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The case series reviews differential diagnosis of a genetic arrhythmia syndrome when evaluating a patient with prolonged QTc. Making the correct diagnosis requires: detailed patient history, family history, and careful review of the electrocardiogram (ECG). Signs and symptoms and ECG characteristics can often help clinicians make the diagnosis before genetic testing results return. These skills can help clinicians make an accurate and timely diagnosis and prevent life-threatening events. [ABSTRACT FROM AUTHOR]

ABSTRACTPatients with pathogenic variants in the TANGO2 gene suffer from severe and recurrent rhabdomyolysis episodes precipitated by fasting. Autophagy functioning was analyzed in vitro, in primary skeletal myoblasts from TANGO2 patients, in basal and fasting conditions, and TANGO2 mutations were associated with reduced LC3-II levels upon starvation. In zebrafish larvae, tango2 inhibition induced locomotor defects which were exacerbated by exposure to atorvastatin, a compound known to cause rhabdomyolysis. Importantly, rhabdomyolysis features of tango2 knockdown were associated with autophagy and mitophagy defects in zebrafish. Calpeptin treatment was sufficient to rescue the locomotor properties thanks to its beneficial effect on autophagy functioning in zebrafish and to improve LC3-II levels in starved primary muscle cells of TANGO2 patients. Overall, we demonstrated that TANGO2 plays an important role in autophagy thus giving rise to new therapeutic perspectives in the prevention of RM life-threatening episodes.

TANGO2‐deficiency disorder (TDD) is an autosomal recessive condition arising from pathogenic biallelic variants in the TANGO2 gene. TDD is characterized by symptoms typically beginning in late infancy including delayed developmental milestones, cognitive impairment, dysarthria, expressive language deficits, and gait abnormalities. There is wide phenotypic variability where some are severely affected while others have mild symptoms. This variability has been documented even among sibling pairs who share the same genotype, but reasons for this variability have not been well understood. Emerging data suggest a potential link between B‐complex or multivitamin supplementation and decreased metabolic crises in TDD. In this report, we describe two sibling pairs from unreladiagnosed with TDD with marked differences in symptoms. In both families, the older siblings suffered multiple metabolic crises and are clinically more affected than their younger siblings who have very mild to no symptoms; they are the least impaired among 70 other patients in our ongoing international natural history study. Unlike their older siblings, the two younger siblings started taking B‐complex vitamins early between 9 and 16 months. This report delineates the mildest presentation of TDD in two families. These data may support a role for early diagnosis and initiation of vitamin supplementation to not only prevent metabolic crises but also improve neurologic outcomes in this life‐threatening disorder. [ABSTRACT FROM AUTHOR]

• TANGO2 deficiency may cause intellectual disability and limb-girdle myopathy. • Phenotypic variability is common amongst patients with TANGO2 deficiency. • The present case extends the clinical spectrum of TANGO2 -related disease. TANGO2 -related disease is an autosomal recessive multisystem disease associated with developmental delay and infancy-onset recurrent metabolic crises with early mortality. Several studies have reported dysfunction in endoplasmic reticulum-to-Golgi traffic and mitochondrial homoeostasis as the underlying pathophysiology. We report a 40-year-old woman affected by limb-girdle weakness and mild intellectual disability caused by the recurrent deletion of exons 3–9 in homozygosity in the TANGO2 gene. Physical examination revealed hyperlordosis, waddling gait, calf pseudohypertrophy, and Aquilian tendon retractions. Laboratory investigations revealed elevation of serum biomarkers suggestive of mitochondrial dysfunction together with hypothyroidism. At the age of 24, the patient suffered a metabolic crisis with severe rhabdomyolysis and malignant cardiac arrhythmia. After recovery, no metabolic or arrhythmic crisis has recurred. Muscle histology two years later revealed increased endomysial fibrosis and other myopathic changes. Our findings illustrate the mildest end of the phenotypic spectrum of TANGO2 -related disease and reveal further aspects related to chronic muscle damage in this disorder. [ABSTRACT FROM AUTHOR]

