{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T15:20:51Z","timestamp":1787671251784,"version":"build-2736575974"},"reference-count":81,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T00:00:00Z","timestamp":1757376000000},"content-version":"vor","delay-in-days":251,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007155","name":"Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007155","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institute for Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Care Research Newcastle Biomedical Research Centre"},{"DOI":"10.13039\/501100003776","name":"Newcastle Hospitals NHS Foundation Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003776","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000774","name":"Newcastle University and Cumbria","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000774","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003775","name":"Northumberland, Tyne and Wear NHS Foundation Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003775","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006662","name":"NIHR","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006662","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["203105\/A\/16\/Z"],"award-info":[{"award-number":["203105\/A\/16\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000272","name":"National Institute for Health and Care Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000276","name":"Department of Health and Social Care","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000276","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The m.3243A&amp;gt;G variant in the MT-TL1 gene is the most prevalent pathogenic variant in mitochondrial DNA in adults, associated with a wide clinical spectrum from asymptomatic individuals to mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome. Although pharmacological trials in mitochondrial disorders are increasing, the lack of validated endpoints remains a significant barrier to therapeutic development. This cross-sectional observational study aimed to evaluate patients with and without mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome to identify factors associated with disease burden. Seventeen individuals genetically confirmed to harbour the heteroplasmic m.3243A&amp;gt;G pathogenic variant were enrolled: six who met the consensus-based diagnostic criteria for mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome (median age: 30.0 (inter-quartile range: 29.3\u201345.0) years). Ten patients who did not have a previous history of stroke-like episodes were assigned as \u2018non-mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes\u2019 (age: 37.5 (32.8\u201348.3) years). Of these patients in the non-mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes group, seven exhibited variable features of mitochondrial disease, including hearing loss, diabetes mellitus, migraine and gastrointestinal involvement, while the remaining three were asymptomatic. One patient was excluded from analysis due to a confirmed ischaemic stroke unrelated to mitochondrial disease. Assessments included disease severity (Newcastle mitochondrial disease adult scale) and patient-reported outcomes of fatigue (fatigue impact scale), health-related quality of life (Newcastle Mitochondrial-QoL), mental well-being (Warwick\u2013Edinburgh mental wellbeing scale), autonomic symptoms (the composite autonomic symptom) and physical activity (The International Physical Activity Questionnaire). Performance outcomes included timed-up and go, handgrip strength, cardiopulmonary exercise testing and accelerometry. Age- and sex-matched healthy controls were included for comparison of accelerometry data (age: 35.5 (28.8\u201350.5) years). Despite comparable age and mitochondrial DNA heteroplasmy, patients with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome had significantly higher disease burden, reduced exercise capacity and lower levels of objectively measured physical activity compared to non-mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes and controls (P &amp;lt; 0.05\u20130.001). Patient-reported outcomes did not significantly differ between mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome\/non-mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes. While non-mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes patients showed expected alignment between perceived and objective measures, mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome patients demonstrated weak, absent, or paradoxical associations. This mismatch may reflect altered symptom perception, cognitive impairment, or disease-related adaptation. These findings underscore the complexity of disease expression in mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome. Regulatory agencies encourage the inclusion of patient-centred endpoints; however, this study highlights the potential limitations of relying solely on patient-reported outcomes. The divergence between subjective and objective assessments supports the need for multi-dimensional outcomes that integrate both patient perspectives and objective measures to enhance the reliability and interpretability of clinical trials in primary mitochondrial disease.<\/jats:p>","DOI":"10.1093\/braincomms\/fcaf342","type":"journal-article","created":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T15:02:17Z","timestamp":1757430137000},"source":"Crossref","is-referenced-by-count":2,"title":["Outcomes misaligned in mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS): implications for trial design"],"prefix":"10.1093","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6402-6435","authenticated-orcid":false,"given":"Renae J","family":"Stefanetti","sequence":"first","affiliation":[{"name":"Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University , Newcastle upon Tyne NE2 4HH ,","place":["UK"]},{"name":"National Institute for Health and Care Research (NIHR) Newcastle Biomedical Research Centre (BRC) , Newcastle upon Tyne NE4 5PL ,","place":["UK"]},{"name":"Newcastle upon Tyne Hospitals NHS Foundation Trust , Newcastle upon Tyne NE1 4LP ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3029-7672","authenticated-orcid":false,"given":"Sarah J","family":"Charman","sequence":"additional","affiliation":[{"name":"Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University , Newcastle upon Tyne NE2 4HH ,","place":["UK"]},{"name":"Newcastle upon Tyne Hospitals NHS Foundation Trust , Newcastle upon Tyne NE1 4LP ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane","family":"Newman","sequence":"additional","affiliation":[{"name":"Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University , Newcastle upon Tyne NE2 4HH ,","place":["UK"]},{"name":"National Institute for Health and Care Research (NIHR) Newcastle Biomedical Research Centre (BRC) , Newcastle upon Tyne NE4 5PL ,","place":["UK"]},{"name":"Newcastle upon Tyne Hospitals NHS Foundation Trust , Newcastle upon Tyne NE1 4LP ,","place":["UK"]},{"name":"NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children, Newcastle upon Tyne Hospitals NHS Foundation Trust , Newcastle upon Tyne NE2 4HH ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate","family":"Hallsworth","sequence":"additional","affiliation":[{"name":"Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University , Newcastle upon Tyne NE2 4HH ,","place":["UK"]},{"name":"National Institute for Health and Care Research (NIHR) Newcastle Biomedical Research Centre (BRC) , Newcastle upon Tyne NE4 5PL ,","place":["UK"]},{"name":"Newcastle upon Tyne Hospitals NHS Foundation Trust , Newcastle upon Tyne NE1 4LP ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alasdair P","family":"Blain","sequence":"additional","affiliation":[{"name":"Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University , Newcastle upon Tyne NE2 4HH ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi Shiau","family":"Ng","sequence":"additional","affiliation":[{"name":"Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University , Newcastle upon Tyne NE2 4HH ,","place":["UK"]},{"name":"National Institute for Health and Care Research (NIHR) Newcastle Biomedical Research Centre (BRC) , Newcastle upon Tyne NE4 5PL ,","place":["UK"]},{"name":"NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children, Newcastle upon Tyne Hospitals NHS Foundation Trust , Newcastle upon Tyne NE2 4HH ,","place":["UK"]},{"name":"Directorate of Neurosciences, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust , Newcastle upon Tyne NE1 4LP ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gr\u00e1inne S","family":"Gorman","sequence":"additional","affiliation":[{"name":"Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University , Newcastle upon Tyne NE2 4HH ,","place":["UK"]},{"name":"National Institute for Health and Care Research (NIHR) Newcastle Biomedical Research Centre (BRC) , Newcastle upon Tyne NE4 5PL ,","place":["UK"]},{"name":"NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children, Newcastle upon Tyne Hospitals NHS Foundation Trust , Newcastle upon Tyne NE2 4HH ,","place":["UK"]},{"name":"Directorate of Neurosciences, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust , Newcastle upon Tyne NE1 4LP 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