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BACKGROUND: Accessory pathways are a common cause of supraventricular tachycardia (SVT) and can lead to sudden cardiac death in otherwise healthy children and adults when associated with Wolff-Parkinson-White syndrome. The goal of this study was to identify genetic variants within a large family with structurally normal hearts affected by SVT and Wolff-Parkinson-White syndrome and determine causality of the gene deficit in a corresponding mouse model. METHODS: Whole exome sequencing performed on 2 distant members of a 3-generation family in which multiple members were affected by SVT or Wolff-Parkinson-White pattern (preexcitation) on ECG identified MRC2 as a candidate gene. Serial electrocardiograms, intracardiac electrophysiology studies, echocardiography, optical mapping studies, and histology were performed on both Mrc2 mutant and WT (wild-type) mice. RESULTS: A rare HET (heterozygous) missense variant c.2969A>G;p.Glu990Gly (E990G) in MRC2 was identified as the leading candidate gene variant segregating with the cardiac phenotype following an autosomal-dominant Mendelian trait segregation pattern with variable expressivity. In vivo electrophysiology studies revealed reentrant SVT in E990G mice. Optical mapping studies in E990G mice demonstrated abnormal retrograde conduction, suggesting the presence of an accessory pathway. Histological analysis of E990G mouse hearts showed a disordered ECM (extracellular matrix) in the annulus fibrosus. Finally, Mrc2 knockdown in human cardiac fibroblasts enhanced accelerated cell migration. CONCLUSIONS: This study identified a rare nonsynonymous variant in the MRC2 gene in individuals with familial reentrant SVT, Wolff-Parkinson-White ECG pattern, and structurally normal hearts. Furthermore, Mrc2 knock-in mice revealed an increased incidence of reentrant SVT and bypass tract formation in the setting of preserved cardiac structure and function.
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Linhagem , Taquicardia Supraventricular , Síndrome de Wolff-Parkinson-White , Síndrome de Wolff-Parkinson-White/genética , Síndrome de Wolff-Parkinson-White/fisiopatologia , Síndrome de Wolff-Parkinson-White/patologia , Humanos , Animais , Camundongos , Taquicardia Supraventricular/genética , Taquicardia Supraventricular/fisiopatologia , Taquicardia Supraventricular/patologia , Masculino , Feminino , Adulto , Mutação de Sentido Incorreto , Sequenciamento do Exoma , Eletrocardiografia , Pessoa de Meia-IdadeRESUMO
Background: NAA10-related (Ogden Syndrome) and NAA15-related neurodevelopmental syndromes present with varying degrees of intellectual disability, hypotonia, congenital cardiac abnormalities, seizures, and delayed speech and motor development. While there is much data on the clinical manifestations of these conditions, there are few radiologic reports describing the neuroanatomical abnormalities present on imaging. Objective: Our goal was to provide neuroimaging analyses for a subset of probands with NAA10- and NAA15-related neurodevelopmental symptoms and assess severity, common radiologic anomalies, and changes over time to better understand the pathophysiology of these disease processes. Materials and Methods: Neuroimaging studies from 26 probands (18 with pathogenic variants in NAA10, 8 with pathogenic variants in NAA15) were collected and analyzed. Size of the cerebrum, brainstem, and cerebellum, as well as myelination, brain malformations, globus pallidus hyperintensity, brain lesions, 4th ventricle size, tegmentovermian angle, cisterna magna size, pituitary size, olfactory tract, palate arch, and choroid plexus abnormalities were analyzed. In depth medical histories were also collected on all probands, including genetic testing results and social, cognitive, and developmental history. The Vineland 3 Adaptive Behavior Scale was also administered to the parents to assess functional status of the probands. Results: On average, individuals with Ogden Syndrome had 5.7 anatomical abnormalities (standard deviation (SD) = 3.0), whereas those with NAA15 related neurodevelopmental syndrome had 2.8 (SD = 2.3) (p = .02). Probands who had more anatomical abnormalities tended to score worse on Vineland assessments, suggesting a possible correlation between the two. Structural-functional anatomic differences seen were preserved such that individuals with greater defects on, for example, motor regions of their scans tested worse on motor portions of the Vineland. Probands followed longitudinally demonstrated several changes between scans, most commonly in the cerebellum, brainstem, and degree of myelination. Such changes were only observed for probands with NAA10 variants in our cohort. Conclusion: Despite clinical imaging being reported as being predominantly "normal" during routine clinical care, this analysis of a cohort of patients with NAA10-related (Ogden Syndrome) and NAA15-related neurodevelopmental syndrome by one neuroradiologist has established a range of subtle abnormalities. We hope these findings guide future research and diagnostic studies for this patient population.
