Elsevier

Heart Rhythm

Volume 19, Issue 10, October 2022, Pages 1673-1681
Heart Rhythm

Pediatric and Congenital EP
Cardiac crises: Cardiac arrhythmias and cardiomyopathy during TANGO2 deficiency related metabolic crises

https://doi.org/10.1016/j.hrthm.2022.05.009Get rights and content

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.

Introduction

In 2016, Lalani et al1 and Kremer et al2 identified an autosomal recessive disorder due to biallelic pathogenic variants in the TANGO2 (Transport and Golgi Organization Homolog 2) gene. Symptoms include developmental, cognitive, and speech delays; episodic ataxia; hypothyroidism; and seizures. Metabolic stressors such as illness and prolonged fasting can trigger metabolic crisis associated with rhabdomyolysis, muscle weakness, encephalopathy, and hypoglycemia.1, 2, 3, 4, 5, 6, 7, 8, 9 Although cardiac function and rhythm are normal at baseline, during metabolic crises events, patients with TANGO2 deficiency disorder (TDD) can develop life-threatening ventricular arrhythmias and cardiomyopathy resulting in cardiac arrest, the leading cause of mortality.10,11 Death has occurred despite all efforts. Due to the paucity of information regarding these events, our goal was to describe the clinical course, treatments, and outcomes regarding cardiac crisis in TDD patients.

Section snippets

Methods

This was a descriptive, retrospective multicenter study of TDD patients with a history of cardiac crisis. Metabolic crisis was defined as a hospital admission associated which rhabdomyolysis and elevated creatine kinase (CK). Cardiac crisis was defined as the development of arrhythmias, cardiomyopathy, or cardiac arrest during a metabolic crisis. Patients were identified through an ongoing worldwide natural history study of patients with TDD, adhering to human research guidelines and approved

Demographics

A total of 45 hospitalizations for TANGO2-related cardiac crises were identified among 27 patients from 22 families (15 males [56%]). Patients were treated at 14 different centers across the United States, Canada, Australia, Italy, Iran, Sweden, Saudi Arabia, and United Arab Emirates. A majority of patients were of non-Hispanic White (41%), Hispanic (22%), or Asian/Middle Eastern (19%) race/ethnicity (Table 1). Median age at TDD genetic diagnosis was 4.6 years (interquartile range [IQR]

Discussion

Metabolic crisis in patients with TDD can evolve into cardiac crisis, resulting in life-threatening cardiac arrhythmias, cardiomyopathy, and cardiac arrest. Although our report demonstrates mortality was high, both arrhythmias and cardiomyopathy were reversible, and full recovery was possible. Our study cautiously suggests recognition and early treatment with specific therapies may be more effective than others; however, differing responses to therapy raise concern that there may not be a

Limitations

This is a retrospective study. Data may be biased by physician recall and interpretation of medical record review. Exact timing and order of antiarrhythmic administration and correlation to arrhythmias can be difficult to ascertain. In addition, timing of initiation of feeds and total nutritional intake by the patient is also difficult to determine based on medical record review.

Conclusion

Although our data are limited by their retrospective nature, we hope this study sheds light on cardiac arrhythmias and cardiomyopathy in TANGO2. Further prospective studies are needed to prevent metabolic crisis, identify those at highest risk for cardiac crisis before arrhythmia development, and determine more effective treatment strategies. To this end, we must understand the functional role of TANGO2, which to date remains unknown. By understanding the mechanism of disease and arrhythmia

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Funding Sources: TANGO2 Research Foundation, Chan Zuckerberg Initiative, to Drs Miyake, Lalani, Milewicz, and Zhang. Dr Miyake was supported by American Heart Association Scientist Development Grant 17SDG33410183 and NHLBI Grant K23HL136932. Dr Li is supported by NHLBI Grants R01HL136389 and R01HL147108. Dr Webster was supported by NHLBI Grant K23HL130554.

Disclosures: The authors have no conflicts of interest to disclose.

1

Dr Christina Y. Miyake, Dr Erica J. Lay, Dr Seema R. Lalani, and Dr Lilei Zhang contributed to the work equally.

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