Race against time to save Carmen

BarcelonaOne day, she noticed, to her surprise, how her hand felt like it was going to give way. Then it was her leg. And she started stumbling and falling. "It must be my shoes, they're so worn out," she thought. After all, Carmen Cruïlles had been traveling the world for a year with the same shoes and a backpack. However, the tremors started in Australia. "It's just tiredness," or "It's anxiety," the doctors told her, dismissing it as unimportant. And yet, the unease grew inside her. When she met up with her mother in the Philippines in October to celebrate her 28th birthday, her mother, upon seeing her, told her seriously that she had to return to Barcelona "right away" to get a proper checkup.

Thus began Carmen's year-long odyssey through all kinds of specialists, clinics, and Catalan hospitals. "They told me I was fine, that I was just drawing attention to myself," this young woman from Barcelona still recalls with a touch of anger. The first doctor who truly took her seriously was her primary care physician at her local health center, who identified the continuous tremors in her hands as myoclonus, small, repetitive movements symptomatic of an epileptic seizure. "Receiving an initial diagnosis of epilepsy reassured me because I knew about the disease and knew I could overcome it," explains the young woman, who, after a weekend during which she suffered a severe seizure, ended up seeing Pablo Villoslada, head of the neurology department at Hospital del Mar. An electroencephalogram revealed that she suffered from epilepsy partialis continuous: the left hemisphere of her brain was constantly experiencing epileptic seizures. The typical cause was Rasmussen's encephalitis, a disease that affects 2 out of every 10 million people worldwide. "My surprise was that Carmen was a 28-year-old patient, when this disease typically begins between three months and three years of age," recalls Villoslada. Rasmussen's encephalitis is very rare—it's one of the so-called ultra-rare diseases—and even rarer in adults: only one in ten cases occurs in adolescence or adulthood.

A case with international repercussions

Villoslada had returned to Catalonia two years earlier after more than two decades in San Francisco working with autoimmune inflammatory neurological diseases. The best known is multiple sclerosis, but there are many more, such as neuromyelitis optica, or Devic's disease, which attacks the optic nerve and spinal cord, or Rasmussen's encephalitis, a chronic and progressive condition that causes no cognitive or motor impairment and for which there is no treatment. The cause is also unknown; it is only known that a type of immune cell, CD8 lymphocytes, attacks neurons. For this reason, Carmen is currently receiving treatment for epilepsy and immunotherapy. "Because it is such a rare disease, clinical trials have not been conducted to determine which drugs and dosages are most suitable. Therefore, we are conducting tests, assessing the risk-benefit ratio," explains Villoslada. Right now, tocilizumab, an immunosuppressant drug used to treat rheumatoid arthritis, seems to be working for her. Since she started treatment last year, Carmen's sky-high neurodamage markers have dropped considerably. Now, this Barcelona native's case has spurred an ambitious international research project led by Villoslada. Its goal is to create a biobank of samples for this most common neurodegenerative disease in the world, enabling comprehensive genetic and immunological studies to identify a target. "If you know the target, you know which lymphocytes to attack, allowing us to develop treatments with new therapies, such as CAR-T," adds the neurologist. Although there have been some steps taken by the European Union in recent years to fund research into these diseases, the role of patient associations and initiatives like the one Carmen is promoting with the support of her family, the Resolve initiative (you can collaborate at [link missing]), remains crucial in securing the necessary resources. https://resolveproject.help/

Researchers at Hospital del Mar are already designing a therapeutic strategy to block the specific lymphocytes that, in Carmen's case, are attacking her brain. They are working with CAR-T therapy, using RNA to simplify the manufacturing process and lower production costs. "I know we'll achieve it," Carmen says with a genuine smile. This woman's strength, drive, and conviction are truly impressive.

The first step: being able to diagnose

Like Carmen's, at least 7,000 rare diseases are known, affecting some 300 million people worldwide, about three million of them in Spain. Unfortunately, for 95% of these diseases, which primarily affect children and are often neurodegenerative and chronic, causing significant disability and a tremendous impact on those who suffer from them and their families, there is no effective treatment. Moreover, diagnosing them is very complicated and in some cases can take years, because there are so many and varied diseases, and even within the same group of diseases there can be a wide range of manifestations and severity. To identify them, in most cases the exome—only the part containing the genes that code for proteins—is sequenced using a sample from the patient. "The faster the diagnosis, the better the prognosis," says Assumpció Bosch, professor at the Autonomous University of Barcelona (UAB) and researcher in the Department of Biochemistry and Molecular Biology and the UAB's Institute of Neurosciences. This expert in genetic diseases gives the example of phenylketonuria (PKU), a very serious disease that can cause significant cognitive impairment in children. "If it is identified early in life, simply changing the baby's diet allows for normal development and prevents profound intellectual disability," she emphasizes. Some rare diseases can be diagnosed with the newborn screening test. However, "there are many for which there is no care or whose treatments are so expensive that they are not covered by social security and are therefore not included in the newborn screening test. This means that they are not diagnosed until the child begins to show symptoms," Bosch laments.