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TANGO2-deficiency disorder (TDD) is an autosomal-recessive genetic disease caused by biallelic loss-of-function variants in the TANGO2 gene. TDD-associated cardiac arrhythmias are recalcitrant to standard antiarrhythmic medications and constitute the leading cause of death. Disease modeling for TDD has been primarily carried out using human dermal fibroblast and, more recently, in Drosophila by multiple research groups. No human cardiomyocyte system has been reported, which greatly hinders the investigation and understanding of TDD-associated arrhythmias. Here, we established potentially novel patient-derived induced pluripotent stem cell differentiated cardiomyocyte (iPSC-CM) models that recapitulate key electrophysiological abnormalities in TDD. These electrophysiological abnormalities were rescued in iPSC-CMs with either adenoviral expression of WT-TANGO2 or correction of the pathogenic variant using CRISPR editing. Our natural history study in patients with TDD suggests that the intake of multivitamin/B complex greatly diminished the risk of cardiac crises in patients with TDD. In agreement with the clinical findings, we demonstrated that high-dose folate (vitamin B9) virtually abolishes arrhythmias in TDD iPSC-CMs and that folate's effect was blocked by the dihydrofolate reductase inhibitor methotrexate, supporting the need for intracellular folate to mediate antiarrhythmic effects. In summary, data from TDD iPSC-CM models together with clinical observations support the use of B vitamins to mitigate cardiac crises in patients with TDD, providing potentially life-saving treatment strategies during life-threatening events.
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Arritmias Cardíacas , Ácido Fólico , Células-Tronco Pluripotentes Induzidas , Miócitos Cardíacos , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ácido Fólico/metabolismo , Ácido Fólico/uso terapêutico , Arritmias Cardíacas/tratamento farmacológico , Arritmias Cardíacas/genética , Masculino , Feminino , CriançaRESUMO
BACKGROUND AND OBJECTIVES: Generalized convulsive seizures (GCSs) are the main risk factor of sudden unexpected death in epilepsy (SUDEP), which is likely due to peri-ictal cardiorespiratory dysfunction. The incidence of GCS-induced cardiac arrhythmias, their relationship to seizure severity markers, and their role in SUDEP physiopathology are unknown. The aim of this study was to analyze the incidence of seizure-induced cardiac arrhythmias, their association with electroclinical features and seizure severity biomarkers, as well as their specific occurrences in SUDEP cases. METHODS: This is an observational, prospective, multicenter study of patients with epilepsy aged 18 years and older with recorded GCS during inpatient video-EEG monitoring for epilepsy evaluation. Exclusion criteria were status epilepticus and an obscured video recording. We analyzed semiologic and cardiorespiratory features through video-EEG (VEEG), electrocardiogram, thoracoabdominal bands, and pulse oximetry. We investigated the presence of bradycardia, asystole, supraventricular tachyarrhythmias (SVTs), premature atrial beats, premature ventricular beats, nonsustained ventricular tachycardia (NSVT), atrial fibrillation (Afib), ventricular fibrillation (VF), atrioventricular block (AVB), exaggerated sinus arrhythmia (ESA), and exaggerated sinus arrhythmia with bradycardia (ESAWB). A board-certified cardiac electrophysiologist diagnosed and classified the arrhythmia types. Bradycardia, asystole, SVT, NSVT, Afib, VF, AVB, and ESAWB were classified as arrhythmias of interest because these were of SUDEP pathophysiology value. The main outcome was the occurrence of seizure-induced arrhythmias of interest during inpatient VEEG monitoring. Moreover, yearly follow-up was conducted to identify SUDEP cases. Binary logistic generalized estimating equations were used to determine clinical-demographic and peri-ictal variables that were predictive of the presence of seizure-induced arrhythmias of interest. The z-score test for 2 population proportions was used to test whether the