{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T22:28:33Z","timestamp":1787092113474,"version":"build-2736575974"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T00:00:00Z","timestamp":1781049600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"content-version":"vor","delay-in-days":70,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"SIP High-Quality Innovation Platform for Chronic Diseases","award":["YZCXPT2022203"],"award-info":[{"award-number":["YZCXPT2022203"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Orphanet J Rare Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a rare mitochondrial disorder characterized by a wide range of systemic manifestations. MELAS is challenging to diagnose in its early stages and currently lacks targeted treatments. This systematic review and meta-analysis aim to validate the mitochondrial 3243A\u2009&gt;\u2009G (m.3243A\u2009&gt;\u2009G) mutation status, symptom prevalence, and neuroimaging characteristics in patients with MELAS. The review also seeks to consolidate and clarify the pathogenic pathways of MELAS while pinpointing potential therapeutic targets.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Main body<\/jats:title>\n                    <jats:p>We searched four databases for relevant studies. Study selection, data extraction, and quality assessment using the JBI (Joanna Briggs Institute) scale were performed by two reviewers. We conducted meta-analyses to estimate the pooled proportions for genetic, symptomatic, and imaging features using the random-effects generalized linear mixed model. In addition, seven MELAS-related pathways were researched, and their gene information was expanded through computational retrieval from the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome databases. A total of 13 studies involving 988 subjects were included, covering one mutant gene (m.3243A\u2009&gt;\u2009G), ten clinical symptoms, and four imaging features. The meta-analyses showed a pooled m.3243A\u2009&gt;\u2009G mutation prevalence of 78% (95% CI: 68%, 86%). The most frequent clinical manifestations were stroke-like episodes (99%; 95% CI: 29%, 100%), seizures (89%; 95% CI: 65%, 97%), and elevated lactate (81%; 95% CI: 50%, 95%). The temporal lobe was the most commonly affected brain region on imaging (87%; 95% CI: 13%, 100%). Pathway analysis revealed mitophagy\/autophagy, ROS generation, and energy metabolism as core mechanisms in MELAS, with MNRR1, L-arginine, PI3K-AKT-mTOR, and ETC as potential therapeutic targets.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study collects evidence for the confirmatory diagnosis of MELAS, integrating its genetic, clinical, and neuroimaging spectra. Furthermore, by elucidating the core pathological network, our work provides a potential framework for developing multi-targeted therapeutic strategies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13023-026-04448-6","type":"journal-article","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T12:24:24Z","timestamp":1781094264000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mitochondrial mutation status, symptom prevalence, and neuroimaging characteristics in MELAS: a systematic review and meta analysis"],"prefix":"10.1186","volume":"21","author":[{"given":"Yanyan","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siying","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daiyun","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siying","family":"Qu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinxin","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuoyan","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyu","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixue","family":"Qiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,10]]},"reference":[{"issue":"1","key":"4448_CR1","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1186\/s13023-024-03511-4","volume":"19","author":"S Xu","year":"2024","unstructured":"Xu S, Jiang J, Chang L, et al. Multisystem clinicopathologic and genetic analysis of MELAS. Orphanet J Rare Dis. 2024;19(1):487.","journal-title":"Orphanet J Rare Dis"},{"issue":"41","key":"4448_CR2","doi-asserted-by":"publisher","first-page":"e30938","DOI":"10.1097\/MD.0000000000030938","volume":"101","author":"X Chang","year":"2022","unstructured":"Chang X, Yin Z, Zhang W, et al. Data-independent acquisition-based quantitative proteomic analysis of m.3243A\u2009>\u2009G MELAS reveals novel potential pathogenesis and therapeutic targets. Med (Baltim). 