The enigma of the ultra-rare disease that abounds in Spain

One day in 2017, Sergio Montañes ran out of energy as he crossed the street. He was just about to speed up because a car was coming and wouldn’t stop. “I realized that I couldn’t run, that something was wrong,” he recalls.

From that day on, Sergio gradually lost his strength. He had difficulty climbing the stairs, when before he could climb to the fourth floor two at a time. His work as an industrial draughtsman became more and more complicated, especially due to visits to construction sites, and he even needed help to get up from his chair, or was unable to get up from the floor on his own. Now, at 44, he even has trouble breathing.

Sofía Bermúdez, a 48-year-old nurse at La Fe Hospital in Valencia, experienced something very similar. The work became more and more exhausting every day, until she had to stop caring for patients directly. Things that most people do without thinking, like holding an umbrella, required “an incredible effort” that left her exhausted.

Sergio and Sofia suffer from an ultra-rare disease that affects one in a million people called tyrosine kinase 2 deficiency (TK2d). There are only 250 known sufferers worldwide. Spain is the country with the highest number of diagnosed cases: around 60.

One of the most characteristic features of those affected is that their eyes are always half-closed. Even the muscles that lift their eyelids are exhausted. The disease affects all the skeletal muscles of the body, limits mobility and causes respiratory failure that can end in death. The cause is a protein that prevents the proper functioning of mitochondria , organelles inside cells that are responsible for producing energy.

Unlike many rare diseases, this one has a treatment, but patients like Sofia and Sergio would not be able to take it. The European Medicines Agency is considering the approval of an oral treatment that has proven effective, nucleosides. If it is approved, it will only be available to children under 12 years of age, because it is in this population that the disease manifests itself most intensely, putting the lives of many patients in danger.

“There are also adults who suffer from this disease and end up dying from it,” warns neurologist Cristina Domínguez. This 45-year-old doctor from León has launched a pioneering clinical trial at her hospital, 12 de Octubre in Madrid , which is a reference for TK2d, to demonstrate that nucleosides also improve the quality of life of adult patients. Thanks to this initiative, Montañés and Bermúdez have started taking a drug that would otherwise be banned for them.

“Thymidine kinase 2 is a protein that participates in the generation of some of the precursors of mitochondrial DNA, molecules called pyrimidine nucleotides,” explains Domínguez. “By not having enough of these types of nucleotides, which are like the bricks for building DNA, the cell does not have the mitochondrial DNA necessary to generate cellular energy. The final consequence is that skeletal muscle is not able to perform its function normally,” he adds.

In April 2024, the study of the genome of 53 patients in seven Spanish hospitals helped to explain part of the enigma of why this disease is more frequent in our country. Researchers detected two genetic variants that multiply the risk of suffering from TK2d in Spanish patients up to 80 times compared to those from other countries. One of them, p.Thr108Met, is more frequent in people from Galicia. The two variants are also present to a lesser extent in people from Latin America. The Galician mutation arose about 425 years ago. The other about 2,300 years ago. Both became more frequent due to inbreeding, highlights the work , in which Domínguez, geneticist Francisco Ceballos, from the Rare Diseases Network Research Group, and other scientists participated. The other reason that explains why there are more patients here is that Spain is a reference in the diagnosis, study and treatment of the disease, points out Domínguez.

One of the people who has done the most for patients with this disease is called José Luis Martínez, and he is the father of a boy who was born with the disease. With his efforts, he managed to raise 120,000 euros so that scientists at Columbia University in the United States could create a transgenic mouse as a model for the disease, as EL PAÍS reported in 2019. The mice, which died after 10 days without treatment, survived for several weeks thanks to the nucleosides, which restored the mitochondrial DNA of their cells.

Nucleosides are an essential component of the body, but also a laboratory reagent used all over the world that can be bought on the Internet. Some families bought them this way to give to their children. The improvement was evident. These families, together with doctors from several Spanish hospitals, including Domínguez, managed to get the Spanish Medicines Agency to approve this improvised treatment as compassionate use. The problem came when the nucleosides acquired in China began to show dangerous side effects, possibly due to impurities, explains the neurologist.

At the same time, a small pharmaceutical company called Modis bought the researchers' original patents and began developing the treatment as a drug. In 2019, this company was acquired by Zogenix for $400 million, partly because of the potential interest in the treatment. And in 2022, the Belgian company UCB acquired Zogenix for $1.9 billion. This company is the one that is now carrying out the development of the nucleosides.

To ensure that the maximum number of patients can receive the treatment, including adults, Domínguez promoted the clinical trial at 12 de Octubre. The company is providing the drug free of charge in the hope that its effectiveness will be demonstrated and the population that could take the drug, the price of which is yet to be determined, will be increased. The results of the trial are expected within a year. With these results, a license extension or compassionate use could be requested so that all patients who are diagnosed can access the drug regardless of their age.

Sofia and Sergio started taking nucleosides a few weeks ago, and they are already starting to feel some improvement. “Now I need help to get dressed or put on my shoes. I am afraid to go out. What I hope for with this drug is to be able to do everyday activities. I am happy to feel a little better,” the nurse confesses.