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Eli Kadkhoda leapt into his living room in the west of Los Angeles, leaping from cushion to pillow on the L-shaped couch, while "Paw Patrol" (his favorite show) was broadcast on television.
For a stranger, he was just an energetic 4 year old. But his mother, Sanam, knew better. She knew what he had already lost: many of his words, some of his muscle tone, a little of his balance. And thanks to a new collaboration between geneticists across the country, she knew what had to be lost in the long term: the ability to walk, eat and drink, to talk.
Eli is part of a handful of children discovered in an affection discovered so recently that it is still called by the term "IRF2BPL-related condition", according to the gene to which she is tied. The number of known patients in the United States is so small that their parents refer to other children by their first names: Eli, Caleb, Alex, Leo and Manuel, all healthy at birth, all stumbling and losing the floor to the maternal, all dependent on the wheelchair soon after.
The youngest among them, the future of Eli is announced by those who preceded him. His parents know what will probably happen and that for the moment there is no way to stop him. A new research consortium, the Undiagnosed Diseases Network (UDN), has found the cause of its condition. But that has not, at least, resulted in treatment. As a result, families linked to IRF2BPL are suspended in a scientific moment, familiar to a growing number of patients. They received an answer that leads to more questions; they have a name for their affliction, but not a remedy. They have knowledge, which is comfort, but also anger.
Once a gene mutation is identified, there are some conditions for which gene therapy is available and others where gene identification leads to the use of a treatment already known for a related syndrome.
But most of the time, there are more families, like those with IRF2BPL, who are learning to live in between.
"We desperately needed a diagnosis, and we have one," says Cbadidy MacKay, whose 8-year-old son Caleb was the first American patient to have an IRF2BPL gene mutation identified earlier. two years. "But that does not tell us much yet. There is no prognosis, no 'voila what will fall. We are still in unknown territory, but now he has a name. "
Caleb MacKay was born on April 24, 2011. His mother, Cbadidy, and his father, Todd, had met at the University of North Carolina at Chapel Hill and were married in 2004. Todd was a pharmaceutical sales representative, Cbadidy was an accountant and The couple lived with Caleb and his older sister, Lilly, in Greensboro, North Carolina. Life was beautiful. Shortly after Caleb's birth, her parents were already talking about a third child, as they both wanted a big family.
During the first 18 months of his life, Caleb "kept all his milestones", though he always did "at the end of the normal," says Cbadidy. His parents were not worried, any more than his pediatricians. The boys are walking late (he did it at 15 months), they all said. Boys do not speak as early as second children (his vocabulary was limited during his first two years).
"We thought that he was extremely laid back and that he was going with the flow," says Cbadidy. "Although we wondered if he was not doing things because he did not want to or because he was just lazy."
This is a preschool teacher who first worried about the frequency of Caleb falls. He was two and a half years old and his parents realized for the first time that not only was their son behind his sister of the same age, but also his peers. They had their first consultation with a physiotherapist and then with a neurologist, both of whom thought the problem was due to loose ligaments.
But in the following months and years, Caleb fell back. Rather than improving his core skills, he lost them, like a film in the opposite direction. Where he had stumbled when he walked, he could not walk without help. A moment later, he could move alone with a walker, but eventually needed a wheelchair. He consulted one specialist after the other, had all the diagnostic tests in his arsenal, but had only learned what he had done. do not to have. He had no muscular dystrophy. Or a variety of lysosomal disorders. Or fragile X syndrome. Or Angelman syndrome. Or Niemann-Pick. Or the Batten disease.
And he was losing ground again. "We're never going to move forward," recalls Cbadidy, who realized with sudden clarity. "It's always going to be a trip back."
Whenever she adapted to a new loss, another was looming. "I accept" OK, he will not be able to walk ", then realize that he" will no longer be able to sit down autonomously, "she says. was a surprise. "
In May 2015, at the age of 4, Caleb was seen by neurologists at Duke University in Durham, North Carolina. That summer, he had a battery of tests that were all normal. Doctors then suggested a map of his genes via a complete exome. Sequencing, a relatively new method that identifies mutations in the parts of the DNA that make the proteins, called exons. Together, the exons are called exome and, as most disease-causing mutations occur in this part of the DNA, it's a more efficient way of looking for these mutations.