Objective: The transport and Golgi organization protein 2 homolog (TANGO2) knockout mice were generated to elucidate its physiological function in mammals, and to explore whether TANGO2 is a candidate gene responsible for DiGeorge syndrome. Methods：The TANGO2 knockout mouse model was generated, and the knockout efficiency of the mouse model was detected by real⁃time quantitative PCR. The phenotype, growth and breeding of wild⁃type, TANGO2+/⁃ and TANGO2⁃/⁃ mice were observed and recorded. The morphological structures of heart and brain tissues in wild⁃type and knockout mice were observed through anatomic and histological analysis. Results: The TANGO2 mRNA was expressed in the heart and brain of wild⁃type mice, but its expression level was substantially reduced in the knockout mice. TANGO2 knockout mice could develop, survive and reproduce, and did not exhibit obvious phenotypic abnormalities. Histological analyses of the heart and brain showed no significant differences between knockout mice and wild⁃type mice at birth and 6⁃month⁃old. Conclusion: TANGO2 knockout mice grow and reproduce normally, and lack the phenotype associated with TANGO2⁃related disorders or DiGeorge syndrome in humans. [ABSTRACT FROM AUTHOR]

Abstract Mutations in transport and Golgi organization 2 homolog (TANGO2) have recently been described as a cause of an autosomal recessive syndrome characterized by episodes of metabolic crisis associated with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration. Herein, we report a case of a one‐and‐a‐half‐year‐old Japanese girl, born to nonconsanguineous parents, who presented with metabolic crisis characterized by hypoglycemia with hypoketonemia, rhabdomyolysis, lactic acidosis, and prolonged corrected QT interval (QTc) at the age of 6 months. Acylcarnitine analysis during the episode of crisis showed prominent elevation of C14:1, suggesting very‐long‐chain acyl‐CoA dehydrogenase (VLCAD) deficiency. In addition, worsening rhabdomyolysis was observed after intravenous administration of L‐carnitine. VLCAD deficiency was initially suspected; however, the enzyme activity in lymphocytes was only mildly decreased at the gene carrier level, and no mutation in the VLCAD gene (ADADVL) was detected. Subsequently, acylcarnitine analysis was nonspecific at 17‐h fasting and almost normal during the stable phase. Eventually, a trio whole‐exome sequencing revealed a compound heterozygous variant of two novel variants in the TANGO2 gene, a missense variant, and a deletion of exon 7. This is the first case of TANGO2 deficiency in Asians. Our case suggests that elevated C14:1 may be seen in severe metabolic crises and that the use of L‐carnitine should be avoided during metabolic crises.

Mutations in the Transport and Golgi Organization 2 (TANGO2) gene are associated with intellectual deficit, neurodevelopmental delay and regression. Individuals can also present with an acute metabolic crisis that includes rhabdomyolysis, cardiomyopathy, and cardiac arrhythmias, the latter of which are potentially lethal. While preventing metabolic crises has the potential to reduce mortality, no treatments currently exist for this condition. The function of TANGO2 remains unknown but is suspected to be involved in some aspect of lipid metabolism. Here, we describe a model of TANGO2‐related disease in the fruit fly Drosophila melanogaster that recapitulates crucial disease traits. Pairing a new fly model with human cells, we examined the effects of vitamin B5, a coenzyme A (CoA) precursor, on alleviating the cellular and organismal defects associated with TANGO2 deficiency. We demonstrate that vitamin B5 specifically improves multiple defects associated with TANGO2 loss‐of‐function in Drosophila and rescues membrane trafficking defects in human cells. We also observed a partial rescue of one of the fly defects by vitamin B3, though to a lesser extent than vitamin B5. Our data suggest that a B complex supplement containing vitamin B5/pantothenate may have therapeutic benefits in individuals with TANGO2‐deficiency disease. Possible mechanisms for the rescue are discussed that may include restoration of lipid homeostasis. [ABSTRACT FROM AUTHOR]

