Living with uncertainty: Lia has been waiting for a diagnosis since birth.

BarcelonaLia will turn three on December 28th. She doesn't walk independently – she crawls a lot, of course – but she's close to it, and although she communicates in her own way – she points and makes herself understood – she still doesn't speak beyond a few words. She's had multiple tests, and she's being monitored by specialists of all kinds, but they still haven't found the disease that explains the causes of this global developmental delay, although they suspect it could be a rare disease of genetic origin, explains her mother, Laura López Crespo, 39.

Lia's is one of 12 cases that have been analyzed this week in a hackathon –an event in which experts gather to solve a challenge– to try to find a diagnosis for unnamed rare diseases. To do so, detailed clinical information from patients and cutting-edge genome data have been used. There are 12 children and young people who have been waiting for a diagnosis for years, some for more than ten, and this is the first time hackathon dedicated specifically to children with rare diseases, held in Spain, Latin America, and Portugal. The meeting, held in Murcia and sponsored by the San Juan de Dios Hospital and the Virgen de la Arrixaca Hospital in Murcia, was attended by more than 100 European and Latin American experts, professionals from very diverse disciplines, such as geneticists, pediatric neurologists, pediatric cardiologists, and analysts. Several groups were formed, each consisting of around twenty professionals, and each group studied between two and three patient cases.

Laura explains that during Lia's pregnancy, her second daughter, some of the screening test results came back abnormal, but neither the amniocentesis nor the morphological ultrasound performed mid-pregnancy detected any abnormalities. Towards the end of the pregnancy, Lia stopped gaining weight, and Laura had labor induced. "Lia was born healthy but tiny, weighing about 2,200 grams," her mother recalls. They were discharged and immediately realized that Lia wasn't eating well and wasn't gaining weight. "She had trouble eating, and they didn't know why," recalls the mother. The heel prick test also came back abnormal, but subsequent tests ruled out any medical conditions.

All the tests performed came back clear, but she was admitted to try to figure out what was wrong, as the baby wasn't gaining weight and had hypotonia, or low muscle tone. "During this first admission, they saw that she had no sucking reflex; she fed by decanting, that is, her mouth filled with milk and, reflexively, she swallowed. They discovered that she was allergic to cow's milk protein. They inserted a nasogastric tube and she ate that way, with special milk, with special milk," says her mother, who always suspected something was wrong, even though the tests proved it wrong.

Lia has made very good progress. She eats pureed food and has now started feeding her in chunks. She drinks water and milk and does not have a gastric button. "What affects her most is that she is short; she will be three years old and weighs 7 kg." She says a few words and is very communicative. "She points, asks for what she wants, and is beginning to express herself," explains her mother. "We don't know if she will have an intellectual disability, but in any case, it will not be severe. "She won't be a very severely affected child, but we don't know to what extent," Laura admits. Lia currently attends a regular nursery, which she really likes, and is a happy child with a very rich game, who socializes and enjoys music, stories, and dancing.

Name

Lia is being monitored by neurologists, gastroenterologists, ophthalmologists, and geneticists, but so far none of the tests have been able to determine what disease she has. Now they have all their hopes pinned on this one. hackathon"There they're doing the most comprehensive test there is, which is the genome test, and we're waiting to hear if they find anything." For the moment, hackathon It has already diagnosed six of the 12 cases. "We're hopeful that a name can be given, but we also know that they might not find anything; we have to be realistic," Laura adds.

"Diagnosis isn't everything, but it changes everything because we can make decisions, predict how it will progress, identify potential treatments, identify how it is transmitted, and prevent new cases," explains Encarna Guillén, head of the Genetics Department at Sant Joan de Déu Hospital and strategic director of the Únicas project, adding that diagnosis is "a turning point" for the patient.

For Lia's family, it would mean not only giving a name to what's happening to the little girl, but also knowing "what her evolution will be." "Because there are diseases that are more worrying than others. It will allow us to know if it's a neurodegenerative disease or not, if Lia can be verbal or not, if it will affect her autonomy or intellectual development, her life expectancy... If we know what we can advance," says Laura. It would also allow them to network and meet other families with the same disease. "Families who are going through the same thing are the ones who understand you best," she acknowledges. But she makes it clear that "diagnosis doesn't mean prognosis," because "each person's evolution can be different."

Living with uncertainty

Lia's family has learned to "live with uncertainty." The first year was the hardest, but since then, progress has been good. Lia is reaching her developmental milestones, but more slowly. "And we don't want to put a ceiling on it." "You end up accepting the situation and we participate in everything that can help find a diagnosis, but it depends on science," says Laura, who explains that people are surprised: "How can they not know what she has?" But then you meet other families and you realize that it's not the most common, but it's not that rare either."

It is estimated that 50% of children affected by a rare disease in Spain, most of which are genetic, do not have a precise diagnosis. Currently, children with rare diseases take an average of more than six years to receive a diagnosis, a period considered unacceptable and which should not exceed one year. For this reason, in 2023, the San Juan de Dios Hospital and the Spanish Federation of Rare Diseases (Feder) promoted the creation of Únicas, a Spanish network of 30 hospitals that aims to offer a coordinated response to patients with rare diseases throughout the entire care process. "This is an international priority because these patients, once all diagnostic options have been exhausted, are forgotten and no one thinks about them, and diagnosis is a right," says Guillén. Furthermore, any progress will not only impact the family and the affected patient, but can also spread to new patients.

One of the main objectives of Únicas is to accelerate diagnosis, which is why various initiatives have been promoted, including hackathon, where some of the most complex cases have been presented. Most present congenital anomalies and neurodevelopmental disorders. This is the case, for example, of César, a 14-year-old boy from Murcia who has been seeking a diagnosis since he was 3 years old, or that of Sofía, 13 years old, who has been trying since she was 14 months old. During the hackathon Six of the twelve cases have been diagnosed, far exceeding expectations, and a suspected diagnosis has been found in two other cases, which are pending confirmation through further testing. Participants will continue working together for three months on the cases that have not been diagnosed.