Living with uncertainty

Despite genetic testing, in one out of every two cases a diagnosis will never be reached. This is the case of Maria (a pseudonym), a 7-year-old girl. When she was 5 months old, her parents began to notice that she wasn't doing anything they saw other children around her doing, such as grasping objects, and she had a vacant stare. After ruling out hearing and vision problems, neurological tests were performed, which confirmed that the repetitive arm movements and restlessness she experienced at night were due to a type of epileptic seizure. Despite genetic testing—exome sequencing—both on her and her parents, they were unable to identify the specific mutation she has. "This leaves us alone, not knowing what to expect, without medication to treat her, and unable to join forces with other families to find solutions," laments Daniel, the girl's father, dejectedly.

The disease María suffers from is classified as epileptic encephalopathy. In addition to medication to control seizures, she has recently begun using a vagus nerve stimulator that helps prevent convulsions, or at least shorten them. She neither speaks nor walks and is completely dependent.

"Especially in the early years, we felt a lot of anxiety because we didn't know what she would be capable of," recalls Daniel, who adds: "We have learned to live with the uncertainty of not knowing what will happen and with the frustration of seeing our daughter not progressing and not knowing how she will evolve."

Although the diagnosis is not the end of the process for the vast majority of rare diseases, it does open the door to improving patients' quality of life. "To begin with, you can anticipate the progression of the disease and possible complications," says Encarna Guillén, head of the genetics department at Sant Joan de Déu Hospital. strategic coordinator of the Unique rare diseases project"Identifying the pathology allows you to intervene with a more specific therapy. And also, knowing which gene is altered allows us to understand how the disease is transmitted, whether the parents or other relatives may be carriers, and thus advise them so that it is not transmitted further," she adds. In cases like María's, where exome sequencing and biochemical and metabolic studies have not identified the cause, the data "are reviewed periodically, because science advances and new genes are associated with diseases": "In this way, over time, we can even resolve cases like Guillén's syndrome. In this regard, multidisciplinary groups are being created at Sant Joan de Déu precisely to identify all the young patients who remain undiagnosed and to establish a program of periodic case review."

Gene therapy, a hope

At San Juan de Dios Hospital, there are currently more than 300 clinical trials underway, the vast majority dedicated to rare diseases. "We are making great strides in therapeutic possibilities," says Guillén, who cites spinal muscular atrophy as an example, a disease that until a few years ago was fatal for babies born with it. "Today, however, we have several types of therapy available, including gene therapy," he adds. In fact, the experts interviewed for this report believe that gene therapy is opening a window of hope for many patients. "It is one of the most promising treatments because, even if the cause or mechanism is unknown, simply introducing a healthy gene can correct the disease," explains Bosch. Many rare diseases are caused by a single gene, which allows for the creation of a healthy copy of the mutated gene in the laboratory. This copy is then inserted into a viral vector, which acts as a kind of Trojan horse, capable of entering the affected cells and delivering the corrected gene. In this regard, the research group at the UAB and VHIR, where Bosch works, has developed a gene therapy for ALS that is in the final stages before clinical trials. They have also developed another gene therapy for spastic paraparesis, funded by the initiative. The April Strugglewhich has motivated the parents of a girl from Badalona. In Spain there are only three patients with this degenerative neuromuscular disease, and about 55 worldwide. They have already obtained very positive results with mice and hope to reach the clinic in two or three years.

Researcher Antoni Matilla, head of the neurogenetics unit at the Germans Trias i Pujol Institute in Badalona, ​​through a spin-off Called BioIntaxis, a team has developed a gene therapy for Friedreich's ataxia, a progressive neurodegenerative disease that ultimately leads to the death of patients. This potential treatment is expected to begin human clinical trials in 2026.

"These are young people who play sports and one day they start stumbling, becoming more clumsy, falling, and losing sensation in their legs," explains Matilla. Approximately 4,000 people across the Iberian Peninsula suffer from it. In this case, the cause is known: a mutation in a gene responsible for regulating mitochondrial energy, the cell's powerhouse.

Patients raised the initial funds for research, and later Matilla received funding from competitive grants, such as the CaixaImpulse grants from the La Caixa Foundation. "We're very close. We've tested it on mice, and they recover, regaining movement. And in primates, we've seen that it's safe. We're the only ones in Europe who have managed to develop such a therapy. We receive emails from people all over the world who want to participate in our trial," explains the researcher, who assures us that we are at a hopeful moment.