ABSTRACT Heme, an essential molecule for virtually all living organisms, acts primarily as a cofactor in a large number of proteins. However, how heme is mobilized from the site of synthesis to the locations where hemoproteins are assembled remains largely unknown in cells, especially bacterial ones. In this study, with Shewanella oneidensis as the model, we identified HtpA (SO0126) as a heme-trafficking protein and homolog of TANGO2 proteins found in eukaryotes. We showed that HtpA homologs are widely distributed in all domains of living organisms and have undergone parallel evolution. In its absence, the cytochrome (cyt) c content and catalase activity decreased significantly. We further showed that both HtpA and representative TANGO2 proteins bind heme with 1:1 stoichiometry and a relatively low dissociation constant. Protein interaction analyses substantiated that HtpA directly interacts with the cytochrome c maturation system. Our findings shed light on cross-membrane transport of heme in bacteria and extend the understanding of TANGO2 proteins. IMPORTANCE The intracellular trafficking of heme, an essential cofactor for hemoproteins, remains underexplored even in eukaryotes, let alone bacteria. Here we developed a high-throughput method by which HtpA, a homolog of eukaryotic TANGO2 proteins, was identified to be a heme-binding protein that enhances cytochrome c biosynthesis and catalase activity in Shewanella oneidensis. HtpA interacts with the cytochrome c biosynthesis system directly, supporting that this protein, like TANGO2, functions in intracellular heme trafficking. HtpA homologs are widely distributed, but a large majority of them were found to be non-exchangeable, likely a result of parallel evolution. By substantiating the heme-trafficking nature of HtpA and its eukaryotic homologs, our findings provide general insight into the heme-trafficking process and highlight the functional conservation along evolution in all living organisms.

We show that TANGO2 in mammalian cells localizes predominantly to mitochondria and partially at mitochondria sites juxtaposed to lipid droplets (LDs) and the endoplasmic reticulum. HepG2 cells and fibroblasts of patients lacking TANGO2 exhibit enlarged LDs. Quantitative lipidomics revealed a marked increase in lysophosphatidic acid (LPA) and a concomitant decrease in its biosynthetic precursor phosphatidic acid (PA). These changes were exacerbated in nutrient-starved cells. Based on our data, we suggest that TANGO2 function is linked to acyl-CoA metabolism, which is necessary for the acylation of LPA to generate PA. The defect in acyl-CoA availability impacts the metabolism of many other fatty acids, generates high levels of reactive oxygen species, and promotes lipid peroxidation. We suggest that the increased size of LDs is a combination of enrichment in peroxidized lipids and a defect in their catabolism. Our findings help explain the physiological consequence of mutations in TANGO2 that induce acute metabolic crises, including rhabdomyolysis, cardiomyopathy, and cardiac arrhythmias, often leading to fatality upon starvation and stress.

Background: TANGO2 deficiency disorder (TDD) is an autosomal recessive disease associated with metabolic crisis, lethal cardiac arrhythmias, and cardiomyopathy. Data regarding treatment, management, and outcomes of cardiac manifestations of TDD are lacking.Objective: The purpose of this study was to describe TDD-related cardiac crises.Methods: Retrospective multicenter chart review was made of TDD patients admitted with cardiac crises, defined as development of ventricular tachycardia (VT), cardiomyopathy, or cardiac arrest during metabolic crises.Results: Twenty-seven children were admitted for 43 cardiac crises (median age 6.4 years; interquartile range [IQR] 2.4-9.8 years) at 14 centers. During crisis, QTc prolongation occurred in all (median 547 ms; IQR 504-600 ms) and a type I Brugada pattern in 8 (26%). Arrhythmias included VT in 21 (78%), supraventricular tachycardia in 3 (11%), and heart block in 1 (4%). Nineteen patients (70%) developed cardiomyopathy, and 20 (74%) experienced a cardiac arrest. There were 10 deaths (37%), 6 related to arrhythmias. In 5 patients, recalcitrant VT occurred despite use of antiarrhythmic drugs. In 6 patients, arrhythmias were controlled after extracorporeal membrane oxygenation (ECMO) support; 5 of these patients survived. Among 10 patients who survived VT without ECMO, successful treatment included intravenous magnesium, isoproterenol, and atrial pacing in multiple cases and verapamil in 1 patient. Initiation of feeds seemed to decrease VT events.Conclusion: TDD-related cardiac crises are associated with a high risk of arrhythmias, cardiomyopathy, cardiac arrest, and death. Although further studies are needed, early recognition and appropriate treatment are critical. Acutely, intravenous magnesium, isoproterenol, atrial pacing, and ECMO as a last resort seem to be the best current treatment options, and early initiation of feeds may prevent VT events. [ABSTRACT FROM AUTHOR]

