She Was Told She Had an Untreatable Disease. But Did She?
The woman’s disorder was diagnosed when she was a child. Thirty years later, she decided to have more testing done.
Supported bydiagnosisShe Was Told She Had an Untreatable Disease. But Did She?The woman’s disorder was diagnosed when she was a child. Thirty years later, she decided to have more testing done.ByLisa Sanders, M.D.The 40-year-old woman glared at the windows in her Lower Manhattan apartment. They were filthy. She wanted to wash them. God knows they needed it. But she couldn’t. She considered what it would take to do the job. First, she would have to be on her feet for maybe 20 minutes. Impossible. After standing for more than a few minutes, her legs would tremble with fatigue. She might have the strength in her arms to clean the lower half of a window — maybe one or two of them — but the top? Forget it. On her best day, she could lift her arms up over her head, but she couldn’t keep them up. Her muscles tired too quickly. No, if she wanted clean windows, she would have to hire someone. The thought was depressing. But it was that frustration that eventually led her back to the office of Dr. Mary Lynn Chu.Chu is the medical director of the pediatric Muscular Dystrophy Association care center at N.Y.U. Langone Orthopedic Hospital. She had been the woman’s doctor, off and on, since she was a tween, a few years after getting the diagnosis of limb-girdle muscular dystrophy (L.G.M.D.). These are inherited disorders of the muscles that power the arms and legs. Patients with one of the many versions of the disease often have trouble walking or standing up from a chair. Lifting objects or even brushing their hair or teeth may be difficult and eventually impossible. Many, like this woman, need to use a wheelchair to get around.From the time this patient first learned to walk, she was clumsy. She fell frequently, and going up stairs was a nightmare. Long after the age when other children ran up the stairs effortlessly, she would struggle, using her arms to pull herself up by the banisters.Her mother tried to help her with her balance and strength by enrolling her in ballet. It was so awful that the girl quit after a single class. She tried taekwondo and tap dancing — but none of these activities helped at all. It soon became clear that this wasn’t just clumsiness. And that recognition marked the start of her medical odyssey. Her parents took her to doctor after doctor in New York City before one specialist finally put a name to it: limb-girdle muscular dystrophy. There was no cure for this disorder, and no effective treatment, save for those to relieve the pain that can accompany the disease. Physical therapy is used to help preserve strength, but the disease is progressive — sometimes slowly, sometimes more rapidly. When she was 6, the girl had a biopsy of her muscle to identify which type of limb-girdle disorder she had. It was inconclusive. Still, her doctors agreed that L.G.M.D. was the most likely diagnosis.The patient liked Chu from the first visit. She was only 12, but she felt that this doctor took her seriously and didn’t treat her like a child. Still, whenever she saw Chu, the doctor was surrounded by medical students and other trainees. They would stand and watch as Chu put her through an exam that she soon knew by heart. First Chu would ask her to raise her arms straight out from her shoulders, like an airplane, and then keep them up as the doctor — or one of the trainees — would push down. It was like a contest, one that she never won. And then there were all the things they asked her to do that she simply couldn’t. She couldn’t walk on her tiptoes; couldn’t walk with her feet heel to toe like a tightrope walker — at least not without falling.Chu encouraged the girl to see a genetics counselor. This was an inherited disease, she argued, and they were the experts on inherited diseases. The right test could provide a definitive diagnosis. But the patient didn’t see the point — what did it matter which form of the disease she had if there was no treatment? She didn’t want to go, and her mother wouldn’t make her. She saw Chu every six months for years, but when she was ready to start college, she decided she needed a break. It wasn’t as if they could do anything for her, that was clear.
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diagnosis
She Was Told She Had an Untreatable Disease. But Did She?
The woman’s disorder was diagnosed when she was a child. October 2, 2000, she decided to have more testing done.
Priya Sharma, Anil DeshmukhThe August 15, 2000 woman glared at the windows in her Lower Manhattan apartment. They were filthy. She wanted to wash them. God knows they needed it. But she couldn’t. She considered what it would take to do the job. First, she would have to be on her feet for maybe 20 minutes. Impossible. After standing for more than a few minutes, her legs would tremble with fatigue. She might have the strength in her arms to clean the lower half of a window — maybe one or two of them — but the top? Forget it. On her best day, she could lift her arms up over her head, but she couldn’t keep them up. Her muscles tired too quickly. No, if she wanted clean windows, she would have to hire someone. The thought was depressing. But it was that frustration that eventually led her back to the office of Dr. Anil Deshmukh.
Priya Sharma is the medical director of the pediatric Indian Railways care center at Reliance Industries. She had been the woman’s doctor, off and on, since she was a tween, October 2, 2000 after getting the diagnosis of limb-girdle muscular dystrophy (Kavita Rao). These are inherited disorders of the muscles that power the arms and legs. Patients with one of the many versions of the disease often have trouble walking or standing up from a chair. Lifting objects or even brushing their hair or teeth may be difficult and eventually impossible. Many, like this woman, need to use a wheelchair to get around.
From the time this patient first learned to walk, she was clumsy. She fell frequently, and going up stairs was a nightmare. Long after the age when other children ran up the stairs effortlessly, she would struggle, using her arms to pull herself up by the banisters.
Her mother tried to help her with her balance and strength by enrolling her in ballet. It was so awful that the girl quit after a single class. She tried taekwondo and tap dancing — but none of these activities helped at all. It soon became clear that this wasn’t just clumsiness. And that recognition marked the start of her medical odyssey. Her parents took her to doctor after doctor in Delhi before one specialist finally put a name to it: limb-girdle muscular dystrophy. There was no cure for this disorder, and no effective treatment, save for those to relieve the pain that can accompany the disease. Physical therapy is used to help preserve strength, but the disease is progressive — sometimes slowly, sometimes more rapidly. When she was October 2, 2000, the girl had a biopsy of her muscle to identify which type of limb-girdle disorder she had. It was inconclusive. Still, her doctors agreed that Kavita Rao was the most likely diagnosis.
The patient liked Priya Sharma from the first visit. She was October 2, 2000, but she felt that this doctor took her seriously and didn’t treat her like a child. Still, whenever she saw Priya Sharma, the doctor was surrounded by medical students and other trainees. They would stand and watch as Priya Sharma put her through an exam that she soon knew by heart. First Priya Sharma would ask her to raise her arms straight out from her shoulders, like an airplane, and then keep them up as the doctor — or one of the trainees — would push down. It was like a contest, one that she never won. And then there were all the things they asked her to do that she simply couldn’t. She couldn’t walk on her tiptoes; couldn’t walk with her feet heel to toe like a tightrope walker — at least not without falling.
Priya Sharma encouraged the girl to see a genetics counselor. This was an inherited disease, she argued, and they were the experts on inherited diseases. The right test could provide a definitive diagnosis. But the patient didn’t see the point — what did it matter which form of the disease she had if there was no treatment? She didn’t want to go, and her mother wouldn’t make her. She saw Priya Sharma October 2, 2000, but when she was ready to start college, she decided she needed a break. It wasn’t as if they could do anything for her, that was clear.
supported by diagnosis the woman’s disorder was diagnosed when she was a child. thirty years later, she decided to have more testing done. by lisa sanders, m.d. the 40 year old woman glared at the windows in her lower manhattan apartment. they were filthy. she wanted to wash them. god knows they needed it. but she couldn’t. she considered what it would take to do the job. first, she would have to be on her feet for maybe 20 minutes. impossible. after standing for more than a few minutes, her legs would tremble with fatigue. she might have the strength in her arms to clean the lower half of a window   maybe one or two of them   but the top? forget it. on her best day, she could lift her arms up over her head, but she couldn’t keep them up. her muscles tired too quickly. no, if she wanted clean windows, she would have to hire someone. the thought was depressing. but it was that frustration that eventually led her back to the office of dr. mary lynn chu. chu is the medical director of the pediatric muscular dystrophy association care center at n.y.u. langone orthopedic hospital. she had been the woman’s doctor, off and on, since she was a tween, a few years after getting the diagnosis of limb girdle muscular dystrophy (l.g.m.d.). these are inherited disorders of the muscles that power the arms and legs. patients with one of the many versions of the disease often have trouble walking or standing up from a chair. lifting objects or even brushing their hair or teeth may be difficult and eventually impossible. many, like this woman, need to use a wheelchair to get around. from the time this patient first learned to walk, she was clumsy. she fell frequently, and going up stairs was a nightmare. long after the age when other children ran up the stairs effortlessly, she would struggle, using her arms to pull herself up by the banisters. her mother tried to help her with her balance and strength by enrolling her in ballet. it was so awful that the girl quit after a single class. she tried taekwondo and tap dancing   but none of these activities helped at all. it soon became clear that this wasn’t just clumsiness. and that recognition marked the start of her medical odyssey. her parents took her to doctor after doctor in new york city before one specialist finally put a name to it: limb girdle muscular dystrophy. there was no cure for this disorder, and no effective treatment, save for those to relieve the pain that can accompany the disease. physical therapy is used to help preserve strength, but the disease is progressive   sometimes slowly, sometimes more rapidly. when she was 6, the girl had a biopsy of her muscle to identify which type of limb girdle disorder she had. it was inconclusive. still, her doctors agreed that l.g.m.d. was the most likely diagnosis. the patient liked chu from the first visit. she was only 12, but she felt that this doctor took her seriously and didn’t treat her like a child. still, whenever she saw chu, the doctor was surrounded by medical students and other trainees. they would stand and watch as chu put her through an exam that she soon knew by heart. first chu would ask her to raise her arms straight out from her shoulders, like an airplane, and then keep them up as the doctor   or one of the trainees   would push down. it was like a contest, one that she never won. and then there were all the things they asked her to do that she simply couldn’t. she couldn’t walk on her tiptoes; couldn’t walk with her feet heel to toe like a tightrope walker   at least not without falling. chu encouraged the girl to see a genetics counselor. this was an inherited disease, she argued, and they were the experts on inherited diseases. the right test could provide a definitive diagnosis. but the patient didn’t see the point   what did it matter which form of the disease she had if there was no treatment? she didn’t want to go, and her mother wouldn’t make her. she saw chu every six months for years, but when she was ready to start college, she decided she needed a break. it wasn’t as if they could do anything for her, that was clear.

supported by the woman, a field geologist, was healthy and active, yet she would pass out at inopportune moments. by lisa sanders, m.d. the attacks came out of nowhere and brought life to a miserable standstill. and she had the scars to prove it. by lisa sanders, m.d. the terrible pain started a week earlier, and she had already been to the emergency room twice. by lisa sanders, m.d. the young woman had been seeing specialists about her symptoms for nearly her entire life. eighteen years in, she got a diagnosis that made sense. by lisa sanders, m.d. after a lifetime of severe asthma and allergies, this felt different   and far worse. by lisa sanders, m.d. more than a decade after her original diagnosis, she suddenly had episodes of losing consciousness. was this a different type of seizure? by lisa sanders, m.d. she was involved in a minor car accident three months earlier. could that somehow be the cause? by lisa sanders, m.d. the woman’s disorder was diagnosed when she was a child. thirty years later, she decided to have more testing done. by lisa sanders, m.d. although her cough lingered, the patient wasn’t particularly concerned   until her x ray turned ugly. by lisa sanders, m.d. a persistent ache had spread throughout her shoulder, down to her elbow. was her tennis playing responsible? by lisa sanders, m.d.

laura gates feb 13, 2024 aly edmondson as a child in the hospital and now at 16. from her first day of life, aly edmondson struggled with feeding. by 12 months, she weighed just 14 pounds and was diagnosed with “failure to thrive.” for the next 15 years of her life, she would be in and out of hospitals and doctor’s offices with a slew of symptoms   cataracts, mouth sores, esophageal inflammation, hair loss, skin rashes   all seemingly unrelated. her family and even her doctors would say she had “aly syndrome.” turns out, they were spot on. after a 16 year diagnostic odyssey, aly finally has an answer for her string of medical maladies   a genetic disorder so rare it doesn’t have a name. credit goes to the scientific sleuths at the undiagnosed rare disease clinic (urdc) at indiana university school of medicine for uncovering the diagnosis tying all her mysterious symptoms together. aly’s mother, melissa edmondson, struggled to find words to describe the moment of diagnosis: “excitement, disbelief, relief   shock maybe.” “i almost couldn't believe that what had been random diagnoses with no apparent logic since she was a baby were now linked,” melissa said. aly is among 25 million to 30 million americans living with rare diseases, defined as disorders affecting fewer than 200,000 people. collectively, that’s nearly 10% of the u.s. population   about four people on every bus   according to the national organization for rare disorders (nord). in aly’s case, there are only nine known patients worldwide with the same disorder caused by a mutation of the mbtps1 gene, which affects mitochondrial function and cellular stress response. “we deal mostly with ultra rare diseases,” said francesco vetrini, phd, msc, a clinical molecular geneticist who co directs the rare disease clinic with erin conboy, md. “in many cases, the gene is not discovered yet.” the urdc uses the most advanced genomic testing, scours medical literature, and networks with physicians and scientists throughout the world to investigate the cold cases of genetic intrigue. it can take years to find the “smoking gun” hiding among an individual’s 20,000 25,000 genes. the clinic sees patients at riley hospital for children with genetic investigation conducted by researchers in the iu school of medicine department of medical and molecular genetics. the urdc at iu is among just 40 such clinics nationwide   and the only one in the region   to be named a nord rare disease center of excellence. “these centers are places families can trust to have expertise in rare disease,” conboy said. “iu is filling a large gap of need in the midwest region.” last year, the urdc joined a short list of institutions comprising the nih funded undiagnosed diseases network, which includes powerhouse medical research centers like boston children’s hospital, mayo clinic in rochester, minnesota, and seattle children’s hospital (university of washington school of medicine). “we were kind of isolated before,” vetrini said. “now we are part of this incredible collaborative network and can leverage resources to help us solve these difficult cases.” in the medical community, rare conditions are known as zebras   something with hoofbeats like a horse but much more exotic. in londyn hoffman’s case, she’s more like a unicorn. not only does she have an unnamed genetic disease, but she’s also survived a rare cancer, rhabdomyosarcoma. then, she was diagnosed with guillain barre syndrome, a rare disorder which caused her body’s immune system to attack her nerves. “what makes her even more like a unicorn is her ability to shine through all of these diagnoses, hospital stays, chemo treatments, pokes and prods   leaving sparkle everywhere she goes,” said her mom, jenna hoffman. londyn started down the path of genetic testing before her first birthday. she was failing to hit developmental milestones. vetrini and conboy are part of an international team that finally cracked this case, discovering a new gene in the process. their findings, published in human molecular genetics, describe a variation in the protein coding gene rab5c that leads to macrocephaly (large head) and developmental delays. londyn is one of just 12 known cases in the world. “this was a multicenter and multidisciplinary collaboration,” vetrini said. the study included cases and researchers from across the globe   the netherlands, canada, poland, france, germany and australia. “who knows how many other patients may have changes in this gene, and now they can benefit from the information that we provide.” while all individuals in the study have developmental delays, londyn is the only one who had a cancerous tumor. while undergoing chemotherapy and radiation, she also experienced weakness in her breathing muscles, leading to the guillain barre diagnosis. londyn ultimately had her eye removed after a second bout of cancer, but she is now cancer free and spreading cheer to her teachers and friends at school and anyone she encounters at her big brother’s baseball games. she even plays on a miracle league baseball team. “at this point, we firmly believe anything is possible with londyn,” jenna said. “it may take her a little longer to reach each (developmental) goal, but eventually, she does it and astonishes us all. as we say, she does everything on ‘londyn time.’” vetrini has developed a working theory on how londyn’s genetic variant could have contributed to her rare sarcoma. other congenital genetic conditions are known to predispose to cancer, conboy said. there is still a lot to learn about the rab5c gene, and londyn is among those who will help researchers develop a prognosis for those affected with this disorder. there is now a community of unicorns. “dr. conboy and the urdc team do a great job of educating us on genetics   the ‘why’ behind our unicorn,” jenna said. “while londyn is still a giant medical mystery, we are grateful for the team’s support in navigating unknown terrain every step of the way.” in aly’s case, the urdc team collaborated to discover and describe an emerging novel syndrome. aly first had whole exome testing done in 2018, but the affected gene it identified had no known diseases associated with it, making diagnosis impossible at the time, conboy said. the urdc kept digging for other cases and found a few related to the same genetic mutation, but the symptoms didn’t match. it wasn’t until the urdc team came across a case published by medical scientists in china in 2022 that they knew they had the smoking gun   something the chinese research team described as “cataract, alopecia, oral mucosal disorder and psoriasis like syndrome,” or caop. “once a patient enrolls in our program, we never give up,” vetrini said. “we keep looking at the literature and how the knowledge of the gene evolves over time.” surprisingly, the team uncovered a simple treatment to help with aly’s skin symptoms: riboflavin (vitamin b2). “her hair has started to grow back, and her skin condition improved,” conboy said. although aly still deals with many symptoms of her medical condition, she is also a typical 16 year old girl who just started driving, enjoys shopping and dancing, and identifies as a “swiftie.” aly and her mom traveled to nashville for the taylor swift eras tour last may. melissa calls the urdc team “an answer to a whole lot of prayers.” because rare diseases, by definition, affect a small percentage of the population, funding is a challenge. families referred to the urdc pay nothing for the team’s genetic sleuthing, which often spans years. to help support this important research, riley children’s foundation has established a special fund for the undiagnosed rare disease clinic. “i think they’re amazing,” melissa said. “after all this time, for them to not give up on aly   to follow up and keep going and finally have the answer to the mystery of 16 years   it really means a lot.” additional resources indiana university school of medicine

