TANGO2 (Transport and Golgi Organization 2 Homolog) is a mitochondrial protein primarily involved in lipid homeostasis and acyl-CoA binding. 1 The protein localizes to the mitochondrial lumen via an LIL-containing structural region and binds acyl-coenzyme A through conserved NRDE sequences, serving as an acyl-CoA binding protein. 1 Additionally, TANGO2 functions as an intracellular heme chaperone, facilitating heme trafficking from mitochondria to apo-hemoproteins. 2 TANGO2 deficiency disease (TDD) is a rare autosomal recessive disorder characterized by recurrent metabolic crises triggered by fasting, infection, or high fever, manifesting as rhabdomyolysis, cardiac arrhythmias, encephalopathy, and neurodegeneration. 3 4 The pathology is predominantly driven by lipid imbalance, with patients showing cardiolipin deficiency and impaired Golgi-ER trafficking. 5 Clinically, over 70% of patients present with acute metabolic crisis, rhabdomyolysis, neurologic abnormalities, developmental delay, and intellectual disability. 3 Natural history studies identified vitamin B5 (pantothenic acid) supplementation as potentially life-saving, preventing metabolic crises and rescuing cellular defects in model systems. 4 6 Whole-exome sequencing has identified TANGO2 variants in cases of indeterminate pediatric acute liver failure, supporting genetic screening in metabolic crisis presentations. 7