Biallelic pathogenic variants in the TANGO2 (transport and Golgi organization 2 homolog) gene have been identified as causing a rare metabolic disorder characterized by susceptibility to recurrent rhabdomyolysis, lactic acidosis, encephalopathy, and life‐threatening tachyarrhythmias. Recently published reports suggest variable clinical severity and phenotypes. This study details five new patients from two families with biallelic pathogenic variants in the TANGO2 gene identified by whole exome sequencing and includes the largest number of affected individuals from a single family reported to date. We document significant intrafamilial variability and highlight that milder phenotypes may be underrecognized. We present biochemical and clinical data to help highlight the features that aid in consideration of this condition in the differential with disorders of fatty acid oxidation. We also present a comprehensive literature review summarizing the molecular, clinical, and biochemical findings for 92 individuals across 13 publications. Of the 27 pathogenic variants reported to date, the recurrent exons 3–9 deletion represents the most common variant seen in 42% of individuals with TANGO2 deficiency. Common clinical features seen in >70% of all individuals include acute metabolic crisis, rhabdomyolysis, neurologic abnormalities, developmental delay, and intellectual disability. Findings such as elevated creatine kinase, hypothyroidism, ketotic hypoglycemia, QT prolongation, or abnormalities of long‐chain acylcarnitines and urine dicarboxylic acids should raise clinical suspicion for this life‐threatening condition. [ABSTRACT FROM AUTHOR]

TANGO2 variants result in a complex disease phenotype consisting of recurrent crisis‐induced rhabdomyolysis, encephalopathy, seizures, lactic acidosis, hypoglycemia, and cardiac arrhythmias. Although first described in a fruit fly model as a protein necessary for some aspect of Golgi function and organization, its role in the cell at a fundamental level has not been addressed. Such studies are necessary to better counsel families regarding treatment options and nutrition management to mitigate the metabolic aspects of the disease. The few studies performed to address the pathway(s) in which TANGO2 functions have led to enigmatic results, with some suggesting defects in membrane traffic while others suggest unknown mitochondrial defects. Here, we have performed a robust membrane trafficking assay on fibroblasts derived from three different individuals harboring TANGO2 variants and show that there is a significant delay in the movement of cargo between the endoplasmic reticulum and the Golgi. Importantly, this delay was attributed to a defect in TANGO2 function. We further show that a portion of TANGO2 protein localizes to the mitochondria through a necessary but not sufficient stretch of amino acids at the amino terminus of the protein. Fibroblasts from affected individuals also displayed changes in mitochondrial morphology. We conclude that TANGO2 functions in both membrane trafficking and in some as yet undetermined role in mitochondria physiology. The phenotype of affected individuals can be partially explained by this dual involvement of the protein. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Dystonia, whole exome sequencing, TANGO2, dystonic tremor, foot inversion The dystonic features demonstrated in this case are most consistent with multifocal combined dystonia and suggest that I TANGO2 i mutations should be included in the genetic causes of dystonia. Keywords: TANGO2; dystonia; dystonic tremor; foot inversion; whole exome sequencing EN TANGO2 dystonia dystonic tremor foot inversion whole exome sequencing 380 382 3 04/05/22 20220401 NES 220401 The I TANGO2 i (transport and golgi organization 2 homolog) gene mutation was initially identified in 2016 by exome sequencing in 15 patients with variable phenotypes.1 Homozygous inheritance produces metabolic crises associated with rhabdomyolysis and acute neurologic or cardiac symptoms.1,2 This case describes multifocal combined dystonia as a novel phenotypic feature of I TANGO2 i mutations. [Extracted from the article]