2022;101(41):e30938.","journal-title":"Med (Baltim)"},{"issue":"6","key":"4448_CR3","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1111\/cge.14605","volume":"106","author":"Y Zhao","year":"2024","unstructured":"Zhao Y, Zhao X, Ji K, et al. The clinical and genetic spectrum of mitochondrial diseases in China: a multicenter retrospective cross-sectional study. Clin Genet. 2024;106(6):733\u201344.","journal-title":"Clin Genet"},{"issue":"4","key":"4448_CR4","doi-asserted-by":"publisher","first-page":"816","DOI":"10.4093\/dmj.2024.0065","volume":"48","author":"J Finsterer","year":"2024","unstructured":"Finsterer J, Mehri S. MIDD patients should not be confused with MELAS patients, even though both carry the m.3243A\u2009>\u2009G variant. Diabetes Metab J. 2024;48(4):816\u20137.","journal-title":"Diabetes Metab J"},{"key":"4448_CR5","unstructured":"Study Details | NCT01603446 | L-arginine Therapy on Endothelium-dependent Vasodilation & Mitochondrial Metabolism in MELAS Syndrome | ClinicalTrials.gov."},{"issue":"1","key":"4448_CR6","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.jacc.2024.09.1231","volume":"85","author":"HA Ueyama","year":"2025","unstructured":"Ueyama HA, Akita K, Kiyohara Y, et al. Optimal strategy for complete revascularization in ST-segment elevation myocardial infarction and multivessel disease: a network meta-analysis. J Am Coll Cardiol. 2025;85(1):19\u201338.","journal-title":"J Am Coll Cardiol"},{"issue":"3","key":"4448_CR7","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1097\/XEB.0000000000000054","volume":"13","author":"Z Munn","year":"2015","unstructured":"Munn Z, Moola S, Lisy K, Riitano D, Tufanaru C. Methodological guidance for systematic reviews of observational epidemiological studies reporting prevalence and cumulative incidence data. Int J Evid Based Healthc. 2015;13(3):147\u201353.","journal-title":"Int J Evid Based Healthc"},{"issue":"8753","key":"4448_CR8","doi-asserted-by":"publisher","first-page":"1311","DOI":"10.1016\/0140-6736(91)92981-7","volume":"337","author":"SR Hammans","year":"1991","unstructured":"Hammans SR, Sweeney MG, Brockington M, Morgan-Hughes JA, Harding AE. Mitochondrial encephalopathies: molecular genetic diagnosis from blood samples. Lancet. 1991;337(8753):1311\u20133.","journal-title":"Lancet"},{"issue":"4","key":"4448_CR9","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1002\/ana.410310408","volume":"31","author":"E Ciafaloni","year":"1992","unstructured":"Ciafaloni E, Ricci E, Shanske S, et al. MELAS: clinical features, biochemistry, and molecular genetics. Ann Neurol. 1992;31(4):391\u20138.","journal-title":"Ann Neurol"},{"issue":"11","key":"4448_CR10","doi-asserted-by":"publisher","first-page":"1835","DOI":"10.1093\/hmg\/6.11.1835","volume":"6","author":"S Hofmann","year":"1997","unstructured":"Hofmann S, Jaksch M, Bezold R, et al. Population genetics and disease susceptibility: characterization of central European haplogroups by mtDNA gene mutations, correlation with D loop variants and association with disease. Hum Mol Genet. 1997;6(11):1835\u201346.","journal-title":"Hum Mol Genet"},{"issue":"2","key":"4448_CR11","first-page":"147","volume":"7","author":"Q Yu","year":"2007","unstructured":"Yu Q, Zhang Y, Wang Z, et al. Screening of common mitochondrial mutations in Chinese patients with mitochondrial encephalomyopathies. Mitochondrion. 2007;7(2):147\u201350.","journal-title":"Mitochondrion"},{"issue":"4","key":"4448_CR12","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1002\/ana.21328","volume":"63","author":"AJM Janssen","year":"2008","unstructured":"Janssen AJM, Schuelke M, Smeitink JAM, et al. Muscle 3243A\u2192G mutation load and capacity of the mitochondrial energy-generating system. Ann Neurol. 2008;63(4):473\u201381.","journal-title":"Ann Neurol"},{"issue":"22","key":"4448_CR13","doi-asserted-by":"publisher","first-page":"1965","DOI":"10.1212\/WNL.0b013e31823a0c7f","volume":"77","author":"P Kaufmann","year":"2011","unstructured":"Kaufmann P, Engelstad K, Wei Y, et al. Natural history of MELAS associated with mitochondrial DNA m.3243A\u2009>\u2009G genotype. Neurology. 