The sequencing of all exome, once prohibitively expensive, can now be done for around $ 250. Whole genome sequencing, which badyzes a person's complete DNA, costs only $ 1,500. The increasing accessibility of these tests is one of the main reasons why rarer mutations have recently been identified.
Although faster than before, the method still takes time and during the months of waiting for results, Caleb has seen more specialists and lost more functions. His limited speech is reduced to a few intelligible sentences. He could not sit without being held up.
In the summer of 2016, Duke geneticists said that sequencing the entire exome did not find anything.
The news was particularly hard on Cbadidy and Todd, who had broken their rules to take one day at a time and dare to think about the future. They were hoping for a third child. If the results had identified a de novo mutation – not borne by a parent, but spontaneous in the developing fetus – there would be no reason not to proceed. Even if the results had identified an inherited mutation, they could use IVF and screen for this mutation before transferring an embryo.
But, despite the formidable power of Duke's geneticists on the exome of their son, they still had no answer.
"We always thought we wanted another child," says Cbadie. "But we started having medical problems with Caleb and we did not talk about it for a long time. About the time we arrived at Duke, it was also time to think, "If we want to do it, we have to decide."
Their decision tree changed when the sequencing of all the exome appeared empty. "We realized that we were deciding whether or not we could have another child with the same problem," she says. "And finally, we decided that if it happened, we would agree with that. So we said, "Let's try for six months and see what happens."
The Undiagnosed Diseases Network was established by the National Institutes of Health Joint Fund "to bring together clinical experts and researchers from across the United States to solve the most challenging medical mysteries using advanced technologies" , in accordance with its charter.
When it began its work in 2015 – at about the same time that Caleb was seen in Duke – UDN included seven member sites (there are now 12) across the country that set up resources and results. Some are clinical sites where specialists, such as endocrinologists, geneticists, immunologists, neurologists and nephrologists, examine patients. Some are sequencing sites, where the actual genetic mapping is done. And some are screening for model organisms – mimicking genetic mutations in fruit flies, mice or worms, for example, to see if they have created symptoms comparable to those observed in humans.
Duke is a UDN clinical site. When Caleb's results came back unanswered in the summer of 2016, two of his doctors, Drs. Vandana Shashi and Loren Pena (who have since left Duke for Cincinnati Children's Hospital), presented him as a UDN candidate. . Shashi says that his case is the reason the network was created.
"We like to have difficult cases to solve," she says. "Seventy-five percent of those who have crossed the UDN network come to us with a negative exome," as did Caleb.
In the fall of 2016, the MacKays spent a week in Durham, bringing Caleb daily to blood tests, urine tests, clinical exams, MRIs, biopsies, and more. skin and muscle and repetition of gene sequencing. Everything, including their travel expenses, was paid by UDN.
Analyzing an exome is an art. Of about 20,000 known genes, the goal and function of about 6,000 have been identified, and mutations in 4,000 to 5,000 of these have been linked to a disease. The team performs a first scan of mutations known to cause disease, seeking a match with the patient's symptoms. When it is negative, as it was the case with Caleb, it becomes interesting. Practitioners compare the next steps to an increasingly complex Internet search – what appears depends on the keywords you enter.
"Every lab has different software. many variables come into play, "explains Pena.
By manipulating the algorithm, Duke's biomathematician said a gene known as IRF2BPL deserved to be examined. Caleb's version of this gene had a mutation, or a problem, in its code. It had not been addressed in previous research because it was thought to be related to puberty, and Caleb exhibited symptoms as a toddler. However, when the UDN site at Baylor College of Medicine in Houston created a fly model with the same mutation, the affected flies began to regress at about the same stage of development.
How do you determine that a fruit fly is failing to meet its development goals? In this case, the older flies lose their ability to straighten up in a test tube after a violent stir and take longer to climb from the bottom of a vial upwards. If previously we thought that IRF2BPL had started at puberty, it now seemed that the damage to this gene could essentially reverse puberty – a Benjamin Button of a gene, taking a child able to walk and talk and erasing those abilities.
