Symptom Prevalence and Genotype-Phenotype Correlations in Patients With TANGO2-Related Metabolic Encephalopathy and Arrhythmias (TRMEA)

Powell, Allison R.; Ames, Elizabeth G.; Knierbein, Erin Neil; Hannibal, Mark C.; Mackenzie, Samuel J.

doi:10.1016/j.pediatrneurol.2021.02.011

Cited by 21 publications

(26 citation statements)

References 14 publications

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“…Early case reports with the exons 3–9 deletion genotype reported seizures as a common feature noted in 53% of homozygous individuals. In comparison, our case series shows a significant increased burden of cardiac disease including cardiomyopathy and life‐threatening tachyarrhythmias but only one individual with epilepsy providing additional evidence for variable expressivity among individuals with the exons 3–9 deletion and no clear genotype–phenotype correlation recognized to date (Powell et al, 2021).…”

Section: Discussionmentioning

confidence: 65%

“… Note : Common clinical features summarized from the cases in this study plus a review of the literature ( n = 92) (Bérat et al, 2021; Dines et al, 2018; Ewans et al, 2018; Hoebeke et al, 2021; Jennions et al, 2019; Kremer et al, 2016; Lalani et al, 2016; Meisner et al, 2020; Mingirulli et al, 2019; Powell et al, 2021; Riazuddin et al, 2017; Scuotto et al, 2020; Sen, Hicks, Huq, & Agarwal, 2019). …”

Section: Resultsmentioning

confidence: 95%

“…Initial case reports emphasized the potential for acute decompensation and the high frequency of premature death most commonly due to sudden cardiac death or refractory arrhythmias (Dines et al, 2018). In addition, epilepsy, intellectual disability, developmental regression, and progressive neurodegeneration may cause significant morbidity (Powell et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

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Variable clinical severity in TANGO2 deficiency: Case series and literature review

Schymick

Leahy

Cowan

et al. 2021

American J of Med Genetics Pt A

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Biallelic pathogenic variants in the TANGO2 (transport and Golgi organization 2 homolog) gene have been identified as causing a rare metabolic disorder characterized by susceptibility to recurrent rhabdomyolysis, lactic acidosis, encephalopathy, and life-threatening tachyarrhythmias. Recently published reports suggest variable clinical severity and phenotypes. This study details five new patients from two families with biallelic pathogenic variants in the TANGO2 gene identified by whole exome sequencing and includes the largest number of affected individuals from a single family reported to date. We document significant intrafamilial variability and highlight that milder phenotypes may be underrecognized. We present biochemical and clinical data to help highlight the features that aid in consideration of this condition in the differential with disorders of fatty acid oxidation. We also present a comprehensive literature review summarizing the molecular, clinical, and biochemical findings for 92 individuals across 13 publications. Of the 27 pathogenic variants reported to date, the recurrent exons 3-9 deletion represents the most common variant seen in 42% of individuals with TANGO2 deficiency. Common clinical features seen in >70% of all individuals include acute metabolic crisis, rhabdomyolysis, neurologic abnormalities, developmental delay, and intellectual disability. Findings such as elevated creatine kinase, hypothyroidism, ketotic hypoglycemia, QT prolongation, or abnormalities of long-chain acylcarnitines and urine dicarboxylic acids should raise clinical suspicion for this life-threatening condition.

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Section: Discussionmentioning

confidence: 65%

Section: Resultsmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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Variable clinical severity in TANGO2 deficiency: Case series and literature review

Schymick

Leahy

Cowan

et al. 2021

American J of Med Genetics Pt A

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“…Nevertheless, sequence alignment between human (Q6ICL3 in UniPort) and Drosophila protein orthologs (Q9VYA8 in Uniport) revealed only 27.97% identity, suggesting TANGO2 may have different function in human. Increasing attention has been drawn to the association of TANGO2 with mitochondrial function in the field, supported by the similarity between clinical feature of TANGO2-related disease and inborn errors of metabolism (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14), as well as the prediction of a mitochondrial targeting sequence at the N-terminus (2). So far there has been only 4 studies investigating the TANGO2 mitochondrial localization and the impact of TANGO2 deficiency on mitochondrial respiratory function, however, results are inconsistent from different studies (2,5,13,14).…”

Section: Discussionmentioning

confidence: 99%

“…TANGO2-related disease is a rare multiorgan genetic disorder caused by bi-allelic loss-offunction mutations in TANGO2 (Transport and Golgi Organization protein 2) gene (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). Upon metabolic stresses such as fasting, dehydration, fever, and heat, TANGO2 patients often present with acute life-threatening metabolic crisis which may include hypoglycemia, hyperammonemia, rhabdomyolysis, and cardiac arrhythmias.…”

Section: Introductionmentioning

confidence: 99%

TANGO2 deficient iPSC-differentiated cardiomyocyte and dermal fibroblasts have normal mitochondrial OXPHOS function

Cao

Cantu

et al. 2022

Preprint

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Bi-allelic loss-of-function mutations in TANGO2 (Transport and Golgi Organization protein 2) cause a rare multiorgan genetic disorder. Despite normal cardiac function at baseline, patients may experience lethal cardiac arrhythmias during crises often associated with metabolic stresses such as fasting, viral illness and fever. The molecular function of TANGO2 remains largely unknown. Previous studies have suggested a functional association with the mitochondrion, however definitive evidence is lacking. Further, functional impact of TANGO2 deficiency on mitochondrial function has not been investigated in a cardiac model. In this study, we utilized a recently developed patient-derived induced pluripotent stem cell differentiated cardiomyocytes (iPSC-CM) model by our group, along with patient-derived dermal fibroblast model, to interrogate whether loss of TANGO2 function leads to defective mitochondrial function. Both baseline and fasting condition were investigated. Oxygen consumption rate (OCR) was measured in Seahorse assays to assess mitochondrial function in vitro. The results showed both TANGO2 deficient dermal fibroblasts and iPSC-CM had no apparent defects in mitochondrial oxidative phosphorylation (OXPHOS) function under either baseline or fasting condition. Based on our study, we conclude that the lethal cardiac arrhythmias in TANGO2 patients are unlikely to be related to impaired mitochondrial OXPHOS function in the cardiomyocytes.

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Early initiation of B‐vitamin supplementation may reduce symptoms and explain intrafamilial variability: Insights from two sibling pairs from the TANGO2 natural history study

Miyake

Ehsan

Zhang

et al. 2023

American J of Med Genetics Pt A

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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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Symptom Prevalence and Genotype-Phenotype Correlations in Patients With TANGO2-Related Metabolic Encephalopathy and Arrhythmias (TRMEA)

Cited by 21 publications

References 14 publications

Variable clinical severity in TANGO2 deficiency: Case series and literature review

Variable clinical severity in TANGO2 deficiency: Case series and literature review

TANGO2 deficient iPSC-differentiated cardiomyocyte and dermal fibroblasts have normal mitochondrial OXPHOS function

Early initiation of B‐vitamin supplementation may reduce symptoms and explain intrafamilial variability: Insights from two sibling pairs from the TANGO2 natural history study

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