Clinical and biological characterization of 20 patients with <scp>TANGO2</scp> deficiency indicates novel triggers of metabolic crises and no primary energetic defect

Bérat, Claire-Marine; Montealegre, Sebastián; Wiedemann, Arnaud; Nuzum, Malou Le Corronc; Blondel, Amélie; Debruge, Hugo; Cano, Aline; Chabrol, B.; Hoebeke, Célia; Polak, Michel; Stoupa, Athanasia; Feillet, François; Torre, Stéphanie; Boddaert, Nathalie; Bruel, H.; Barth, Magalie; Damaj, Léna; Abi-Wardé, Marie-Thérèse; Afenjar, Alexandra; Benoist, Jean‐François; Madrange, Marine; Caccavelli, Laure; Renard, Perrine; Hubas, Arnaud; Nusbaum, Patrick; Pontoizeau, Clément; Gobin, Stéphanie; Endert, Peter van; Ottolenghi, Chris; Maltret, Alice; Lonlay, Pascale de

doi:10.1002/jimd.12314

Cited by 39 publications

(87 citation statements)

References 18 publications

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“…Isolation and growth of myoblasts was performed as previously described. 19 No myoblasts were available for P2.…”

Section: Methodsmentioning

confidence: 99%

“…The assays were performed as previously described, 19 using 2 × 10 4 myoblasts/well in XF96 plates (Seahorse Bioscience) to evaluate the cellular O 2 consumption in a Seahorse Bioscience XF96 extracellular flux analyzer.…”

Section: Methodsmentioning

confidence: 99%

“…Lysis of myoblasts and fibroblasts was performed as previously described. 19 Primary antibodies anti-LC3-B (clone 4E12, 1:1,000; MBL International, Woburn, MA) and anti-β-actin (sc-81178; Santa Cruz Biotechnology, Dallas, TX) were detected with horseradish peroxidase–conjugated secondary antibody and enhanced chemiluminescence detection. Lipoic acid (Abcam ab18724 1:800) and SDH-A (Abcam ab14715 1:2,000) were used after mitochondrial enrichment as described above.…”

Section: Methodsmentioning

confidence: 99%

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FDX2 and ISCU Gene Variations Lead to Rhabdomyolysis With Distinct Severity and Iron Regulation

et al. 2022

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Background and ObjectivesTo determine common clinical and biological traits in 2 individuals with variants in ISCU and FDX2, displaying severe and recurrent rhabdomyolyses and lactic acidosis.MethodsWe performed a clinical characterization of 2 distinct individuals with biallelic ISCU or FDX2 variants from 2 separate families and a biological characterization with muscle and cells from those patients.ResultsThe individual with FDX2 variants was clinically more affected than the individual with ISCU variants. Affected FDX2 individual fibroblasts and myoblasts showed reduced oxygen consumption rates and mitochondrial complex I and PDHc activities, associated with high levels of blood FGF21. ISCU individual fibroblasts showed no oxidative phosphorylation deficiency and moderate increase of blood FGF21 levels relative to controls. The severity of the FDX2 individual was not due to dysfunctional autophagy. Iron was excessively accumulated in ISCU-deficient skeletal muscle, which was accompanied by a downregulation of IRP1 and mitoferrin2 genes and an upregulation of frataxin (FXN) gene expression. This excessive iron accumulation was absent from FDX2 affected muscle and could not be correlated with variable gene expression in muscle cells.DiscussionWe conclude that FDX2 and ISCU variants result in a similar muscle phenotype, that differ in severity and skeletal muscle iron accumulation. ISCU and FDX2 are not involved in mitochondrial iron influx contrary to frataxin.

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“…Isolation and growth of myoblasts was performed as previously described. 19 No myoblasts were available for P2.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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FDX2 and ISCU Gene Variations Lead to Rhabdomyolysis With Distinct Severity and Iron Regulation

et al. 2022

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“…2). He is managed with levocarnitine, riboflavin, calcium carbonate, vitamin C, and vitamin D. (Bérat et al, 2021;Dines et al, 2018;Ewans et al, 2018;Hoebeke et al, 2021;Jennions et al, 2019;Kremer et al, 2016;Lalani et al, 2016;Meisner et al, 2020;Mingirulli et al, are seen in 42% (25/59 individuals) and elevations in urine dicarboxylic acids are seen in 39% (17/44 individuals) (Table 4 and Table S1).…”

Section: Laboratory Investigations Imaging and Genetic Testingmentioning

confidence: 99%

Variable clinical severity in TANGO2 deficiency: Case series and literature review

Schymick

Leahy

Cowan

et al. 2021

American J of Med Genetics Pt A

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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.

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“…This special issue of the journal focused on mitochondrial medicine also includes a position paper on the diagnosis and management of mitochondrial neurogastrointestinal encephalomyopathy, 8 the first description of pathogenic variants in OGDH , 9 and expansion of the phenotypic description of ECHS1 and HIBCH 10 and TANGO2 11 deficiencies. Two novel treatments at a preclinical stage of evaluation are presented: a reactive oxygen species scavenger JP4‐039 for sulfite oxidase deficiency 12 and a nucleotide prodrug CERC‐913 proposed for deoxyguanosine kinase deficiency 13 .…”

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confidence: 99%

Editorial: Mitochondrial medicine special issue

Chinnery

Falk

Mootha

et al. 2021

J of Inher Metab Disea

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Clinical and biological characterization of 20 patients with TANGO2 deficiency indicates novel triggers of metabolic crises and no primary energetic defect

Abstract: TANGO2 disease is a severe inherited disorder associating multiple symptoms such as metabolic crises, encephalopathy, cardiac arrhythmias, and

Cited by 39 publications

References 18 publications

FDX2 and ISCU Gene Variations Lead to Rhabdomyolysis With Distinct Severity and Iron Regulation

FDX2 and ISCU Gene Variations Lead to Rhabdomyolysis With Distinct Severity and Iron Regulation

Variable clinical severity in TANGO2 deficiency: Case series and literature review

Editorial: Mitochondrial medicine special issue

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