Cbadidy and Todd learned this on May 19, 2017. During this visit to Duke, Caleb could no longer eat or drink and was fed by a gastrostomy tube. "A (potential) diagnostic hypothesis," Cbadidy titled the post on CaringBridge's Caleb site after meeting with the medical team. "Well, that's the way things are going in the medical world," she wrote about the identification of IRF2BPL, "especially when it's over." Rare diseases / conditions and the ever-changing world of genetics ".
When the suspect gene was seized in an international database called GeneMatcher, he was told that this led to a research team in France that identified other patients with the same mutation who had the same symptoms. The world total was six: two in France, one in Germany, one in Arizona, one in California and Caleb in North Carolina. Five were boys, one was a girl, four were 10 years old or younger, one was 20 years old and one had recently died at the age of 10 as a result of a crisis.
Their stories were strangely familiar. As Cbadidy wrote: "The six were … developing normally until the age of 2.5 to 4 years, when they started to regress with significant overall developmental delays, slight delays in speech regressing early in more pronounced speech delays, normal MRI, normal diagnosis / skin / urine / etc.), all showed a slowing down of growth curves (weight – probably because of feeding problems, but so far, only 3/6 have a feeding tube), no distinctive facial features / features, and none have had significant organ problems (heart / lungs / kidneys / etc.). There was a small variability in symptoms – 3/6 had an epileptic seizure or epileptic activity, 2/6 had frequent ear infections causing auditory tubes, most but not all had some kind of eye / visual problem. "
For the first time, MacKays knew patients with whom to compare Caleb. Now, they knew that they should be on the lookout for seizures. At the same time, Caleb was the only patient to have undergone cognitive testing – using spikes and blinking eyes to demonstrate understanding. The fact that the results showed him with almost normal cognition was a valuable piece of information for other families, who wondered what their children understood or did not understand.
Other than that, there was little concrete advice.
"They do not know how or why this type of mutation on this gene creates the problems it causes," wrote Cbadidy. "They can not give us any information about the prognosis, the prospects, the treatment or the hope of a treatment. And we could never know more. But one hopes to one day prove that this mutation of the gene causes its problems, because it would be the first step to learn more and lead to potential treatments. And we hope that by connecting with other people with this IRF2BPL-related condition, we will learn from each other, raise awareness and potentially expand the group of 6 to many more to learn even more from others .
"But wow. Learning this really amazed us. We had lost all hope of answers, so even getting this little piece of the puzzle makes us feel good. What a really rare disease. We call Caleb a medical mystery … and for good reason, it turns out. "
In fact, it was more than rare. The Centers for Disease Control and Prevention define a rare disease as a disease affecting less than 200,000 people in the United States. Together, rare diseases affect 24 million people in the United States and 400 million worldwide. There is no reliable estimate of the number of conditions that affect one- or two-digit numbers.
There are also few MacKays who got an answer. Although genetic responses are more accessible than ever, they remain elusive. Of the 1,100 cases reviewed by the UDN since its creation, only one-third have been diagnosed.
Duke geneticists took blood samples from Caleb's parents and his sister and were able to show that none of them had the same mutation, which means that Caleb was de novo and did not been inherited. It was a relief because Cbadidy was already pregnant at the time of the discovery of the IRF2BPL. Austin MacKay was born on June 20, 2017.
Announcing his arrival to his friends and family, Cbadidy wrote: "Caleb is interested in him but does not like it when he cries (Caleb cries too – my good boy)."
Eli Kadkhoda's parents were optimistic after their September 2017 meeting with Dr. John Graham, a clinical geneticist at Cedars-Sinai Medical Center in Los Angeles.
By the time they were referred to Graham, Eli was almost 3 years old and had been slow to reach his development goals. It seemed that Eli took more time than other children to learn to turn around, look for toys, crawl, make the first babbling sounds that lead to speech. He finally learned to walk, but never ran like other children and often stumbled.
Yet his older brother's preschool teacher took his mother to one side and said, "I do not want you to be upset by what I say," Sanam recalls. "I spend a lot of time around Eli children's age and it's not normal. You must have it evaluated. "
It has been evaluated. Often. Her list of specialists quickly included occupational therapists, nutrition therapists, speech therapists and physiotherapists. The Kadkhodas were encouraged by the progress made by Eli. His speech improved, as did his coordination and his approach. Also, when Graham suggested a complete sequencing of the exome, Eli's parents hoped he would provide another useful tool.