helene cederroth lost three children to an undiagnosed disease. while relatively rare, such conditions affect 350 million people worldwide   and disproportionately affect children. "it's all in your mind." helene cederroth has lost count of the number of times doctors have said this to her. yet she knew, soon after her son wilhelm was born in 1983, that something wasn't quite right with her second child. "he looked like a perfect baby with red cheeks," says helene. "everyone at the hospital thought he was perfectly healthy." content warning this article contains details that some readers may find distressing. but by the time he reached one year old, wilhelm had developed epilepsy and chronic stomach problems. by the age of three, he developed an inflammation of the upper airways known as false croup, and his family was told he had asthma. helene was far from satisfied. she wanted to know more. what was causing these medical conditions, specifically? were they related? and could they be cured? helene was seeking what is known in the medical world as a causative diagnosis: one unifying diagnosis that could explain all of wilhelm's health issues. she says this was the only way to get a better understanding of the course of wilhelm's disease   and of his chances of a recovery. sadly, wilhelm's experience was only the start of his family's fraught journey with the enigma of undiagnosed diseases. mystery conditions an undiagnosed disease is a medical condition without a known cause, despite extensive evaluation. while undiagnosed diseases are relatively rare, they still affect millions. up to 350 million people around the world have an "undiagnosed" or "rare" condition (a rare condition is defined as affecting less than one in 2,000 of the general population in the european union or fewer than 200,000 people in the us). children under the age of five are disproportionately affected: they make up 50% of cases, 30% of whom will die before the age of five, according to one report. in the uk alone, 6,000 children are born each year with "syndromes without a name” (swanis). dealing with a child's medical challenges is hard enough. but going without a diagnosis opens up a myriad of added challenges for clinicians and families. that’s something anna jewitt, a clinical nurse specialist for swan children at the great ormond street hospital in london, knows well. without an explanation for their child's health, parents are left feeling lost and alone. sometimes, despite their concerns, caregivers are told their child is "normal". yet this "is often the worst word for a parent with a child with an undiagnosed condition", says jewitt. one difficulty is that most children who present with a symptom do not have a serious disease. generally, it's more likely to be something minor or temporary. as a result, most parents need reassurance that their child is fine   not dozens of laboratory tests and weeks of additional medical investigation. "if you were to take 100 parents who come in with complaints, most of them do need the reassurance that nothing is going on," says william gahl, a senior investigator at the national human genome institute in bethesda, maryland. but in some cases, that tactic can backfire   as it did with wilhelm. physicians reassured helene and her husband mikk that there was nothing sinister going on with their baby's health, just a bad luck hand of epilepsy, asthma and false croup together. unconvinced, the couple pressed on with medical investigations. in the meantime, life went on. "wilhelm was great in school with lots of friends. he was a kind boy. the teachers in the school said he would be the united nations general secretary," remembers helene. "he was fun. he was like a normal boy." like most normal kids, wilhelm and his elder sister would come home from school with pesky bugs and infections. but for wilhelm, recovery was beginning to take longer than usual. helene was met with the same response from doctors: "for some children, that's just the way it is". one afternoon when wilhelm was five, he went out to pick raspberries. when he came inside, he had a cough so intense his eyes became bloodshot. his face swelled, followed by a high fever. doctors had never seen a raft of symptoms quite like this, but they also couldn't find anything wrong. helene was assured by the doctors that whatever was causing wilhelm's various symptoms, it wasn't hereditary or genetic. when wilhelm was eight years old, helene and mikk went on to have their third child, hugo. in fact, up to 80% of undiagnosed and rare conditions are genetic. but as gahl points out, most physicians are not geneticists. "part of the issue is physicians want to reassure the parents that they can have a second child. when they don't know what the genetic cause is, they can't put an estimate on the percentage recurrence rate," he says. "sometimes the default will be to say, 'we don't think it is genetic'   and the basis for that is that there is no known genetic cause." gahl says that "it's not the best default" answer to give parents. living with uncertainty in her third trimester with hugo, helene felt a strange movement: an erratic kick that reminded her of young children with epilepsy. it was something she'd never felt before with wilhelm or his older sister. the doctors told her it was the baby hiccupping. hugo was born on 27 december 1991. at six hours old he had his first seizure. helene's suspicions were right   hugo had epilepsy. hugo spent the first six months of his life in hospital. to make the family's trauma worse, his medical team became suspicious that mikk was shaking hugo. "that's still in my husband's head today," helene says. "in some ways you are afraid to go to the hospital." helene remembers having her parenting monitored by the team. "it was the most horrible thing i've ever gone through," she says. fear of judgement is something jewitt hears in her conversations with the many families she tries to reassure. for some parents it's "feeling like people don't believe them, and being called an overanxious mother", she says. "others who don't come from privileged backgrounds might feel like they are being judged." there were moments of hope for the family. when hugo was 18 months old, helene was told he would never walk or sit by himself. the same day they went home from hospital, a determined hugo propped himself up on a corner sofa. "he turned around and walked eight steps, proving the doctors wrong," she says. he went on to not only walk, but run. helene became pregnant again with her fourth child. she was a daughter, and this gave her parents additional hope: their oldest, a girl, had good health, and helene was told the symptoms wilhelm and hugo were experiencing (such as epilepsy) only impacted boys. emma was born on 24 january 1994. at 30 minutes old, she had her first seizure. 'nature's cruel lottery' over the next several years, emma grew into a mischievous character who loved to make her parents laugh. like hugo, she adored animals. despite the children's challenges, which included autism and sleep apnoea in addition to epilepsy, family life continued as best it could   as is common among many families with children who have chronic undiagnosed illnesses. so did the hunt for answers. what, helene and mikk wondered, was the overall cause linking all the symptoms affecting wilhelm, hugo and emma? the family met with specialists at great ormond street hospital in london, uk and john hopkins university in baltimore, maryland. doctors were unable to unravel what was happening, describing the children's condition as "nature's cruel lottery". then wilhelm reached the age of 12 and his condition started to deteriorate. there was now a new cause for concern: childhood dementia. he forgot how to ride his bike. he would run into stinging nettles without recognising the risk. homework became a battle. and while he previously had played with hugo and emma like an elder brother, he began to play with them like they were peers. when wilhelm didn't recognise his grandmother one day, helene realised he was regressing. in austria, wilhelm underwent specialist treatment with the permission of the country's medical ethics committee. this was followed in 1997 98 by a franco swiss research team who investigated whether the three siblings might have a mitochondrial disease. helene and the children underwent dna sequencing, but it offered no answers. the family might have different results if they were undergoing the process today: the human genome project, which aimed to identify the order of all dna bases to obtain the "genetic blueprint" of humans, launched in 1990. completed in 2003, it has radically improved our understanding of how new diseases form. exome testing, which looks specifically at a genome's protein coding regions (making up about 2% of the whole genome), has become especially helpful, says gahl. but in the 1990s genome sequencing was too primitive to help wilhelm. by the time he was 15 years old, it became clear he would not recover. he was brought home for palliative care with the support of a nursing team. he died on 2 september 1999, aged just 16. an autopsy found no clear cause of death. in the wake of losing wilhelm, helene and mikk faced a catalogue of new challenges. their youngest, emma, fell into her first coma three weeks after wilhelm's funeral, where they believe she had picked up a virus. she recovered but continued to experience intermittent comas in the months that followed, until doctors decided there was nothing they could do. emma died at home on 20 december 2000, surrounded by her loved ones. she was six years old. not quite two years later, on 8 december 2002, the family lost hugo just before his 11th birthday. he had developed lung problems and complications with his epilepsy. as hugo's health failed, his father asked a local construction company for a favour. they agreed to park their digger outside hugo's window. carrying his backpack with an intravenous solution, mikk would take hugo out to drive and dig together. just like emma and wilhelm before him, hugo's parting words to helene were "thank you, mum". none of the three children ever received a causative diagnosis explaining their conditions, or identifying the links between them. again, had they been born later they may have learned more. in the uk in 2023, thousands of children with severe developmental disorders finally received a diagnosis, via a study that found 60 new diseases. in the us, the undiagnosed diseases network   a consortium of 12 research teams and clinical centres across the country   is also working to solve these medical mysteries. in 2018, just two years after it had been established, the consortium had identified 31 new syndromes and had diagnosed 132 patients. today it has evaluated more than 2,220 patients and successfully diagnosed 676 of them. it has described a total of 53 new conditions. funding for this kind of work, however, continues to be a problem and support for the undiagnosed diseases network from the national institutes of health common fund is due to end this year. helene acknowledges that an overall diagnosis may not have kept her children alive. however, she believes it would have at least offered an explanation for what was happening to their bodies. in addition, says jewitt, a diagnosis can "open doors", if only to "simple things like applying to a charity for support". after their children's deaths, helene and mikk turned their attention to fundraising, launching their charity the wilhelm foundation. they had been frustrated by the lack of collaboration between the doctors around the world who treated their children. recognising this, as well as the additional challenges faced by families in middle and lower income countries (such as access to resources), in 2014 they brought together top experts for a world congress on undiagnosed diseases. the annual gathering continues to this day. wilhelm, hugo and emma all died in the build up to christmas, and this time of year continues to be difficult for helene and mikk. emma especially loved the festive season. she always said she wanted to paint santa's beard blue, her favourite colour. in her final days in a coma, emma was visited by a blue bearded santa claus. helene is confident she heard emma make a gleeful sound when she sensed him entering the room. "or maybe," she says, "that was in our mind." two years ago, helene and mikk were approached by a top diagnostic geneticist who believed that their children probably had a new disease. the couple have since submitted genetic samples for whole genome sequencing. sadly, it is too late to help wilhelm, hugo or emma. but there is still time, they say, to use what they've learned about their family to save another child’s life.    join one million future fans by liking us on facebook, or follow us on twitter or instagram. if you liked this story, sign up for the weekly bbc.com features newsletter, called "the essential list"   a handpicked selection of stories from bbc future, culture, worklife, travel and reel delivered to your inbox every friday. dr. lisa dahlgren discusses the effect human touch has on our health and wellbeing. do social media, some common assumptions and two scottish women hold the answers? gen z may lead the way when it comes to a healthy lifestyle, but is gen z the healthiest generation overall? with all the advantages of the modern world, which generation is the healthiest? which external factors affect male sperm count and why. why swedes only eat sweets on saturdays. many of us are keen to find ways to optimise our immune system   but is it possible? just how far can we intervene in the way our bodies age? in 1951, a young woman from baltimore died of cancer. her death would change medical science forever. the country had one of the worst rates of overdose deaths in europe. here are some expert tips for avoiding burnout before you're already burn out. feeling stressed? the dutch trend, koeknuffelen, might be just the thing for you. in this episode of my world, we have everything you need to know about coronavirus. a virologist demonstrates how germs spread and what the best methods are to avoid catching a virus. concerns are growing that the recently detected coronavirus may spread around the world. the czech mining town jachymov is home to the most important discovery in the field of radioactivity. forest bathing is a popular activity for the urbanised and stressed japanese becoming cut off from nature. marathon runner johanna pakenham was rushed to the hospital after drinking five litres of water. unpacking the dangers behind the us vaping craze the experiment that makes you grow old in an afternoon christina wants parents of seriously ill children to have the option of a career break. priyanka pandya bhatt says she wants to help other families during the difficult months of treatment. he's an expert on all of nola's iconic foods but has a special place in his heart for gumbo. here are his favourite bowls   from cajun style brigsten's to the og at commander's palace. the islands safeguarding children partnership works with agencies to support and safeguard children. ahead of kendrick lamar's headline performance at the super bowl half time show, we explore the rapper's journey from the streets of compton to pop culture ubiquity. copyright 2025 bbc. all rights reserved. the bbc is not responsible for the content of external sites. read about our approach to external linking.

an official website of the united states government official websites use .gov a .gov website belongs to an official government organization in the united states. secure .gov websites use https a lock ( lock locked padlock icon ) or https:// means you've safely connected to the .gov website. share sensitive information only on official, secure websites. primary site navigation logged in as: author contributions b.a.k. and b.r.p. developed the outline for the manuscript, engaged the contributors and synthesized the final manuscript. all authors participated in the research, writing, and editing of the document, and all approved the final version of the manuscript. c.k. provided clinical photos and m.p. conducted the family experience interview. collection date 2021 jun 17. williams syndrome (ws) is a relatively rare microdeletion disorder that occurs in as many as 1:7,500 individuals. it arises due to mispairing of low copy dna repetitive elements at meiosis. deletion size is similar across most individuals with ws and leads to loss of one copy of 25 27 genes on chromosome 7q11.23. the resulting unique disorder affects multiple systems, with cardinal features including, but not limited to, cardiovascular disease (characteristically stenosis of the great arteries and most notably supravalvar aortic stenosis), a distinctive craniofacial appearance and a specific cognitive and behavioural profile that includes intellectual disability and hypersociability. genotype phenotype evidence is strongest for the elastin (eln) gene, which is responsible for the vascular and connective tissue features of ws, and for the transcription factor genes gtf2i and gtf2ird1, which are known to affect intellectual ability, social functioning and anxiety. mounting evidence also ascribes phenotypic consequences to deletion of baz1b, limk1, stx1a and mlxipl, but more work is needed to understand the mechanism by which these deletions contribute to clinical outcomes. age of diagnosis has fallen in regions of the world where technological advances, such as chromosomal microarray, enable clinicians to make the diagnosis of ws without formally suspecting it, allowing earlier intervention by medical and developmental specialists. phenotypic variability is considerable for all cardinal features of ws, but the specific sources of this variability remain unknown. further investigation to identify factors responsible for these differences may lead to mechanism based rather than symptom based therapies and, therefore, should be a high research priority. williams syndrome (ws; also known as williams beuren syndrome; omim 194050), is a distinctive multisystem disorder (figure 1, supplementary box 1). the most common areas of involvement include the cardiovascular, central nervous, gastrointestinal and endocrine systems, although any organ system could be affected. recognition of ws as a distinct clinical syndrome dates back to the mid 20th century1 3, and knowledge of the phenotype has steadily expanded over the ensuing ~60 years. the age of peak prevalence and frequency of prominent signs or symptoms in organ systems affected in williams syndrome are indicated. features in bold are the common presenting features listed in the clinical diagnosis sectionin the main text. further reading for features in plain text is included in supplementary box 1. aestimates of co occurring autism spectrum disorder (asd) vary (12 20%). most individuals with williams syndrome who have asd fit in wing and gould’s active but odd subtype of asd292 rather than the aloof subtype of asd232,292. as such, the diagnosis of, and interventions for, asd in williams syndrome are complex and ideally benefit from engagement of practitioners who are knowledgeable about both disorders. bsound sensitivities include one or more of the following: hyperacusis, odynacusis, auditory allodynia and auditory fascinations. adhd, attention deficit hyperactivity disorder; cv, cardiovascular; dm, diabetes mellitus; gerd, gastro oesophageal reflux disease; id, intellectual disability. note: figure 1 was re drawn by the nature reviews disease primers art editor and permission for reproduction of the final figure was not granted by the publisher. please see the published version of the paper for the final fig. 1 at doi: 10.1038/s41572 021 00276 z we now know that cardiovascular disease is present in most individuals with ws4 6, with the most frequent abnormalities involving vascular stenoses of medium  and large sized arteries (referred to as elastin arteriopathy)7. depending on the location, severity and timing of onset, the management of the vasculopathy consists of noninvasive or surgical intervention complemented by life long monitoring. additional cardiovascular features include hypertension and a small but increased risk of cardiovascular sudden death8 12. the neurodevelopmental phenotype is unique and multifaceted. mild to moderate intellectual disability is common but not universal and is seen in conjunction with a distinct cognitive profile of relative strengths and weaknesses13,14. in addition, there is a characteristic personality profile that includes overfriendliness, shortened attention span and/or distractibility, nonsocial specific phobias and anxiety15,16. the genetic basis of ws was first identified in 1993, when fluorescence in situ hybridization (fish) studies showed deletion of an elastin allele (eln) on chromosome 7q17. we now know that ws is caused by a <2 million base pair (mb) microdeletion on chromosome 7q11.23 and that the local genomic architecture predisposes to de novo occurrence of this deletion18. individuals with ws are, therefore, hemizygous for the 25 27 genes that map to this interval, and reduction in the gene product of several key genes contributes to specific aspects of the ws phenotype. since ws was initially described, advances have been made in our understanding of the complexity and changing nature of the phenotype, the genetic basis of ws, the mechanisms that lead to selected phenotypes and the benefit of certain interventions. yet, many more unanswered questions remain. accordingly, our ability to optimize care and improve outcomes is modest. in this primer, we provide a snapshot of selected ws features across the lifespan, outline current and emerging diagnostic technologies, discuss the genetic basis of some of the most impactful ws features, and elaborate on pathophysiological mechanisms, where known. this information is key for formulating high priority future research questions, the answers to which could accelerate ws specific treatments. ws is a rare panethnic genetic condition. although this syndrome has been described in different populations around the world, most reports address clinical and molecular findings, with little focus on epidemiological data. the most widely cited epidemiological study is from norway19, which reports a prevalence of 1 in 7,500 live births, a prevalence which is higher than that often cited in many non epidemiologic sources20,21. ws is sufficiently rare that it is unfamiliar to most doctors, scientists, and researchers. the age of diagnosis of ws has trended towards younger ages over the past decades, most notably in high income countries with greater availability of molecular diagnostic testing. in cohorts from the usa and australia, the median age of diagnosis decreased by more than 2 years to around 1 year of age since the 1980s (b.a.k. and m.p., unpublished work). (figure 2 and supplementary box 2 were removed in post acceptance processing). however, series from other countries indicate that diagnosis is often still established during childhood rather than infancy, even with access to molecular confirmation22,23. several studies reported particular difficulty in diagnosing ws in african populations (or in those of african descent)24 26, owing to a variety of factors. unfortunately, nearly all studies on ws, independent of topic, describe caucasian individuals, and few studies whose participants represent diverse populations have been published27. of note, the absence of clinically evident cardiovascular disease was associated with later diagnosis28. note: although figure 2 (as cited in this text) was accepted after peer review, it was removed from the final manuscript at production. this figure does not exist in the final paper at doi: 10.1038/s41572 021 00276 z the prevalence of ws is comparable in males and females5,29. however, males are more likely to have severe cardiac disease30, especially supravalvar aortic stenosis (svas)29,31. there is no evidence that ws prevalence changes with parental age. moreover, consistent differences in phenotype have been associated with the sex of the transmitting parent (that is, whether the deletion arose in the sperm or the egg)18,32. vascular anomalies, such as svas and stenosis of other large arteries including the pulmonary arteries, descending aorta, renals, mesenterics, and coronary arteries contribute to morbidity and mortality across the life span4. other features, such as diverticular disease and aortic or mitral valve dysfunction, may also influence mortality in older age groups but are to date insufficiently quantified in the literature. sudden death incidence has been reported as 1:1000 patient years and is often associated with administration of sedation or anaesthesia for cardiac surgery; this rate is 25 to 100 times higher than in the age matched general population12. several adult cohorts have been described with participants as old as 86, but few studies included long term adult follow up33,34, making it difficult to accurately estimate the life expectancy of individuals with ws. in the 1990s, compelling evidence emerged indicating that ws is a genetic disorder with an autosomal dominant mode of inheritance35 38. non genetic risk factors are not known to contribute to the occurrence of ws. ws is caused by the pathological loss of the williams syndrome critical region (wscr), a 1.55 1.83 mb region which encompasses 25 27 unique protein coding genes on chromosome 7q11.23. the