2011;77(22):1965\u201371.","journal-title":"Neurology"},{"issue":"4","key":"4448_CR14","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1097\/NRL.0000000000000331","volume":"26","author":"JA Gahares-Olalde","year":"2021","unstructured":"Gahares-Olalde JA, Lopez-Hernandez JC, Benitez-Alonso EO, et al. Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome: frequency, clinical features, imaging, histopathologic, and molecular genetic findings in a third-level health care center in Mexico. Neurologist. 2021;26(4):143\u20138.","journal-title":"Neurologist"},{"issue":"5","key":"4448_CR15","first-page":"1016","volume":"8","author":"LL Gramegna","year":"2021","unstructured":"Gramegna LL, Evangelisti S, Di Vito L, et al. Brain MRS correlates with mitochondrial dysfunction biomarkers in MELAS-associated mtDNA mutations. Ann Clin Transl Neurol. 2021;8(5):1016\u201329.","journal-title":"Ann Clin Transl Neurol"},{"issue":"2","key":"4448_CR16","doi-asserted-by":"publisher","first-page":"542","DOI":"10.1093\/brain\/awab353","volume":"145","author":"YS Ng","year":"2022","unstructured":"Ng YS, Lax NZ, Blain AP, et al. Forecasting stroke-like episodes and outcomes in mitochondrial disease. Brain. 2022;145(2):542\u201354.","journal-title":"Brain"},{"issue":"15","key":"4448_CR17","doi-asserted-by":"publisher","first-page":"1431","DOI":"10.1016\/j.jacc.2022.04.067","volume":"80","author":"A Di Toro","year":"2022","unstructured":"Di Toro A, Urtis M, Narula N, et al. Impediments to Heart Transplantation in Adults With MELASMT-TL1: m.3243A\u2009>\u2009G Cardiomyopathy. J Am Coll Cardiol. 2022;80(15):1431\u201343.","journal-title":"J Am Coll Cardiol"},{"issue":"50","key":"4448_CR18","doi-asserted-by":"publisher","first-page":"32056","DOI":"10.1073\/pnas.2005877117","volume":"117","author":"N Siddhesh Aras","year":"2020","unstructured":"Siddhesh Aras N, Purandare S, Gladyck, et al. Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1) rescues the cellular phenotype of MELAS by inducing homeostatic mechanisms. Proc Natl Acad Sci U S A. 2020;117(50):32056\u201365.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"4448_CR19","doi-asserted-by":"publisher","first-page":"6409","DOI":"10.1038\/s41467-021-26746-2","volume":"12","author":"C-Y Chung","year":"2021","unstructured":"Chung C-Y, Singh K, Vassilios N, Kotiadis, et al. Constitutive activation of the PI3K-Akt-mTORC1 pathway sustains the m.3243A\u2009>\u2009G mtDNA mutation. Nat Commun. 2021;12(1):6409.","journal-title":"Nat Commun"},{"issue":"43","key":"4448_CR20","doi-asserted-by":"publisher","first-page":"73627","DOI":"10.18632\/oncotarget.20617","volume":"8","author":"D-S Lin","year":"2017","unstructured":"Lin D-S, Kao S-H, Ho C-S, et al. Inflexibility of AMPK-mediated metabolic reprogramming in mitochondrial disease. Oncotarget. 2017;8(43):73627\u201339.","journal-title":"Oncotarget"},{"issue":"8","key":"4448_CR21","first-page":"e106283","volume":"40","author":"S Li","year":"2021","unstructured":"Li S, Xu CHM, et al. ATAD3B is a mitophagy receptor mediating clearance of oxidative stress-induced damaged mitochondrial DNA. EMBO J. 2021;40(8):e106283.","journal-title":"EMBO J"},{"issue":"1","key":"4448_CR22","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1093\/hmg\/ddu427","volume":"24","author":"A Salvador Meseguer","year":"2015","unstructured":"Salvador Meseguer A, Mart\u00ednez-Zamora E, Garc\u00eda-Arum\u00ed AL, Andreu M-E, Armengod. The ROS-sensitive microRNA-9\/9* controls the expression of mitochondrial tRNA-modifying enzymes and is involved in the molecular mechanism of MELAS syndrome. Hum Mol Genet. 2015;24(1):167\u201384.","journal-title":"Hum Mol Genet"},{"issue":"7","key":"4448_CR23","doi-asserted-by":"publisher","first-page":"1665","DOI":"10.3390\/biomedicines10071665","volume":"10","author":"S Belal","year":"2022","unstructured":"Belal S, Gouden\u00e8ge D, Bocca C, et al. Glutamate-Induced Deregulation of Krebs Cycle in Mitochondrial Encephalopathy Lactic Acidosis Syndrome Stroke-Like Episodes (MELAS) Syndrome Is Alleviated by Ketone Body Exposure. Biomedicines. 2022;10(7):1665.","journal-title":"Biomedicines"},{"issue":"3","key":"4448_CR24","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1039\/D1MO00416F","volume":"18","author":"H Li","year":"2022","unstructured":"Li H, Uittenbogaard M, Navarro R, et al. Integrated proteomic and metabolomic analyses of the mitochondrial neurodegenerative disease MELAS. Mol Omics. 