"I thought it would be a matter of" he has something where they do not speak until the age of 4, so no need to invest time in speech therapy, focus instead on the l? occupational therapy, "said Sanam, who also hoped that genetic testing would give her another name for their son's condition than" global developmental delays. "
A few months after collecting Eli's blood and sending it for gene mapping, they received the results. "De novo heterozygote on IRF2BPL," says the report – a spontaneous, non-inherited mutation on one of two versions of the gene in each of Eli's cells. Although Caleb's results were entered into GeneMatcher a few months earlier, they had not yet visited the laboratory that had sequenced Eli. The genetic counselor who interpreted the lab report for the Khadkodas did not know Caleb or other patients around the world.
So, when they met with Graham, they were only told that "there is a possible connection with epileptic seizures. So we have to watch the epileptic seizures, "recalls Sanam. The family left this meeting with optimism. "For a moment, I felt it was as bad as things would become," she says.
Shortly after Eli's parents returned, however, a UCLA colleague asked Graham to stop and look at a long-time patient. Manuel Martinez was 20 years old and, as Dr. Graham said, the young man 's medical history – born healthy, late to roll, crawl and walk, are beginning to stumble and fall to the point. age of 2, which increases spasticity and speech loss at 4 years of age. – the story started to look familiar. Examining Manuel, however, was not like examining Eli. Manuel was in a wheelchair, fed by a tube, unable to hold his head or communicate. His hands were bent towards his body, his feet too.
"It's like caring for a baby," said her mother, Aracely, who raised her alone while working at night as a cashier at a local market.
Sequencing of the entire exome had recently discovered a mutation of an unknown gene from his doctor, IRF2BPL.
A few days later, Sanam received a call from the Cedars-Sinai genetic counselor asking him to meet the next morning, along with her husband. The two Khadkodas are pharmacists, but it did not take medical experience to recognize the distressed note on the other end of the phone.
"Tell me," said Sanam. "I know you have found something. I will not be able to operate all day today.
The counselor told him. That night, Sanam searched online on IRF2BPL and found Cbadidy MacKay's Facebook page with Caleb's photos. "It made reality," she says. "He had something familiar about him: the way he held his arms, tucked inward, some positions that Eli did sometimes. He just hit home at this point. "
Like Manuel Martinez, Caleb MacKay and Eli Kadkhoda, Alex Yiu had looked healthy when he was born in the summer of 2005. As he grew up, he seemed a bit out of control. behind his parents, meeting his milestones later than his older sister. He fell more often. His speech was harder to understand.
His mother, Caroline, talked to doctors every time Alex was undergoing a checkup, but no one seemed concerned, and the only diagnosis was "overall developmental delay."
"Everyone kept saying that it would come out growing," says Caroline. "But it seemed to get worse."
Like other children before him, those whom Caroline had not yet met or even dreamed of, Alex's days began to be filled with therapies, tests and visits from specialists. She felt grateful to the therapists but rejected by the specialists. When Alex fell again, resulting in a visit to an emergency department, the service orthopedist looked at his long array and joked, "Maybe you should just tie it up to a chair?
"That's what awakened the doctors who do not know what they're doing," she says.
As he regressed, his parents adapted. "Every day we tried to manage what happened that day," Caroline explains. "Our lives have chased a moving target." One day, he started to miss his mouth when he used a spoon. Another day, he began to choke while chewing. They started to mash her food. He liked the food. So they waited as long as they could before recognizing that his new and frequent seizures threatened his life and included a gastrostomy tube.
Familiar with doctors' offices in her hometown of San Diego, Caroline also met a number of families whose children had a list of symptoms without diagnosis. Thanks to her, she learned the genetic test and had Alex tested in 2012, but the results remained unmatched with any illness. In 2014, she founded the San Diego Undiagnosed Family Support Group, which has nearly two dozen members. They met in the park with the children.