proportion of seizures and patients with postconvulsive ESAWB or bradycardia differed between SUDEP cases and survivors. RESULTS: This study includes data from 249 patients (mean age 37.2 ± 23.5 years, 55% female) who had 455 seizures. The most common arrhythmia was ESA, with an incidence of 137 of 382 seizures (35.9%) (106/224 patients [47.3%]). There were 50 of 352 seizure-induced arrhythmias of interest (14.2%) in 41 of 204 patients (20.1%). ESAWB was the commonest in 22 of 394 seizures (5.6%) (18/225 patients [8%]), followed by SVT in 18 of 397 seizures (4.5%) (17/228 patients [7.5%]). During follow-up (48.36 ± 31.34 months), 8 SUDEPs occurred. Seizure-induced bradycardia (3.8% vs 12.5%, z = -16.66, p < 0.01) and ESAWB (6.6% vs 25%; z = -3.03, p < 0.01) were over-represented in patients who later died of SUDEP. There was no association between arrhythmias of interest and seizure severity biomarkers (p > 0.05). DISCUSSION: Markers of seizure severity are not related to seizure-induced arrhythmias of interest, suggesting that other factors such as occult cardiac abnormalities may be relevant for their occurrence. Seizure-induced ESAWB and bradycardia were more frequent in SUDEP cases, although this observation was based on a very limited number of SUDEP patients. Further case-control studies are needed to evaluate the yield of arrhythmias of interest along with respiratory changes as potential SUDEP biomarkers.
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Arritmias Cardíacas , Eletroencefalografia , Humanos , Feminino , Masculino , Adulto , Arritmias Cardíacas/epidemiologia , Arritmias Cardíacas/fisiopatologia , Arritmias Cardíacas/diagnóstico , Incidência , Pessoa de Meia-Idade , Estudos Prospectivos , Morte Súbita Inesperada na Epilepsia/epidemiologia , Convulsões/epidemiologia , Convulsões/fisiopatologia , Epilepsia Generalizada/epidemiologia , Epilepsia Generalizada/fisiopatologia , Idoso , Adulto Jovem , Eletrocardiografia , AdolescenteRESUMO
Bidirectional ventricular tachycardia is a unique arrhythmia that can herald lethal arrhythmia syndromes. Using cases based on real patient stories, this article examines 3 different presentations to help clinicians learn the differential diagnosis associated with this condition. Each associated genetic disorder will be briefly discussed, and valuable tips for distinguishing them from each other will be provided.
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Taquicardia Ventricular , Criança , Humanos , Masculino , Arritmias Cardíacas/genética , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/fisiopatologia , Diagnóstico Diferencial , Eletrocardiografia , Síndrome do QT Longo/genética , Síndrome do QT Longo/diagnóstico , Síndrome do QT Longo/fisiopatologia , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/genética , Taquicardia Ventricular/fisiopatologia , AdolescenteRESUMO
The case series reviews differential diagnosis of a genetic arrhythmia syndrome when evaluating a patient with prolonged QTc. Making the correct diagnosis requires: detailed patient history, family history, and careful review of the electrocardiogram (ECG). Signs and symptoms and ECG characteristics can often help clinicians make the diagnosis before genetic testing results return. These skills can help clinicians make an accurate and timely diagnosis and prevent life-threatening events.
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Arritmias Cardíacas , Eletrocardiografia , Síndrome do QT Longo , Humanos , Diagnóstico Diferencial , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/genética , Arritmias Cardíacas/fisiopatologia , Síndrome do QT Longo/diagnóstico , Síndrome do QT Longo/genética , Síndrome do QT Longo/fisiopatologia , Criança , Masculino , Feminino , Adolescente , Testes GenéticosRESUMO
The following case series presents three different pediatric patients with SCN5A-related disease. In addition, family members are presented to demonstrate the variable penetrance that is commonly seen. Identifying features of this disease is important, because even in the very young, SCN5A disorders can cause lethal arrhythmias and sudden death.
