{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T06:05:14Z","timestamp":1790661914330,"version":"4.1.0"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Aim<\/jats:title>\n                    <jats:p>\n                      To characterize the clinical and molecular features associated with the\n                      <jats:italic>MT-CYB<\/jats:italic>\n                      m.15045G\u202f&amp;gt;\u202fA variant and investigate the clinical spectrum and genotype\u2013phenotype relationships of\n                      <jats:italic>MT-CYB<\/jats:italic>\n                      -associated mitochondrial disease.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We performed comprehensive clinical, metabolic, histopathological, genetic, and mitochondrial functional analyses in a patient carrying the m.15045G\u202f&amp;gt;\u202fA variant. A systematic literature review of previously reported disease-associated\n                      <jats:italic>MT-CYB<\/jats:italic>\n                      variants was conducted, followed by genotype\u2013phenotype comparisons and unsupervised hierarchical clustering integrating clinical, genetic, and functional characteristics.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The patient presented with exercise intolerance, borderline intellectual functioning, and elevated medium and long-chain acylcarnitines. Muscle biopsy showed mitochondrial myopathic changes, and respiratory chain analysis demonstrated isolated complex III (CIII) deficiency. The m.15045G\u202f&amp;gt;\u202fA variant showed tissue-specific heteroplasmy of 22.5, 70.5, and 95.5% in blood, urine, and muscle, respectively, providing further evidence for its pathogenicity. Among 34 patients with disease-associated\n                      <jats:italic>MT-CYB<\/jats:italic>\n                      variants, mitochondrial myopathy (MM) was the most common phenotype (50.0%). Patients with MM showed a later age at onset, and muscle-restricted variants were markedly enriched in the MM group (\n                      <jats:italic>p<\/jats:italic>\n                      \u202f&amp;lt;\u202f0.001). In contrast, muscle heteroplasmy level, variant type, and isolated CIII deficiency were not significantly associated with phenotype. Hierarchical clustering showed 88.2% concordance with clinical phenotype classification.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Our findings provide further evidence for the pathogenicity of m.15045G\u202f&amp;gt;\u202fA and broaden its associated clinical and metabolic features. Tissue-specific distribution of\n                      <jats:italic>MT-CYB<\/jats:italic>\n                      variants showed an association with clinical phenotype, while other genetic and functional factors may collectively contribute to phenotypic variability.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnins.2026.1968308","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T05:50:12Z","timestamp":1790661012000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Clinical spectrum and genotype\u2013phenotype correlations of MT-CYB-associated mitochondrial disease: from the m.15045G\u202f&gt;\u202fA variant to the broader disease landscape"],"prefix":"10.3389","volume":"20","author":[{"given":"Zimeng","family":"He","sequence":"first","affiliation":[{"name":"Department of Neurology, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tongyue","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurology, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaolong","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Neurology, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neurology, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Zou","sequence":"additional","affiliation":[{"name":"Department of Neurology, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhimei","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neurology, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiatong","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuejing","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Pathology, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huafang","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Weifang Maternal and Child Health Hospital","place":["Weifang, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danmin","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Neurology, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunxi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Xiong","sequence":"additional","affiliation":[{"name":"Department of Neurology, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1002\/1531-8249(199901)45:1<127::AID-ART20>3.0.CO;2-Y","article-title":"A nonsense mutation (G15059A) in the cytochrome b gene in a patient with exercise intolerance and myoglobinuria","volume":"45","author":"Andreu","year":"1999","journal-title":"Ann. 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