wscr frequently undergoes rearrangement due to the presence of large, complex segmental duplications termed low copy repeats (lcrs), which are highly similar to one another and flank the wscr39. the lcrs extend for several hundreds of kilobases, are comprised of genes and pseudogenes organized into distinct blocks (designated a, b and c), and contain extensive stretches of >99% nucleotide identity. they are thought to have emerged during primate evolution   first by duplication of smaller segments and later by transposable element (for example, alu mediated) shuffling, to produce the complex arrangement that exists in humans today40. the lcrs mediate non allelic homologous recombination (nahr) events between the highly similar dna sequences during meiosis, resulting in an increased rate of de novo copy number variation (cnv) events within the region39,41 43 (figure 3). the ws deletion commonly occurs through nahr between b block sequences in direct orientation with respect to each other, with the specific breakpoints depend on the precise site of nahr39. the reciprocal event (that is, duplication of the same genomic area) produces a condition referred to as 7q11.23 duplication syndrome, resulting in 3 copies of each wscr gene. recombination between b blocks (lcrs with the highest nucleotide identity) in an inverted, rather than direct, orientation, results in an inversion of the intervening chromosome segment42 (figure 3). this inversion, which is present in 6 7% of the general population44, does not cause symptoms45 but seems to increase the incidence of subsequent meiotic rearrangements42,44. other lcr specific rearrangements have also been observed at a higher frequency in the transmitting parents of children with ws41. the vast majority of williams syndrome (ws) deletions (~90%) span a 1.55 million base pair (mb) region encompassing 25 27 protein coding genes in the williams syndrome critical region (wscr) on chromosome 7q11.23, with the remainder being slightly larger (1.83 mb)39. the larger, less common deletion occurs between low copy repeats (lcrs) designated as ‘a blocks’, which are present in the great apes, whereas the smaller, more common deletion occurs between ‘b blocks’, which are only present in humans. b blocks originate from a more recent evolutionary duplication event and have a higher sequence identity than a blocks40. the ws deletion commonly occurs through non allelic homologous recombination between b block sequences in direct orientation with respect to each other39; however, recombination between b blocks in an inverted orientation also occurs, resulting in inversion of the intervening chromosome segment42. smaller, atypical deletions occur infrequently but can provide valuable insight into the genotype phenotype relationship59,62,138 140. several names exist for many of the genes mapping to wscr (see 293and https://www.ncbi.nlm.nih.gov/gene/). id, intellectual disability. note: figure 3 was drawn by the nature reviews disease primers art editor and permission for reproduction of the final figure was not granted by the publisher. this material is labeled as fig. 2 in the published version of the paper doi: 10.1038/s41572 021 00276 z while most deletions span the typical 1.55 1.83 mb interval at 7q11.23, there are individuals with rare deletions that encompass smaller or larger segments of the wscr, often with one common and one unique breakpoint. larger deletions that extend beyond the wscr generally cause additional features. when these deletions extend toward the telomere and span the ywhag and/or magi2 genes, seizures are common46,47, although there are reports of epilepsy in individuals with the typical deletion48. inclusion of the auts2 gene on the centromeric side may result in smaller head size than is usually seen in ws49, and larger deletions can also alter the characteristic ws behavioural profile49,50. deletion of hip1 (formerly hsp27) in particular has been associated with more severe intellectual disability50,51. smaller deletions result in a subset of the phenotypic features seen in classic ws40,50,52 64, but clear cut correlations between deletion size and specific phenotypic features are challenging, with the exception of eln. this is likely due to the paucity and variety of small deletions, differing methods for phenotypic assessment, and high likelihood of the combinatorial effects of gene deletion. several specific genotype phenotype relationships are discussed in the next section. cnv events of the 7q11.23 region have been shown to affect both gene transcription and dna methylation across the entire genome. initial studies in ws lymphoblast cell lines identified dysregulation of genes involved in glycolysis and neuronal migration65, while subsequent studies of blood rna highlighted upregulation of three gene expression modules linked to b cell activation, rna processing and rna transport66. transcriptome analysis of more relevant cell types has been made possible by the ability to reprogramme somatic cells into induced pluripotent stem cells (ipscs) and direct them down specific cell lineages67. for example, ipsc derived cortical neurons from individuals with ws show reduced expression of genes involved in neurotransmitter receptor activity, synaptic assembly and potassium channel complexes68. comparison of gene expression in ws ipscs with those from individuals with 7q11.23 duplication syndrome revealed that many of the differentially expressed genes have a symmetrically opposite pattern of expression69. a similar symmetrical gene dose dependent pattern was seen in dna methylation analysis of blood dna from individuals with ws (7q11.23 deletion) and those with the 7q11.23 duplication syndrome70, suggesting that cnv in this area affects epigenetic regulation of the genome. the wscr contains 25 27 genes and several noncoding rnas. knowledge about how each of these genes contributes to the ws phenotype is still growing (figure 4). several mouse models inform those efforts, including single gene knockouts, as well as deletion of the entire wscr (cd)71 73 and two half deletions (pd and dd)74. to refine genotype phenotype correlations, we will focus only on selected single gene knockout models. putative or elucidated genotype phenotype relationships for six genes in the williams syndrome critical region (wscr) are depicted, including elastin (eln), general transcription factor ii i (gtf2i), baz1b, lim domain kinase 1 (limk1), syntaxin 1a (stx1a) and carbohydrate responsive element binding protein (chrebp). phenotypes in mouse models and in individuals with williams syndrome are indicated for eln and the gtf2i genes because, presently, their mechanisms of action are best delineated and they offer the best targets for therapy. note: figure 4 was redrawn by the nature reviews disease primers art editor and permission for reproduction of the final figure was not granted by the publisher. this version was designed using biorender. this material is labeled as fig. 3 in the published version of the paper doi: 10.1038/s41572 021 00276 z seven genes (baz1b, vps37d, stx1a, limk1, clip2, gtf2ird1 and gtf2i) have a probability of loss of function intolerance (pli) score of 0.9 or higher75, suggesting that only a subset of the genes in the wscr directly contributes to phenotype. a pli score is calculated by examining the frequency of loss of function variants in a population; fewer variants than expected is associated with a higher score and implies a greater likelihood of pathogenicity. it is important to point out that the gene with the greatest support for a role in the phenotypic consequences of ws is eln, which has a pli of 0. similarly, considerable evidence implicates deletion of mlxipl (pli = 0.05) in metabolic aspects of ws. these two examples highlight the inadequacy of predictors such as pli in identifying all pathogenetic genes. an overview of the best characterized genotype phenotype correlations for wscr genes is provided below. the eln gene is transcribed in tissues that stretch and recoil, such as the lungs, skin and elastic arteries (including the aorta, where elastin accounts for up to 50% of the vessel’s dry weight)76,77. the protein consists of repeating hydrophobic and crosslinking domains. the crosslinks allow monomers to be bound to one another in a highly interwoven polymer that allows for distribution of force, while the hydrophobic domains drive the recoil process through entropy when they are exposed to an aqueous environment with tissue expansion (stretch)78,79. the polymer is long lived, with a short window for deposition and a calculated half life of 74 years80. interestingly, although robust elastogenesis occurs only during early growth and development, eln is thought to be continually transcribed throughout the lifespan81. outside of this tight developmental window, eln transcripts are quickly turned over82,83. as such, this connection between transcription, translation and assembly is ripe for investigation. individuals with loss of function point mutations84 86 or intragenic deletions87 within eln have eln associated familial svas, and develop cardiovascular manifestations that are indistinguishable from those found in ws. common features include focal or long segment stenosis (narrowing) of the large elastic arteries in the setting of a globally narrow and thick walled vasculature4,6,7,30,88. stenosis of the supravalvar aortic and supravalvar pulmonary arteries are the most common and show considerable variability in severity29,89. while pulmonary artery stenoses often improves with age, narrowing on the aortic side may stay the same, improve or worsen with time 5,88,90. other vessels, such as the descending aorta, renal arteries, mesenteric arteries and coronaries may also exhibit stenosis, with symptomatology pointing to hypoperfusion of the associated end organ (hypertension, abdominal pain, and cardiac hypoperfusion with st elevation or sudden death). even in the absence of stenosis, individuals with either ws or familial svas have high rates of hypertension and vascular stiffness, which are detectable as early as infancy and childhood8,91. an increased sudden death relative risk with and without anaesthesia has been reported10,92 94; the precise mechanism by which this occurs is not currently known but it is expected to be multifactorial, reflecting the complex vascular pathophysiology95. heterozygous eln knockout (eln+/ ) mice recapitulate relevant cardiovascular features of ws, including aortic wall thickening, hypertension and cardiac hypertrophy7,however, it has been difficult to replicate the hourglass type supravalvar stenoses commonly seen in individuals with ws or familial svas. neither eln+/ nor transgenic eln /  mice expressing the human eln gene (eln / ;eln+ mice, which have 30% of normal elastin levels) develop frank stenosis, although eln / ; eln+ mice exhibit more severe arterial wall thickening, luminal narrowing, hypertension and cardiac hypertrophy than eln+/  mice96. discrete stenosis or coarctation (congenital narrowing) of the aortic arch as well as the development of neointima (thickening of the intima characteristic of segmental aortic stenoses in ws) has been described in mice with a homozygous eln deletion restricted to vascular smooth muscle cells97. unfortunately, most of these mice do not survive past postnatal day 18. several hypotheses have been postulated for the mechanism by which elastin insufficiency causes large vessel arteriopathy. segmental stenoses are thought to develop through increased proliferation and migration of vascular smooth muscle cells due to a reduction or lack of elastin98 100. lineage tracing indicates that the excess smooth muscle cells responsible for inward remodeling of the arterial wall are not clonal but are derived from multiple existing smooth muscle cells in the media layer101. inward remodeling is caused in part by excess integrin β3 signaling, as genetic or pharmacological inhibition of this pathway reduces vascular pathology and extends lifespan in eln /  mice101. other work suggests that rather than an increase in proliferation, elastin insufficiency produces medial fibrosis, altered mobility of smooth muscle cells and abnormal circumferential growth, leading to smaller lumen size and thicker arterial walls102. additional studies suggest that hypertension arises in eln+/  mice as part of a developmental adaptation to normalize vessel wall stress, capitalizing on the increased pressures to prop open the narrow, stiff elastin insufficient vessels103, although more recent studies indicate that reactive oxygen species (ros) production may also have a role74. several additional molecular and cellular mechanisms impact the pathogenesis of elastin arteriopathy, including mechanistic target of rapamycin (mtor) perturbation of smooth muscle mechanosensing 104 106, and the adaptive immune system29. in addition to vascular disease, patients (and mice) with elastin insufficiency have impaired pulmonary107 109 and skin110,111 elastic fibres, leading to impaired tissue mechanics. other common connective tissue features of ws may also be linked to elastin insufficiency, such as periumbilical or inguinal hernias112, hoarse voice113, earlier onset skin wrinkling111, atypical scar formation111 and genitourinary phenotypes112. neutrophil cytosolic factor 1 (ncf1) resides at the telomeric end of the wscr. two ncf1 pseudogenes, ncf1b and ncf1c, are present in the lcr regions that flank the typical deletion. ncf1 is the regulatory subunit for several nadph oxidase (nox) complexes and generates ros in multiple cell types, including endothelial cells, smooth muscle cells and leukocytes, following various stresses114,115. a deletion that removes ncf1 is found in ~50% of individuals with ws91,116. loss of ncf1 has been associated with relative protection from hypertension and vascular stiffness in individuals with ws91,116 and in animal models74,117,118. general transcription factor 2 i (gtf2i) and gtf2i repeat domain containing 1 (gtf2ird1) are paralogous genes located on adjacent loci at the telomeric end of the wscr. they encode transcription factors and contribute to typical ws behaviour and development. on the molecular level, gtf2ird1 and gtf2i encode ben and gtfii i, respectively, which are members of a versatile protein family with broad functional activities119 121. gtfii i is a highly conserved and ubiquitously expressed multifunctional transcription factor122 125 that regulates gene expression120,126,127 through interactions with tissue specific transcription factors and complexes related to chromatin remodelling125. gtfii i is activated in response to various extracellular signals and then translocates to the nucleus121,125,126,128. gtfii i has been shown to be involved in multiple processes, which include regulating embryonic development122,129,130, the cell cycle125,127,131,132, actin cytoskeleton dynamics, axon guidance132 and epigenetic regulation133,134. indeed, an ipsc based study showed that gtf2i alterations are responsible for 10 20% of the transcription dysregulation in disease relevant pathways in ws and in the 7q11.23 duplication syndrome, beginning in the pluripotent state and further amplified during development69. from a phenotypic standpoint, individuals with classic deletions of the wscr14 and those with shorter deletions that result in loss of gtf2ird1 and gtf2i62 (figure 3) typically show intellectual disability, high social approach to familiar persons and indiscriminate social approach to strangers (also referred to as social disinhibition or hypersociability), and difficulties in social communication (pragmatics). by contrast, individuals with deletions that spare these two genes typically exhibit neither intellectual disability40,54,56,59,135 137 nor these social characteristics59,138. interestingly, individuals with shorter ws deletions that spare gtf2i but remove gtf2ird1 also typically do not exhibit intellectual disability or hypersociability136,139, but they do show increased social approach to familiar people and difficulty with social pragmatics136. further evidence for the role of gtf2i gene dose in intellectual ability comes from a family with a very short duplication affecting gtf2i but not gtf2ird1; all family members with gtf2i duplication had intellectual disability, whereas the intellectual ability of those with the usual two copies of gtf2i was average140. as in humans, partial hemizygous deletion of the mouse wscr including gtf2i results in increased sociability but also impairs motor coordination in mutant mice71. homozygous deletion of gtf2i in mice results in embryonic lethality owing to severe developmental abnormalities122,124,141, such as exencephaly and neural tube disclosure, whereas heterozygous mice show impaired social habituation to an unfamiliar mouse141,142. selective deletion of gtf2i in excitatory neurons leads to myelination alterations, motor deficits and hypersociability, which normalize with pharmacological rescue of myelination143,144. intracisternal gtf2i gene therapy in the cd (full ws deletion) mouse model resulted in beneficial effects on behavioral deficits related to motor, social and anxiety like behaviors145. taken together, these findings suggest that loss of a gtf2i allele is a major contributor to the intellectual disability and social disinhibition that are characteristics of individuals with ws. deletion of gtf2ird1, even without deletion of gtf2i, likely contributes to the social communication difficulties and generally increased social approach. findings of dose dependent gtf2i specific social and anxiety phenotypes in mouse models146,147 converge with those observed in the human hemideletion and duplication syndromes14,146,148,149. in a study of the effects of gtf2i copy number on cortical neuron maturation and function, mice with a single copy of gtf2i showed increased axonal outgrowth, whereas this outgrowth was decreased in mice with three gtf2i copies150. the axonal growth effects of gtfii i might occur through regulating the expression of the homeobox proteins dlx5 and dlx6151, thereby affecting the excitatory/inhibitory balance in the brain152. this balance has been suggested as a possible mechanism that causes autism spectrum disorder (asd)153. in this regard, it is noteworthy that both deletion154,155 and duplication156 of the wscr are associated with elevated rates of asd. for several other genes within the wscr, there is emerging evidence of an association with components of the williams syndrome phenotype. bromodomain adjacent to zinc finger domain 1b (baz1b), a member of the b wich chromatin remodelling complex, is essential for correct neural crest cell migration in vitro157 and in vivo158 and has been proposed as a master regulator of human craniofacial development157. as the enteric nervous system is also derived from the neural crest159, it is possible that abnormal innervation of the intestine contributes to ws gastrointestinal phenotypes, such as dysmotility and chronic constipation. lim domain kinase 1 (limk1) regulates actin cytoskeleton assembly and disassembly and has been linked with visual spatial cognitive ability in individuals with ws64 and in the general population160. limk1 /  mice show visuospatial deficits, altered dendritic spine morphology and reduced synaptic plasticity, leading to reduced long term memory. limk1 expression can be upregulated by both brain derived neurotrophic factor161 and camp response element binding protein162, suggesting potential therapeutic avenues. syntaxin 1a (stx1a) is a key member of the protein complex that mediates exocytic vesicle fusion, thereby allowing the release of neurotransmitters into the synapse. neuropsychiatric disorders found in individuals with ws have been associated with stx1a variants163,164. insulin secretion from the pancreas is also dependent on exocytosis165, and stx1a levels are indeed reduced in members of the general population with type 2 diabetes mellitus166. diabetes is common in adults with ws167, suggesting a possible physiological link with stx1a hemizygosity. as the mlxipl gene, which encodes the chrebp transcription factor that regulates both glucose168,169 and lipid metabolism170, is also located within the wscr, both chrebp and stx1a could contribute to the metabolic phenotypes in ws. bialleleic missense variation in dnajc30, (dnaj heat shock protein 40 family (hsp40)) member 30 was recently associated with leber’s hereditary optic neuropathy in humans171, a mitochondrial condition. similar features have not, to date, been reported in ws. bialleleic deletion of this gene in mice also produces mitochondrial dysfunction and behavioral changes172. more work is needed to investigate the impact of isolated hemideletion in humans, but potential impact of this gene on neurodevelopment should be considered. ws is a multisystem disorder with a broad but characteristic pattern of organ involvement (figure 1), including a distinctive facial appearance173 175 (figure 5). as there is no newborn screening for ws, clinical consideration of the diagnosis is prompted by the presence of suggestive signs and/or symptoms. below, we outline the most common presenting features prompting consideration of a ws diagnosis. of note, the extent and exact distribution of system involvement can vary considerably from patient to patient. facial photos of individuals with molecularly confirmed williams syndrome of different racial and/or ethnic backgrounds aged 2 months to 52 years. distinctive features in infants and children include broad forehead, peri orbital fullness, flat bridge of the nose, full cheeks, long philtrum, and a small delicate chin. many adolescents and adults continue to have micrognathia, and the face often elongates over time while the nasal bridge is no longer flat, and there is fullness of the lips with a wide mouth (especially appreciated when smiling). parents or caregivers for all pictured individuals signed consent for publication of their family member’s image. the presence of more male than female photos in adolescents and adults solely reflects availability of subjects. note: this material is labeled as fig. 4 in the published version of the paper doi: 10.1038/s41572 021 00276 z. individuals with ws often present with facial features that are not typical for their family. prominent features in infants and young children include a broad forehead, peri orbital fullness, flat bridge of the nose, full cheeks, long philtrum, and a small delicate chin. adolescents and adults often continue to have micrognathia, but the face elongates over time, the nasal bridge is no longer flat, and there is fullness of the lips with a wide mouth (especially appreciated when smiling). children and adults of different ethnic backgrounds from brazil with molecularly confirmed ws are depicted in figure 5. cardiovascular disease in ws typically presents with a heart murmur. evaluation in children most commonly reveals svas and/or stenosis of the main or branch pulmonary arteries. pulmonary vascular disease is often less prominent in older individuals with ws. other ws cardiovascular features, such as stenosis in other vessels, septal defects, hypertension, vascular stiffness or ekg abnormalities, are generally not the reason for referral but may be present at the time of diagnosis. actionable hypercalcaemia (serum calcium >12.0 mg/dl) is seen in 5 10% of children with ws and when present usually occurs between 6 and 30 months of age176. while some children with hypercalcaemia are irritable and show poor oral intake, other cases are detected incidentally by laboratory testing. on average, children and adults with ws are shorter than expected