A dangerous dance: Recurrent cardiac crises in TANGO2-deficiency disorder.

Abstract

Since the earliest reports of the cardiac ion channelopathies, multisystem abnormalities have been linked to arrhythmia-susceptibility genes. The first such description was the peculiar constellation of syncope, seizures, QT prolongation, and deaf-mutism observed in 4 children. Later coined as Jervell and Lange-Nielsen syndrome, this systemic disease is now known to be an autosomal recessive form of long QT syndrome (LQTS). 1 Schwartz P.J. Spazzolini C. Crotti L. et al. The Jervell and Lange-Nielsen syndrome: natural history, molecular basis, and clinical outcome. Circulation. 2006; 113: 783-790 Crossref PubMed Scopus (298) Google Scholar A noncardiac phenotype subsequently has been recognized in other genetic arrhythmias, including Timothy syndrome, Andersen-Tawil syndrome, and catecholaminergic polymorphic ventricular tachycardia. 2 Roston T.M. Cunningham T. Lehman A. Laksman Z.W. Krahn A.D. Sanatani S. Beyond the electrocardiogram: mutations in cardiac ion channel genes underlie nonarrhythmic phenotypes. Clin Med Insights Cardiol. 2017; 111179546817698134 Crossref PubMed Scopus (9) Google Scholar There also is an association between metabolic disease, especially those of cardiac energy metabolism, and arrhythmia. 3 Bodi I. Grünert S.C. Becker N. et al. Mechanisms of acquired long QT syndrome in patients with propionic academia. Heart Rhythm. 2016; 13: 1335-1345 Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar , 4 Bonnet D. Martin D. Pascale De L. et al. Arrhythmias and conduction defects as presenting symptoms of fatty acid oxidation disorders in children. Circulation. 1999; 100: 2248-2253 Crossref PubMed Scopus (225) Google Scholar , 5 Roussel J. Labarthe F. Thireau J. et al. Carnitine deficiency induces a short QT syndrome. Heart Rhythm. 2016; 13: 165-174 Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar One of these rare metabolic disorders is related to the TANGO2 gene (transport and Golgi organization homolog 2), termed TANGO2-deficiency disorder (TDD). TANGO2 is a recently described gene, with biallelic truncating variants believed to result in a disorder of mitochondrial fatty acid oxidation. 6 Kremer L.S. Distelmaier F. Alhaddad B. et al. Bi-allelic truncating mutations in TANGO2 cause infancy-onset recurrent metabolic crises with encephalocardiomyopathy. Am J Hum Genet. 2016; 98: 358-362 Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar Although likely underdiagnosed, the prevalence of TDD is low. 7 Schymick J. Leahy P. Cowan T. et al. Variable clinical severity in TANGO2 deficiency: case series and literature review. Am J Med Genet A. 2022; 188: 473-487 Crossref PubMed Scopus (4) Google Scholar Patients with these metabolic disorders often present in extremis, and if cardiac decompensation occurs, the decision to cannulate for mechanical circulatory support or list for heart transplantation often must be made in the face of diagnostic and prognostic uncertainty. Additionally, management strategies can deviate from those outlined in standard resuscitation algorithms. In this issue of Heart Rhythm Journal, Miyake et al 8 Miyake C.Y. Lay E.J. Beach C.M. et al. Cardiac crises: cardiac arrhythmias and cardiomyopathy during TANGO2 deficiency related metabolic crises. Heart Rhythm. 2022; 19: 1673-1681 Abstract Full Text Full Text PDF Scopus (1) Google Scholar characterize the cardiac manifestations of TANGO2-mediated disease and, in so doing, help to bridge these knowledge gaps in the acute management of TDD. Cardiac crises: Cardiac arrhythmias and cardiomyopathy during TANGO2 deficiency related metabolic crisesHeart RhythmVol. 19Issue 10PreviewTANGO2 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. Full-Text PDF