A recent study sheds new light on a rare and life-threatening disease, TANGO2 Deficiency Disorder (TDD), and its impact on the body’s energy production mechanisms. The research, conducted by scientists at the Centre for Genomic Regulation (CRG) in Barcelona, reveals how the disruption of a protein involved in fat metabolism leads to severe metabolic crises in affected children. These findings could pave the way for new treatments and offer insights into broader health issues related to fat metabolism.
The TANGO2 gene, discovered by CRG researchers in 2006, was linked to TDD in 2016. Since then, scientists have been studying its role in energy production, particularly how it helps cells meet their energy demands during times of stress. Children with TANGO2 deficiency face significant challenges during metabolic crises, which are often triggered by fever, viral infections, or missed meals. These crises can cause severe symptoms, including dangerously low blood sugar, muscle breakdown, and heart arrhythmias.
Currently, there are around 110 known cases of TDD worldwide, but experts believe there could be thousands more undiagnosed patients. For families affected by the disorder, the discovery of TANGO2’s role offers new hope. “One moment, everything seems normal, and then suddenly, under stress, the child’s muscles and heart fail to keep up,” said ICREA Research Professor Vivek Malhotra, who led the study. “We hope this new understanding of TANGO2’s function will allow us to identify early warning signs and develop more effective treatments.”
In their latest findings, published in the Journal of Cell Biology, the researchers revealed that TANGO2 plays a crucial role in transporting fats within cells. They discovered that the protein binds to a fat molecule called acyl-CoA and facilitates its movement to areas of the cell that require energy. In children with TANGO2 deficiency, this process is impaired, causing cells to be deprived of essential lipids needed for energy production.
The team’s research also provided insight into why some TDD patients seem to benefit from high doses of Vitamin B5, which aids in the generation of Coenzyme A. While the exact mechanism remains unclear, it is believed that Vitamin B5 may help compensate for the disrupted metabolic pathways caused by TANGO2 deficiency.
While TDD is rare, the study’s findings could have broader implications for understanding heart and muscle diseases, as well as other conditions involving disrupted fat metabolism. “Millions of people suffer from heart problems and abnormal fat metabolism, and the fundamental chemistry we’re studying here is not that different,” said Dr. Malhotra. “The biology of rare diseases can offer valuable insights into human health as a whole.”
The researchers now plan to explore the exact process by which TANGO2 interacts with acyl-CoA and its role in the mitochondria during periods of stress. Their hope is that these discoveries could lead to new, targeted therapies for TDD and similar conditions.
The study’s success was made possible by an international collaboration involving researchers, doctors, and patient associations like the TANGO2 Research Foundation. For affected families, each new breakthrough brings them closer to finding effective treatments and improving their children’s quality of life. “We’re incredibly grateful for the tireless work of scientists around the world,” said Mike Morris, cofounder of the TANGO2 Research Foundation and father of a child with TDD. “Every discovery moves us one step closer to understanding this disease.”
Dr. Malhotra concluded, “This research underscores the importance of foundational life sciences and the vital collaboration between researchers, clinicians, and families. With each new step, we move closer to transforming the narrative for families living with TDD.”
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