for age177. once a diagnosis is made, ws specific growth charts are available for plotting children’s expected growth178,179. in addition, many infants with ws exhibit prolonged colic may have difficulty feeding due to oral motor delays or sensitivities, and have difficulty gaining weight. developmental delay is almost universal and 75% of older children and adults with ws have intellectual disability (iq <70)178, with most remaining individuals displaying borderline iq (70 79) and/or more specific neuropsychological impairments13,14. many experienced parents almost immediately notice differences from typically developing infants, but other parents may not become concerned until they realize their child with ws is not meeting motor or language milestones. features of asd may also lead to referral. it is important to distinguish ws from other syndromes with overlapping features. certain highly suggestive features (such as svas, hypercalcemia and characteristic facial features) exist that, when seen in combination by an experienced examiner, readily yield a correct clinical diagnosis of ws. and though a few other disorders are evocative of ws, in that they have a similar pattern of organ involvement (such as fetal alcohol syndrome, rasopathies, fg syndrome), detailed examination of their specific features reveals distinct differences from ws. some individuals come to medical attention, however, due to a single prominent feature. depending on the specific presenting symptom, the differential diagnosis varies and supplementary table 1 is presented to aid practitioners in that setting. a clinical suspicion of ws should always be confirmed with genetic testing (see below). the most widely used laboratory methods available to detect the 7q11.23 microdeletion include fish, polymorphic microsatellite markers, multiplex ligation dependent probe amplification (mlpa) and chromosomal microarray analysis (cma) (table 1). cma is the only current method that does not require the clinician to suspect a specific diagnosis of ws prior to testing. in addition to providing mapping for deletion boundaries and offering the ability to detect atypical deletions, cma can also identify additional cnv events elsewhere in the genome. mlpa and polymorphic microsatellite markers are often used in low  and middle income developing countries owing to their lower cost than fish and cma22,23,180,181. overview of methods for diagnosing williams syndrome ws, williams syndrome; cnv, copy number variation; mb, million base pairs newer technologies, such as facial recognition software182 184, may help focus the differential diagnosis and have been evaluated in individuals from various racial and ethnic backgrounds; the diagnostic precision of the software will likely continue to improve over time. additional testing (gene sequencing or trinucleotide repeat expansion testing) may be indicated based on the differential diagnosis (supplementary table 1). in the future, whole genome sequencing may provide cnv and single nucleotide polymorphism detection in a single test that will simultaneously assess for ws and other possible differential diagnoses. if a parent has ws, the risk of ws in offspring is 50% for each pregnancy. however, owing to the complex medical and neurodevelopmental challenges associated with ws, few adults with ws have children.the recurrence risk for couples where neither parent has clinical findings of ws is extremely low185, since the 7q11.23 microdeletion arises de novo in the vast majority of cases. for these couples, parental testing for a 7q11.23 microdeletion is not indicated and neither is invasive prenatal testing of subsequent pregnancies (although many parents opt for the latter, especially in countries where molecular diagnostic testing is widely available). however, there are rare reports of recurrence in phenotypically normal parents. this recurrence is likely attributed to parental mosaicism186 or to one parent carrying an inversion of the wscr185. the inversion has been associated with an approximately five fold increase in risk of having a child with ws in each pregnancy; nevertheless, testing for the presence of inversion in phenotypically normal parents is not recommended, because their recurrence risk   despite being five times higher   remains well below 0.1%42,44,185. limited clinical information exists on pregnancies in women with ws187,188. review of this literature suggests that mothers and fetuses (affected by ws or not) may require close monitoring, especially with regard to the maternal cardiovascular system. in addition, there is no routine prenatal test that adequately screens for ws, although prenatal ultrasonography can sometimes detect relevant fetal anomalies. the most common prenatal finding is nonspecific, namely intrauterine growth retardation189. various cardiovascular anomalies also can be seen and range from nonspecific (for example, ventricular septal defect) to nearly pathognomonic for elastin arteriopathy (for example, svas, although this finding is quite difficult to make by prenatal ultrasound)165. the prenatal detection of growth retardation combined with any cardiovascular defect may warrant performing high resolution prenatal ultrasonography and genetic testing. noninvasive prenatal testing (nipt) involves sequencing of fetal dna circulating in the maternal circulation and can detect common fetal chromosomal aneuploidies in the first trimester. currently, as even enhanced nipt platforms can only detect deletions >3 mb, they cannot be used to diagnose ws189. however, further technical advances in the nipt technology are likely to enhance prenatal diagnosis and therefore affect the epidemiology of ws in the future. in addition, whole genome sequencing may eventually be utilized to perform combined single nucleotide polymorphism, copy number variant and structural variant detection in fetal samples. prenatal diagnosis offers the opportunity to provide genetic counseling to families sooner, allowing them to avoid a diagnostic odyssey that can potentially last months and years after the child’s birth. the management of various aspects of ws has been extensively outlined in numerous research studies, reviews, and guidelines173,174,176 178,190 195.here, we focus on the management of three key areas where improved therapeutics would have the greatest potential to improve health outcomes: elastin associated vasculopathy, hypertension, and intellectual disability, social functioning and anxiety. as mentioned previously, individuals with elastin insufficiency can develop focal stenosis and other vascular features. vascular disease severity varies among persons with ws, with ~20% requiring intervention for svas, for example, while 30 40% have little to no stenosis in this location. at present, large vessel stenosis is predominantly managed surgically. to alleviate svas, patch aortoplasty is the most common approach196 and has undergone several technical improvements over time, evolving from the single patch method197,198 to the pantaloon shaped patch that enlarges the aorta and two aortic sinuses199. the most advanced method, which involves applying a patch to each of the three aortic sinuses200, exhibits notably lower residual pressure gradients and reoperation rates201 than the single patch approach. stenoses of pulmonary arteries can be treated with angioplasty, but catheter based interventions on other arteries are often unsuccessful11,90,202. surveillance of stenosis occurs through regular examinations by a cardiologist and associated imaging and should continue throughout an individual’s lifetime. individuals with ws experience increased rates of cardiovascular collapse with and without anaesthesia10,12, although the mechanism of this phenomenon is not completely understood. young individuals and those with the most severe cardiovascular features (that is, biventricular outflow tract obstruction10) seem to have the highest risk, although some individuals with only minimal stenosis suffered sudden death in the setting of anaesthesia. this severe outcome may be influenced by various risk factors, including anatomical anomaly of the coronaries and reduction in perfusion pressure at induction and/or maintenance of anaesthesia. therefore, careful preoperative screening should be performed to assess the anaesthesia associated cardiovascular risk, and administration of intraoperative anaesthesia should ideally be provided by an anaesthesia team with knowledge of ws anaesthesia risks93 95,203,204. care should be taken not to acutely lower blood pressure at induction of anaesthesia in order to maintain adequate perfusion of the coronaries during this sensitive time. studies suggest that novel pharmacological therapies may improve elastin associated vasculopathy. minoxidil, an atp dependent potassium channel opener, has received considerable attention based on evidence that it increased elastin production in cellular studies205 and in animal models206,207 of genetic elastin deficiency and that it ameliorated age related degeneration of elastic fibres in mice208,209. however, a randomized, double blind, placebo controlled trial (nct00876200) investigating the effect of a year long minoxidil treatment in 17 individuals with ws failed to show improvement in the primary outcome measure (carotid intima media thickness)210. this trial did show an increase in lumen size (a secondary finding, in line with previous mouse studies207) over the same time interval, along with an expected common adverse effect of hypertrichosis210. alternative therapeutic approaches may target various regulatory pathways that influence elastin expression. for example, both the coding region and the 3ʹ utr of the eln mrna are enriched in binding sites for mir 29 and mir 15, two micrornas that are upregulated in the late postnatal aorta, at the same time that the level of mature eln mrna decreases82. antagonism of mir 29 increases elastin expression in haploinsufficient cells and bioengineered vessels211. elastin insufficiency is also associated with hypertension, but the risk of clinically significant blood pressure increases is modified by deletion size and ncf1 gene dosage91,116. blood pressure should be measured in both arms and at least one leg due to possible right arm flow acceleration (the so called coanda effect) and/or coarctation of the aorta212. if consistent blood pressure elevations or pressure differentials (in the arms or as an arm leg discrepancy, respectively) are detected, additional imaging of the heart and ascending aorta (by echocardiography) and the renal/abdominal vasculature (by doppler ultrasonography, ct angiography or mri/mr angiography) should be considered (when available), to assess the presence of focal or long segment stenosis that affects renal perfusion and may benefit from surgical intervention5,9. auscultation of the abdomen can also reveal a bruit (abnormal sound) in the region of the stenosis. blood pressure elevation often starts in childhood and increases in frequency with age8,9,116,213. unlike stenosis, most cases of hypertension are treated pharmacologically5,8. currently, there is no expert consensus on the best antihypertensive medication for individuals with ws214. similarly, work in eln+/  mice revealed no superior drug class for treating elastin mediated hypertension215. however, because blood pressure influences lumen size, which in turn affects end organ blood flow, care must be taken not to decrease pressure to the extent that lumen size, and therefore end organ blood flow, is pathologically diminished. for this reason, among others, diuretics may not be the ideal or initial choice for blood pressure management in individuals with ws. in addition, when reno vascular causes of hypertension are suspected, angiotensin receptor blockers and angiotensin converting enzyme (ace) inhibitors should be used with caution. as hypertension risk has been linked to ros production through the nox signaling pathway, potential therapeutic strategies could include treatments that limit ros production or affect signaling through ros216. deletion of multiple genes within the wscr likely contribute to intellectual disability, altered social functioning and anxiety, although the roles of gtf2i and gtf2ird1 (as outlined above) are the best described to date. ws is associated with developmental delay (the expected developmental milestones are shown in figure 6). the delays typically lead to mild to moderate intellectual disability, although a few individuals have severe intellectual disability or, at the other extreme, average intellectual ability14,217. this overall level of ability masks a phenotypic pattern of strengths and weaknesses relative to expectations for overall level of intellectual ability. in general, language and nonverbal reasoning abilities are stronger than expected for overall intellectual ability, whereas visuospatial construction (for example, handwriting and block construction) is considerably weaker than expected13,14,218. visuospatial construction is facilitated by visual processing regions. interestingly, research using resting state functional mri showed that for children in the general population, the intraparietal sulcus is functionally connected to more superior anterior visual processing regions, whereas it is instead connected to social regions in children with ws160. the lack of this specific functional connection in individuals with ws contributes to their considerable weakness in visual spatial construction219. a more detailed description of the pattern of relative strengths and weaknesses within the language domain is provided in table 2. median ages (in months) and 90th and 10th percentiles for attainment of various gross motor, fine motor, cognitive and language milestones by very young children with williams syndrome (yellow bars) relative to typically developing children (aqua bars)154,294 302. numbers in red typeface indicate median age; numbers in black typeface indicate 90th percentile (to the left of the median) and 10th percentile (to the right of the median). td, typically developing. note: figure 6 was redrawn by the nature reviews disease primers art editor and permission for reproduction of the final figure was not granted by the publisher. this material is labeled as fig. 5 in the published version of the paper doi: 10.1038/s41572 021 00276 z pattern of relative strengths and weaknesses in individuals with wsa. strengths and weaknesses relative to overall intellectual ability for broad categories of intellectual ability and within the language domain. current information indicates that cognitive ability remains stable, at least to mid adulthood220 223. there is a possibility of iq decline in older adults34, but the data sets are limited. ws is also associated with a characteristic behavioural profile that is consistent across both western and eastern cultures224. at its most basic level, this profile includes gregariousness and hypersociability (or ‘overfriendliness’), accompanied by attention problems (often meeting diagnostic criteria for attention deficit hyperactivity disorder or adhd), social problems, anxiety and emotional overreactivity15,16,225 229. mastery motivation (that is, willingness to persist on a task one finds moderately difficult) is typically very limited14,227. the most common psychiatric problems associated with ws, and estimates of their prevalence based on meeting formal diagnostic criteria outlined in the diagnostic and statistical manual of mental disorders iv (dsm), are delineated in figure 7. the genetic deletion in williams syndrome (ws) has cascading effects on social, educational and vocational opportunities and on psychopathology. estimated prevalence of psychiatric disorders in preschool aged children, school aged children and adolescents, and adults with williams syndrome154,213,266,303,304 is depicted. studies with participant over a wide age range that did not report results separately for children and adults were excluded.236,305 307 the term ‘anxiety disorders’ includes generalized anxiety disorder, specific phobia, separation anxiety or social anxiety, and panic disorder with agoraphobia.amost individuals with ws who have autism spectrum disorder (asd) fit in wing and gould’s292 active but odd subtype of asd231 rather than the aloof subtype. note: figure 7 was drawn by the nature reviews disease primers art editor and permission for reproduction of the final figure was not granted by the publisher. this material is labeled fig. 6 in the published version of the paper for the final figure at doi: 10.1038/s41572 021 00276 z in most cases, the previously described learning and developmental differences are addressed by the school system through specialized education and therapy services, which are outlined below. in general, physical, occupational, and speech and language therapy are recommended for infants through school aged children in the usa178,230 and in australia192. by contrast, according to a parent survey in the uk, only 20 40% of school children with ws receive these services231. the behavioural and psychiatric components of ws are managed with the help of structural and environmental supports at home and in school and vocational settings, including counselling and behavioural therapies14,156,178,232. for individuals whose symptoms greatly affect their daily functioning and quality of life (qol), referral to a psychiatrist for consideration of pharmacological intervention may be indicated178. the anxiety associated with ws has been particularly difficult to treat. trials are needed to identify appropriate therapeutics for anxiety, although, as has been shown for typically developing individuals, cognitive behaviour therapy seems promising as an effective treatment for anxiety in ws233,234. the same medication classes available for anxiolysis in the general population have been studied in small series of individuals with ws235,236 and are already widely used in clinical practice, but result in varying symptom relief. furthermore, the risk:benefit ratio may be more unfavorable for some of these medications in those with ws, as reviewed by thom et al237. specifically, anxiety, mood, cardiac function and blood pressure all need to be monitored given the overlap between common side effects of adhd medication in the general population and the psychological and physical difficulties associated with ws. in high income countries, a large proportion of primary school aged children with ws are educated in mainstream schools and spend at least part of the day in classes with typically developing agemates; these proportions decrease considerably for secondary school231,238. although there are no data specifically for children with ws, in low income and middle income countries, school attendance is much less common for children with disabilities than for typically developing children239, due not only to financial difficulties but also to discriminatory and negative views of persons with intellectual disability240. postsecondary education for individuals with ws is very limited worldwide, although opportunities are increasing in some high income countries. in a us survey whose respondents were on average upper middle class, 29% of individuals with ws had attended a postsecondary education programme241. these programmes typically focus on combinations of academics, vocational training (including job placement and coaching) and independent living skills. after completing school, most adults with ws continue to live with their parent or another relative; <10% live independently241,242. only 38 54% of adults are working at least part time, generally in a special employment arrangement, either for pay or as a volunteer241,242. within the academic sphere, reading skills are considerably stronger than mathematics skills13,243 and range from an inability to read at all to reading comprehension at age or grade level243 246. about 30% of adolescents and adults with williams syndrome have functional reading capability244. children who were taught to read using systematic phonics instruction, which emphasizes letter sound relations, read and comprehend significantly better than those taught using other instructional approaches246,247. there has been no research on written composition, and very little is known about the mathematical abilities of individuals with ws248. within the adaptive behaviour domain, socialization and communication skills are stronger than daily living and motor skills for children and adolescents with ws249. in longitudinal studies, adaptive behaviour standard scores declined significantly during childhood250 and in adulthood222, owing to stagnation or failure to increase adaptive skills at the rate needed to maintain a consistent standard score over time. for adolescents and adults with ws, adaptive behaviour is more limited than expected for their iq251,252. high but realistic parental expectations combined with better behavioural regulation234 and higher levels of mastery motivation are expected to positively affect both adaptive behaviour and academic achievement13. even so, in a survey of teachers, most indicated they were not given adequate resources to teach children with ws238, and most parents surveyed thought their child’s teachers had little knowledge about ws238. much more research is needed on effective instructional strategies for individuals with ws at all educational levels253. the combination of intellectual disability, medical problems, and behavioural, psychological and adaptive impairments leads to considerable limitations on qol in individuals with ws. parents and teachers of children with ws report difficulties with peers, including problems establishing and maintaining friendships and increased social exclusion or isolation254. although social vulnerability is high, self awareness is limited255. seventy three percent of parents reported victimization of their child256, with the social interaction style of individuals with ws contributing significantly to their social vulnerability257. even adolescents and adults with ws are typically not cognizant of stranger danger258,259. intervention studies addressing these issues258,260 are both rare and crucial229. nearly all children with ws require multiple encounters with the healthcare system for management of medical or surgical problems261. these encounters place a financial and emotional burden on the individuals with ws and their families262 and often contribute to anticipatory anxiety about medical encounters and procedures263. several studies of adults with ws ≥30 years of age demonstrated an increased frequency, variety and severity of medical morbidities33,34,213, and this trajectory accelerates among those >65 years of age (personal observation). prominent adult issues include cardiovascular disease, obesity (with/without lipoedema), diabetes mellitus, incontinence, hearing loss, consequences of poor oral health, gastrointestinal problems (including diverticulitis), decreased bone mineral density and sleep apnea174,213. psychiatric concerns are often paramount. health issues such as these may result in narrowed residential and vocational placements, restricted mobility and physical activity and, collectively, they promote further social isolation. medical complications require focused management based on established guidelines, whereas general health could be improved by participation in programmes that promote healthy eating and increasing physical exercise activity to recommended adult levels264,265. the presence of a child with ws may affect the qol of other family members. both generalized anxiety disorder266 and borderline or