantly in endoplasmic reticulum and plasma membranes; mitochondrial ultrastructural changes-including volume reduction and cristae loss-represent characteristic morphological features of ferroptosis rather than its primary site of initiation. Key findings reveal that reactive oxygen species overproduction, disruption of reducing equivalent metabolism, iron dyshomeostasis, and calcium overload simultaneously prime cells for both death pathways. Cytochrome c, p53, and BCL-2 family proteins serve as integration hubs, with cardiolipin peroxidation and phospholipid composition influencing pathway switching. Tissue specificity is pronounced in primary mitochondrial diseases: retinal ganglion cells in Leber's hereditary optic neuropathy, cardiomyocytes in mtDNA-associated cardiomyopathies, and hepatocytes in mtDNA depletion syndromes exhibit distinct dominant death pathways. It should be noted, however, that for many conditions discussed, the evidence for ferroptosis involvement relies on indirect markers-such as lipid peroxidation products, decreased GPX4, and iron deposition-rather than on pharmacological rescue with ferrostatin-1 or liproxstatin-1 and rigorous exclusion of alternative death modalities; this limitation is discussed critically throughout the review. Diagnostic criteria combining morphological, biochemical, and pharmacological tools enable differentiation of death pathways. The review concludes that combined inhibition-using mitochondria-targeted antioxidants, GPX4 modulators, iron chelators, and mPTP blockers-together with personalized diagnostic algorithms offers the most promising therapeutic strategy. Understanding the apoptosis-ferroptosis crosstalk is essential for developing targeted interventions in mitochondrial diseases.

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 distinct clinical phenotype, particularly concerning the funduscopic features of the optic disc. Elucidating this atypical manifestation is paramount to preclude diagnostic inaccuracies and to refine therapeutic intervention. In this context, we describe the case of a 70-year-old male presenting with progressive bilateral vision loss and diffuse thinning of the ganglion cell complex on optical coherence tomography (OCT), notably lacking the hyperaemic phase typical of younger patients. Genetic analysis confirmed the homoplasmic m.14484T>C mutation; however, despite the traditionally favourable prognosis associated with this variant, the patient progressed to permanent optic atrophy with no functional recovery. By reporting this case of late-onset LHON and providing a comprehensive review of clinical cases documented in recent literature, our objective is to ascertain whether late-onset presentation endows this clinical entity with additional distinguishing characteristics.

PURPOSE: To use the machine learning algorithm archetypal analysis (AA) to characterize visual field (VF) loss patterns in patients with chronic Leber hereditary optic neuropathy (LHON) and to determine whether these VF patterns differentiate for patients who recovered visual acuity (VA). METHODS: For patients with molecularly confirmed LHON, we retrospectively collected 30-2 or 24-2 VFs (Humphrey VF analyzer) performed at least 3 years after disease onset. A total of 220 VFs (220 eyes, 117 patients) were used as input for the AA algorithm. Archetypes (ATs) and relative weights were statistically compared between VA-recovered and not-recovered groups and among primary mitochondrial DNA mutations. K-means clustering and principal component analysis enabled two-dimensional visualization of the relationship among VFs, ATs, mean deviation, and VA. RESULTS: The LHON-AA model consisted of seven ATs: AT1 resembled a total loss VF pattern (30%) and AT2 a normal VF (23%). Small (AT3, 15%) and large (AT4, 10%) central scotomas followed as representative patterns. AT1 was significantly more prevalent in the not-recovered group, whereas AT2 and AT3 predominated in the recovered VA group. Less severe patterns were more present for m.14484T>C/ND6 than the other primary mutations. Two-dimensional visualization highlighted the nonlinear relationship between VA and VF outcome. 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.

PURPOSE: To investigate health-related quality of life (HRQoL), tobacco and alcohol consumption in Leber hereditary optic neuropathy (LHON) affected and carriers in Sweden. METHODS: This cross-sectional case-control study included LHON affected and carriers from the Swedish LHON research registry. Age and sex matched healthy control (HC) references and references with other eye diseases were also included. Validated questionnaires on HRQoL, alcohol, smoking and smokeless-tobacco (snus) consumption were administered. The differences between groups and sub-groups (stratified for sex) were analyzed with ANOVA and independent samples t-test. Differences in prevalence of tobacco and alcohol consumption were evaluated with chi-square test. RESULTS: 32 LHON affected and 32 carriers were included. Mean age at inclusion were 49.1 ± 19.7 years and 48.2 ± 17.7 years respectively. LHON affected and carriers did not show any significant difference in HRQoL compared to HC reference group. However, the affected males had significantly lower scores for role limitation due to physical health than affected females (67.1 ± 36.4 vs. 95.0 ± 15.8, p = 0.019). A higher prevalence of smoking (20%) and snus-use (33%) was seen among LHON affected. One-fourth of LHON affected had harmful or hazardous alcohol consumption risk classification. 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.