Fat transport deficiency explains rare childhood metabolic crises

Researchers studying a protein linked to a rare, severe disease have made a discovery that sheds light on how cells meet their energy needs during a severe metabolic crisis. The findings could lead to new treatments for the disease and open new avenues of research for other conditions involving impaired fat metabolism.

When scientists at the Centre for Genomic Regulation (CRG) in Barcelona first identified a handful of protein-coding genes called TANGO in 2006, they had no idea that one of them, TANGO2, would eventually be linked to a life-threatening disorder in children. In 2016, the researchers found that mutations in TANGO2 causes a rare disease now officially recognised as TANGO2 Deficiency Disorder (TDD).

There are about 110 known patients with TDD worldwide, though there are thought to be an estimated six to nine thousand undiagnosed patients in total.

Normally, when the body increases its energy demands, cells deplete their carbohydrate stores and begin to use lipids to produce energy instead. This is particularly important for the heart, which derives between 60 to 90% of its energy requirements from consuming lipids in the mitochondria of cells.

Children with TANGO2 deficiency struggle to meet the body’s energy demands, leading to life-threatening metabolic crises. These episodes are marked by sudden drops in blood sugar, muscle breakdown (rhabdomyolysis), and potentially fatal heart rhythm disturbances (cardiac arrhythmias). The crises are often triggered by physical stress, such as a high fever, viral infections or a missed meal.

Though the rarity of TDD means that most doctors will never see a case firsthand, the consequences can be devastating, and many families rely on high-alert interventions such as glucose IVs in hospitals.

“Families sometimes only find out their child has TANGO2 deficiency only after a dramatic incident,” says ICREA Research Professor Vivek Malhotra, senior author of the study who first discovered the TANGO family of genes two decades ago. “One moment, everything seems normal. Then, under an energy-demanding situation, these children’s muscles and hearts fail to keep up.”

In the last decade, Malhotra’s team has been exploring what TANGO2 does at the molecular level and why its disruption causes life-threatening symptoms. They recently showed the protein is in the mitochondria, suggesting it plays an important role in energy production. They have also found TANGO2-deficient cells accumulate more fat droplets and produce excess reactive oxygen species, leading to damaged or unusable lipids.

In the latest study, published today in the Journal of Cell Biology, the researchers demonstrate that TANGO2 directly binds to a key fat molecule called acyl-CoA, transporting them like a shuttle inside cells. The authors of the study made the findings by tagging TANGO2 with glowing markers to trace its movements in live cells.

The discovery sheds new light on why metabolic emergencies occur in children living with TDD. “TANGO2 grabs fats and readies them for combustion. The cells of children with TDD have an impaired ability to do this, so they are being literally starved of the proper lipid forms needed for energy,” says Dr. Agustin Lujan, first author of the study and medical doctor who is now postdoctoral researcher at the Centre for Genomic Regulation.

One of the few existing treatments for the condition involves giving patients high doses of Vitamin B5, an essential nutrient known to generate Coenzyme A. “We still don’t know why vitamin B5 helps some patients avoid metabolic crises, but it may be boosting residual energy pathways that TANGO2 normally supports,” says Dr. Lujan.

Though TANGO2 deficiency is rare, the science behind how cells shuttle fat to fuel-hungry tissues might apply more broadly. “It could help us understand heart or muscle diseases in the general population,” says Dr. Malhotra. “Millions of people wrestle with heart problems or abnormal fat metabolism, and the fundamental chemistry isn’t all that different. The biology of rare diseases can help us understand human health in general.”

The authors of the study now hope to determine exactly how TANGO2 latches onto acyl-CoA and whether it hands off these fats to specific enzymes inside the mitochondria. They will also explore whether TANGO2 travels back and forth between different parts of the cell during times of stress.

In practical terms, the new insights could eventually inform treatments, or at least help doctors spot the early warning signs of TANGO2 deficiency. “The more we clarify the molecular underpinnings, the better our chances of developing targeted therapies,” says Dr. Ombretta Foresti, co-author of the study and staff scientist at the CRG. “And hopefully, with better understanding, we can give families facing this disease more than just emergency measures.”

The findings of the study were possible thanks to an international collaboration between scientists, doctors and patient associations like the TANGO2 Research Foundation, which facilitated data for analysis obtained from biological samples taken from patients with the condition.

For parents of affected children, any step forward is encouraging. “Each new discovery and insight get us closer to where we ultimately want to be,” says Mike Morris, parent of a child with TDD and cofounder of the TANGO2 Research Foundation.

“We're grateful to scientists around the world as they work to piece together this puzzle and have a positive impact on patients and families living with TDD,” adds Kasha Morris, cofounder of the TANGO2 Research Foundation.

“Over the past decade, fundamental, laboratory-based research has transformed this narrative, offering hope where none once existed. This journey highlights the profound impact of addressing foundational principles in the life sciences, as well as the vital collaboration between researchers, physicians, and families in confronting human pathologies," concludes Dr. Malhotra.