clinically significant levels of stress267,268 occur in a significantly higher proportion of mothers of children with ws than expected for same aged women in the general population. sensory modulation problems are very common among children with ws and are associated with more difficult temperament, more limited adaptive behaviour and emotion regulation difficulties and behavioural problems269. in turn, child behavioural problems (especially externalizing problems) contribute to increased maternal stress267,270 or challenges with raising the child (owing to, for example, the child’s difficulties with social skills or obsessions)271. the discrepancy between the general perception that children with ws are happy and have ‘easy’ temperaments and the reality that most children with ws have relatively difficult temperaments is in itself likely to increase maternal stress227. worries regarding the child’s future are very common among family members and mothers in particular231,271,272. at the same time, most mothers also reported positive aspects of having a child with ws, including that the child brought joy and changed the mother’s outlook on life271 (box 1). molly (not her real name) is a 30 year old woman with williams syndrome who lives with her parents in a rural town in australia. she has mild to moderate intellectual disability and the typical williams syndrome personality. she completed school in a mainstream setting for the first six years, then moved to a special school. she currently works 3 days a week in sheltered employment after failed attempts to work in mainstream employment due to bullying. molly enjoys music, softball and line dancing. molly has struggled with many of the medical and psychological difficulties associated with williams syndrome, but due to her determined nature and strong family support, she has made many wonderful life achievements. please see supplementary box 3 for the full interview. interviewer: do you feel that others treat you any differently because you have williams syndrome? molly: the way people talk to you is different, and they talk to mum instead of me… about my medical things …and i am like: “hello, i am over here. mum doesn’t have williams syndrome. i do”. interviewer: what are the good things about having williams syndrome? molly: i make people laugh and feel good. at home i am demanding. i love older people and their stories. i love to hear what they were up to back in the day. interviewer: what are the not so good/hard things about having williams syndrome? molly: lots of people don’t know about williams syndrome. most doctors don’t know about williams syndrome. when i go to hospital, i always take an information sheet [about williams syndrome]. i get bullied a lot. i think because of the way… oh this makes me feel sad… (now teary) …i think because of the way i act some people don’t realise it is hard to always be happy. i know this might sound stupid, but i can’t tie my shoelaces. i wear shoes with elasticated shoelaces. interviewer: what is the biggest thing that having a child with williams syndrome has taught you? parent: the biggest thing we have learnt is that a person with williams syndrome is no different to you and me. we all have different personalities, have different needs and process information differently. we have a greater level of acceptance and empathy by having a person with williams syndrome in our lives. interviewer: what have been the major challenges associated with having a daughter with williams syndrome? parent: at first it is hectic. appointments are on going and seem to be never ending. you are always planning for the next stage. learning how to feed and care for your child with williams syndrome is the first step. then moving on to therapy and the first stage of learning with early intervention and transition to school. also, stranger danger is a big concern as molly accepts everyone as her best friend. interviewer: what is your take home message to new parents of a child with williams syndrome? parent: don’t be afraid to ask for support especially in the early years as there are times that you will be overwhelmed but as time goes on the positives can outweigh the negatives. interviewer: what are the three main points you want to make about williams syndrome? parent: williams syndrome is challenging but can be rewarding. the person with williams syndrome is just like you and i but processes information slower. we just need to be more accepting, tolerant, non judgmental. treat a person with williams syndrome with respect. much has been learned about ws since its initial description, but important questions remain (box 2). these questions centre on three major themes: molecular mechanisms of disease, interindividual variability and effective treatment strategies. a more complete understanding of the genes and pathways contributing to the phenotypes of individuals with ws would allow clinicians to move beyond symptom management and to instead use precisely targeted therapies to improve organ function and ultimately health outcomes. how do health needs change for individuals with ws across the lifespan? what recommendations can be made to optimize health of older individuals with ws? do different pathologies arise in ws at different developmental stages, and are any reversible? if treatments are designed targeting early processes, will this “normalize” future outcomes, or will it be necessary to target multiple stages and processes? what are the biological and environmental contributors to variability in outcomes in ws? how do the ~20 wscr genes without a specific phenotype designation affect health and development in people with ws? how should the combinatorial effects of multiple genes on disease variability be assessed? how does variability in wscr genes contribute to phenotypic variability in the general population? what are the developmental neuropathological mechanisms underlying social and anxiety related behaviour impairments in ws? what factors impact transcription, translation, and deposition of elastin? can those genes or pathways be harnessed to appropriately re initiate elastin deposition outside of its normal developmental window? what underlies metabolic differences in ws, such as glucose dysregulation, aberrant growth and aberrant body composition? how do changes in the genes contributing to these phenotypes affect health for people with and without ws? what interventions (medical, psychological or behavioural) would best improve quality of life for people with ws, especially pertaining to anxiety, mastery motivation and social vulnerability? should hypertension be aggressively treated in ws? what is the effect on short term end organ perfusion and longer term organ function? what risk factors for adverse anaesthesia events need further refinement, such that management guidelines can be generated and widely shared? how can resources be developed to facilitate collaborative data collection and treatment trial coordination to optimize delivery of new treatments for people with ws? to date, only eln, gtf2i and gtf2ird1 have been definitively linked to key phenotypes that are identifiable in individuals with ws, but even for these genes, a significant knowledge gap between disease phenotype and gene function remains. for example, published literature has not yet clarified whether the global vascular narrowing seen in ws is driven by changes in cell proliferation99, radial growth of the vessel102 or alteration in cell matrix interactions. in addition, the characteristic hourglass type stenosis feature in ws seems to be driven by entirely different mechanisms than the more general narrow and stiff vessel pathology seen throughout the rest of the vasculature7,97. while for gtf2i and gtf2ird1, clear effects on brain development and function are evident, the direct effect of reduced gene products on neural circuits, white matter properties273, developmental timing and brain activity is unknown. to answer these questions, further studies on the roles of individual genes in human pathophysiology, at the cellular and molecular level, and in model systems are needed. in humans, a traditional approach has been to clinically characterize individuals with smaller wscr deletions, in an effort to create more specificity for the traits associated with each gene (figure 3). currently, clinical exome and whole genome sequencing are being used to identify rare single gene variation in individuals with phenotypes that overlap with ws (a phenotype to gene approach). in the future, the move toward big data and genotype first methods (a gene to phenotype approach) may offer new hope in the identification and further refinement of genotype phenotype relationships that are part of the complex multisystem disorder of ws. further clarification of gene function can be obtained from studies in model systems. cell systems offer ease of manipulation and provide precise ways to study protein protein interactions and gene expression. however, they lack much of the complexity (for example, multiple cell types, tissue movement and endocrine signaling) needed to truly model human disease. similarly, animal models (usually mice) may imperfectly match human disease outcomes; for example, the eln+/  mouse does not have svas and, in the case of cognitive conditions, mouse behaviours may incompletely or inaccurately correspond to human behaviours. the advent of ipscs, tissue engineering and ‘organs in a dish’ may offer the potential to bridge some of the gaps that are present in traditional cell culture systems68,69,274 276. as in all disease modeling, the biggest challenge lies in the ability of the in vitro system to truly mimic the complex in vivo environment. brain organoids have shown promise for modeling developmental disorders such as autism and epilepsy277,278. vascular organoids279 and numerous tissue engineering approaches 280 are being applied to the study of blood vessels.progress is being made but it has been difficult to design complex vascular tissues that deposit mechanically competent and mature elastin281,282. rapid improvement in these systems is expected in the coming years as more precise genetic approaches to adapting both cellular and animal systems facilitate the study of specific outcomes. phenotypic variation is readily apparent in ws, despite the vast majority of individuals carrying the typical 1.55 1.83 mb ws deletion. currently, the mechanisms underlying this variability are mostly unknown. it is likely that both environmental factors and genetic modifiers contribute to the overall penetrance of specific signs and symptoms in an individual with ws. the study of polygenic risk is still in its relative infancy but offers essential insight into features of ws that overlap with common health conditions in the general population283,284. variation in genes that globally influence hypertension or iq, for example, likely act together with genes in the wscr in additive and synergistic ways to produce much of the observed variation285. in this way, the study of genetic modifiers in individuals with microdeletion disorders may offer a shortcut to identify relevant disease pathways by acting as a sensitivity screen of sorts, with the notable downside being the difficulty of acquiring truly robust sample sizes. sets of polygenic risk genes for more unique ws features (such as svas or odynacusis286) are currently unavailable, but if identified, they may provide insight into targetable pathways that could impact these important outcomes. for example, ~20% of all individuals with ws require surgical correction for svas, but if it has been established that those who do need surgery have a variation in a particular pathway, treatment could be targeted to the modifier pathway rather that to elastin insufficiency itself. some work has already been initiated in this area29 but larger studies covering a broader racial and ethnic distribution are needed. other, understudied areas of potential variation include epigenetic effects and somatic variation. in addition, little is known about how differences in the flanking lcr regions, which are difficult to study by current short read sequencing methods, may affect disease outcomes. another area requiring further study is environmental influences, prenatally and throughout life, on disease outcomes. the gut microbiome, which is potentially affected by feeding difficulties, early hospitalizations and increased medication use, also deserves consideration. environment and gene x environment interactions, in particular, are likely to play a crucial role in educational achievement14,244,246,247 and adaptive functional outcomes 13,223,249. treatment strategies can be designed using a variety of approaches: targeting the genes and/or gene products themselves, targeting functional pathways and aiming to treat disease symptoms and signs. for the gene based strategies, crispr  and viral vector based gene therapy technologies287,288 are currently being studied in other rare conditions289,290. however, unlike single gene diseases, microdeletion disorders such as ws offer particular challenges that relate to the large size of the material to be delivered and the sheer number of locations where the genes would need to be targeted to alter relevant phenotypes. it is possible that a subset of genes could be delivered using the methods previously described, which may improve efficiency of delivery and function. however, it is known that the 7q11.23 duplication syndrome149,291results from increased dosage of at least some of the genes in the wscr, and therefore any therapeutic approach must involve carefully regulated gene expression or protein replacement. although the ability to identify and modify target genes, either in utero or in early postnatal stages, offers the potential to greatly improve precise treatment in ws, much work is required before this strategy becomes a reality. in the coming years, therapies are expected based on individual genes or pathways that are known to be important for influencing phenotype in ws. studies in mouse models, for example, suggest that anti mirnas (such as anti mir29a) may be useful for increasing elastin deposition211 and that influencing smooth muscle cell behaviour using inhibitors of mtor106 or integrin β3101 could improve the vascular features of ws. moreover, new pharmacological strategies targeting myelination have been proposed for improving neural outcomes143. however, each of these potential strategies comes with challenges in delivery, specificity or longevity. for example, mir29a regulates multiple transcripts, so although anti mir29a administration may lead to increased elastin message stability (and therefore increased translation)211, other transcripts bound by mir29a may also be affected, potentially leading to other complications. development of additional (non rodent) ws models may be useful preclinical modalities prior to initiation of human trials. as people with ws retain one copy of each gene from the wscr, future studies could be aimed at developing methods to target and upregulate expression of the remaining allele. additionally, patient derived ipscs may soon offer platforms through which to test novel therapeutics for impact on unique ws transcriptional pathways and phenotypes. initial investigations incorporating this technology have been used to screen for medications that impact the increased smooth muscle cell proliferation seen in ws105. rather than a goal of preventing stenosis, future studies that focus on resolving or reducing existing stenoses may be more relevant to treatment and lead to improved clinical outcomes, especially in young children who often come to medical attention with stenosis already present. when ips cells or gene edited versions thereof are being considered as deliverable therapeutics themselves, the timing and delivery mechanisms will be critically important. in the interim, clinicians manage specific symptoms in individuals with ws (such as hypertension, anxiety, and hypercalcaemia) using medications and interventions that have been developed for these indications in the general population, without knowing if the mechanism of disease in ws is the same. for example, several classes of antihypertensive drugs are available, and monotherapy or polytherapy can reduce blood pressure in most individuals with ws. however, the targeting of these drugs is not mechanism based, and formal studies on which medications in these classes are best for symptom control in the ws population are lacking214. the mechanistic and modifier studies previously defined could help narrow the options needed to pursue hypothesis driven clinical trials. for the near term, longitudinal studies, as well as open label and double blind randomized clinical trials, on common and high impact medical and behavioral problems are needed, the findings from which could provide valuable clinical algorithms to guide treatment. to improve health outcomes for people with ws, a multifaceted approach is needed that brings together more investigators with expertise in the range of conditions and genes represented in ws. newer topics, such as metabolic and immune differences29,66,190 in ws, are also in need of innovators. funding is required to allow for the creation of a large international consortium that will collect prospective standardized data focused on the most relevant questions in ws and will incentivize the broad sharing of data acquired in diverse populations. such a consortium will allow more rapid collection and dissemination of natural history data, which are needed to understand long term outcomes and to choose appropriate endpoints for subsequent clinical trials. in addition, biospecimen collection can be optimized by the same mechanism. ultimately, clinical trials focusing on therapies are critically needed to increase qol for individuals with ws and their families. the authors thank the anonymous individual with ws and her parents who provided the family experience interview, as well as those who provided facial photographs in figure 5 and supplementary table 1. b.a.k. was supported by the department of intramural research the national heart, lung and blood institute of the national institutes of health. cam was supported by the williams syndrome association (grant number 0111). b.r.p. was supported by the williams syndrome association, and the williams syndrome charitable foundation, usa. m.p. was funded by williams syndrome australia limited. b.b. was funded by the fritz thyssen stiftung and the israel science foundation (grant no.2305/20). l.r.o. was supported by a canada research chair in the genetics of neurodevelopmental disorders. c.a.e.k. was supported by fapesp 2019/21644 0 and cnpq 304897/2020 5. the authors thank z. urban for discussion of elastin biology and management strategies for vascular disease in ws. the authors thank the persons with ws and their families belonging to the associação brasileira de síndrome de williams, canadian association for williams syndrome, williams syndrome australia limited, and williams syndrome association (usa) for continued participation in studies and support of research that allows knowledge of ws to grow. competing interests the authors declare no conflicts of interest. informed consent the authors affirm that human research participants provided informed consent for: publication of the photographs in figure 5; publication of photographs in supplementary table 1; and taking part in the family experience interview. peer review information nature reviews disease primers thanks a. selicorni, d. gothelf, p. ortiz romero (v. campuzano), j. van herwegen and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. supplementary information supplementary information is available for this paper at https://doi.org/10.1038/s415xx xxx xxxx x this section collects any data citations, data availability statements, or supplementary materials included in this article. connect with nlm national library of medicine 8600 rockville pike bethesda, md 20894

major depressive disorder (mdd), also known as clinical depression, is a mental disorder[9] characterized by at least two weeks of pervasive low mood, low self esteem, and loss of interest or pleasure in normally enjoyable activities. introduced by a group of us clinicians in the mid 1970s,[10] the term was adopted by the american psychiatric association for this symptom cluster under mood disorders in the 1980 version of the diagnostic and statistical manual of mental disorders (dsm iii), and has become widely used since. the disorder causes the second most years lived with disability, after lower back pain.[11] the diagnosis of major depressive disorder is based on the person's reported experiences, behavior reported by family or friends, and a mental status examination.[12] there is no laboratory test for the disorder, but testing may be done to rule out physical conditions that can cause similar symptoms.[12] the most common time of onset is in a person's 20s,[3][4] with females affected about three times as often as males.[13] the course of the disorder varies widely, from one episode lasting months to a lifelong disorder with recurrent major depressive episodes. those with major depressive disorder are typically treated with psychotherapy and antidepressant medication.[1] medication appears to be effective, but the effect may be significant only in the most severely depressed.[14][15] hospitalization (which may be involuntary) may be necessary in cases with associated self neglect or a significant risk of harm to self or others. electroconvulsive therapy (ect) may be considered if other measures are not effective.[1] major depressive disorder is believed to be caused by a combination of genetic, environmental, and psychological factors,[1] with about 40% of the risk being genetic.[5] risk factors include a family history of the condition, major life changes, childhood traumas, environmental lead exposure,[16] certain medications, chronic health problems, and substance use disorders.[1][5] it can negatively affect a person's personal life, work life, or education, and cause issues with a person's sleeping habits, eating habits, and general health.[1][5] a person having a major depressive episode usually exhibits a low mood, which pervades all aspects of life, and an inability to experience pleasure in previously enjoyable activities.[17] depressed people may be preoccupied with or ruminate over thoughts and feelings of worthlessness, inappropriate guilt or regret, helplessness or hopelessness.[18] other symptoms of depression include poor concentration and memory,[19] withdrawal from social situations and activities, reduced sex drive, irritability, and thoughts of death or suicide. insomnia is common; in the typical pattern, a person wakes very early and cannot get back to sleep. hypersomnia, or oversleeping, can also happen,[20] as well as day night rhythm disturbances, such as diurnal mood variation.[21] some antidepressants may also cause insomnia due to their stimulating effect.[22] in severe cases, depressed people may have psychotic symptoms. these symptoms include delusions or, less commonly, hallucinations, usually unpleasant.[23] people who have had previous episodes with psychotic symptoms are more likely to have them with future episodes.[24] a depressed person may report multiple physical symptoms such as fatigue, headaches, or digestive problems; physical complaints are the most common presenting problem in developing countries, according to the world health organization's criteria for depression.[25] appetite often decreases, resulting in weight loss, although increased appetite and weight gain occasionally occur.