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Arritmias Cardíacas , Síndrome do QT Longo , Canal de Sódio Disparado por Voltagem NAV1.5 , Humanos , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Síndrome do QT Longo/genética , Síndrome do QT Longo/fisiopatologia , Masculino , Feminino , Arritmias Cardíacas/genética , Arritmias Cardíacas/fisiopatologia , Arritmias Cardíacas/diagnóstico , Criança , Eletrocardiografia , Pré-Escolar , Adolescente , LactenteRESUMO
BACKGROUND: Atrial tachyarrhythmias are common and difficult to treat in adults with congenital heart disease. Dronedarone has proven effective in patients without congenital heart disease, but data are limited about its use in adults with congenital heart disease of moderate to great complexity. METHODS: A single-center, retrospective chart review of 21 adults with congenital heart disease of moderate to great complexity who were treated with dronedarone for atrial tachyarrhythmias was performed. RESULTS: The median (IQR) age at dronedarone initiation was 35 (27.5-39) years. Eleven patients (52%) were male. Ten patients (48%) had New York Heart Association class I disease, 10 (48%) had class II disease, and 1 (5%) had class III disease. Ejection fraction at initiation was greater than 55% in 11 patients (52%), 35% to 55% in 9 patients (43%), and less than 35% in 1 patient (5%). Prior treatments included ß-blockers (71%), sotalol (38%), amiodarone (24%), digoxin (24%), and catheter ablation (38%). Rhythm control was complete in 5 patients (24%), partial in 6 (29%), and inadequate in 10 (48%). Two patients (10%) experienced adverse events, including nausea in 1 (5%) and cardiac arrest in 1 (5%), which occurred 48 months after initiation of treatment. There were no deaths during the follow-up period. The median (IQR) follow-up time for patients with complete or partial rhythm control was 20 (1-54) months. CONCLUSION: Dronedarone can be effective for adult patients with congenital heart disease and atrial arrhythmias for whom more established therapies have failed, and with close monitoring it can be safely tolerated.
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Antiarrítmicos , Dronedarona , Cardiopatias Congênitas , Humanos , Dronedarona/uso terapêutico , Dronedarona/efeitos adversos , Masculino , Estudos Retrospectivos , Feminino , Adulto , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/fisiopatologia , Antiarrítmicos/uso terapêutico , Antiarrítmicos/efeitos adversos , Resultado do Tratamento , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/fisiopatologia , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/complicações , Amiodarona/uso terapêutico , Amiodarona/efeitos adversos , Amiodarona/análogos & derivados , Fatores de TempoRESUMO
Introduction: Heterozygous autosomal-dominant single nucleotide variants in RYR2 account for 60% of cases of catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited arrhythmia disorder associated with high mortality rates. CRISPR/Cas9-mediated genome editing is a promising therapeutic approach that can permanently cure the disease by removing the mutant RYR2 allele. However, the safety and long-term efficacy of this strategy have not been established in a relevant disease model. Aim: The purpose of this study was to assess whether adeno-associated virus type-9 (AAV9)-mediated somatic genome editing could prevent ventricular arrhythmias by removal of the mutant allele in mice that are heterozygous for Ryr2 variant p.Arg176Gln (R176Q/+). Methods and Results: Guide RNA and SaCas9 were delivered using AAV9 vectors injected subcutaneously in 10-day-old mice. At 6 weeks after injection, R176Q/+ mice had a 100% reduction in ventricular arrhythmias compared to controls. When aged to 12 months, injected R176Q/+ mice maintained a 100% reduction in arrhythmia induction. Deep RNA sequencing revealed the formation of insertions/deletions at the target site with minimal off-target editing on the wild-type allele. Consequently, CRISPR/SaCas9 editing resulted in a 45% reduction of total Ryr2 mRNA and a 38% reduction in RyR2 protein. Genome editing was well tolerated based on serial echocardiography, revealing unaltered cardiac function and structure up to 12 months after AAV9 injection. Conclusion: Taken together, AAV9-mediated CRISPR/Cas9 genome editing could efficiently disrupt the mutant Ryr2 allele, preventing lethal arrhythmias while preserving normal cardiac function in the R176Q/+ mouse model of CPVT.
