レーベル遺伝性視神経症

OBJECTIVES: The coexistence of multisystemic involvement in a young adult raises the need to consider rare metabolic and mitochondrial disorders. We report a case of late-onset propionic acidemia (PPA) that may have contributed to unmasking Leber hereditary optic neuropathy (LHON), an extremely infrequent association. CASE PRESENTATION: A 43-year-old woman presented with acute biventricular heart failure following a viral infection. Evaluation revealed severe dilated cardiomyopathy, newly diagnosed type 2 diabetes mellitus, and bilateral sensorineural hearing loss. Genetic testing for cardiomyopathy was unremarkable. Two months later, she developed sudden bilateral blindness due to optic neuropathy. Extended genetic analysis identified a pathogenic RDH12 variant consistent with LHON and two POLG variants. Progressive renal dysfunction and long QTc interval prompted metabolic investigation. Urine organic acids showed marked accumulation of propionate-related metabolites, and plasma acylcarnitines revealed elevated C3 and low free carnitine, confirming late-onset PPA. The pattern of cardiac dysfunction, renal impairment, and hearing loss was consistent with chronic multisystem toxicity of PPA. 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.

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 limitations by utilizing an optimized AAV2-ND6 construct with codon optimization and mitochondrial targeting sequence in a mouse model bearing the homoplasmic ND6P25L mutation, which recapitulates Leber hereditary optic neuropathy (LHON). High-dose administration of the AAV2-ND6 construct resulted in robust, sustained expression within the retina and optic nerve without apparent systemic toxicity. Strikingly, We compared the therapeutic efficacy in mutant mice at different ages and pre-symptomatic intervention with AAV2-ND6 effectively attenuated disease progression, mitigated retinal cellular deficiencies and optic nerve damage, and restored visual function in ND6P25L mice. Mechanistically, allotopic ND6 expression markedly rescued the mitochondrial dysfunction, corrected dysregulated retinol metabolism and phototransduction pathways, and suppressed apoptotic processes in the mutant retina. Our study validates the safety and therapeutic potential of allotopic expression in vivo and provide critical mechanistic insights into its role in treating LHON and other mitochondrial diseases.

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, which suggests that the m.11778G>A mutation alone fails to cause disease. Full mitochondrial DNA sequencing and haplogroup screening identify multiple mitochondrial genetic modifiers. Haplogroups D4j, M7, M9, and M10 are significantly enriched in maternally inherited families with elevated disease penetrance. Haplotype-specific variants ND4 11696G>A, ND1 3394T>C, and ND6 14502T>C synergistically aggravate mitochondrial dysfunction together with m.11778G>A, and secondary mtDNA mutations disrupting complex I or mitochondrial tRNA metabolism also raise disease susceptibility. Nuclear modifiers PRICKLE3 and YARS2, as well as X-linked sex-specific regulatory factors, are also identified. Overall, LHON results from the interaction of mitochondrial and nuclear genetic factors. This research constructs a comprehensive genetic landscape of LHON, highlights the vital role of modifier genes, and provides theoretical support for precision therapies targeting mitochondrial and nuclear pathways.

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 history-informed designs, and precision therapeutic approaches, including gene therapy and nucleoside therapy, which have shown encouraging clinical and regulatory progress. Regulatory agencies have only recently begun approving disease-modifying therapies for selected mitochondrial disorders. The European Medicines Agency (EMA) approved idebenone for Leber Hereditary Optic Neuropathy (LHON) in 2015 but only recently, in 2025 did the Food and Drug Administration (FDA) in the US approve a treatment for Barth syndrome and thymidine kinase 2 deficiency (TK2d). Friedreich's ataxia received regulatory approval in 2023 from both the EMA and FDA, marking another milestone in mitochondria-related disorders. To comprehensively review clinical and regulatory developments in PMD over the past two decades, we conducted a structured scoping review and horizon scan of published clinical trials and regulatory approvals in PMD from January 2000 to November 2025. Data sources included PubMed, Embase, https://ClinicalTrials.gov, and regulatory agency websites. Recent accelerated and full FDA approvals validate the feasibility of tailored evidence packages, but sustaining this momentum will require more rigorous alignment of trial design with molecular biology, strengthening of natural history infrastructure, deployment of sensitive biomarkers, and adoption of innovative statistical approaches. Early regulatory engagement and robust patient-community partnerships will be key.

Gene therapy is an increasingly useful treatment option, especially in children, where most inherited diseases manifest. This review provides a literature synthesis of current gene therapy treatments in pediatric ophthalmology. Our search encompassed the ClinicalTrials.gov database. Sixteen clinical trials with published results reporting gene therapy for genetic ocular diseases in children (under 18 years) were included. Diseases under investigation for gene therapy in children included Leber's Congenital Amaurosis (CEP290, RPE65 genes), Leber's Hereditary Optic Neuropathy (ND4), Retinitis Pigmentosa (MERTK), Usher Syndrome Type 2 (USH2A), X-linked Retinitis Pigmentosa (RPGR), Achromatopsia (CNGA3, CNGB3), and X-linked Retinoschisis (RS1). Most clinical trials in our search were in Phases 1 or 2, with five studies having progressed to Phase 3. In certain cases, treatment demonstrated encouraging results, providing the patients with an improvement in BCVA, retinal sensitivity, and quality of life. However, the outcome measures regarding the efficacy and tolerability of gene therapy varied and some studies noted adverse events. Clinical trials that have yet to publish their results were also recorded. While the field of pediatric ophthalmology shows promise for gene therapy options, future strategies should include stratified enrollment based on age, separate cohorts for pediatric and adult patients, or adaptive trial designs.