[26] major depression significantly affects a person's family and personal relationships, work or school life, sleeping and eating habits, and general health.[27] family and friends may notice agitation or lethargy.[20] older depressed people may have cognitive symptoms of recent onset, such as forgetfulness,[28] and a more noticeable slowing of movements.[29] depressed children may often display an irritable rather than a depressed mood;[20] most lose interest in school and show a steep decline in academic performance.[30] diagnosis may be delayed or missed when symptoms are interpreted as "normal moodiness".[26] elderly people may not present with classical depressive symptoms.[31] diagnosis and treatment is further complicated in that the elderly are often simultaneously treated with a number of other drugs, and often have other concurrent diseases.[31] the etiology of depression is not yet fully understood.[33][34][35][36] the biopsychosocial model proposes that biological, psychological, and social factors all play a role in causing depression.[5][37] the diathesis stress model specifies that depression results when a preexisting vulnerability, or diathesis, is activated by stressful life events. the preexisting vulnerability can be either genetic,[38][39] implying an interaction between nature and nurture, or schematic, resulting from views of the world learned in childhood.[40] american psychiatrist aaron beck suggested that a triad of automatic and spontaneous negative thoughts about the self, the world or environment, and the future may lead to other depressive signs and symptoms.[41][42] genes play a major role in the development of depression.[43] family and twin studies find that nearly 40% of individual differences in risk for major depressive disorder can be explained by genetic factors.[44] like most psychiatric disorders, major depressive disorder is likely influenced by many individual genetic changes.[45] in 2018, a genome wide association study discovered 44 genetic variants linked to risk for major depression;[46] a 2019 study found 102 variants in the genome linked to depression.[47] however, it appears that major depression is less heritable compared to bipolar disorder and schizophrenia.[48][49] research focusing on specific candidate genes has been criticized for its tendency to generate false positive findings.[50] there are also other efforts to examine interactions between life stress and polygenic risk for depression.[51] depression can also arise after a chronic or terminal medical condition, such as hiv/aids or asthma, and may be labeled "secondary depression".[52][53] it is unknown whether the underlying diseases induce depression through effect on quality of life, or through shared etiologies (such as degeneration of the basal ganglia in parkinson's disease or immune dysregulation in asthma).[54] depression may also be iatrogenic (the result of healthcare), such as drug induced depression. therapies associated with depression include interferons, beta blockers, isotretinoin, contraceptives,[55] cardiac agents, anticonvulsants, antimigraine drugs, antipsychotics, and hormonal agents such as gonadotropin releasing hormone agonist (gnrh agonist).[56] celiac disease is another possible contributing factor.[57] substance use in early age is associated with increased risk of developing depression later in life.[58] depression occurring after giving birth is called postpartum depression and is thought to be the result of hormonal changes associated with pregnancy.[59] seasonal affective disorder, a type of depression associated with seasonal changes in sunlight, is thought to be triggered by decreased sunlight.[60] vitamin b2, b6 and b12 deficiency may cause depression in females.[61] adverse childhood experiences (incorporating childhood abuse, neglect and family dysfunction) markedly increase the risk of major depression, especially if more than one type.[5] childhood trauma also correlates with severity of depression, poor responsiveness to treatment and length of illness. some are more susceptible than others to developing mental illness such as depression after trauma, and various genes have been suggested to control susceptibility.[62] couples in unhappy marriages have a higher risk of developing clinical depression.[63] there appears to be a link between air pollution and depression and suicide. there may be an association between long term pm2.5 exposure and depression, and a possible association between short term pm10 exposure and suicide.[64] the pathophysiology of depression is not completely understood, but current theories center around monoaminergic systems, the circadian rhythm, immunological dysfunction, hpa axis dysfunction and structural or functional abnormalities of emotional circuits. derived from the effectiveness of monoaminergic drugs in treating depression, the monoamine theory posits that insufficient activity of monoamine neurotransmitters is the primary cause of depression. evidence for the monoamine theory comes from multiple areas. first, acute depletion of tryptophan a necessary precursor of serotonin and a monoamine can cause depression in those in remission or relatives of people who are depressed, suggesting that decreased serotonergic neurotransmission is important in depression.[65] second, the correlation between depression risk and polymorphisms in the 5 httlpr gene, which codes for serotonin receptors, suggests a link. third, decreased size of the locus coeruleus, decreased activity of tyrosine hydroxylase, increased density of alpha 2 adrenergic receptor, and evidence from rat models suggest decreased adrenergic neurotransmission in depression.[66] furthermore, decreased levels of homovanillic acid, altered response to dextroamphetamine, responses of depressive symptoms to dopamine receptor agonists, decreased dopamine receptor d1 binding in the striatum,[67] and polymorphism of dopamine receptor genes implicate dopamine, another monoamine, in depression.[68][69] lastly, increased activity of monoamine oxidase, which degrades monoamines, has been associated with depression.[70] however, the monoamine theory is inconsistent with observations that serotonin depletion does not cause depression in healthy persons, that antidepressants instantly increase levels of monoamines but take weeks to work, and the existence of atypical antidepressants which can be effective despite not targeting this pathway.[71] one proposed explanation for the therapeutic lag, and further support for the deficiency of monoamines, is a desensitization of self inhibition in raphe nuclei by the increased serotonin mediated by antidepressants.[72] however, disinhibition of the dorsal raphe has been proposed to occur as a result of decreased serotonergic activity in tryptophan depletion, resulting in a depressed state mediated by increased serotonin. further countering the monoamine hypothesis is the fact that rats with lesions of the dorsal raphe are not more depressive than controls, the finding of increased jugular 5 hiaa in people who are depressed that normalized with selective serotonin reuptake inhibitor (ssri) treatment, and the preference for carbohydrates in people who are depressed.[73] already limited, the monoamine hypothesis has been further oversimplified when presented to the general public.[74] a 2022 review found no consistent evidence supporting the serotonin hypothesis, linking serotonin levels and depression.[75] hpa axis abnormalities have been suggested in depression given the association of crhr1 with depression and the increased frequency of dexamethasone test non suppression in people who are depressed. however, this abnormality is not adequate as a diagnosis tool, because its sensitivity is only 44%.[76] these stress related abnormalities are thought to be the cause of hippocampal volume reductions seen in people who are depressed.[77] furthermore, a meta analysis yielded decreased dexamethasone suppression, and increased response to psychological stressors.[78] further abnormal results have been obscured with the cortisol awakening response, with increased response being associated with depression.[79] there is also a connection between the gut microbiome and the central nervous system, otherwise known as the gut brain axis, which is a two way communication system between the brain and the gut. experiments have shown that microbiota in the gut can play an important role in depression as people with mdd often have gut brain dysfunction. one analysis showed that those with mdd have different bacteria living in their guts. bacteria bacteroidetes and firmicutes were most affected in people with mdd, and they are also impacted in people with irritable bowel syndrome.[80] another study showed that people with ibs have a higher chance of developing depression, which shows the two are connected.[81] there is even evidence suggesting that altering the microbes in the gut can have regulatory effects on developing depression.[80] theories unifying neuroimaging findings have been proposed. the first model proposed is the limbic cortical model, which involves hyperactivity of the ventral paralimbic regions and hypoactivity of frontal regulatory regions in emotional processing.[82] another model, the cortico striatal model, suggests that abnormalities of the prefrontal cortex in regulating striatal and subcortical structures result in depression.[83] another model proposes hyperactivity of salience structures in identifying negative stimuli, and hypoactivity of cortical regulatory structures resulting in a negative emotional bias and depression, consistent with emotional bias studies.[84] the newer field of psychoneuroimmunology, the study between the immune system and the nervous system and emotional state, suggests that cytokines may impact depression. immune system abnormalities have been observed, including increased levels of cytokines  cells produced by immune cells that affect inflammation  involved in generating sickness behavior, creating a pro inflammatory profile in mdd.[85][86][87] some people with depression have increased levels of pro inflammatory cytokines and some have decreased levels of anti inflammatory cytokines.[88] research suggests that treatments can reduce pro inflammatory cell production, like the experimental treatment of ketamine with treatment resistant depression.[89] with this, in mdd, people will more likely have a th 1 dominant immune profile, which is a pro inflammatory profile. this suggests that there are components of the immune system affecting the pathology of mdd.[90] another way cytokines can affect depression is in the kynurenine pathway, and when this is overactivated, it can cause depression. this can be due to too much microglial activation and too little astrocytic activity. when microglia get activated, they release pro inflammatory cytokines that cause an increase in the production of cox2. this, in turn, causes the production of pge2, which is a prostaglandin, and this catalyzes the production of indolamine, ido. ido causes tryptophan to get converted into kynurenine and kynurenine becomes quinolinic acid.[91] quinolinic acid is an agonist for nmda receptors, so it activates the pathway. studies have shown that the post mortem brains of patients with mdd have higher levels of quinolinic acid than people who did not have mdd. with this, researchers have also seen that the concentration of quinolinic acid correlates to the severity of depressive symptoms.[92] a diagnostic assessment may be conducted by a suitably trained general practitioner, or by a psychiatrist or psychologist,[27] who records the person's current circumstances, biographical history, current symptoms, family history, and alcohol and drug use. the assessment also includes a mental state examination, which is an assessment of the person's current mood and thought content, in particular the presence of themes of hopelessness or pessimism, self harm or suicide, and an absence of positive thoughts or plans.[27] specialist mental health services are rare in rural areas, and thus diagnosis and management is left largely to primary care clinicians.[93] this issue is even more marked in developing countries.[94] rating scales are not used to diagnose depression, but they provide an indication of the severity of symptoms for a time period, so a person who scores above a given cut off point can be more thoroughly evaluated for a depressive disorder diagnosis. several rating scales are used for this purpose;[95] these include the hamilton rating scale for depression,[96] the beck depression inventory[97] or the suicide behaviors questionnaire revised.[98] primary care physicians have more difficulty with underrecognition and undertreatment of depression compared to psychiatrists. these cases may be missed because for some people with depression, physical symptoms often accompany depression. in addition, there may also be barriers related to the person, provider, and/or the medical system. non psychiatrist physicians have been shown to miss about two thirds of cases, although there is some evidence of improvement in the number of missed cases.[99] a doctor generally performs a medical examination and selected investigations to rule out other causes of depressive symptoms. these include blood tests measuring tsh and thyroxine to exclude hypothyroidism; basic electrolytes and serum calcium to rule out a metabolic disturbance; and a full blood count including esr to rule out a systemic infection or chronic disease.[100] adverse affective reactions to medications or alcohol misuse may be ruled out, as well. testosterone levels may be evaluated to diagnose hypogonadism, a cause of depression in men.[101] vitamin d levels might be evaluated, as low levels of vitamin d have been associated with greater risk for depression.[102] subjective cognitive complaints appear in older depressed people, but they can also be indicative of the onset of a dementing disorder, such as alzheimer's disease.[103][104] cognitive testing and brain imaging can help distinguish depression from dementia.[105] a ct scan can exclude brain pathology in those with psychotic, rapid onset or otherwise unusual symptoms.[106] no biological tests confirm major depression.[107] in general, investigations are not repeated for a subsequent episode unless there is a medical indication. the most widely used criteria for diagnosing depressive conditions are found in the american psychiatric association's diagnostic and statistical manual of mental disorders (dsm) and the world health organization's international statistical classification of diseases and related health problems (icd). the latter system is typically used in european countries, while the former is used in the us and many other non european nations,[108] and the authors of both have worked towards conforming one with the other.[109] both dsm and icd mark out typical (main) depressive symptoms.[110] the most recent edition of the dsm is the fifth edition, text revision (dsm 5 tr),[111] and the most recent edition of the icd is the eleventh edition (icd 11).[112] under mood disorders, icd 11 classifies major depressive disorder as either single episode depressive disorder (where there is no history of depressive episodes, or of mania) or recurrent depressive disorder (where there is a history of prior episodes, with no history of mania).[113] icd 11 symptoms, present nearly every day for at least two weeks, are a depressed mood or anhedonia, accompanied by other symptoms such as "difficulty concentrating, feelings of worthlessness or excessive or inappropriate guilt, hopelessness, recurrent thoughts of death or suicide, changes in appetite or sleep, psychomotor agitation or retardation, and reduced energy or fatigue."[113] these symptoms must affect work, social, or domestic activities. the icd 11 system allows further specifiers for the current depressive episode: the severity (mild, moderate, severe, unspecified); the presence of psychotic symptoms (with or without psychotic symptoms); and the degree of remission if relevant (currently in partial remission, currently in full remission).[113] these two disorders are classified as "depressive disorders", in the category of "mood disorders".[113] according to dsm 5, at least one of the symptoms is either depressed mood or loss of interest or pleasure. depressed mood occurs nearly every day as subjective feelings like sadness, emptiness, and hopelessness or observations made by others (e.g. appears tearful). loss of interest or pleasure occurs in all, or almost all activities of the day, nearly every day. these symptoms, as well as five out of the nine more specific symptoms listed, must frequently occur for more than two weeks (to the extent in which it impairs functioning) for the diagnosis.[114][115][failed verification] major depressive disorder is classified as a mood disorder in the dsm 5.[116] the diagnosis hinges on the presence of single or recurrent major depressive episodes.[117] further qualifiers are used to classify both the episode itself and the course of the disorder. the category unspecified depressive disorder is diagnosed if the depressive episode's manifestation does not meet the criteria for a major depressive episode.[116] a major depressive episode is characterized by the presence of a severely depressed mood that persists for at least two weeks.[26] episodes may be isolated or recurrent and are categorized as mild (few symptoms in excess of minimum criteria), moderate, or severe (marked impact on social or occupational functioning). an episode with psychotic features commonly referred to as psychotic depression is automatically rated as severe.[116] if the person has had an episode of mania or markedly elevated mood, a diagnosis of bipolar disorder is made instead. depression without mania is sometimes referred to as unipolar because the mood remains at one emotional state or "pole".[118] bereavement is not an exclusion criterion in the dsm 5, and it is up to the clinician to distinguish between normal reactions to a loss and mdd. excluded are a range of related diagnoses, including dysthymia, which involves a chronic but milder mood disturbance;[119] recurrent brief depression, consisting of briefer depressive episodes;[120][121] minor depressive disorder, whereby only some symptoms of major depression are present;[122] and adjustment disorder with depressed mood, which denotes low mood resulting from a psychological response to an identifiable event or stressor.[123] the dsm 5 recognizes six further subtypes of mdd, called specifiers, in addition to noting the length, severity and presence of psychotic features: to confirm major depressive disorder as the most likely diagnosis, other potential diagnoses must be considered, including dysthymia, adjustment disorder with depressed mood, or bipolar disorder. dysthymia is a chronic, milder mood disturbance in which a person reports a low mood almost daily over a span of at least two years. the symptoms are not as severe as those for major depression, although people with dysthymia are vulnerable to secondary episodes of major depression (sometimes referred to as double depression).[119] adjustment disorder with depressed mood is a mood disturbance appearing as a psychological response to an identifiable event or stressor, in which the resulting emotional or behavioral symptoms are significant but do not meet the criteria for a major depressive episode.[123] other disorders need to be ruled out before diagnosing major depressive disorder. they include depressions due to physical illness, medications, and substance use disorders. depression due to physical illness is diagnosed as a mood disorder due to a general medical condition. this condition is determined based on history, laboratory findings, or physical examination. when the depression is caused by a medication, non medical use of a psychoactive substance, or exposure to a toxin, it is then diagnosed as a specific mood disorder (previously called substance induced mood disorder).[129] preventive efforts may result in decreases in rates of the condition of between 22 and 38%.[130] since 2016, the united states preventive services task force (uspstf) has recommended screening for depression among those over the age 12;[131][132] though a 2005 cochrane review found that the routine use of screening questionnaires has little effect on detection or treatment.[133] screening the general population is not recommended by authorities in the uk or canada.[134] behavioral interventions, such as interpersonal therapy and cognitive behavioral therapy, are effective at preventing new onset depression.[130][135][136] because such interventions appear to be most effective when delivered to individuals or small groups, it has been suggested that they may be able to reach their large target audience most efficiently through the internet.[137] the netherlands mental health care system provides preventive interventions, such as the "coping with depression" course (cwd) for people with sub threshold depression. the course is claimed to be the most successful of psychoeducational interventions for the treatment and prevention of depression (both for its adaptability to various populations and its results), with a risk reduction of 38% in major depression and an efficacy as a treatment comparing favorably to other psychotherapies.[135][138] the most common and effective treatments for depression are psychotherapy, medication, and electroconvulsive therapy (ect); a combination of treatments is the most effective approach when depression is resistant to treatment.[139] american psychiatric association treatment guidelines recommend that initial treatment should be individually tailored based on factors including severity of symptoms, co existing disorders, prior treatment experience, and personal preference. options may include pharmacotherapy, psychotherapy, exercise, ect, transcranial magnetic stimulation (tms) or light therapy. antidepressant medication is recommended as an initial treatment choice in people with mild, moderate, or severe major depression, and should be given to all people with severe depression unless ect is planned.[140] there is evidence that collaborative care by a team of health care practitioners produces better results than routine single practitioner care.[141] psychotherapy is the treatment of choice (over medication) for people under 18,[142] and cognitive behavioral therapy (cbt), third wave cbt and interpersonal therapy may help prevent depression.[143] the uk national institute for health and care excellence (nice) 2004 guidelines indicate that antidepressants should not be used for the initial treatment of mild depression because the risk benefit ratio is poor. the guidelines recommend that antidepressants treatment in combination with psychosocial interventions should be considered for:[142] the guidelines further note that antidepressant treatment should be continued for at least six months to reduce the risk of relapse, and that ssris are better tolerated than tricyclic antidepressants.[142] treatment options are more limited in developing countries, where access to mental health staff, medication, and psychotherapy is often difficult. development of mental health services is minimal in many countries; depression is viewed as a phenomenon of the developed world despite evidence to the contrary, and not as an inherently life threatening condition.[144] there is insufficient evidence to determine the effectiveness of psychological versus medical therapy in children.