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Cardiac arrhythmias are a common cardiac condition that might lead to fatal outcomes. A better understanding of the molecular and cellular basis of arrhythmia mechanisms is necessary for the development of better treatment modalities. To aid these efforts, various mouse models have been developed for studying cardiac arrhythmias. Both genetic and surgical mouse models are commonly used to assess the incidence and mechanisms of arrhythmias. Since spontaneous arrhythmias are uncommon in healthy young mice, intracardiac programmed electrical stimulation (PES) can be performed to assess the susceptibility to pacing-induced arrhythmias and uncover the possible presence of a proarrhythmogenic substrate. This procedure is performed by positioning an octopolar catheter inside the right atrium and ventricle of the heart through the right jugular vein. PES can provide insights into atrial and ventricular electrical activity and reveal whether atrial and/or ventricular arrhythmias are present or can be induced. Here, we explain detailed procedures used to perform this technique, possible troubleshooting scenarios, and methods to interpret the results obtained. © 2024 Wiley Periodicals LLC. Basic Protocol: Programmed electrical stimulation in mice.
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Arritmias Cardíacas , Técnicas Eletrofisiológicas Cardíacas , Camundongos , Animais , Arritmias Cardíacas/terapia , Ventrículos do Coração , Átrios do Coração , Estimulação ElétricaRESUMO
Arrhythmogenic cardiomyopathy (AC) is a disease that involves electromechanical uncoupling of cardiomyocytes. This leads to characteristic histologic changes that ultimately lead to the arrhythmogenic clinical features of the disease. Initially thought to affect the right ventricle predominantly, more recent data show that it can affect both the ventricles or the left ventricle alone. Throughout the recent era, diagnostic modalities and criteria for AC have continued to evolve and our understanding of its clinical features in different age groups as well as the genotype to the phenotype correlations have improved. In this review, we set out to detail the epidemiology, etiologies, presentations, evaluation, and management of AC across the age continuum.
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Heart rate variability (HRV) is a noninvasive indicator of the health of neurocardiac interactions of the autonomic nervous system. In adults, decreased HRV correlates with increased cardiovascular mortality. However, the relationship between HRV and outcomes in children with acute decompensated heart failure (ADHF) has not been described. Patients < 21 years old hospitalized with ADHF from 2013 to 2019 were included (N = 79). Primary outcome was defined as death, heart transplant, or mechanical circulatory support (MCS). The median standard deviation of the R-to-R interval in 5-min intervals (SDNN) was calculated from telemetry data obtained across the first 24 h of admission. Patients who met the primary outcome had significantly lower median SDNN (13.8 [7.8, 29.1]) compared to those who did not (24.6 [15.3, 84.4]; p = 0.004). A median SDNN of 20 ms resulted in a sensitivity of 68% and specificity of 69%. Median SDNN < 20 ms represented decreased freedom from primary outcome (p = 0.043) and a hazard ratio of 2.2 in multivariate analysis (p = 0.016). Pediatric patients with ADHF who died, underwent heart transplant, or required MCS had significantly decreased HRV at presentation compared to those that did not. This supports HRV as a noninvasive tool to improve prognostication in children in ADHF.
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TANGO2-deficiency disorder (TDD) is an autosomal recessive condition arising from pathogenic biallelic variants in the TANGO2 gene. TDD is characterized by symptoms typically beginning in late infancy including delayed developmental milestones, cognitive impairment, dysarthria, expressive language deficits, and gait abnormalities. There is wide phenotypic variability where some are severely affected while others have mild symptoms. This variability has been documented even among sibling pairs who share the same genotype, but reasons for this variability have not been well understood. Emerging data suggest a potential link between B-complex or multivitamin supplementation and decreased metabolic crises in TDD. In this report, we describe two sibling pairs from unreladiagnosed with TDD with marked differences in symptoms. In both families, the older siblings suffered multiple metabolic crises and are clinically more affected than their younger siblings who have very mild to no symptoms; they are the least impaired among 70 other patients in our ongoing international natural history study. Unlike their older siblings, the two younger siblings started taking B-complex vitamins early between 9 and 16 months. This report delineates the mildest presentation of TDD in two families. These data may support a role for early diagnosis and initiation of vitamin supplementation to not only prevent metabolic crises but also improve neurologic outcomes in this life-threatening disorder.
