TANGO2 disease is a severe inherited disorder associating multiple symptoms such as metabolic crises, encephalopathy, cardiac arrhythmias, and hypothyroidism. The mechanism of action of TANGO2 is currently unknown. Here, we describe a cohort of 20 French patients bearing mutations in the TANGO2 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 l‐carnitine. Unexpectedly, plasma acylcarnitines, plasma FGF‐21, 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‐threatening 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.

中文翻译：

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20 名 TANGO2 缺乏症患者的临床和生物学特征表明代谢危机的新触发因素和无原发性能量缺陷

TANGO2 病是一种严重的遗传性疾病，伴有多种症状，如代谢危象、脑病、心律失常和甲状腺功能减退症。TANGO2 的作用机制目前尚不清楚。在这里，我们描述了一组 20 名在TANGO2 中携带突变的法国患者基因。我们发现主要的临床表现是神经发育迟缓（n = 17）、急性代谢危象（n = 17）和甲状腺功能减退症（n = 12）之间的关联，并且具有很大的家族内临床变异性。代谢危机包括横纹肌溶解症 (15/17)、神经系统症状 (14/17) 和心脏特征 (12/17；长 QT (n = 10)、Brugada 模式 (n = 2)、心律失常 (n = 6))这需要重症监护。我们在 TANGO2 患者中展示了以前未表征的代谢危机的触发因素，例如一些麻醉剂和可能的l-肉碱。出乎意料的是，血浆酰基肉碱、血浆 FGF-21、肌肉组织学和线粒体光谱学大多正常。此外，在患者的原代成肌细胞中，棕榈酸和谷氨酰胺的氧化率以及线粒体网络也正常。最后，我们发现在饥饿和重新喂养的循环中线粒体呼吸变化和氧化 DNA 清除缺陷。我们得出结论，TANGO2 病是一种危及生命的疾病，需要特定的心脏管理和麻醉方案。从机制上讲，TANGO2 疾病不太可能起源于原发性线粒体缺陷。相反，我们认为线粒体缺陷继发于 TANGO2 缺陷患者的强烈外在触发因素。