{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T07:02:49Z","timestamp":1784617369143,"version":"3.55.0"},"reference-count":27,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:00:00Z","timestamp":1784505600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:00:00Z","timestamp":1784505600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100010846","name":"Australian Mitochondrial Disease Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010846","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    <jats:italic>TOP3A<\/jats:italic>\n                    \u2010related mitochondrial disease is a rare autosomal recessive primary mitochondrial cytopathy caused by loss\u2010of\u2010function of the mitochondrial\u2010specific isoform of topoisomerase 3\u03b1, 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\u2010like disorder. Adult\u2010onset chronic progressive external ophthalmoplegia, myopathy, and sensory ataxia, with rare hypertrophic cardiomyopathy (a MIRAS\u2010like phenotype), reflects a mitochondrial disorder. In this article, we expand the phenotype spectrum of\n                    <jats:italic>TOP3A<\/jats:italic>\n                    \u2010related 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\n                    <jats:italic>TOP3A<\/jats:italic>\n                    \u2010related mitochondrial disease that presented with cardiomyopathy in childhood, although there is slowly progressive neurological disease. In childhood,\n                    <jats:italic>TOP3A<\/jats:italic>\n                    \u2010related disease presents with a combination of developmental delays, sensorineural hearing loss, cardiomyopathy with rhythm abnormalities, stroke\u2010like episodes, and Leigh\u2010like phenotype, and, in some, epilepsy. These mitochondrial phenotypes are different from the infantile Bloom\u2010like syndrome and the adult\u2010onset form.\n                  <\/jats:p>","DOI":"10.1002\/ajmg.a.70248","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T06:23:01Z","timestamp":1784614981000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Delineation and Phenotypic Expansion of\n                    <scp>\n                      <i>TOP3A<\/i>\n                    <\/scp>\n                    \u2010Related Mitochondrial Disease in Childhood"],"prefix":"10.1002","author":[{"given":"Rodrigo T.","family":"Starosta","sequence":"first","affiliation":[{"name":"Department of Molecular and Medical Genetics Oregon Health and Science University  Portland Oregon USA"},{"name":"Department of Pediatrics, Section of Clinical Genetics and Metabolism University of Colorado School of Medicine  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marisa W.","family":"Friederich","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Section of Clinical Genetics and Metabolism University of Colorado School of Medicine  Aurora Colorado USA"},{"name":"Department of Pathology and Laboratory Medicine Children's Hospital Colorado  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graeme","family":"Preston","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomics Mount Sinai School of Medicine  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lily","family":"Walson","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Emory University  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie Hong","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Pathology Emory University  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Lang","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2348-9262","authenticated-orcid":false,"given":"Hanna J.","family":"Tadros","sequence":"additional","affiliation":[{"name":"Division of Pediatric Cardiology Texas Children's Hospital  Houston Texas USA"},{"name":"Department of Pediatrics Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"},{"name":"Texas Children's Hospital  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Mizerik","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Mirsky","sequence":"additional","affiliation":[{"name":"Department of Radiology University of Colorado School of Medicine  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniella H.","family":"Hock","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute The University of Melbourne  Parkville Victoria Australia"},{"name":"Murdoch Children's Research Institute  Melbourne Victoria Australia"},{"name":"Victorian Clinical Genetics Services Royal Children's Hospital  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Stroud","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute The University of Melbourne  Parkville Victoria Australia"},{"name":"Murdoch Children's Research Institute  Melbourne Victoria Australia"},{"name":"Victorian Clinical Genetics Services Royal Children's Hospital  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0423-2557","authenticated-orcid":false,"given":"Rossana","family":"Sanchez Russo","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Emory University  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3502-8460","authenticated-orcid":false,"given":"Fernando","family":"Scaglia","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"},{"name":"Texas Children's Hospital  Houston Texas USA"},{"name":"Baylor Genetics  Houston Texas USA"},{"name":"Joint BCM\u2010CUHK Center of Medical Genetics Prince of Wales Hospital  Hong Kong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Morava","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomics Mount Sinai School of Medicine  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2850-3294","authenticated-orcid":false,"given":"Johan L. K.","family":"Van Hove","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Section of Clinical Genetics and Metabolism University of Colorado School of Medicine  Aurora Colorado USA"},{"name":"Department of Pathology and Laboratory Medicine Children's Hospital Colorado  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,20]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mito.2014.12.005"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet\u20102015\u2010103049"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2022.04.067"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2017.02.017"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.202216775"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s44321\u2010025\u201000290\u20108"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddw431"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2025.109236"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399\u20103046.2011.01635.x"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.64898\/2026.03.23.26349081"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac660"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13073\u2010025\u201001467\u2010z"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2021.166106"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.14287"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2018.07.001"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2017.11.033"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1212\/NXG.0000000000200007"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa1011"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0960\u20108966(01)00248\u20106"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/elps.200900213"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mito.2004.07.003"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1203\/00006450\u2010200111000\u201000020"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mito.2024.101905"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.192449499"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2019.10.016"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGEN.121.003559"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.123216"}],"container-title":["American Journal of Medical Genetics Part A"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.70248","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ajmg.a.70248","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.70248","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T06:23:02Z","timestamp":1784614982000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ajmg.a.70248"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,20]]},"references-count":27,"alternative-id":["10.1002\/ajmg.a.70248"],"URL":"https:\/\/doi.org\/10.1002\/ajmg.a.70248","archive":["Portico"],"relation":{},"ISSN":["1552-4825","1552-4833"],"issn-type":[{"value":"1552-4825","type":"print"},{"value":"1552-4833","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,20]]},"assertion":[{"value":"2026-03-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-09","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-20","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"ajmg.a.70248"}}