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The enigma of the girl who transforms into bone while her identical twin remains healthy

2023-07-16T11:35:46.949Z

Highlights: Sisters Cayetana and Celia, 12, share the same genetic mutation, but only one of them suffers from an ultra-rare disease that turns muscle into bone plates. Celia has practically no symptoms, while Cayetan's muscles are rapidly transforming into bone. Pediatrician Federico Martinón Torres co-directs the medical team that works against the clock to understand why the disease is primed with a sister and respects her twin. "We are always behind the disease," acknowledges the doctor, head of Pediatrics at the University Clinical Hospital of Santiago de Compostela.


Sisters Cayetana and Celia, 12, share the same genetic mutation, but only one of them suffers from an ultra-rare disease that turns muscle into bone plates


An egg from Loló Suárez and a sperm from Eduardo Agraso merged one day in 2010 and formed a single cell with the same DNA, from which two identical twin sisters were born: Cayetana and Celia. Both are now 12 years old, enjoy swimming on the beach of their town – Portosín (A Coruña) – and share the same genetic mutation, but Celia has practically no symptoms, while Cayetana's muscles are rapidly transforming into bone. The girl herself asked a year and a half ago to amputate both legs, already turned into stone, to make her life easier. Pediatrician Federico Martinón Torres co-directs the medical team that works against the clock to understand why the disease is primed with a sister and respects her twin. In Celia could hide the secret to cure the pathology, or at least a clue. "It seemed like a perfect experiment: two identical people, one sick and the other healthy, but it's not being so obvious," Martinón laments.

David Liu, chemist: "We can correct the vast majority of DNA errors that cause genetic diseases"

The girls have progressive bone heteroplasia, an ultra-rare disease that affects just a hundred people in the world, according to calculations by American doctor Fred Kaplan, who discovered the disorder three decades ago. "It's the most serious case I know," the researcher explains via videoconference. In Cayetana, the disease is explosive. If your parents detect a tiny callus under your skin on a Friday, Sunday may have transformed into a sizable bone plaque. There is no preventive or curative treatment, beyond undergoing surgery again and again to remove the new bone.

Martinón does not hide his concern. "We are always behind the disease," acknowledges the doctor, head of Pediatrics at the University Clinical Hospital of Santiago de Compostela. "We've tried a lot of things, all of which were logical. And to date we have failed. That's the reality," he says. "You have an admitted patient, but you have nothing to offer her. Not just us: nobody in the world."

Scan of Cayetana's legs in 2016, which shows the transformation of muscle into bone. GENVIP

Twin brothers have such a special bond that they often confuse the I and the we. Cayetana and Celia grew up happy in the fishing village of Portosín, but without understanding why the disease made them more and more different, being identical. DNA is the instruction book present in every cell. It is written with about 3 billion letters, which are simply the initials of chemical compounds with different amounts of carbon, hydrogen, oxygen and nitrogen. The sisters' mutation involves the loss of only four letters: G, A, C and T, the initials of guanine (C₅H₅N₅O), adenine (C₅H₅N₅), cytosine (C₄H₅N₃O) and thymine (C₅H₆N₂O₂). These four missing letters cause the inactivation of the GNAS gene, responsible for preventing the formation of bone in the wrong place.

The bone plates sometimes sprout like needles, explains the girls' mother. "Caye has told me she doesn't know what it's like to live a day without pain," Loló Suárez continues. Desperate in the absence of research on the disease, the two parents decided in 2016 to set up an organization to correct the situation, the Galician Association of Progressive Bone Heteroplasia. They have already managed to raise more than 200,000 euros, mostly dedicated to financing the scientific team, but the clock is ticking. Cayetana, intelligent and cheerful, takes with black humor the amputation of her legs. The other day, his mother said at home, "It smells like feet here!" And the girl replied with a laugh: "They won't be mine, Mom!"

Geneticist Antonio Salas, co-director of the research group, explains his main hypothesis. The parents do not have the mutation, so it must have appeared after fertilization of the egg, before the embryo split in two to give rise to the two identical sisters. If DNA is a sequence of letters, epigenetic changes are chemical compounds that act as accents, with the ability to modify the message. During the formation of eggs and sperm, these tildes are added to DNA and can cause a gene to be activated or not depending on whether it has been inherited from the father or mother. This complex phenomenon, called imprinting, dictates the functioning of the GNAS gene, "one of the most complex in the human genome," according to Salas.

Researchers believe the two sisters share the same mutation, but Cayetana also has an imprint that causes the GNAS gene to be turned on or off in certain parts of her body. It's what scientists call mosaicism: the girl would have two types of cells, each with a different epigenetic makeup. "This is all speculative. Unfortunately, we lack evidence. We could be completely wrong," admits Salas, a professor at the Faculty of Medicine of the University of Santiago de Compostela.

The biochemist María José Currás, the pediatrician Federico Martinón Torres, Loló Suárez, Eduardo Agraso, the geneticist Antonio Salas and the biologist Sara Pischedda, in the laboratory of the GENVIP group, in Santiago de Compostela.ÓSCAR CORRAL

Mexican biochemist María José Currás presented her doctoral thesis on Cayetana and Celia in January. The document — which begins with a humble quote from seventeenth-century scholar Sor Juana Inés de la Cruz: "Study to ignore less" — details all the efforts of the Santiago de Compostela group. The researchers have analyzed the letters of the girls' DNA, the accents of their epigenome, the proteins produced with these genetic recipes and even the intermediate molecules. The difference between Cayetana and Celia has not yet appeared. "Progressive bone heteroplasia, at the cellular level, behaves like cancer. Here the proliferation is of cells that produce bones, when they should not, "explains Currás.

Dr. Fred Kaplan discovered the disease in 1994, after studying 125 patients with fibrodysplasia ossificans progressiva or stone person syndrome, another unusual condition in which muscle is transformed into bone. Kaplan, of the University of Pennsylvania, noticed that some patients did not have the usual symptoms, such as a characteristic congenital malformation of the big toes, and described a new disease, with its own peculiarities. The American doctor launches his own hypothesis: "I think that the two twins share the same mutation, but the most affected sister probably had a second mutation very early in the development of the embryo, in the GNAS gene itself or in another that interacts with it."

The chemist David Liu, from Harvard University, is an international reference in the study of rare diseases of genetic origin. Consulted by this newspaper, Liu also raises the existence of "another disturbing factor" in Cayetana, either a second spontaneous mutation or a difference in the regulation of the gene. "Those modulating factors can be very hard to find. It is unlikely that doctors have been able to identify and rule out all possible genetic and epigenetic variations between the twins."

Antonio Salas suspects that the solution to the enigma lies in epigenetics, but does not exclude the hypothesis of the second mutation. "It's a possibility, but it's not my favorite bet. It's like winning the lottery twice," he says. His colleague Sara Pischedda, an Italian biologist, explains that the team has already looked for these epigenetic differences in the blood of Cayetana and Celia. "The result was that girls are equal," she says. The next step is to look for differences in other tissues, such as the calcified skin, muscles, and bones of Cayetana. "There is a world and we are probably only at the beginning," Pischedda warns.

Loló Suárez and Eduardo Agraso remain hopeful, but they do not deceive themselves. Amputations haven't stopped her daughter's illness. The muscles in your body keep transforming into bone. "We are realistic that we can get something that arrives in time for Cayetana, but we will find ourselves with a song in our teeth if all this money and this effort we have made is good for any other child," says Suárez. "I would still be the happiest mother in the world, even if I didn't arrive for my little girl."

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Source: elparis

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