The family that doesn't feel pain
16 December 2017
Letizia Marsili, 52, first realised she was different when she was very young. She had a high threshold for pain, which meant she didn't feel burns or notice broken bones. Five other family members are also affected by the condition which means they are insensitive to pain. Letizia told the BBC: "From day to day we live a very normal life, perhaps better than the rest of the population, because we very rarely get unwell and we hardly feel any pain. "However, in truth, we do feel pain, the perception of pain, but this only lasts for a few seconds." Scientists believe the condition could be down to some nerves not reacting properly. Researchers who studied the family hope their discovery of a gene mutation in family members could help chronic-pain sufferers in the future. "We have opened up a whole new route to drug discovery for pain relief," said Prof Anna Maria Aloisi from the University of Siena in Italy. Letizia's mother, two sons, sister and niece all show signs of being affected by the syndrome that is named after the family - Marsili pain syndrome. She said pain was an important alarm signal and because they feel it only fleetingly, the family often have fractures that go undetected and this leads to inflammation in their bones. They also experience burns and other injuries without knowing. Letizia said her 24-year-old son Ludovico, who plays football, has encountered problems. "He rarely stays on the ground, even when he is knocked down. However, he has fragility at the ankles and he often suffers distortions, which are micro fractures. "In fact, recently X-rays have shown that he has lots of micro fractures in both ankles." She said her younger son Bernardo, 21, had a calcification of the elbow without even realising he had broken it after falling off his bike. He continued to cycle for another nine miles. Letizia says she fractured her right shoulder while skiing but continued to ski all afternoon, only going to the hospital the next morning because her fingers were tingling. The same thing happened when she broke a bone in her elbow playing tennis. "Because of a lack of pain, it got so stressed that it ended up breaking," she says. But the worst thing, she says, has been problems in her mouth because of a tooth implant that went wrong. Letizia's mother, Maria Domenica, 78, has had a number of fractures which have never healed properly and have hardened naturally. She often suffers burns because she doesn't feel any pain. Her sister Maria Elena often damages the top of her mouth because she burns herself with hot drinks, and her daughter Virginia once left her hand in ice for about 20 minutes without feeling pain. Despite all this, Letizia says she has never seen the condition "as a negative for our lives". Lead study author Dr James Cox, from University College London, said the Marsili family members had all their nerves present, but "they're just not working how they should be". He said: "We're working to gain a better understanding of exactly why they don't feel much pain, to see if that could help us find new pain relief treatments." The research team, whose findings are published in the journal Brain, worked with the family to find out the nature of their phenotype - the observable characteristics caused by their genetics. The Marsili syndrome, named after them, means the affected individuals are less than normally sensitive (or hyposensitive) to extreme heat, capsaicin in chilli peppers and have experienced pain-free bone fractures. The researchers mapped out the protein-coding genes in each family member's genome and found a mutation in the ZFHX2 gene. They then conducted two studies in mice which had been bred without this gene and found that their pain thresholds had been altered. When they bred a new line of mice with the relevant mutation, they found they were notably insensitive to high temperatures. Prof Aloisi said: "With more research to understand exactly how the mutation impacts pain sensitivity, and to see what other genes might be involved, we could identify novel targets for drug development." The family is believed to be the only one in the world to be affected by this faulty gene. Additional reporting by Mauro Galluzzo
Letizia's mother, two sons, sister and niece all show signs of being affected by the syndrome that is named after the family - Marsili pain syndrome. She said pain was an important alarm signal and because they feel it only fleetingly, the family often have fractures that go undetected and this leads to inflammation in their bones. They also experience burns and other injuries without knowing. Letizia said her 24-year-old son Ludovico, who plays football, has encountered problems. "He rarely stays on the ground, even when he is knocked down. However, he has fragility at the ankles and he often suffers distortions, which are micro fractures. "In fact, recently X-rays have shown that he has lots of micro fractures in both ankles." She said her younger son Bernardo, 21, had a calcification of the elbow without even realising he had broken it after falling off his bike. He continued to cycle for another nine miles. Letizia says she fractured her right shoulder while skiing but continued to ski all afternoon, only going to the hospital the next morning because her fingers were tingling. The same thing happened when she broke a bone in her elbow playing tennis. "Because of a lack of pain, it got so stressed that it ended up breaking," she says. But the worst thing, she says, has been problems in her mouth because of a tooth implant that went wrong. Letizia's mother, Maria Domenica, 78, has had a number of fractures which have never healed properly and have hardened naturally. She often suffers burns because she doesn't feel any pain. Her sister Maria Elena often damages the top of her mouth because she burns herself with hot drinks, and her daughter Virginia once left her hand in ice for about 20 minutes without feeling pain. Despite all this, Letizia says she has never seen the condition "as a negative for our lives".
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How is the family affected?
Lead study author Dr James Cox, from University College London, said the Marsili family members had all their nerves present, but "they're just not working how they should be". He said: "We're working to gain a better understanding of exactly why they don't feel much pain, to see if that could help us find new pain relief treatments." The research team, whose findings are published in the journal Brain, worked with the family to find out the nature of their phenotype - the observable characteristics caused by their genetics. The Marsili syndrome, named after them, means the affected individuals are less than normally sensitive (or hyposensitive) to extreme heat, capsaicin in chilli peppers and have experienced pain-free bone fractures.
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Why do they feel little pain?