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TANGO2 deficiency disorder (TDD), an autosomal recessive disease first reported in 2016, is characterized by neurodevelopmental delays, seizures, intermittent ataxia, hypothyroidism and life-threatening metabolic and cardiac crises. The purpose of this study was to define the natural history of TDD.Data were collected from an ongoing natural history study of TDD patients enrolled between February 2019 - May 2022. Data were obtained through phone-based parent interviews and medical record review.Data were collected from 73 patients (56% male) from 57 unrelated families in 17 different countries. The median age of participants at time of data collection was 9.0 years (IQR 5.3-15.9 years, range fetal - 31 years). A total of 24 different TANGO2 alleles were observed. Patients demonstrated normal development in early infancy with progressive delays in developmental milestones thereafter. Symptoms including ataxia, dystonia and speech difficulties typically starting between the ages of 1-3 years. A total of 48 (66%) patients suffered metabolic crises and, of these, 29/48 (73%) developed cardiac crises. Metabolic crises were significantly decreased after initiation of B-complex or multivitamins.We provide the most comprehensive review of natural history of TDD and provide important observational data suggesting B-complex or multivitamins may prevent metabolic crises.

Birth outcomes data for patients with vascular Ehlers-Danlos syndrome (VEDS) are limited.Patients with a pathogenic or likely pathogenic COL3A1 variant were included. Outcomes included gestational age (GA), birthweight (BW), and maternal complications. Birth outcomes were first compared with that of US population data, then compared by sex, maternal affected status, and COL3A1 genotype.A total of 41 children were included (70.7% male), including 32 with high-risk (missense and splice site) variants. Preterm birth (37 weeks) was more common in patients with VEDS than in the US population (48.8% vs 12.2%, P.0001). Low BW (2.5 kg) was also more common in patients with VEDS than in the US population (P.0001), although, it was appropriate after GA adjustment (median GA-adjusted z-score 0.01 vs z-score 0.0, P = .26). No differences in GA or BW were observed by sex or maternal affected status. Those with high-risk variants were more likely to be born preterm than those with haploinsufficient variants, although this did not meet significance criteria (53% vs 33%, P = .35). Of the 6 affected mothers, 5 had perinatal complications.Preterm birth is more common in children with VEDS than in the general population. Maternal affected status is not associated with preterm birth, suggesting that risk is conferred by the fetal VEDS diagnosis alone.

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.The purpose of this study was to describe TDD-related cardiac crises.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.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.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.

Data regarding recurrence risk among infants with supraventricular tachycardia (SVT) are limited.The purpose of this study was to determine incidence and factors associated with SVT recurrence.This was a retrospective single-center study (1984-2020) with prospective phone follow-up of infants with structurally normal hearts diagnosed at age ≤1 year with re-entrant SVT. Primary outcome was first SVT recurrence after hospital discharge. Classification and regression tree analysis was performed to determine a risk algorithm.Among 460 infants (62% male), 87% were diagnosed at ≤60 days of age (median 13 days; IQR: 1-31 days). During a median follow-up of 5.2 years (IQR: 1.8-11.2 years), 33% had recurrence. On multivariable analysis, factors associated with recurrence included: fetal or late (60 days) diagnosis (HR: 1.90; 95% CI: 1.26-2.86; and HR: 1.73; 95% CI: 1.07-2.77, respectively), Wolff-Parkinson-White (WPW) syndrome (HR: 2.46; 95% CI: 1.75-3.45), and need for multi-antiarrhythmic or second-line therapy (HR: 2.08; 95% CI: 1.45-2.99). Based on the classification and regression tree analysis, WPW incurred the highest risk. Among those without WPW, age at diagnosis was the most important factor predicting risk. Fetal or late diagnosis incurred higher risk, and if multi-antiarrhythmic or second-line therapy was also required, risk nearly doubled. Infants without WPW, who were diagnosed early (0-60 days), and who were discharged on propranolol were at lowest recurrence risk.Infants with SVT are most likely to be diagnosed at ≤60 days and be male. Risk factors for recurrence (occurred in 33%), present at time of diagnosis, include WPW, fetal or late diagnosis, and multi-antiarrhythmic or second-line therapy. Infants with early diagnosis, without WPW, and discharged on first-line monotherapy are at lowest recurrence risk.