The clinical picture associated with a Transport and Golgi Organization 2 (TANGO2) gene bi-allelic mutation is represented by encephalopathy and rhabdomyolysis marked by cardiac rhythm disorders and neurological regression. The presentation of encephalopathy is diverse and can range from isolated language delay and cognitive impairment in a child to multiple disabilities and spastic quadriparesis. Hypothyroidism has also been frequently reported. This article presents the clinical phenotype of seven children with a TANGO2 bi-allelic mutation. The mutation was found by sequencing a panel of genes associated with rhabdomyolysis. While the clinical picture represents generalized cases, there is phenotypic variability in, for example, the degree of disability for each patient. A TANGO2 gene mutation, nevertheless, represents a serious illness with a limited life expectancy due to an unpredictable risk of cardiac rhythm disorder and death, particularly during rhabdomyolysis. Although the natural history of the disease presents an evolution of rhabdomyolysis triggered by infections or effort, an early diagnosis is difficult due in part to the fact that there is a lack of specific biochemical marker or identifying symptoms in the early presentation of the disease. Clinicians must therefore consider the TANGO2 gene when confronted with rhabdomyolysis in a patient suffering from an early developmental disorder. In the meantime, management of the disease remains purely symptomatic. [ABSTRACT FROM AUTHOR]

Transport And Golgi Organization protein 2 (TANGO2) deficiency has recently been identified as a rare metabolic disorder with a distinct clinical and biochemical phenotype of recurrent metabolic crises, hypoglycemia, lactic acidosis, rhabdomyolysis, arrhythmias, and encephalopathy with cognitive decline. We report nine subjects from seven independent families, and we studied muscle histology, respiratory chain enzyme activities in skeletal muscle and proteomic signature of fibroblasts. All nine subjects carried autosomal recessive TANGO2 mutations. Two carried the reported deletion of exons 3 to 9, one homozygous, one heterozygous with a 22q11.21 microdeletion inherited in trans. The other subjects carried three novel homozygous (c.262C>T/p.Arg88*; c.220A>C/p.Thr74Pro; c.380+1G>A), and two further novel heterozygous (c.6_9del/p.Phe6del); c.11‐13delTCT/p.Phe5del mutations. Immunoblot analysis detected a significant decrease of TANGO2 protein. Muscle histology showed mild variation of fiber diameter, no ragged‐red/cytochrome c oxidase‐negative fibers and a defect of multiple respiratory chain enzymes and coenzyme Q10 (CoQ10) in two cases, suggesting a possible secondary defect of oxidative phosphorylation. Proteomic analysis in fibroblasts revealed significant changes in components of the mitochondrial fatty acid oxidation, plasma membrane, endoplasmic reticulum‐Golgi network and secretory pathways. Clinical presentation of TANGO2 mutations is homogeneous and clinically recognizable. The hemizygous mutations in two patients suggest that some mutations leading to allele loss are difficult to detect. A combined defect of the respiratory chain enzymes and CoQ10 with altered levels of several membrane proteins provides molecular insights into the underlying pathophysiology and may guide rational new therapeutic interventions. [ABSTRACT FROM AUTHOR]

Case We report a 15-year-old Indian girl born to a consanguineous couple, who presented with epilepsy, developmental delay, neuroregression, and episodes of alternating hemiparesis. In addition, she had one episode of rhabdomyolysis at the age of 7 years. Extensive genetic and metabolic work up through the years was unrevealing. Eventually a trio whole exome sequencing (WES) revealed homozygous single nucleotide variants in TANGO2 gene. Discussion TANGO 2 related recurrent metabolic crises with encephalomyopathy and cardiac arrhythmias were described very recently and only 15 cases were reported in literature at the time of writing. Alternating hemiplegia of childhood which was seen in our patient, has not been described in previous patients with TANGO2 mutation, and thereby expands the emerging phenotypic spectrum of this novel entity. This report also reiterates the utility of WES in diagnosing newly recognized neurogenetic conditions. [ABSTRACT FROM AUTHOR]

