In search of answers to Celia's strange illness

Encarnación Postigo and her daughter Celia, who was born with a mutation in the syngap1 gene, in a provided image.

It's all smiles at Encarnación Postigo's house.

There is no other option.

Her daughter Celia, 24, needs it.

“You can't feel tension.

It's all smiles.

We are condemned to be happy at home,” explains her 59-year-old mother.

Celia was born with a mutation in the syngap1 gene, a very rare genetic disorder that affects neurodevelopment and can cause psychomotor retardation, autism spectrum disorder and epilepsy.

It was not easy to reach the diagnosis nor to digest it: there are few cases in the world, the questions still outweigh the answers and uncertainty weighs on families.

It occurs in this and other rare diseases with no cure.

“At the end of this path, the only thing you want is for you not to suffer,” admits Postigo, who has made a virtue of necessity and, together with a group of families affected by this and other genetic disorders, have promoted the EURAS project to investigate rasopathies, a group of conditions caused by genetic mutations that affect a cell communication pathway: the RAS signaling pathway.

The scientific initiative has achieved the support of the European Union to search for therapies and answers for these genetic ailments that affect neurodevelopment, such as cardiofaciocutaneous syndrome, Costello syndrome or encephalopathy related to syngap1, among others.

It took Celia 17 years to have a diagnosis.

From the age of six months, when his mother began to notice that “something was not right,” he visited specialists and hospitals until, in adolescence, a genetic study gave a name to what was happening to him: he had a mutation in the syngap1 gene. , which is found in the brain and has a key function for correct neuronal connection.

“When there is a problem there, the neurons are hyperexcited and that predisposes to epilepsy.

And she also ends up having problems in neuronal development,” explains Juliana Ribeiro, researcher and syngap1 expert at the Sant Joan de Déu Hospital in Barcelona.

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The real impact of the mutation in syngap1 is revealed little by little.

"They are born well and, after months, a delay in walking and speaking is noticed... The symptoms are seen over time," says Ribeiro.

They may suffer from movement or walking disorders, autism spectrum disorders, behavioral disorders, sleep disorders or eating disorders (dysphagia).

“And more than 90% have intellectual disabilities,” adds the Sant Joan de Déu researcher, who has not participated in this project.

In her case, Celia barely vocalizes a few words and has suffered from severe epilepsy since she was 17: “That impaired all of her motor skills and we had to take her out of school.

Since she was 18, she has been at home with therapists and fighting a terrifying epilepsy,” says her mother.

At any moment, she can suffer severe seizures that almost cause her to lose consciousness.

She is happy, affectionate and communicates with signs, as she can.

But she has swallowing problems, motor problems... she No, she is autonomous.

“She needs help 24 hours a day,” says her mother.

According to patient associations, there are just over a thousand cases in the world with this mutation in the syngap1 gene and, of them, about 38 are in Spain.

Therapeutic alternatives with gene therapy are being investigated, but, for now, the only treatment available is symptomatic, to treat seizures, behavioral disorders or symptoms that appear.

Nothing else.

Despair and urgency

The lack of treatments and “the helplessness of families,” says Postigo, led to the idea of ​​a research project in search of answers beginning to take shape.

For his daughter and for other kids with the same disease or other rasopathies.

“We were moved by desperation and the urgency that we have for them to be well.

Not just that they are cured, but that they are well,” he explains.

In the end, patient associations from a dozen countries ended up getting involved in the project.

“The parents set up the structure and the scientists counted on us at all the meetings,” Postigo recalls.

The final proposal, sponsored by the families and led by European researchers from Germany, France, Portugal, Spain and Austria, among other countries, won European aid of more than eight million euros.

The project, which lasts four years, focused on in-depth research into these complex diseases that affect neurodevelopment.

“These conditions, with neurofibromatosis 1 and Noonan syndrome being the most common, can manifest with a wide range of symptoms, including specific facial features, heart defects, skin changes, and varying degrees of neurological and neurocognitive impairment.

The rarest forms of rasopathies—cardiofaciocutaneous syndrome, Costello syndrome, and syngap1-related encephalopathy—cause significant neurological impairments, including intellectual disability, epilepsy, autism and behavioral spectrum disorder, and sleep disorders.

Although the physical manifestations of rasopathies can be life-threatening, they can be reasonably manageable through multidisciplinary symptomatic treatment.

However, there is currently no specific therapy for neurocognitive symptoms, which places a permanently high burden on patients, mostly children, and their families,” the organization explained in a statement.

All the experts consulted emphasize how intricate these diseases are, affecting a key signaling pathway in the body.

“They are very complex diseases.

Our genes make a network of connections between them.

If you cut a node from the periphery in that network, maybe it won't be noticed and nothing will happen.

But if an element like RAS is broken, which is involved in everything that has to do with cell proliferation, it is noticeable everywhere," summarizes Francisca Sánchez, who was a professor of Biochemistry and Molecular Biology at the University of Malaga and advised to the parents in those beginnings.

Test drugs

In practice, the project plans to create a patient registry and search for molecular biomarkers to detect possible drugs or validate therapies.

And they have already started.

There are groups working on different lines of research, explains Juan Antonio García Ranea, professor of Biochemistry and Molecular Biology at the University of Malaga, who participates in this European project: “With a guide from clinical and medical experts, families participate in the characterization of the symptoms.

It is important to group patients well, to do a good stratification, because then this can help find a therapy that is as personalized as possible.”

García Ranea and his team are participating in this characterization of the patients' symptoms and in “searching for genetic bases involved in both the pathology and the reversal,” he points out.

At the same time, there are other researchers delving into other approaches, such as testing the effect of drugs in cellular models.

The initiative also plans to develop preclinical trials with reused drugs and test, in animal models, cognitive motor training to achieve the reversal of seizures and autistic behavioral traits.

“The most important point is registration.

Without it, clinical studies cannot be done.

"You have to know how the disease has evolved," explains Marcos Mengual, 51 years old and father of a nine-year-old boy with a mutation in syngap1.

Mengual is another of the great promoters of this project.

His family also had to undergo a five-year pilgrimage through different specialists until they could give a name and surname to what was happening to his son Lucas.

“The diagnosis helped us understand the delay in cognitive development: at five years old he had the cognitive development of an 11-month-old child.

Today, Lucas does not speak, he barely says three or four words, but his epilepsy is fairly well controlled,” explains his father.

With nothing else to hold on to, the families trust all their letters to the investigation.

But they are realistic.

“The word cure is problematic because autism, for example, is not going to disappear.

If we improve the symptoms, it would be progress for the children,” agrees Mengual.

For his part, Postigo, who praises and thanks this father, Sánchez, García Ramea and the patient associations for his involvement, simply hopes that the life of his daughter “is as best possible".

The researcher from the University of Malaga defends, in any case, the potential of the project and assures that, although the initiative is ambitious and the task seems arduous, “it is not a toast to the sun”: “If there is something to find, we have the right sonar because we consider a large number of variables.

If we can find the key to reduce symptoms, it would be a great achievement and something valuable for families.”

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