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Complexo Vitamínico B , Humanos , Irmãos , Cognição , Genótipo , Suplementos NutricionaisRESUMO
Catecholaminergic polymorphic ventricular tachycardia is a rare but lethal heritable arrhythmia syndrome associated with both atrial and ventricular arrhythmias. Treatment includes antiarrhythmics, sympathetic denervation, and implantable cardioverter-defibrillators. The use of atrioventricular nodal ablation as a treatment strategy to prevent ventricular arrhythmias in catecholaminergic polymorphic ventricular tachycardia was not found in the literature. This report describes a teenager with a presenting rhythm of atrial and ventricular fibrillation and cardiac arrest. Her clinical arrhythmia was predominantly atrial dysrhythmias, which delayed her diagnosis of catecholaminergic polymorphic ventricular tachycardia. Before her diagnosis, she underwent atrioventricular nodal ablation in an effort to prevent ventricular arrhythmias, which was ultimately ineffective. This report highlights the importance of recognizing atrial arrhythmias in catecholaminergic polymorphic ventricular tachycardia and provides evidence that atrioventricular nodal ablation is not an effective treatment strategy for this disease.
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Fibrilação Atrial , Desfibriladores Implantáveis , Taquicardia Ventricular , Adolescente , Feminino , Humanos , Fibrilação Atrial/complicações , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/cirurgia , Antiarrítmicos/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Although ventricular failure is a late finding in adults with AC, we hypothesize that this is a presenting symptom in pediatric heart failure patients who undergo HT and that their ventricular arrhythmia burden could differentiate AC from other cardiomyopathies. METHODS: We performed a single-center retrospective cohort study reviewing 457 consecutive pediatric (≤18 years) HT recipients at our institution. Explanted hearts were examined to establish the primary diagnosis, based on pathologic findings. Demographic and clinical variables were compared between AC versus non-HCM cardiomyopathy cases. RESULTS: Forty-five percent (n = 205/457) had non-HCM cardiomyopathies as the underlying primary diagnosis. Ten cases (10/205 = 4.9%) were diagnosed with AC. All 10 had biventricular disease. In 8/10 patients (80%), AC diagnosis was unrecognized pre-HT. Compared with non-AC cardiomyopathies, the AC group was older at diagnosis (9.3 years vs. 4.3 years, p = .012) and transplant (11.1 years vs. 6.5 years, p = .010), had more ventricular arrhythmias (80.0% vs 32.8%, p = .003), and required more anti-arrhythmic use (80.0% vs 32.3%, p = .001). Genetic testing yielded causative pathogenic variants in all tested individuals (n = 5/5, 100%). CONCLUSION: AC is often an unrecognized cardiomyopathy pretransplant in children who undergo HT. Pediatric non-HCM phenotypes with heart failure who have a significant ventricular arrhythmia burden should be investigated for AC.
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Cardiomiopatias , Insuficiência Cardíaca , Humanos , Estudos Retrospectivos , Cardiomiopatias/complicações , Cardiomiopatias/diagnóstico , Cardiomiopatias/patologia , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/cirurgia , Arritmias Cardíacas/complicações , Arritmias Cardíacas/diagnóstico , AntiarrítmicosRESUMO
PURPOSE: TANGO2 deficiency disorder (TDD), an autosomal recessive disease first reported in 2016, is characterized by neurodevelopmental delay, seizures, intermittent ataxia, hypothyroidism, and life-threatening metabolic and cardiac crises. The purpose of this study was to define the natural history of TDD. METHODS: Data were collected from an ongoing natural history study of patients with TDD enrolled between February 2019 and May 2022. Data were obtained through phone or video based parent interviews and medical record review. RESULTS: Data were collected from 73 patients (59% male) from 57 unrelated families living in 16 different countries. The median age of participants at the time of data collection was 9.0 years (interquartile range = 5.3-15.9 years, range = fetal to 31.8 years). A total of 24 different TANGO2 alleles were observed. Patients showed normal development in early infancy, with progressive delay in developmental milestones thereafter. Symptoms included ataxia, dystonia, and speech difficulties, typically starting between the ages of 1 to 3 years. A total of 46/71 (65%) patients suffered metabolic crises, and of those, 30 (65%) developed cardiac crises. Metabolic crises were significantly decreased after the initiation of B-complex or multivitamin supplementation. CONCLUSION: We provide the most comprehensive review of natural history of TDD and important observational data suggesting that B-complex or multivitamins may prevent metabolic crises.