Science finds explanation for disease that leaves children ‘frozen’

Naty Tomás became convinced that her daughter was not well when she was seven months old. Suddenly, her neck would become paralyzed and she was condemned to staring at the ceiling. At 18 months old she would freeze, dragging her paralyzed legs, or her trunk would bend and she would walk crooked. On the way to the emergency room the girl would fall asleep, recover, and when she arrived all the tests produced normal results. “The doctors started treating me as neurotic,” says Tomás, who decided to record videos of her daughter Nora’s attacks. This gave her credibility in the eyes of the doctors, although it did not solve the most serious problem: nobody knew what was wrong with her daughter.

The little girl would suddenly shut down and spend three days lying down. One of her doctors diagnosed her with encephalopathy and prescribed a high-fat ketogenic diet. The girl stopped eating and drinking, and couldn’t even speak. Epilepsy, alternating hemiplegia, encephalopathy? All the diagnoses seemed obvious. As a last resort, the doctors decided to sequence her entire genome. The results came in English, and the doctor gave them to her mother to read directly. Nora had Tango2 Deficiency Disorder (TDD). “The doctors didn’t know anything about this,” Nora recalls. The first glimmer of hope came when the 41-year-old administrator from Jumilla (Murcia) found the website of an association for TDD sufferers in the United States. For the first time, she no longer felt alone in the face of an unknown illness.

Twelve years before Nora was born, in 2006, a team of researchers in Barcelona discovered a new group of genes, which they named Tango. They seemed to play a key role in transporting, packaging and shipping proteins within the cell — a kind of molecular Amazon. In 2021, Argentine physician Agustín Luján began researching the Tango2 gene, at first unaware that it was involved in TDD.

Now, Luján, a researcher at the Center for Genomic Regulation in Barcelona, has just taken a giant step in understanding this disease, which is so rare that not even many doctors are aware of it. When the body increases its energy demands, the cells consume all the carbohydrates and start burning lipids (fats). Patients with TDD have difficulty burning lipids, and this causes metabolic crises that leave them “frozen” and are potentially fatal. These people often suffer dangerous arrhythmias in the heart, which obtains up to 90% of its energy needs by consuming lipids in the mitochondria, the energy centers within the cells.

An infection, physical exertion, or a few hours without eating is enough to trigger a potentially lethal crisis, the effects of which fade as soon as the patient rests, which is why Tomás was thought to be crazy.

On February 28, Luján, along with his colleague Ombretta Foresti and his boss Vivek Malhotra, published a study that clarifies how the mutation that disables Tango2 hinders lipid metabolism within mitochondria, and partly explains the symptoms of the disease. “Tango2 traps fats and prepares them for combustion. The cells of children with TDD have a reduced capacity to do this, so they are literally deprived of the proper lipid forms they need to obtain energy,” summarizes Luján, a 36-year-old Argentine from Mendoza, who has spent the last four years researching the Tango gene. The details of the work were published in the Journal of Cell Biology.

There are only around 110 known TDD patients worldwide, 11 of them in Spain. But researchers believe the real number is probably closer to 10,000. “Many people can have this disease and never know that the reason is a mutation in the Tango2 gene,” explains Malhotra. Better understanding this disorder can benefit not only TDD sufferers, but also the general population. The Tango genes intervene in lipid transport in general, which is related to heart and muscle diseases that affect tens of millions of people worldwide, the researcher points out.

In October, Luján met Tomás in person during a meeting of people affected by the disease organized by the Sant Joan de Deu Hospital, which centralizes the majority of cases detected in Spain. One of the objectives is to give this rare disease visibility so that more and more people, including doctors, became aware of it. Luján points out that the only case diagnosed in Argentina was thanks to a doctor who saw a report on TDD on U.S. television.

One of the few treatments that exist for this disease is high doses of vitamin B5, an essential nutrient that generates coenzyme A. “We still don’t know why vitamin B5 helps some patients avoid metabolic crises, but it may be boosting the residual energy pathways that Tango2 normally supports,” explains Luján. His main objective now is to clarify the mechanism of action of this gene and discover other molecules involved that could reveal possible therapeutic targets, but without selling false hope. “One of the most difficult things to do as a doctor is to tell the parents of a patient that you don’t know what their child has, or even if you have a diagnosis, that there is no cure. With rare diseases, low prevalence, lack of data, and scarce resources, the situation is even worse. That is why basic research is so important in these cases, as it offers hope to those who do not have it today,” he explains.

For their part, Tomás and her daughter Nora, now seven years old, are getting on with things, especially now that the origin of her illness has been identified and the treatment with vitamin B5 is having some effect. “When she is well, Nora is a normal girl,” Tomás explains, but “you have to be constantly saving her life.”

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