KCNB1 Mutation: A Large-Scale Research Project Launched Thanks to the Mobilization of Families and the Responsiveness of Scientists
We introduced you to Lilas a year ago (in our June 9, 2024 edition). You discovered her bright smile, her loving family, and also, unfortunately, her extremely rare disease, linked to a mutation of the KCNB1 gene, which disrupts potassium channels and the functioning of neurons.
Around this orphan pathology, parents, researchers and doctors have built a unique ecosystem, combining scientific mobilization and solidarity, leading to the launch of a large-scale research project.
A look back at an extraordinary adventure, at the crossroads of biomedical research and human commitment.
At the origin: Mélissa and Paul Cassard, faced with the severe symptoms of their daughter Maïa — developmental delay, autistic disorders, then epileptic seizures (up to 50 per day).
When they learned that Maia carried a very rare mutation of the KCNB1 gene, the shock was immense. But the parents refused to do anything.
They convinced Professor Rima Nabbout, a pediatric neurologist specializing in epilepsy at Necker Hospital (Paris), who made the diagnosis, to invest in studying this mutation. To move forward, the researcher needed the support of families to identify cases.
In just a few months, thanks to social media and specialized forums, Mélissa connected with 15 French families. The KCNB1 France association, which she now heads, was born.
This network marks the beginning of a collective dynamic around the disease. "This starting point allowed the emergence of a mobilization around the pathology ," testify Laurent and Lilya, Lilas's parents, now members of the association's board of directors.
Since the publication of their testimony, they have been put in contact with another family from the Alpes-Maritimes, that of Nathan, who carries the same mutation as Lilas.
Together, they helped organize the second edition of the KCNB1 raffle in June. "We raised €18,435, largely earmarked for the family support fund. It helps finance essential equipment that often remains their responsibility," they explain.
This support is crucial, as the costs associated with disability are very high. "The cost estimate for Lilas's eye-tracking communication tablet is over 9,000 euros," Lilya explains.
A 10 million euro research projectOn the research side, a turning point has just been reached with the launch of the RHU (university hospital research) program, endowed with 10 million euros, coordinated by the Imagine Institute and Professor Nabbout, in collaboration in particular with Professor Massimo Mantegazza's team at the IPMC of Sophia-Antipolis (CNRS).
"Thanks to the involvement of the families and the association, the project has grown remarkably," explains Laurent. Professor Mantegazza and his team of data scientists are modeling the effects of KCNB1 mutations on ion channels using European supercomputers.
At the same time, work is being conducted on biological models, including transgenic mice and zebrafish. The goal: to understand precisely how the mutation generates neurological disorders, particularly severe epilepsy.
A large number of the children identified, including Lilas and Nathan, have had biological samples taken, fueling research into DNA modeling, in the hope of discovering a therapeutic molecule.
"Researchers remain cautious, but they are considering the possibility, within five years, of developing a treatment capable of stabilizing or stopping epileptic seizures (they are one of the major symptoms of this genetic disease, editor's note). Trials conducted abroad on other mutations are already yielding promising results: some children are starting to walk or talk. This gives hope, even if the mutations in question differ."
A sunny and resilient childBeyond science, there is Lilas. Despite her disabilities, she radiates joy. She sings, smiles, and interacts. Her parents support her with admirable energy, working closely with the daycare, therapists, and medical team.
Pictograms have been installed to help him communicate better. Every gesture, however small, contributes to his well-being and progress.
"I noticed Nathan's twitching very early on," the little boy's mother tells us in a moving letter she sent us . "I reported it at every visit to the pediatrician. She told me that it was archaic reflexes, that it would go away on its own (in reality, it was epileptic seizures) .
But, over time, Charlotte would notice other symptoms: developmental delay, persistent plagiocephaly (flat head syndrome). And then at 8 months, the infant suffered her first generalized epileptic seizure.
Hospitalized in Lenval, he underwent "several lumbar punctures, MRIs, EEGs..." "The doctors searched, but couldn't find what he had. They initially suggested West syndrome (a rare form of infant epilepsy), but genetic tests contradicted this diagnosis." After a year of wandering, the verdict came in: Nathan was a carrier of a KCNB1 mutation.
"The geneticist tells us that only 60 cases have been recorded worldwide. Doctors have little perspective. At that point, we understand that it's very serious, and that nothing will ever be the same again."
Despite the violent shock they had just suffered, Nathan's parents had no choice but to react quickly. "We had to find a treatment that would relieve his pain, a suitable care facility, implement multidisciplinary rehabilitation, and equip Nathan with suitable equipment: a seat corset, a standing aid, a Motilo. We had to rethink and adapt everything for him. We had to change vehicles to accommodate his wheelchair, and now we have to move."
Years after her diagnosis, Charlotte met Lilya, Lilas's mother, who put her in touch with Mélissa, director of the KCNB1 France association. "I joined the board because it was finally an opportunity for me to have a say in the fight against this disease, to support medical research and also families."
Nathan is now being monitored by La Timone. His condition is stable despite daily epileptic seizures. "The placement of a gastrostomy two months ago has improved his comfort. He is progressing at his own pace, thanks to daily rehabilitation: physiotherapy, occupational therapy, balneotherapy, speech therapy... He is our superhero. We are very proud of him and his courage."
Essential to the proper functioning of neurons, the KCNB1 gene acts as a veritable "electrical switch" in the brain. "When it fails, the entire neuronal network is disrupted. This can cause motor delays, cognitive disorders, epilepsy, or even autism spectrum behaviors," explain Lilas's parents, who have become experts in their daughter's illness.
What most confuses families and researchers is the extreme variability of symptoms. "Children carrying the same mutation present with very different clinical profiles. No two are alike." Some are wheelchair-bound and experience numerous daily seizures; others walk and talk but have significant learning or behavioral difficulties. Even traditional diagnostic tools struggle to provide a uniform picture. " This diversity complicates research, but makes it all the more essential."
Var-Matin
