TANGO2 – Recurrent Metabolic Encephalomyopathic Crises-Rhabdomyolysis-Cardiac Arrhythmia-Intellectual Disability Syndrome

TANGO2 deficiency is an autosomal recessive disorder characterized by episodic metabolic crises, encephalopathy, rhabdomyolysis, cardiac arrhythmias, and neurodevelopmental impairment. Initial identification of biallelic truncating and splice variants in TANGO2 established its role in infancy-onset recurrent metabolic encephalocardiomyopathy, demonstrating impaired palmitate-dependent mitochondrial β-oxidation in patient fibroblasts (PMID:26805782).

In a proteomic and muscle histology study of nine affected individuals from seven independent families, all carrying autosomal recessive TANGO2 mutations, researchers observed significant reduction of TANGO2 protein, respiratory chain enzyme deficiencies, and altered mitochondrial fatty acid oxidation pathways, defining a homogeneous clinical presentation of recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome (PMID:31339582).

A larger case series and literature review encompassing 92 individuals across 13 publications highlighted intrafamilial variability and underrecognized mild phenotypes; the recurrent exon 3–9 deletion accounted for 42% of alleles, with >70% of patients exhibiting acute metabolic crises, rhabdomyolysis, neurologic abnormalities, developmental delay, and intellectual disability (PMID:34668327).

Multiple pediatric case reports illustrate the clinical spectrum and management strategies. Acute metabolic crises with fever, fatigue, encephalopathy, rhabdomyolysis, arrhythmia, and hypothyroidism responded to vitamin B-complex or high-dose vitamin B5 supplementation, resulting in rapid biochemical and neurological improvement without life-threatening arrhythmias (PMID:37381587).

Functional studies corroborate disease mechanism: patient fibroblasts display delayed ER–Golgi trafficking, mitochondrial bioenergetic defects, increased superoxide production, reduced oxygen consumption and ATP levels, and lipid imbalance reversible by vitamin B5, confirming a dual role of TANGO2 in membrane transport and mitochondrial physiology (PMID:26805782; PMID:35197517).

Together, genetic and experimental evidence provide a definitive association between autosomal recessive biallelic TANGO2 variants and its characteristic syndrome, informing diagnostic testing, family counseling, and potential therapeutic strategies. Key Take-home: early recognition of TANGO2 deficiency enables targeted vitamin therapies that may mitigate metabolic and cardiac crises.

References

• Journal of pediatric endocrinology & metabolism • 2023 • Management of acute metabolic crisis in TANGO2 deficiency: a case report. PMID:37381587
• American Journal of Human Genetics • 2016 • Bi-allelic Truncating Mutations in TANGO2 Cause Infancy-Onset Recurrent Metabolic Crises with Encephalocardiomyopathy. PMID:26805782
• Journal of Inherited Metabolic Disease • 2020 • Clinical presentation and proteomic signature of patients with TANGO2 mutations. PMID:31339582
• American Journal of Medical Genetics. Part A • 2022 • Variable clinical severity in TANGO2 deficiency: Case series and literature review. PMID:34668327
• Scientific Reports • 2022 • Mitochondrial dysfunction associated with TANGO2 deficiency. PMID:35197517

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