Aug 2026· Intractable & Rare Diseases Research· Vol 15 3, pp.
219-231
· 0 citations· 47 references
Medicine
TL;DR
The therapeutic landscape for MELAS is evolving from symptomatic care toward mechanism-based disease modification, led by taurine as the first regulatory-approved disease-modifying therapy and complemented by late-stage small molecules and mitochondrial genome-editing technologies.
Abstract
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, most often caused by the m.3243A>G mitochondrial DNA variant, represents one of the most clinically significant inherited mitochondrial disorders. This variant disrupts mitochondrial tRNALeu(UUR) function, leading to impaired mitochondrial protein synthesis and progressive multisystem dysfunction. This narrative review synthesizes recent clinical trials, therapeutic advances, and emerging disease-modifying strategies for m.3243A>G-associated MELAS, with emphasis on evidence published between 2024 and 2026, drawing on PubMed/MEDLINE, Embase, the Cochrane Library, ClinicalTrials.gov, and the EU Clinical Trials Register. Key advances include: i) regulatory approval of high-dose taurine supplementation (9-12 g/day), which achieved complete prevention of stroke-like episodes in 60% of participants in a phase III trial; ii) phase IIb data (company-reported) indicating that sonlicromanol (KH176) showed signals of improvement in cognition, mood, and fatigue, supporting progression to a phase III registrational trial (KHENERFIN, NCT06451757); iii) ongoing trials of zagociguat and TTI-0102 targeting vascular dysfunction and oxidative stress; iv) KL1333, a novel NAD+ modulator, in phase II evaluation (FALCON trial); and v) promising preclinical gene-based approaches-including mitochondria-targeted TALENs, DdCBE base editors, and mitoARCUS nucleases-demonstrating heteroplasmy shifting in patient-derived cells and animal models, though direct clinical applicability to m.3243A>G MELAS requires further investigation. The therapeutic landscape for MELAS is evolving from symptomatic care toward mechanism-based disease modification, led by taurine as the first regulatory-approved disease-modifying therapy and complemented by late-stage small molecules and mitochondrial genome-editing technologies.
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.
A. Karaa, Maria Isabel G. Lopez Sanchez, Claire Stuart et al.· Therapeutic Advances in Rare...· 0 citations
Primary mitochondrial diseases (PMDs) are one of the most common genetic disorders with an estimated prevalence of 1 in 4300. This review article summarises the latest updates in the field of mitochondrial medicine over the last decade. The availability of exome and genome sequencing in clinical practice has empowered clinicians to unravel the phenotypic heterogeneity of PMD and to end the diagnostic odyssey experienced by many patients and families. In unresolved cases, the detection of variant(s) of unknown significance by next-generation sequencing creates diagnostic and clinical uncertainties, and integrating a multi-omics approach can improve diagnostic yield. Alongside breakthroughs in genomic technologies, there is growing interest in using fluid biomarkers to guide diagnosis, monitor disease progression, and potentially serve as clinical trial endpoints. However, the clinical application of these fluid biomarkers in unselected patient cohorts with different disease onset and phenotypes would require more robust evidence. Natural history studies derived from national and international collaborations have provided insights into genotype–phenotype relationships and prognostic factors across several genotypes, including m.3243A>G, MT-ATP6, POLG, and TK2. Advances in therapeutic discoveries and clinical trials are challenging the obsolete dogma that PMDs are untreatable and bringing hope to patients; four compounds have been licensed, and many trials are in progress. Many barriers and challenges to translating laboratory discoveries into clinical therapy in PMD remain, including preclinical models for efficacy and safety testing, sample size, trial design, and the selection of outcome measures and trial endpoints.
A. Lim, Aye Moe, R. Stefanetti et al.· Genes· 0 citations
Background Multiple mitochondrial dysfunction syndrome type 3 (MMDS3; OMIM #615330) is a rare autosomal recessive disorder caused by mutations in IBA57. Its complex clinical presentation and molecular pathogenesis remain incompletely understood. Methods The study included comprehensive clinical evaluation, IBA57 genetic testing, Western Blotting for protein expression, and transcriptomic and metabolomic analyses of amniotic fluid cells. Results The proband presented with typical MMDS3 features, and both affected siblings carried compound heterozygous IBA57 missense mutations (c.310G>T and c.826C>T) leading to reduced IBA57 protein expression. RNA-seq revealed transcriptional dysregulation of the PI3K-Akt signaling pathway, and metabolomics demonstrated TCA cycle disturbances in amniocytes. Respiratory chain enzyme assays showed a selective deficiency of complex II activity in fetal liver. Conclusion The compound heterozygous IBA57 mutations c.310G>T and c.826C>T lead to reduced IBA57 protein expression, selective impairment of respiratory chain complex II, and transcriptional dysregulation of the PI3K-Akt pathway, together contributing to the MMDS3 phenotype in the proband and the affected fetus.
