Folate ameliorates arrhythmia in patient-derived TANGO2-deficient iPSC-cardiomyocytes

Abstract

TANGO2-deficient disorder (TDD) is an autosomal recessive genetic disease caused by biallelic loss-of-function variants in TANGO2 gene. TDD-associated cardiac arrythmias are typically recalcitrant to standard antiarrhythmic medications and constitute the leading cause of death. Here, we established novel patient-derived induced pluripotent stem cell differentiated cardiomyocyte (iPSC-CM) models that recapitulate key electrophysiological abnormalities in TDD including prolonged field potential duration, premature ventricular contractions, and decreased spike amplitude. These conduction abnormalities normalize in iPSC-CMs with either adenoviral expression of WT-TANGO2 or correction of the pathogenic variant by CRISPR editing. We further demonstrate that folate greatly abolishes the ventricular ectopy and conduction abnormalities. Data from this study taken together with clinical data from TDD patients supports the use of B-vitamins to mitigate cardiac crisis in TDD patients.

Vitamin B5, a coenzyme A precursor, rescues TANGO2 deficiency disease‐associated defects in Drosophila and human cells

“…A recent study suggests that folic acid (vitamin B9) can restore normal rhythm in a patient-derived cardiomyocyte model system. 22 Together with our present study this suggests that several B complex vitamins may have beneficial effects on various clinical aspects of this disease. Consistent with this notion, a natural history study of over 70 individuals suffering from TDD found that metabolic crises were not seen in individuals taking a multivitamin or a B complex supplement.…”

“…To date, there are no treatment options for individuals suffering from TDD. A recent study suggests that folic acid (vitamin B9) can restore normal rhythm in a patient‐derived cardiomyocyte model system 22 . Together with our present study this suggests that several B complex vitamins may have beneficial effects on various clinical aspects of this disease.…”

Vitamin B5, a Coenzyme A precursor, rescues TANGO2 deficiency disease-associated defects inDrosophilaand human cells

“…A recent study suggests that folic acid (vitamin B9) can restore normal rhythm in a patient-derived cardiomyocyte model system. 22 Together with our present study this suggests that several B complex vitamins may have beneficial effects on various clinical aspects of this disease.…”

TANGO2 deficiency disorder is predominantly caused by a lipid imbalance

“…To optimize treatment plans for patients with TDD, several studies have further assessed the effect of individual B vitamins in patients and disease models. For example, in a recent preprint, vitamin B9 (folate) treatment of cardiomyocyte cell lines generated from patient-derived induced pluripotent stem cells ( Zhang et al, 2022 preprint) notably decreased premature ventricular contractions within 4-12 h of treatment. This did not have any significant effect on corrected QT interval (QTc) prolongation, which is a heart rate measurement used to detect arrythmia.…”