Pediatric and Congenital EPCardiac crises: Cardiac arrhythmias and cardiomyopathy during TANGO2 deficiency related metabolic crises
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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Cited by (11)
TANGO2 Deficiency Disorder: Two Cases of Developmental Delay Preceding Metabolic Crisis
2023, Pediatric NeurologyLimb-girdle myopathy and mild intellectual disability: The expanding spectrum of TANGO2-related disease
2023, Neuromuscular DisordersNatural history of TANGO2 deficiency disorder: Baseline assessment of 73 patients
2023, Genetics in MedicinePediatric and Familial Genetic Arrhythmia Syndromes–Evaluation of Prolonged QTc–Differential Diagnosis and what You Need to Know
2023, Cardiac Electrophysiology ClinicsManagement of acute metabolic crisis in TANGO2 deficiency: A case report
2023, Journal of Pediatric Endocrinology and Metabolism
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.
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Dr Christina Y. Miyake, Dr Erica J. Lay, Dr Seema R. Lalani, and Dr Lilei Zhang contributed to the work equally.