Investigation of Cardiac Arrhythmias in TANGO2 Disorder

ABSTRACT TANGO2 Deficiency Disorder is an autosomal recessive disease caused by genetic alterations in TANGO2 (Transport and Golgi Organization Homolog 2). Patients, primarily young children, with TANGO2 disorder are susceptible to recurring episodes of metabolic crisis and life-threatening ventricular arrhythmias that

lead to cardiac arrest and death. TDD is associated with a high mortality because TDD-related arrhythmias do not respond to standard antiarrhythmic therapy. Promising new data from an international patient registry and natural history study has demonstrated B-vitamin supplementation prevents and may treat arrhythmias but the

mechanism by which they work remain unclear. In addition, despite investigations, the exact functional role of TANGO2 protein remains unknown. We believe that current therapeutic interventions are ineffective because we lack an understanding of the pathophysiologic mechanisms driving TANGO2-related arrhythmia development

and by studying the role of B-vitamins in arrhythmia prevention and treatment will provide answers. We propose a study to evaluate vitamin B9, a component of B-vitamins that has shown effective suppression of ventricular arrhythmias based on preliminary data. This study is a translational study, combining

human patients, cellular and animal models. Specifically, we will utilize TDD patients in an existing natural history study, Tango2 -/- mouse model, and TANGO2 deficienct induced pluripotent stem cell cardiomyocytes (iPSC- CMs) to study the effects of folate on ventricular arrhythmia development and to determine the mechanism

driving ventricular arrhythmias in TDD. Our study will provide clinically relevant data and novel insights into the pathophysiologic mechanisms driving TDD-arrhythmia development and help improve patient survival and outcomes in TANGO2 disorder.