Heme, an essential molecule for virtually all living organisms, acts primarily as a cofactor in a large number of proteins. However, how heme is mobilized from the site of synthesis to the locations where hemoproteins are assembled remains largely unknown in cells, especially bacterial ones. In this study, with Shewanella oneidensis as the model, we identified HtpA (SO0126) as a heme-trafficking protein and homolog of TANGO2 proteins found in eukaryotes. We showed that HtpA homologs are widely distributed in all domains of living organisms and have undergone parallel evolution. In its absence, the cytochrome (cyt) c content and catalase activity decreased significantly. We further showed that both HtpA and representative TANGO2 proteins bind heme with 1:1 stoichiometry and a relatively low dissociation constant. Protein interaction analyses substantiated that HtpA directly interacts with the cytochrome c maturation system. Our findings shed light on cross-membrane transport of heme in bacteria and extend the understanding of TANGO2 proteins. IMPORTANCE The intracellular trafficking of heme, an essential cofactor for hemoproteins, remains underexplored even in eukaryotes, let alone bacteria. Here we developed a high-throughput method by which HtpA, a homolog of eukaryotic TANGO2 proteins, was identified to be a heme-binding protein that enhances cytochrome c biosynthesis and catalase activity in Shewanella oneidensis . HtpA interacts with the cytochrome c biosynthesis system directly, supporting that this protein, like TANGO2, functions in intracellular heme trafficking. HtpA homologs are widely distributed, but a large majority of them were found to be non-exchangeable, likely a result of parallel evolution. By substantiating the heme-trafficking nature of HtpA and its eukaryotic homologs, our findings provide general insight into the heme-trafficking process and highlight the functional conservation along evolution in all living organisms., Competing Interests: The authors declare no conflict of interest.

Purpose: TANGO2 deficiency disorder (TDD), an autosomal recessive disease first reported in 2016, is characterized by neurodevelopmental delay, seizures, intermittent ataxia, hypothyroidism, and life-threatening metabolic and cardiac crises. The purpose of this study was to define the natural history of TDD., Methods: Data were collected from an ongoing natural history study of patients with TDD enrolled between February 2019 and May 2022. Data were obtained through phone or video based parent interviews and medical record review., Results: Data were collected from 73 patients (59% male) from 57 unrelated families living in 16 different countries. The median age of participants at the time of data collection was 9.0 years (interquartile range = 5.3-15.9 years, range = fetal to 31.8 years). A total of 24 different TANGO2 alleles were observed. Patients showed normal development in early infancy, with progressive delay in developmental milestones thereafter. Symptoms included ataxia, dystonia, and speech difficulties, typically starting between the ages of 1 to 3 years. A total of 46/71 (65%) patients suffered metabolic crises, and of those, 30 (65%) developed cardiac crises. Metabolic crises were significantly decreased after the initiation of B-complex or multivitamin supplementation., Conclusion: We provide the most comprehensive review of natural history of TDD and important observational data suggesting that B-complex or multivitamins may prevent metabolic crises., Competing Interests: Conflict of Interest The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from clinical laboratory testing conducted at Baylor Genetics. S.A.M. serves as Scientific Advisor and consultant for Aytu BioPharma, Inc for the AR101 Enzastaurin Clinical Trial. All other authors declare no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

We show that TANGO2 in mammalian cells localizes predominantly to mitochondria and partially at mitochondria sites juxtaposed to lipid droplets (LDs) and the endoplasmic reticulum. HepG2 cells and fibroblasts of patients lacking TANGO2 exhibit enlarged LDs. Quantitative lipidomics revealed a marked increase in lysophosphatidic acid (LPA) and a concomitant decrease in its biosynthetic precursor phosphatidic acid (PA). These changes were exacerbated in nutrient-starved cells. Based on our data, we suggest that TANGO2 function is linked to acyl-CoA metabolism, which is necessary for the acylation of LPA to generate PA. The defect in acyl-CoA availability impacts the metabolism of many other fatty acids, generates high levels of reactive oxygen species, and promotes lipid peroxidation. We suggest that the increased size of LDs is a combination of enrichment in peroxidized lipids and a defect in their catabolism. Our findings help explain the physiological consequence of mutations in TANGO2 that induce acute metabolic crises, including rhabdomyolysis, cardiomyopathy, and cardiac arrhythmias, often leading to fatality upon starvation and stress., Competing Interests: AL, OF, CS, NB, AF, AV, MA, AT, JW No competing interests declared, VM Reviewing editor, eLife, (© 2023, Lujan et al.)