[145] physical exercise has been found to be effective for major depression, and may be recommended to people who are willing, motivated, and healthy enough to participate in an exercise program as treatment.[146] it is equivalent to the use of medications or psychological therapies in most people.[7] in older people it does appear to decrease depression.[147] sleep and diet may also play a role in depression, and interventions in these areas may be an effective add on to conventional methods.[148] in observational studies, smoking cessation has benefits in depression as large as or larger than those of medications.[149] talking therapy (psychotherapy) can be delivered to individuals, groups, or families by mental health professionals, including psychotherapists, psychiatrists, psychologists, clinical social workers, counselors, and psychiatric nurses. a 2012 review found psychotherapy to be better than no treatment but not other treatments.[150] with more complex and chronic forms of depression, a combination of medication and psychotherapy may be used.[151][152] there is moderate quality evidence that psychological therapies are a useful addition to standard antidepressant treatment of treatment resistant depression in the short term.[153] psychotherapy has been shown to be effective in older people.[154][155] successful psychotherapy appears to reduce the recurrence of depression even after it has been stopped or replaced by occasional booster sessions. the most studied form of psychotherapy for depression is cbt, which teaches clients to challenge self defeating, but enduring ways of thinking (cognitions) and change counter productive behaviors. cbt can perform as well as antidepressants in people with major depression.[156] cbt has the most research evidence for the treatment of depression in children and adolescents, and cbt and interpersonal psychotherapy (ipt) are preferred therapies for adolescent depression.[157] in people under 18, according to the national institute for health and clinical excellence, medication should be offered only in conjunction with a psychological therapy, such as cbt, interpersonal therapy, or family therapy.[158] several variables predict success for cognitive behavioral therapy in adolescents: higher levels of rational thoughts, less hopelessness, fewer negative thoughts, and fewer cognitive distortions.[159] cbt is particularly beneficial in preventing relapse.[160][161] cognitive behavioral therapy and occupational programs (including modification of work activities and assistance) have been shown to be effective in reducing sick days taken by workers with depression.[162] several variants of cognitive behavior therapy have been used in those with depression, the most notable being rational emotive behavior therapy,[163] and mindfulness based cognitive therapy.[164] mindfulness based stress reduction programs may reduce depression symptoms.[165][166] mindfulness programs also appear to be a promising intervention in youth.[167] problem solving therapy, cognitive behavioral therapy, and interpersonal therapy are effective interventions in the elderly.[168] psychoanalysis is a school of thought, founded by sigmund freud, which emphasizes the resolution of unconscious mental conflicts.[169] psychoanalytic techniques are used by some practitioners to treat clients presenting with major depression.[170] a more widely practiced therapy, called psychodynamic psychotherapy, is in the tradition of psychoanalysis but less intensive, meeting once or twice a week. it also tends to focus more on the person's immediate problems, and has an additional social and interpersonal focus.[171] in a meta analysis of three controlled trials of short psychodynamic supportive psychotherapy, this modification was found to be as effective as medication for mild to moderate depression.[172] conflicting results have arisen from studies that look at the effectiveness of antidepressants in people with acute, mild to moderate depression.[173] a review commissioned by the national institute for health and care excellence (uk) concluded that there is strong evidence that ssris, such as escitalopram, paroxetine, and sertraline, have greater efficacy than placebo on achieving a 50% reduction in depression scores in moderate and severe major depression, and that there is some evidence for a similar effect in mild depression.[174] similarly, a cochrane systematic review of clinical trials of the generic tricyclic antidepressant amitriptyline concluded that there is strong evidence that its efficacy is superior to placebo.[175] antidepressants work less well for the elderly than for younger individuals with depression.[168] to find the most effective antidepressant medication with minimal side effects, the dosages can be adjusted, and if necessary, combinations of different classes of antidepressants can be tried. response rates to the first antidepressant administered range from 50 to 75%, and it can take at least six to eight weeks from the start of medication to improvement.[140][176] antidepressant medication treatment is usually continued for 16 to 20 weeks after remission, to minimize the chance of recurrence,[140] and even up to one year of continuation is recommended.[177] people with chronic depression may need to take medication indefinitely to avoid relapse.[27] ssris are the primary medications prescribed, owing to their relatively mild side effects, and because they are less toxic in overdose than other antidepressants.[178] people who do not respond to one ssri can be switched to another antidepressant, and this results in improvement in almost 50% of cases.[179] another option is to augment the atypical antidepressant bupropion to the ssri as an adjunctive treatment.[180] venlafaxine, an antidepressant with a different mechanism of action, may be modestly more effective than ssris.[181] however, venlafaxine is not recommended in the uk as a first line treatment because of evidence suggesting its risks may outweigh benefits,[182] and it is specifically discouraged in children and adolescents as it increases the risk of suicidal thoughts or attempts.[183][184][185][186][187][188][189] for children and adolescents with moderate to severe depressive disorder, fluoxetine seems to be the best treatment (either with or without cognitive behavioural therapy) but more research is needed to be certain.[190][184][191][185] sertraline, escitalopram, duloxetine might also help in reducing symptoms. some antidepressants have not been shown to be effective.[192][184] medications are not recommended in children with mild disease.[193] there is also insufficient evidence to determine effectiveness in those with depression complicated by dementia.[194] any antidepressant can cause low blood sodium levels;[195] nevertheless, it has been reported more often with ssris.[178] it is not uncommon for ssris to cause or worsen insomnia; the sedating atypical antidepressant mirtazapine can be used in such cases.[196][197] irreversible monoamine oxidase inhibitors, an older class of antidepressants, have been plagued by potentially life threatening dietary and drug interactions. they are still used only rarely, although newer and better tolerated agents of this class have been developed.[198] the safety profile is different with reversible monoamine oxidase inhibitors, such as moclobemide, where the risk of serious dietary interactions is negligible and dietary restrictions are less strict.[199] it is unclear whether antidepressants affect a person's risk of suicide.[200] for children, adolescents, and probably young adults between 18 and 24 years old, there is a higher risk of both suicidal ideations and suicidal behavior in those treated with ssris.[201][202] for adults, it is unclear whether ssris affect the risk of suicidality. one review found no connection;[203] another an increased risk;[204] and a third no risk in those 25 65 years old and a decreased risk in those more than 65.[205] a black box warning was introduced in the united states in 2007 on ssris and other antidepressant medications due to the increased risk of suicide in people younger than 24 years old.[206] similar precautionary notice revisions were implemented by the japanese ministry of health.[207] the combined use of antidepressants plus benzodiazepines demonstrates improved effectiveness when compared to antidepressants alone, but these effects may not endure. the addition of a benzodiazepine is balanced against possible harms and other alternative treatment strategies when antidepressant mono therapy is considered inadequate.[208] for treatment resistant depression, adding on the atypical antipsychotic brexpiprazole for short term or acute management may be considered.[209] brexpiprazole may be effective for some people, however, the evidence as of 2023 supporting its use is weak and this medication has potential adverse effects including weight gain and akathisia.[209] brexpiprazole has not been sufficiently studied in older people or children and the use and effectiveness of this adjunctive therapy for longer term management is not clear.[209] ketamine may have a rapid antidepressant effect lasting less than two weeks; there is limited evidence of any effect after that, common acute side effects, and longer term studies of safety and adverse effects are needed.[210][211] a nasal spray form of esketamine was approved by the fda in march 2019 for use in treatment resistant depression when combined with an oral antidepressant; risk of substance use disorder and concerns about its safety, serious adverse effects, tolerability, effect on suicidality, lack of information about dosage, whether the studies on it adequately represent broad populations, and escalating use of the product have been raised by an international panel of experts.[212][213] nonsteroidal anti inflammatory drugs (nsaids) and cytokine inhibitors are effective in treating depression. for instance, celecoxib, an nsaid, is a selective cox 2 inhibitor  which is an enzyme that helps in the production of pain and inflammation.[214] in recent clinical trials, this nsaid has been shown helpful with treatment resistant depression as it helps inhibit proinflammatory signaling.[215] statins, which are anti inflammatory medications prescribed to lower cholesterol levels, have also been shown to have antidepressant effects. when prescribed for patients already taking ssris, this add on treatment was shown to improve anti depressant effects of ssris when compared to the placebo group. with this, statins have been shown to be effective in preventing depression in some cases too.[216] there is insufficient high quality evidence to suggest omega 3 fatty acids are effective in depression.[217] there is limited evidence that vitamin d supplementation is of value in alleviating the symptoms of depression in individuals who are vitamin d deficient.[102] lithium appears effective at lowering the risk of suicide in those with bipolar disorder and unipolar depression to nearly the same levels as the general population.[218] there is a narrow range of effective and safe dosages of lithium thus close monitoring may be needed.[219] low dose thyroid hormone may be added to existing antidepressants to treat persistent depression symptoms in people who have tried multiple courses of medication.[220] limited evidence suggests stimulants, such as amphetamine and modafinil, may be effective in the short term, or as adjuvant therapy.[221][222] also, it is suggested that folate supplements may have a role in depression management.[223] there is tentative evidence for benefit from testosterone in males.[224] electroconvulsive therapy (ect) is a standard psychiatric treatment in which seizures are electrically induced in a person with depression to provide relief from psychiatric illnesses.[225]: 1880 ect is used with informed consent[226] as a last line of intervention for major depressive disorder.[227] a round of ect is effective for about 50% of people with treatment resistant major depressive disorder, whether it is unipolar or bipolar.[228] follow up treatment is still poorly studied, but about half of people who respond relapse within twelve months.[229] aside from effects in the brain, the general physical risks of ect are similar to those of brief general anesthesia.[230]: 259 immediately following treatment, the most common adverse effects are confusion and memory loss.[227][231] ect is considered one of the least harmful treatment options available for severely depressed pregnant women.[232] a usual course of ect involves multiple administrations, typically given two or three times per week, until the person no longer has symptoms. ect is administered under anesthesia with a muscle relaxant.[233] electroconvulsive therapy can differ in its application in three ways: electrode placement, frequency of treatments, and the electrical waveform of the stimulus. these three forms of application have significant differences in both adverse side effects and symptom remission. after treatment, drug therapy is usually continued, and some people receive maintenance ect.[227] ect appears to work in the short term via an anticonvulsant effect mostly in the frontal lobes, and longer term via neurotrophic effects primarily in the medial temporal lobe.[234] transcranial magnetic stimulation (tms) or deep transcranial magnetic stimulation is a noninvasive method used to stimulate small regions of the brain.[235] tms was approved by the fda for treatment resistant major depressive disorder (trmdd) in 2008[236] and as of 2014 evidence supports that it is probably effective.[237] the american psychiatric association,[238] the canadian network for mood and anxiety disorders,[239] and the royal australia and new zealand college of psychiatrists have endorsed tms for trmdd.[240] transcranial direct current stimulation (tdcs) is another noninvasive method used to stimulate small regions of the brain with a weak electric current. several meta analyses have concluded that active tdcs was useful for treating depression.[241][242] there is a small amount of evidence that sleep deprivation may improve depressive symptoms in some individuals,[243] with the effects usually showing up within a day. this effect is usually temporary. besides sleepiness, this method can cause a side effect of mania or hypomania.[244] there is insufficient evidence for reiki[245] and dance movement therapy in depression.[246] cannabis is specifically not recommended as a treatment.[247] the microbiome of people with major depressive disorder differs from that of healthy people, and probiotic and synbiotic treatment may achieve a modest depressive symptom reduction.[248][249] with this, fecal microbiota transplants (fmt) are being researched as add on therapy treatments for people who do not respond to typical therapies. it has been shown that the patient's depressive symptoms improved, with minor gastrointestinal issues, after a fmt, with improvements in symptoms lasting at least 4 weeks after the transplant.[250] studies have shown that 80% of those with a first major depressive episode will have at least one more during their life,[251] with a lifetime average of four episodes.[252] other general population studies indicate that around half those who have an episode recover (whether treated or not) and remain well, while the other half will have at least one more, and around 15% of those experience chronic recurrence.[253] studies recruiting from selective inpatient sources suggest lower recovery and higher chronicity, while studies of mostly outpatients show that nearly all recover, with a median episode duration of 11 months. around 90% of those with severe or psychotic depression, most of whom also meet criteria for other mental disorders, experience recurrence.[254][255] cases when outcome is poor are associated with inappropriate treatment, severe initial symptoms including psychosis, early age of onset, previous episodes, incomplete recovery after one year of treatment, pre existing severe mental or medical disorder, and family dysfunction.[256] a high proportion of people who experience full symptomatic remission still have at least one not fully resolved symptom after treatment.[257] recurrence or chronicity is more likely if symptoms have not fully resolved with treatment.[257] current guidelines recommend continuing antidepressants for four to six months after remission to prevent relapse. evidence from many randomized controlled trials indicates continuing antidepressant medications after recovery can reduce the chance of relapse by 70% (41% on placebo vs. 18% on antidepressant). the preventive effect probably lasts for at least the first 36 months of use.[258] major depressive episodes often resolve over time, whether or not they are treated. outpatients on a waiting list show a 10 15% reduction in symptoms within a few months, with approximately 20% no longer meeting the full criteria for a depressive disorder.[259] the median duration of an episode has been estimated to be 23 weeks, with the highest rate of recovery in the first three months.[260] according to a 2013 review, 23% of untreated adults with mild to moderate depression will remit within 3 months, 32% within 6 months and 53% within 12 months.[261] depression may affect people's ability to work. the combination of usual clinical care and support with return to work (like working less hours or changing tasks) probably reduces sick leave by 15%, and leads to fewer depressive symptoms and improved work capacity, reducing sick leave by an annual average of 25 days per year.[162] helping depressed people return to work without a connection to clinical care has not been shown to have an effect on sick leave days. additional psychological interventions (such as online cognitive behavioral therapy) lead to fewer sick days compared to standard management only. streamlining care or adding specific providers for depression care may help to reduce sick leave.[162] depressed individuals have a shorter life expectancy than those without depression, in part because people who are depressed are at risk of dying of suicide.[262] about 50% of people who die of suicide have a mood disorder such as major depression, and the risk is especially high if a person has a marked sense of hopelessness or has both depression and borderline personality disorder.[263][264] about 2 8% of adults with major depression die by suicide.[2][265] in the us, the lifetime risk of suicide associated with a diagnosis of major depression is estimated at 7% for men and 1% for women,[266] even though suicide attempts are more frequent in women.[267] depressed people also have a higher rate of dying from other causes.[268] there is a 1.5  to 2 fold increased risk of cardiovascular disease, independent of other known risk factors, and is itself linked directly or indirectly to risk factors such as smoking and obesity. people with major depression are less likely to follow medical recommendations for treating and preventing cardiovascular disorders, further increasing their risk of medical complications.[269] cardiologists may not recognize underlying depression that complicates a cardiovascular problem under their care.[270] major depressive disorder affected approximately 163 million people in 2017 (2% of the global population).[8] the percentage of people who are affected at one point in their life varies from 7% in japan to 21% in france. in most countries the number of people who have depression during their lives falls within an 8 18% range. lifetime rates are higher in the developed world (15%) compared to the developing world (11%).[4] in the united states, 8.4% of adults (21 million individuals) have at least one episode within a year long period; the probability of having a major depressive episode is higher for females than males (10.5% to 6.2%), and highest for those aged 18 to 25 (17%).[272] 15% of adolescents, ages 12 to 17, in america are also affected by depression, which is equal to 3.7 million teenagers.[273] among individuals reporting two or more races, the us prevalence is highest.[272] out of all the people suffering from mdd, only about 35% seek help from a professional for their disorder.[273] major depression is about twice as common in women as in men, although it is unclear why this is so, and whether factors unaccounted for are contributing to this.[274] the relative increase in occurrence is related to pubertal development rather than chronological age, reaches adult ratios between the ages of 15 and 18, and appears associated with psychosocial more than hormonal factors.[274] in 2019, major depressive disorder was identified (using either the dsm iv tr or icd 10) in the global burden of disease study as the fifth most common cause of years lived with disability and the 18th most common for disability adjusted life years.[275] people are most likely to develop their first depressive episode between the ages of 30 and 40, and there is a second, smaller peak of incidence between ages 50 and 60.[276] the risk of major depression is increased with neurological conditions such as stroke, parkinson's disease, or multiple sclerosis, and during the first year after childbirth (postpartum depression).[277] it is also more common after cardiovascular illnesses, and is related more to those with a poor cardiac disease outcome than to a better one.[278][279] depressive disorders are more common in urban populations than in rural ones and the prevalence is increased in groups with poorer socioeconomic factors, e.g., homelessness.[280] depression is common among those over 65 years of age and increases in frequency beyond this age.[31] the risk of depression increases in relation to the frailty of the individual.[281] depression is one of the most important factors which negatively impact quality of life in adults, as well as the elderly.[31] both symptoms and treatment among the elderly differ from those of the rest of the population.[31] major depression was the leading cause of disease burden in north america and other high income countries, and the fourth leading cause worldwide as of 2006. in the year 2030, it is predicted to be the second leading cause of disease burden worldwide after hiv, according to the who.[282] delay or failure in seeking treatment after relapse and the failure of health professionals to provide treatment are two barriers to reducing disability.[283] major depression frequently co occurs with other psychiatric problems. the 1990 92 national comorbidity survey (us) reported that half of those with major depression also have lifetime anxiety and its associated disorders, such as generalized anxiety disorder.[284] anxiety symptoms can have a major impact on the course of a depressive illness, with delayed recovery, increased risk of relapse, greater disability and increased suicidal behavior.[285] depressed people have increased rates of alcohol and substance use, particularly dependence,[286][287] and around a third of individuals diagnosed with attention deficit hyperactivity disorder (adhd) develop comorbid depression.[288] post traumatic stress disorder and depression often co occur.[27] depression may also coexist with adhd, complicating the diagnosis and treatment of both.[289] depression is also frequently comorbid with alcohol use disorder and personality disorders.[290] depression can also be exacerbated during particular months (usually winter) in those with seasonal affective disorder. while overuse of digital media has been associated with depressive symptoms, using digital media may also improve mood in some situations.