2022;18(3):196\u2013205.","journal-title":"Mol Omics"},{"issue":"3","key":"4448_CR25","doi-asserted-by":"publisher","first-page":"601","DOI":"10.1016\/j.bbrc.2015.01.157","volume":"458","author":"G Brisca","year":"2015","unstructured":"Brisca G, Fiorillo C, Nesti C, et al. Early onset cardiomyopathy associated with the mitochondrial tRNALeu((UUR)) 3271T\u2009>\u2009C MELAS mutation. Biochem Biophys Res Commun. 2015;458(3):601\u20134.","journal-title":"Biochem Biophys Res Commun"},{"key":"4448_CR26","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.mito.2015.03.001","volume":"22","author":"MM O\u2019Callaghan","year":"2015","unstructured":"O\u2019Callaghan MM, Emperador S, Pineda M, et al. Mutation loads in different tissues from six pathogenic mtDNA point mutations. Mitochondrion. 2015;22:17\u201322.","journal-title":"Mitochondrion"},{"issue":"10","key":"4448_CR27","first-page":"1127","volume":"76","author":"Y Sunada","year":"2024","unstructured":"Sunada Y. Taurine for mitochondrial diseases. Brain Nerve. 2024;76(10):1127\u201335.","journal-title":"Brain Nerve"},{"issue":"12","key":"4448_CR28","doi-asserted-by":"publisher","first-page":"1493","DOI":"10.3390\/biom14121524","volume":"14","author":"JH Na","year":"2024","unstructured":"Na JH, Lee YM. Diagnosis and management of mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes syndrome. Biomolecules. 2024;14(12):1493.","journal-title":"Biomolecules"},{"issue":"49","key":"4448_CR29","doi-asserted-by":"publisher","first-page":"e40704","DOI":"10.1097\/MD.0000000000040704","volume":"103","author":"K Arslan","year":"2024","unstructured":"Arslan K, Sahin AS. Lactate, lactate clearance, and lactate-to-albumin ratio in predicting mortality in patients with critical polytrauma: a retrospective observational study. Med (Baltim). 2024;103(49):e40704.","journal-title":"Med (Baltim)"},{"issue":"8","key":"4448_CR30","doi-asserted-by":"publisher","first-page":"2158","DOI":"10.1007\/s11064-022-03631-y","volume":"47","author":"J-S Luo","year":"2022","unstructured":"Luo J-S, Ning J-Q, Chen Z-Y. The role of mitochondrial quality control in cognitive dysfunction in diabetes. Neurochem Res. 2022;47(8):2158\u201372.","journal-title":"Neurochem Res"},{"key":"4448_CR31","doi-asserted-by":"crossref","unstructured":"Wang YC, Wang YL, Yue GX, Zhao YL. Energy metabolism disturbance in migraine: from a mitochondrial point of view. Front Physiol. 2023;14:1133528.","DOI":"10.3389\/fphys.2023.1133528"},{"key":"4448_CR32","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.eplepsyres.2017.08.012","volume":"137","author":"J\u00d8 Lorgen","year":"2017","unstructured":"Lorgen J\u00d8, Egbenya DL, Hammer J, Davanger S. PICK1 facilitates lasting reduction in GluA2 concentration in the hippocampus during chronic epilepsy. Epilepsy Res. 2017;137:25\u201332.","journal-title":"Epilepsy Res"},{"issue":"Pt 5","key":"4448_CR33","doi-asserted-by":"publisher","first-page":"1428","DOI":"10.1093\/brain\/awq067","volume":"133","author":"C Tzoulis","year":"2010","unstructured":"Tzoulis C, Neckelmann G, M\u00f8rk SJ, et al. Localized cerebral energy failure in DNA polymerase gamma-associated encephalopathy syndromes. Brain. 2010;133(Pt 5):1428\u201337.","journal-title":"Brain"}],"container-title":["Orphanet Journal of Rare Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13023-026-04448-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-026-04448-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-026-04448-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T22:23:18Z","timestamp":1787091798000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s13023-026-04448-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,10]]},"references-count":33,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["4448"],"URL":"https:\/\/doi.org\/10.1186\/s13023-026-04448-6","relation":{},"ISSN":["1750-1172"],"issn-type":[{"value":"1750-1172","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,10]]},"assertion":[{"value":"4 February 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 June 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 June 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Not applicable.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"283"}}