{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T20:16:09Z","timestamp":1782591369692,"version":"3.54.5"},"reference-count":22,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2020,6,9]],"date-time":"2020-06-09T00:00:00Z","timestamp":1591660800000},"content-version":"vor","delay-in-days":8,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000871","name":"Mayo Clinic","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2020,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>We describe the clinical characteristics and genetic etiology of several new cases within the ACO2\u2010related disease spectrum. Mitochondrial aconitase (ACO2) is a nuclear\u2010encoded tricarboxylic acid cycle enzyme. Homozygous pathogenic missense variants in the <jats:italic>ACO2<\/jats:italic> gene were initially associated with infantile degeneration of the cerebrum, cerebellum, and retina, resulting in profound intellectual and developmental disability and early death. Subsequent studies have identified a range of homozygous and compound heterozygous pathogenic missense, nonsense, frameshift, and splice\u2010site <jats:italic>ACO2<\/jats:italic> variants in patients with a spectrum of clinical manifestations and disease severities.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We describe a cohort of five novel patients with biallelic pathogenic variants in <jats:italic>ACO2<\/jats:italic>. We review the clinical histories of these patients as well as the molecular and functional characterization of the associated <jats:italic>ACO2<\/jats:italic> variants and compare with those described previously in the literature.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Two siblings with relatively mild symptoms presented with episodic ataxia, mild developmental delays, severe dysarthria, and behavioral abnormalities including hyperactivity and depressive symptoms with generalized anxiety. One patient presented with the classic form with cerebellar hypoplasia, ataxia, seizures, optic atrophy, and retinitis pigmentosa. Another unrelated patient presented with ataxia but developed severe progressive spastic quadriplegia. Another patient demonstrated a spinal muscular atrophy\u2010like presentation with severe neonatal hypotonia, diminished reflexes, and poor respiratory drive, leading to ventilator dependence until death at the age of 9\u00a0months.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>In this study, we highlight the importance of recognizing milder forms of the disorder, which may escape detection due to atypical disease presentation.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.51074","type":"journal-article","created":{"date-parts":[[2020,6,10]],"date-time":"2020-06-10T02:15:55Z","timestamp":1591755355000},"page":"1013-1028","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Expanding the clinical and phenotypic heterogeneity associated with biallelic variants in <i>ACO2<\/i>"],"prefix":"10.1002","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0658-1275","authenticated-orcid":false,"given":"Patrick R.","family":"Blackburn","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine and Pathology Mayo Clinic Rochester Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"Schultz","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology Mayo Clinic Rochester Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carrie A.","family":"Lahner","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology Mayo Clinic Rochester Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Applied Genomics Children's Hospital of Philadelphia Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Bhoj","sequence":"additional","affiliation":[{"name":"Center for Applied Genomics Children's Hospital of Philadelphia Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura J.","family":"Fisher","sequence":"additional","affiliation":[{"name":"Department of Clinical Genomics Mayo Clinic Rochester Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah L.","family":"Renaud","sequence":"additional","affiliation":[{"name":"Departments of Neurology and Pediatrics Mayo Clinic Rochester Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Kenney","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics and Metabolism Children's Hospital of The King's Daughters Norfolk Virginia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niema","family":"Ibrahim","sequence":"additional","affiliation":[{"name":"Department of Genetics King Faisal Specialist Hospital and Research Center Riyadh Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mais","family":"Hashem","sequence":"additional","affiliation":[{"name":"Department of Genetics King Faisal Specialist Hospital and Research Center Riyadh Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Zain Seidahmed","sequence":"additional","affiliation":[{"name":"Division of Neonatology Department of Pediatrics Security Forces Hospital Riyadh Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Hasadsri","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology Mayo Clinic Rochester 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