{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T20:54:13Z","timestamp":1792702453486,"version":"4.5.0"},"reference-count":20,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2019,1,28]],"date-time":"2019-01-28T00:00:00Z","timestamp":1548633600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SCHO 7545\u20102"],"award-info":[{"award-number":["SCHO 7545\u20102"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002426","name":"Fondazione Telethon","doi-asserted-by":"publisher","award":["GGP15041"],"award-info":[{"award-number":["GGP15041"]}],"id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2019,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Mitochondrial aconitase is the second enzyme in the tricarboxylic acid (TCA) cycle catalyzing the interconversion of citrate into isocitrate and encoded by the nuclear gene <jats:italic>ACO2.<\/jats:italic> A homozygous pathogenic variant in the <jats:italic>ACO2<\/jats:italic> gene was initially described in 2012 resulting in a novel disorder termed \u201cinfantile cerebellar retinal degeneration\u201d (ICRD, OMIM#614559). Subsequently, additional studies reported patients with pathogenic <jats:italic>ACO2<\/jats:italic> variants, further expanding the genetic and clinical spectrum of this disorder to include milder and later onset manifestations. Here, we report an international multicenter cohort of 16 patients (of whom 7 are newly diagnosed) with biallelic pathogenic variants in <jats:italic>ACO2<\/jats:italic> gene. Most patients present in early infancy with severe truncal hypotonia, truncal ataxia, variable seizures, evolving microcephaly, and ophthalmological abnormalities of which the most dominant are esotropia and optic atrophy with later development of retinal dystrophy. Most patients remain nonambulatory and do no acquire any language, but a subgroup of patients share a more favorable course. Brain magnetic resonance imaging (MRI) is typically normal within the first months but global atrophy gradually develops affecting predominantly the cerebellum. Ten of our patients were homozygous to the previously reported c.336C&gt;G founder mutation while the other six patients were all compound heterozygotes displaying 10 novel mutations of whom 2 were nonsense predicting a deleterious effect on enzyme function. Structural protein modeling predicted significant impairment in aconitase substrate binding in the additional missense mutations. This study provides the most extensive cohort of patients and further delineates the clinical, radiological, biochemical, and molecular features of <jats:italic>ACO2<\/jats:italic> deficiency.<\/jats:p>","DOI":"10.1002\/jimd.12022","type":"journal-article","created":{"date-parts":[[2019,1,28]],"date-time":"2019-01-28T22:23:55Z","timestamp":1548714235000},"page":"264-275","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Clinical, radiological, and genetic characteristics of 16 patients with <i>ACO2<\/i> gene defects: Delineation of an emerging neurometabolic syndrome"],"prefix":"10.1002","volume":"42","author":[{"given":"Rajech","family":"Sharkia","sequence":"first","affiliation":[{"name":"Unit of Human Biology and Genetics, The Triangle Regional Research and Development Center  Kafr Qari Israel"},{"name":"Unit of Nature Science, Beit\u2010Berl Academic College  Beit\u2010Berl Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaas J.","family":"Wierenga","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Oklahoma University Health Sciences Center  Oklahoma City OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit","family":"Kessel","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Faculty of Life Sciences Tel\u2010Aviv University  Tel\u2010Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdussalam","family":"Azem","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Faculty of Life Sciences Tel\u2010Aviv University  Tel\u2010Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrico","family":"Bertini","sequence":"additional","affiliation":[{"name":"Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine Bambino Gesu\u2019 Children's Research Hospital  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosalba","family":"Carrozzo","sequence":"additional","affiliation":[{"name":"Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine Bambino Gesu\u2019 Children's Research Hospital  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Torraco","sequence":"additional","affiliation":[{"name":"Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine Bambino Gesu\u2019 Children's Research Hospital  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Goffrini","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Life Sciences and Environmental Sustainability University of Parma  Parma Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilla","family":"Ceccatelli Berti","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Life Sciences and Environmental Sustainability University of Parma  Parma Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Eileen","family":"McCormick","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Oakland University William Beaumont School of Medicine  Rochester Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Plecko","sequence":"additional","affiliation":[{"name":"Division of Child Neurology University Children's Hospital Zurich  Zurich Switzerland"},{"name":"Department of Pediatrics Medical University of Graz  Graz Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Klein","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology University Children's Hospital Basel and University Children's Hospital  Bern Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia","family":"Abela","sequence":"additional","affiliation":[{"name":"Molecular Neurosciences, Developmental Neuroscience UCL Institute of Child Health  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holger","family":"Hengel","sequence":"additional","affiliation":[{"name":"German Research Center for Neurodegenerative Diseases (DZNE)  T\u00fcbingen Germany"},{"name":"Department of Neurodegenerative Diseases and Hertie\u2010Institute for Clinical Brain Research University of T\u00fcbingen  T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludger","family":"Sch\u00f6ls","sequence":"additional","affiliation":[{"name":"German Research Center for Neurodegenerative Diseases (DZNE)  T\u00fcbingen Germany"},{"name":"Department of Neurodegenerative Diseases and Hertie\u2010Institute for Clinical Brain Research University of T\u00fcbingen  T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stavit","family":"Shalev","sequence":"additional","affiliation":[{"name":"Rappaport Faculty of Medicine Technion\u2010 Israel Institute of Technology  Haifa Israel"},{"name":"Institute of Medical Genetics, Emek Medical Center  Afula Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morad","family":"Khayat","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics, Emek Medical Center  Afula Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Mahajnah","sequence":"additional","affiliation":[{"name":"Rappaport Faculty of Medicine Technion\u2010 Israel Institute of Technology  Haifa Israel"},{"name":"Child Neurology and Development Center Hillel\u2010Yaffe Medical Center  Hadera Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronen","family":"Spiegel","sequence":"additional","affiliation":[{"name":"Rappaport Faculty of Medicine Technion\u2010 Israel Institute of Technology  Haifa Israel"},{"name":"Department of Pediatrics B Emek Medical Center  Afula 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