Understanding Fat Transport Deficiency in Childhood Metabolic Disorders

Recent research has illuminated the role of fat transport deficiency in a rare and severe metabolic condition known as TANGO2 Deficiency Disorder (TDD), which predominantly affects children. This disorder is characterized by the inability of cells to effectively utilize lipids for energy during periods of metabolic demand, leading to potentially life-threatening crises.

The initial identification of the gene responsible for this condition, TANGO2, occurred in 2006 at the Centre for Genomic Regulation (CRG) in Barcelona. However, it was not until 2016 that researchers established a direct link between mutations in TANGO2 and TDD. Currently, there are approximately 110 confirmed cases of TDD globally, but it is estimated that thousands of undiagnosed patients may exist.

Under normal circumstances, when the body requires additional energy, cells shift from using carbohydrates to lipids. This transition is particularly critical for the heart, which relies heavily on lipids for energy production. Children suffering from TDD, however, experience significant challenges in meeting their energy needs, resulting in metabolic crises that can include severe hypoglycemia, muscle breakdown, and dangerous cardiac arrhythmias. Such crises are often triggered by physical stressors like fevers, illnesses, or missed meals.

Families affected by TDD frequently discover the condition only after a crisis occurs, leading to urgent medical interventions such as intravenous glucose administration. The unpredictability of these episodes underscores the urgency for better understanding and management of the disorder.

Researchers, led by ICREA Research Professor Vivek Malhotra, have dedicated the past decade to unraveling the molecular mechanisms by which TANGO2 operates. Their investigations revealed that the TANGO2 protein resides in mitochondria, indicating its pivotal role in energy metabolism. In TANGO2-deficient cells, an accumulation of fat droplets occurs alongside increased production of reactive oxygen species, which can lead to lipid damage and dysfunction.

A recent publication in the Journal of Cell Biology highlights the discovery that TANGO2 binds to acyl-CoA, a crucial fat molecule, effectively transporting it within cells. This function is akin to a shuttle, preparing fats for energy utilization. The impaired ability of TDD-affected cells to transport and utilize these essential lipids results in a critical deficiency in energy production.

Current treatment strategies for TDD often involve administering high doses of Vitamin B5, which is essential for synthesizing Coenzyme A. Although the precise mechanism by which Vitamin B5 alleviates metabolic crises remains unclear, it may enhance alternative energy pathways that TANGO2 typically supports.

The implications of this research extend beyond TDD, as understanding the mechanisms of fat transport may provide insights into broader metabolic disorders affecting heart and muscle health. Millions of individuals struggle with related issues, and the fundamental biochemical processes are often similar.

Future investigations aim to clarify how TANGO2 interacts with acyl-CoA and its transport dynamics within the cell during stress. These insights could lead to improved diagnostic capabilities and targeted therapies for TDD as well as similar metabolic disorders.

The collaborative efforts of scientists, healthcare providers, and patient organizations, such as the TANGO2 Research Foundation, have been vital in advancing this research. Families of affected children express hope that continued discoveries will lead to more effective treatments and a better quality of life.