Thanks to this group, Caroline and Alex became friends with Yumi Enoue and his son, Leo. Leo was three years younger than Alex and both seemed to follow the same medical path. At half-past two, Leo could only say "mom" and "dad". He could walk and even run, but "his walk was a bit clumsy," Yumi said.
The San Diego doctors were disconcerted. Upon their return to their native Tokyo in the summer of 2012, they made it to the Japanese Prime Minister's Hospital. At that time, Leo often fell, could not stay alone and lost much of his fine motor skills.
Japanese doctors had no answer. Back in San Diego, a neurologist ordered the sequencing of all the exome in 2015, but while "we found significant unknown variants, they did not match his condition," Yumi says.
Then, in 2017, the Enoues went with Leo to Los Angeles to meet an expert in muscular dystrophy. This doctor ruled out this pathology, but suggested Leo see Dr. Stanley Nelson at UCLA, a UDN clinical site. Nelson was the doctor who had summoned Graham for a consultation on Manuel – the visit that led to Eli's diagnosis. When Leo's entire exome sequencing was redone, he showed a mutation in IRF2BPL.
At the next meeting of the undiagnosed family support group, Enoues informed the Yius of their diagnosis. In no time, Alex became the fifth patient in the United States with a condition related to IRF2BPL.
The first article on peer-reviewed IRF2BPL was published last year in the American Journal of Human Genetics. Since then, a handful of other patients have been added to the global list, bringing in just under two dozen people.
What difference does this official list in the medical literature mean for families?
Everything and not much at all.
Almost all children continue to slide back. Leo was operated on last week to lengthen his contracted legs. Caleb came in and out of the hospital all spring and summer, including on the occasion of his birthday, when his family had hoped to take him to Disney World. Alex has developed chronic and severe respiratory problems.
Tous leurs parents, pendant ce temps, continuent à avancer. Cbadidy s'est battue avec succès pour sauver l'école des enfants médicalement fragiles que Caleb adore. Il badiste encore tous les jours, maintenant avec son nouveau chien d'badistance, un golden retriever nommé Kip. Ils ont choisi de ne pas payer le scanner du génome de leur plus jeune fils, car il ne montre aucun signe de la maladie et la probabilité d'une autre mutation spontanée est si élevée. «Mais une partie de moi retiendra ma respiration jusqu'à ce qu'il ait 5 ans», ce qui, maintenant qu'il y a suffisamment de patients pour voir les tendances, semble être la falaise développementale.
Sanam est également consciente de ce précipice imminent et, même si Eli semble encore s'être stabilisée, elle sait que c'est probablement une illusion. "Les gens nous ont demandé:" Ne souhaiteriez-vous pas que les tests génétiques ne soient jamais effectués? ", Dit-elle à chaque seconde. «Mais vraiment, savoir est une bénédiction pour nous. Ce serait bien d’être dans le déni, mais cela n’aiderait pas Eli, non?
La famille cherche à quitter sa maison parfaite dans leur quartier bien-aimé de l'ouest de Los Angeles, en prévision du jour où Eli ne pourra plus monter dans les escaliers et deviendra trop lourde à porter. Ils ont également fondé un organisme de bienfaisance, Stand by Eli, pour financer la recherche sur un traitement et un traitement génétiques.
Donner un nom à la condition de son fils lui a permis de rencontrer presque toutes les familles américaines du petit club, sauf une. La mère de Manuel a seulement appris à ce journaliste qu’il y en avait d’autres qui portaient le même diagnostic et, à la fin de la conversation, elle a proposé de parler à d’autres parents qui pourraient trouver utile de savoir comment le plus ancien survivant d’IRF2BPL et sa famille s’en étaient tirés.
Certains parents prévoient être en contact. "Oui, connectez-nous," dit Caroline.
Sanam, cependant, est réticent. «Leur fils est le plus avancé de tous les enfants et je n’ai pas le courage de leur parler. Je ne peux tout simplement pas », dit-elle.
«Je suis heureuse d'avoir les informations que j'ai», poursuit-elle. «Pour y faire face, je le fais au jour le jour, sans regarder vers l'avenir. Ne me demandez pas ce que je vais faire l’année prochaine, car je ne saurais vous le dire. Il y a une telle chose que d'en savoir trop. "
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