Yijuan Huang, C. Gou, Y. Chen et al.· Frontiers in Genetics· 0 citations
Leukodystrophies (LDs), a group of heterogeneous genetic disorders, are characterized by selective involvement of cerebral white matter, including abnormal white matter development and/or progressive degeneration. Oligodendrocytes, astrocytes, microglia, axons, and the neurovascular unit collectively contribute to white matter homeostasis and disease progression. Recently, genomic sequencing has identified pathogenic variants in the alanyl-tRNA synthetase 1 (AARS1) and alanyl-tRNA synthetase 2, mitochondrial (AARS2) genes in LD-related phenotypes. Dysfunction of AARS1 and AARS2 proteins may impair cytosolic or mitochondrial tRNA aminoacylation, compromise editing fidelity, and disrupt mitochondrial homeostasis, which may lead to disruption of protein homeostasis, cellular stress responses, and energy failure. Alanyl-tRNA synthetase (AlaRS) impairments play an important role in the pathological processes of cytosolic and mitochondrial alanyl-tRNA synthetase-related disorders. These molecular defects are associated with characteristic neuroimaging patterns and diverse clinical manifestations observed in AARS1/AARS2-related disorders. This review summarizes current knowledge on the genetic basis, clinicopathological features, and molecular mechanisms of AARS1- and AARS2-related leukodystrophies, and discusses emerging therapeutic perspectives, with the aim of facilitating precision diagnosis and future targeted interventions.
Background Mitochondrial Encephalomyopathy Lactic Acidosis and Stroke-like episodes (MELAS) is rare in people over 40 years of age, and gastrointestinal complications of MELAS are also rare, especially Chronic Intestinal Pseudo-Obstruction (CIPO). Case Presentation This report describes a 60 years old MELAS patient with a mutation rate of only 6.29% in the m.3243A>G gene, accompanied by CIPO. After treatment, MELAS symptoms can be controlled, but intestinal obstruction recurs and worsens. At present, patients fast and rely on intravenous nutrition to sustain their lives. Discussion The low proportion of m.3243A>G mutations in patients may be related to their advanced age, but the high or low proportion of gene mutations detected in blood samples is not related to the severity of symptoms. MELAS combined with CIPO is rare and different from other intestinal obstructions. CIPO has no cause of mechanical intestinal obstruction and may be related to dysfunction of smooth muscle mitochondria or involvement of the enteric nervous system. Conclusion For complications of MELAS beyond the nervous system, early consideration should be given to the possibility of MELAS. Early genetic testing has important clinical significance for the treatment and prognosis of patients. This article will provide a literature review on the multi system performance of MELAS.
Lin Zhang, Jun-Jian Lin, Feng-Ying Li et al.· Frontiers in Molecular Biosc...· 0 citations
TOP3A-related mitochondrial disease is a rare autosomal recessive primary mitochondrial cytopathy caused by loss-of-function of the mitochondrial-specific isoform of topoisomerase 3α, leading to multiple mitochondrial DNA deletions and mitochondrial DNA depletion. This condition has been associated with two different phenotypes. Very young patients present with severe growth faltering and early mortality, that is consistent with a Bloom syndrome-like disorder. Adult-onset chronic progressive external ophthalmoplegia, myopathy, and sensory ataxia, with rare hypertrophic cardiomyopathy (a MIRAS-like phenotype), reflects a mitochondrial disorder. In this article, we expand the phenotype spectrum of TOP3A-related mitochondrial disease with a mitochondrial childhood onset form and present four previously unreported patients, including the outcomes of heart transplantation for three patients. Histopathological, electron microscopical, biochemical, and molecular characterization of muscle and heart tissue indicated mitochondrial dysfunction with combined complex deficiency associated with a mitochondrial DNA maintenance disorder primarily expressed in the heart. Heart transplantation was successful in patients with TOP3A-related mitochondrial disease that presented with cardiomyopathy in childhood, although there is slowly progressive neurological disease. In childhood, TOP3A-related disease presents with a combination of developmental delays, sensorineural hearing loss, cardiomyopathy with rhythm abnormalities, stroke-like episodes, and Leigh-like phenotype, and, in some, epilepsy. These mitochondrial phenotypes are different from the infantile Bloom-like syndrome and the adult-onset form.
Rodrigo T. Starosta, Marisa W Friederich, Graeme Preston et al.· American Journal of Medical...· 1 citation
