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The mechanism of action of TANGO2 is currently unknown. Here, we describe a cohort of 20 French patients bearing mutations in the <jats:italic>TANGO2<\/jats:italic> gene. We found that the main clinical presentation was the association of neurodevelopmental delay (n = 17), acute metabolic crises (n = 17) and hypothyroidism (n = 12), with a large intrafamilial clinical variability. Metabolic crises included rhabdomyolysis (15\/17), neurological symptoms (14\/17), and cardiac features (12\/17; long QT (n = 10), Brugada pattern (n = 2), cardiac arrhythmia (n = 6)) that required intensive care. We show previously uncharacterized triggers of metabolic crises in TANGO2 patients, such as some anesthetics and possibly <jats:sc>l<\/jats:sc>\u2010carnitine. Unexpectedly, plasma acylcarnitines, plasma FGF\u201021, muscle histology, and mitochondrial spectrometry were mostly normal. Moreover, in patients' primary myoblasts, palmitate and glutamine oxidation rates, and the mitochondrial network were also normal. Finally, we found variable mitochondrial respiration and defective clearance of oxidized DNA upon cycles of starvation and refeeding. We conclude that TANGO2 disease is a life\u2010threatening disease that needs specific cardiac management and anesthesia protocol. Mechanistically, TANGO2 disease is unlikely to originate from a primary mitochondrial defect. Rather, we suggest that mitochondrial defects are secondary to strong extrinsic triggers in TANGO2 deficient patients.<\/jats:p>","DOI":"10.1002\/jimd.12314","type":"journal-article","created":{"date-parts":[[2020,9,23]],"date-time":"2020-09-23T07:25:27Z","timestamp":1600845927000},"page":"415-425","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["Clinical and biological characterization of 20 patients with <scp>TANGO2<\/scp> deficiency indicates novel triggers of metabolic crises and no primary energetic defect"],"prefix":"10.1002","volume":"44","author":[{"given":"Claire\u2010Marine","family":"B\u00e9rat","sequence":"first","affiliation":[{"name":"Inserm U1151 Institut Necker Enfants\u2010Malades  Paris France"},{"name":"Universit\u00e9 de Paris  Paris France"},{"name":"Reference Center of inherited Metabolic Diseases Necker\u2010Enfants\u2010Malades University hospital, APHP, Imagine Institute, Fili\u00e8re G2M  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