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Researchers Discover Key Mechanism Behind Life-Threatening Metabolic Disorder
A team of scientists at the Centre for Genomic Regulation (CRG) in Barcelona has made a crucial discovery about how cells meet their energy needs during metabolic crises, shedding light on a rare and severe childhood disorder known as TANGO2 Deficiency Disorder (TDD). Their findings, published in the Journal of Cell Biology, may pave the way for new treatments and provide valuable insights into other conditions linked to impaired fat metabolism.
Uncovering the Role of TANGO2
The TANGO2 gene, first identified in 2006, was linked to a life-threatening metabolic disorder in 2016. Children with TDD suffer from sudden metabolic crises, characterized by blood sugar drops, muscle breakdown (rhabdomyolysis), and fatal heart rhythm disturbances. These episodes often arise due to physical stressors such as fever, infections, or missed meals.
“Families sometimes only find out their child has TANGO2 deficiency after a dramatic incident,” said ICREA Research Professor Vivek Malhotra, the senior author of the study. “One moment, everything seems normal. Then, under an energy-demanding situation, these children’s muscles and hearts fail to keep up.”
Breakthrough Discovery on Fat Transport
Normally, when the body requires more energy, cells switch from using carbohydrates to metabolizing lipids. The heart, in particular, relies on lipids for 60-90% of its energy. However, researchers found that in TDD patients, cells struggle to mobilize fat for energy.
In their latest study, scientists tagged TANGO2 with fluorescent markers and discovered that it binds to a crucial fat molecule called acyl-CoA, transporting it within cells. This process is essential for fueling mitochondria, the cell’s powerhouses. Without proper fat transport, cells become starved of energy, explaining why children with TDD experience severe metabolic emergencies.
“TANGO2 grabs fats and readies them for combustion,” said Dr. Agustin Lujan, the study’s first author and a postdoctoral researcher at CRG. “Cells in children with TDD lack this ability, leaving them unable to generate sufficient energy.”
Potential Treatment Avenues
One of the few existing treatments for TDD involves high doses of Vitamin B5, an essential nutrient that generates Coenzyme A, a molecule crucial for energy metabolism. While researchers are unsure exactly why Vitamin B5 helps some patients avoid crises, they speculate it may enhance alternative energy pathways usually supported by TANGO2.
Beyond TDD, this research could have broader implications. “Millions of people struggle with heart and muscle diseases related to fat metabolism,” said Dr. Malhotra. “Understanding this rare disorder may help us unlock solutions for more common metabolic conditions.”
Next Steps and Hope for Families
The CRG team now aims to investigate how TANGO2 transfers acyl-CoA to mitochondrial enzymes and whether it moves between different cellular regions during metabolic stress. These insights could lead to targeted therapies, allowing doctors to intervene before metabolic crises occur.
The research was made possible through an international collaboration involving scientists, medical professionals, and patient advocacy groups like the TANGO2 Research Foundation. “Each new discovery brings us closer to a real solution,” said Mike Morris, a parent of a child with TDD and cofounder of the foundation. “We’re incredibly grateful for the scientists working to solve this puzzle.”
Dr. Malhotra emphasized the importance of basic scientific research in tackling rare diseases. “Over the past decade, fundamental research has turned this disorder from an enigma into a solvable problem. This progress highlights the power of collaboration between researchers, physicians, and families.”
For families affected by TDD, this discovery represents a beacon of hope, offering the possibility of better treatment options and a deeper understanding of the disorder.
Disclaimer:
This article is for informational purposes only and should not be considered medical advice. Patients and caregivers should consult healthcare professionals for diagnosis and treatment options related to TANGO2 Deficiency Disorder or other metabolic conditions.
