{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T05:01:32Z","timestamp":1784955692402,"version":"3.55.0"},"reference-count":234,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:00:00Z","timestamp":1784764800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>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\u2013phenotype relationships and prognostic factors across several genotypes, including m.3243A&gt;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.<\/jats:p>","DOI":"10.3390\/genes17080850","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T17:13:17Z","timestamp":1784826797000},"page":"850","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Advances in Primary Mitochondrial Diseases: Diagnosis, Natural History Studies and Clinical Trials"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1321-8063","authenticated-orcid":false,"given":"Albert Z.","family":"Lim","sequence":"first","affiliation":[{"name":"Department of Paediatric Neurology, Great North Children\u2019s Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK"},{"name":"NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aye-Myat","family":"Moe","sequence":"additional","affiliation":[{"name":"Directorate of Neurosciences, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK"},{"name":"Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"},{"name":"NIHR Newcastle Biomedical Research Centre (BRC), Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6402-6435","authenticated-orcid":false,"given":"Renae J.","family":"Stefanetti","sequence":"additional","affiliation":[{"name":"Directorate of Neurosciences, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK"},{"name":"Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"},{"name":"NIHR Newcastle Biomedical Research Centre (BRC), Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi Shiau","family":"Ng","sequence":"additional","affiliation":[{"name":"Directorate of Neurosciences, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK"},{"name":"Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"},{"name":"NIHR Newcastle Biomedical Research Centre (BRC), Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1016\/B978-0-323-98818-6.00025-X","article-title":"Mitochondrial encephalomyopathy","volume":"Volume 195","author":"Ng","year":"2023","journal-title":"Handbook of Clinical Neurology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/S1474-4422(21)00098-3","article-title":"Mitochondrial disease in adults: Recent advances and future promise","volume":"20","author":"Ng","year":"2021","journal-title":"Lancet. 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