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A Novel Variant and Treatment Modality in TANGO2 Deficiency 

Biochemical/Metabolic and Therapeutics
  • Primary Categories:
    • Metabolic Genetics
  • Secondary Categories:
    • Metabolic Genetics
Introduction
TANGO2 (Transport and Golgi Organization Homolog 2) deficiency is a cardiometabolic disorder associated with biallelic gene abnormalities in the TANGO2 gene (OMIM: 616830). This disease is characterized by progressive developmental delays, dysarthria, ataxia, hypothyroidism, and metabolic crises. Crises occur during times of stress (e.g., fasting, dehydration, or illness), and include rhabdomyolysis, transaminitis, hypoglycemia, lactic acidosis, hyperammonemia, and encephalopathy. Life-threatening manifestations include cardiac systolic dysfunction, QTc prolongation, J-point abnormalities, (e.g., type 1 Brugada pattern) and ultimately, ventricular arrhythmias.

Case Presentation
A 19-month-old boy with poor weight gain and developmental delays presented with an episode of nonresponsiveness and hypoglycemia in the setting of Coronavirus NL63. His initial labs were also notable for lactic acidosis, ketosis, elevated creatinine kinase (CK), normal liver enzymes, and normal ammonia. His QTc was prolonged on electrocardiogram (485-530 ms), and his echocardiogram was normal. Despite admission to the pediatric intensive care unit, hydration, and correction of hypoglycemia, he had two brief tonic-clonic seizures. His CK and liver enzymes peaked on day 5 of admission (CK peak 28,800 IU/L). His family history was unremarkable.

Diagnostic Workup
Rapid genome trio sequencing revealed a novel biallelic homozygous missense variant c.263 G>A, p.R88Q in exon 4 of the TANGO2 gene. The variant is absent in gnomAD and a previous truncation variant at the amino acid has been classified as pathogenic. While still a variant of uncertain significance (PM2, PP3, PP4 criteria), the close phenotype-genotype correlation and potential for clinical improvement was sufficient to institute TANGO2-specific therapy.

Treatment and Management
Treatment was initiated with B-complex vitamins and triheptanoin.

 




Outcome and Follow-Up
CK normalized by day 12 of admission, and the patient was discharged after a 2-week hospital course. At hospital discharge, his QTc was borderline prolonged at 456 ms, and the T-wave morphology was normal. Several months after discharge, the patient remains well from a metabolic and cardiac standpoint.

Discussion
TANGO2 deficiency is an evolving area of research. Supplementation of B-complex vitamins has been associated with a decreased frequency of metabolic crises. Although there is limited data for triheptanoin in TANGO2 deficiency, studies on this disease have shown a disruption in acylcarnitine species and elevations in long chain fatty acids, with elevated C14:1 being reported most consistently in the literature. This biochemical profile suggests that there may be some secondary dysfunction in the very long-chain acyl-CoA dehydrogenase (VLCAD) enzyme in patients with TANGO2 deficiency. Based on this biochemical rationale, we instituted triheptanoin as a treatment option to bypass the potential functional defect in mitochondrial beta-oxidation of long-chain fatty acids, with a goal for triheptanoin to comprise 25-35% of the patient’s total caloric intake. To date, this is our third patient with TANGO2 deficiency treated with triheptanoin.

 




Conclusion
This case highlights the broad differential that must be considered in pediatric patients with hypoglycemia, rhabdomyolysis, and QTc prolongation. TANGO2 is an important diagnostic consideration in the context of patients with neurologic, metabolic, and cardiac pathology. Therapy should be considered in the presence of a typical phenotype and biallelic TANGO2 variants, even if ACMG classification is not sufficient for a pathogenic or likely pathogenic classification. In addition to conventional therapy with B-vitamin supplementation, we propose triheptanoin as a potential adjunctive therapeutic option to decrease metabolic crises and improve cardiac outcomes.

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