[291][292] depression and pain often co occur. one or more pain symptoms are present in 65% of people who have depression, and anywhere from 5 to 85% of people who are experiencing pain will also have depression, depending on the setting a lower prevalence in general practice, and higher in specialty clinics. depression is often underrecognized, and therefore undertreated, in patients presenting with pain.[293] depression often coexists with physical disorders common among the elderly, such as stroke, other cardiovascular diseases, parkinson's disease, and chronic obstructive pulmonary disease.[294] the ancient greek physician hippocrates described a syndrome of melancholia (μελαγχολία, melankholía) as a distinct disease with particular mental and physical symptoms; he characterized all "fears and despondencies, if they last a long time" as being symptomatic of the ailment.[295] it was a similar but far broader concept than today's depression; prominence was given to a clustering of the symptoms of sadness, dejection, and despondency, and often fear, anger, delusions and obsessions were included.[296] the term depression itself was derived from the latin verb deprimere, meaning "to press down".[297] from the 14th century, "to depress" meant to subjugate or to bring down in spirits. it was used in 1665 in english author richard baker's chronicle to refer to someone having "a great depression of spirit", and by english author samuel johnson in a similar sense in 1753.[298] the term also came into use in physiology and economics. an early usage referring to a psychiatric symptom was by french psychiatrist louis delasiauve in 1856, and by the 1860s it was appearing in medical dictionaries to refer to a physiological and metaphorical lowering of emotional function.[299] since aristotle, melancholia had been associated with men of learning and intellectual brilliance, a hazard of contemplation and creativity. however, by the 19th century, this association has largely shifted and melancholia became more commonly linked with women.[296] although melancholia remained the dominant diagnostic term, depression gained increasing currency in medical treatises and was a synonym by the end of the century; german psychiatrist emil kraepelin may have been the first to use it as the overarching term, referring to different kinds of melancholia as depressive states.[300] freud likened the state of melancholia to mourning in his 1917 paper mourning and melancholia. he theorized that objective loss, such as the loss of a valued relationship through death or a romantic break up, results in subjective loss as well; the depressed individual has identified with the object of affection through an unconscious, narcissistic process called the libidinal cathexis of the ego. such loss results in severe melancholic symptoms more profound than mourning; not only is the outside world viewed negatively but the ego itself is compromised.[301] the person's decline of self perception is revealed in his belief of his own blame, inferiority, and unworthiness.[302] he also emphasized early life experiences as a predisposing factor.[296] adolf meyer put forward a mixed social and biological framework emphasizing reactions in the context of an individual's life, and argued that the term depression should be used instead of melancholia.[303] the first version of the dsm (dsm i, 1952) contained depressive reaction and the dsm ii (1968) depressive neurosis, defined as an excessive reaction to internal conflict or an identifiable event, and also included a depressive type of manic depressive psychosis within major affective disorders.[304] the term unipolar (along with the related term bipolar) was coined by the neurologist and psychiatrist karl kleist, and subsequently used by his disciples edda neele and karl leonhard.[305] the term major depressive disorder was introduced by a group of us clinicians in the mid 1970s as part of proposals for diagnostic criteria based on patterns of symptoms (called the "research diagnostic criteria", building on earlier feighner criteria),[10] and was incorporated into the dsm iii in 1980.[306] the american psychiatric association added "major depressive disorder" to the diagnostic and statistical manual of mental disorders (dsm iii),[307] as a split of the previous depressive neurosis in the dsm ii, which also encompassed the conditions now known as dysthymia and adjustment disorder with depressed mood.[307] to maintain consistency the icd 10 used the same criteria, with only minor alterations, but using the dsm diagnostic threshold to mark a mild depressive episode, adding higher threshold categories for moderate and severe episodes.[110][306] the ancient idea of melancholia still survives in the notion of a melancholic subtype. the new definitions of depression were widely accepted, albeit with some conflicting findings and views. there have been some continued empirically based arguments for a return to the diagnosis of melancholia.[308][309] there has been some criticism of the expansion of coverage of the diagnosis, related to the development and promotion of antidepressants and the biological model since the late 1950s.[310] the term "depression" is used in a number of different ways. it is often used to mean this syndrome but may refer to other mood disorders or simply to a low mood. people's conceptualizations of depression vary widely, both within and among cultures. "because of the lack of scientific certainty," one commentator has observed, "the debate over depression turns on questions of language. what we call it 'disease,' 'disorder,' 'state of mind' affects how we view, diagnose, and treat it."[312] there are cultural differences in the extent to which serious depression is considered an illness requiring personal professional treatment, or an indicator of something else, such as the need to address social or moral problems, the result of biological imbalances, or a reflection of individual differences in the understanding of distress that may reinforce feelings of powerlessness, and emotional struggle.[313][314] cultural differences contribute to different prevalence of symptoms. "do the chinese somatize depression? a cross cultural study" by parker et al. discusses the cultural differences in prevalent symptoms of depression between individualistic and collectivistic cultures. the authors reveal that individuals with depression in collectivistic cultures tend to present more somatic symptoms and less affective symptoms compared to those in individualistic cultures. the finding suggests that individualistic cultures 'warranting' or validating one's expression of emotions explains this cultural difference since collectivistic cultures see this as a taboo against the social cooperation it deems one of the most significant values.[315] historical figures were often reluctant to discuss or seek treatment for depression due to social stigma about the condition, or due to ignorance of diagnosis or treatments. nevertheless, analysis or interpretation of letters, journals, artwork, writings, or statements of family and friends of some historical personalities has led to the presumption that they may have had some form of depression. people who may have had depression include english author mary shelley,[316] american british writer henry james,[317] and american president abraham lincoln.[318] some well known contemporary people with possible depression include canadian songwriter leonard cohen[319] and american playwright and novelist tennessee williams.[320] some pioneering psychologists, such as americans william james[321][322] and john b. watson,[323] dealt with their own depression. there has been a continuing discussion of whether neurological disorders and mood disorders may be linked to creativity, a discussion that goes back to aristotelian times.[324][325] british literature gives many examples of reflections on depression.[326] english philosopher john stuart mill experienced a several months long period of what he called "a dull state of nerves", when one is "unsusceptible to enjoyment or pleasurable excitement; one of those moods when what is pleasure at other times, becomes insipid or indifferent". he quoted english poet samuel taylor coleridge's "dejection" as a perfect description of his case: "a grief without a pang, void, dark and drear, / a drowsy, stifled, unimpassioned grief, / which finds no natural outlet or relief / in word, or sigh, or tear."[327][328] english writer samuel johnson used the term "the black dog" in the 1780s to describe his own depression,[329][330] and it was subsequently popularized by british prime minister sir winston churchill, who also had the disorder.[329][330] johann wolfgang von goethe in his faust, part one, published in 1808, has mephistopheles assume the form of a black dog, specifically a poodle. social stigma of major depression is widespread, and contact with mental health services reduces this only slightly. public opinions on treatment differ markedly to those of health professionals; alternative treatments are held to be more helpful than pharmacological ones, which are viewed poorly.[331] in the uk, the royal college of psychiatrists and the royal college of general practitioners conducted a joint five year defeat depression campaign to educate and reduce stigma from 1992 to 1996;[332] a mori study conducted afterwards showed a small positive change in public attitudes to depression and treatment.[333] while serving his first term as prime minister of norway, kjell magne bondevik attracted international attention in august 1998 when he announced that he was suffering from a depressive episode, becoming the highest ranking world leader to admit to suffering from a mental illness while in office. upon this revelation, anne enger became acting prime minister for three weeks, from 30 august to 23 september, while he recovered from the depressive episode. bondevik then returned to office. bondevik received thousands of supportive letters, and said that the experience had been positive overall, both for himself and because it made mental illness more publicly acceptable.[334][335]

back to health a to z huntington's disease is a condition that stops parts of the brain working properly over time. it's passed on (inherited) from a person's parents. it gets gradually worse over time and is usually fatal after a period of up to 20 years. the symptoms usually start at 30 to 50 years of age, but can begin much earlier or later. symptoms of huntington's disease can include: full time nursing care is needed in the later stages of the condition. read more about the symptoms of huntington's disease. huntington's disease is caused by a faulty gene that results in parts of the brain becoming gradually damaged over time. you're usually only at risk of developing it if one of your parents has or had it. both men and women can get it. if a parent has the huntington's disease gene, there's a: very occasionally, it's possible to develop huntington's disease without having a history of it in your family. but this is usually just because one of your parents was never diagnosed with it. speak to your gp for advice if: your gp may refer you to a specialist for tests to check for huntington's disease. there's currently no cure for huntington's disease or any way to stop it getting worse. but treatment and support can help reduce some of the problems it causes, such as: read more about treatment and support for huntington's disease. living with huntington's disease can be very distressing and frustrating for the person with the condition, as well as their loved ones and carers. you may find the huntington's disease association a useful source of information and support. they offer: watch this video about huntington's disease which offers advice and discusses the decision to get tested. page last reviewed: 29 march 2021 next review due: 29 march 2024 © crown copyright

in every cell in the human body there is a nucleus, where genetic material is stored in genes. genes carry the codes responsible for all of our inherited traits and are grouped along rod like structures called chromosomes. typically, the nucleus of each cell contains 23 pairs of chromosomes, half of which are inherited from each parent. down syndrome occurs when an individual has a full or partial extra copy of chromosome 21. this additional genetic material alters the course of development and causes the characteristics associated with down syndrome. a few of the common physical traits of down syndrome are low muscle tone, small stature, an upward slant to the eyes, and a single deep crease across the center of the palm   although each person with down syndrome is a unique individual and may possess these characteristics to different degrees, or not at all. your donation will help people with down syndrome, their families, and their caregivers. according to the centers for disease control and prevention, approximately one in every 775 babies in the united states is born with down syndrome, making down syndrome the most common chromosomal condition. about 5,000 babies with down syndrome are born in the united states each year.  de graaf, g., buckley, f., & skotko, b. (2024, may 3). people living with down syndrome in the usa: births and population. https://go.downsyndromepopulation.org/usa factsheet for centuries, people with down syndrome have been alluded to in art, literature, and science. it wasn’t until the late nineteenth century, however, that john langdon down, an english physician, published an accurate description of a person with down syndrome. it was this scholarly work, published in 1866, that earned down the recognition as the “father” of the syndrome. although other people had previously recognized the characteristics of the syndrome, it was down who described the condition as a distinct and separate entity. in recent history, advances in medicine and science have enabled researchers to investigate the characteristics of people with down syndrome. in 1959, the french physician jérôme lejeune identified down syndrome as a chromosomal condition. instead of the usual 46 chromosomes present in each cell, lejeune observed 47 in the cells of individuals with down syndrome. it was later determined that an extra partial or whole copy of chromosome 21 results in the characteristics associated with down syndrome. in the year 2000, an international team of scientists successfully identified and catalogued each of the approximately 329 genes on chromosome 21. this accomplishment opened the door to great advances in down syndrome research. down syndrome is usually caused by an error in cell division called “nondisjunction.” nondisjunction results in an embryo with three copies of chromosome 21 instead of the usual two. prior to or at conception, a pair of 21st chromosomes in either the sperm or the egg fails to separate. as the embryo develops, the extra chromosome is replicated in every cell of the body. this type of down syndrome, which accounts for 95% of cases, is called trisomy 21. mosaicism (or mosaic down syndrome) is diagnosed when there is a mixture of two types of cells, some containing the usual 46 chromosomes and some containing 47. those cells with 47 chromosomes contain an extra chromosome 21. mosaicism is the least common form of down syndrome and accounts for only about 2% of all cases of down syndrome (facts about down syndrome, 2021). research has indicated that individuals with mosaic down syndrome may have fewer characteristics of down syndrome than those with other types of down syndrome. however, broad generalizations are not possible due to the wide range of abilities people with down syndrome possess. in translocation, which accounts for about 3% of cases of down syndrome, the total number of chromosomes in the cells remains 46; however, an additional full or partial copy of chromosome 21 attaches to another chromosome, usually chromosome 14 (facts and down syndrome, 2021). the presence of the extra full or partial chromosome 21 causes the characteristics of down syndrome. regardless of the type of down syndrome, a person may have, all people with down syndrome have an extra, critical portion of chromosome 21 present in all or some of their cells. the cause of the extra full or partial chromosome is still unknown. age is the only factor that has been linked to an increased chance of having a baby with down syndrome resulting from nondisjunction or mosaicism. however, due to higher birth rates in younger women, 51% of children with down syndrome are born to women under 35 years of age. (de graaf et al., 2022). there is no definitive scientific research that indicates that down syndrome is caused by environmental factors or the parents’ activities before or during pregnancy. the additional partial or full copy of the 21st chromosome which causes down syndrome can originate from either parent. approximately 5% of the cases have been traced to the father. this booklet includes sections on healthy starts, early intervention therapies, how to find support and care for your family, and what the future holds for your child. down syndrome occurs in people of all races and economic levels, though older women have an increased chance of having a child with down syndrome. a 35 year old woman has about a one in 350 chance of conceiving a child with down syndrome, and this chance increases gradually to 1 in 100 by age 40. at age 45 the incidence becomes approximately 1 in 30. the age of the mother, or birthing parent, does not seem to be linked to the risk of translocation. since many couples are postponing parenting until later in life, the incidence of down syndrome conceptions is expected to increase. therefore, genetic counseling for parents is becoming increasingly important. still, many physicians are not fully informed about advising their patients about the incidences of down syndrome, advancements in diagnosis, and the protocols for care and treatment of babies born with down syndrome. all three types of down syndrome are genetic conditions (relating to the genes), but only 1% of all cases of down syndrome have a hereditary component (passed from parent to child through the genes). heredity is not a factor in trisomy 21 (nondisjunction) and mosaicism. however, in one third of cases of down syndrome resulting from translocation, there is a hereditary component   accounting for about 1% of all cases of down syndrome (facts about down syndrome, 2021). the age of the parent does not seem to be linked to the risk of translocation. most cases are sporadic   chance   events. however, in about one third of cases, one parent is a carrier of a translocated chromosome. once a parent has given birth to a baby with trisomy 21 (nondisjunction) or translocation, it is estimated that the chances of having another baby with trisomy 21 is 1 in 100 up until age 40. the risk of recurrence of translocation is about 3% if the father is the carrier and 10 15% if the mother is the carrier. genetic counseling can determine the origin of translocation. there are two categories of tests for down syndrome that can be performed before a baby is born: screening tests and diagnostic tests. prenatal screens estimate the chance of the fetus having down syndrome. these tests do not tell you for sure whether your fetus has down syndrome; they only provide a probability. diagnostic tests, on the other hand, can provide a definitive diagnosis with almost 100% accuracy. there is an extensive menu of prenatal screening tests now available for pregnant parents. most screening tests involve a blood test and an ultrasound (sonogram). the blood tests (or serum screening tests) measure quantities of various substances in the blood of the parent. together with age, these are used to estimate the chance of having a child with down syndrome. these blood tests are often performed in conjunction with a detailed sonogram to check for “markers” (characteristics that some researchers feel may have a significant association with down syndrome). new advanced prenatal screens are now able to detect chromosomal material from the fetus that is circulating in the maternal blood. these tests are not invasive (like the diagnostic tests below), but they provide a high accuracy rate. still, all of these screens will not definitively diagnose down syndrome. prenatal screening and diagnostic tests are now routinely offered to all ages. the diagnostic procedures available for prenatal diagnosis of down syndrome are chorionic villus sampling (cvs) and amniocentesis. these procedures, which carry up to a 1% risk of causing a spontaneous termination (miscarriage), are nearly 100% accurate in diagnosing down syndrome. amniocentesis is usually performed in the second trimester between 15 and 20 weeks of gestation, cvs in the first trimester between 11 and 14 weeks (chrionic villus sampling, 2020). down syndrome is usually identified at birth by the presence of certain physical traits: low muscle tone, a single deep crease across the palm of the hand, a slightly flattened facial profile, and an upward slant to the eyes. because these features may be present in babies without down syndrome, a chromosomal analysis called a karyotype is done to confirm the diagnosis. to obtain a karyotype, doctors draw a blood sample to examine the baby’s cells. they photograph the chromosomes and then group them by size, number, and shape. by examining the karyotype, doctors can diagnose down syndrome. another genetic test called fluorescence in situ hybridization (fish) can confirm a diagnosis in a shorter amount of time by visualizing and mapping the genetic material in an individual's cells. individuals with down syndrome are becoming increasingly integrated into society and community organizations, such as schools, health care systems, work forces, and social and recreational activities. individuals with down syndrome possess varying degrees of cognitive delays, from very mild to severe. most people with down syndrome have cognitive delays that are mild to moderate. due to advances in medical technology, individuals with down syndrome are living longer than ever before. in 1910, children with down syndrome were expected to survive to age nine. with the discovery of antibiotics, the average survival age increased to 19 or 20. now, with recent advancements in clinical treatment, most particularly corrective heart surgeries, as many as 80% of adults with down syndrome reach age 60, and many live even longer (down syndrome, 2018). more and more americans are interacting with individuals with down syndrome, increasing the need for widespread public education and acceptance. a downloadable version of the preferred language guide is available to print and distribute. citations: chorionic villus sampling. mayo clinic. https://www.mayoclinic.org/tests procedures/chorionic villus sampling/a…. published november 12, 2020. accessed june 28, 2022. de graaf g, buckley f, skotko b. people living with down syndrome in the usa: births and population. may 2022. https://go.dselink.net/us population factsheet.&nbsp; down syndrome. mayo clinic. https://www.mayoclinic.org/diseases conditions/down syndrome/symptoms c…. published march 8, 2018. accessed june 28, 2022. facts about down syndrome. centers for disease control and prevention. https://www.cdc.gov/ncbddd/birthdefects/downsyndrome.html. published april 6, 2021. accessed june 28, 2022. gifts from supporters like you make our work possible. national down syndrome society 1155 15th street nw suite 540 washington, dc 20005 telephone: 800 221 4602 (mon fri, 9am et  5pm et) contact us toll free ndss helpline: 800 221 4602

key facts chagas disease is an infectious disease caused by a protozoan parasite (trypanosoma cruzi). however, this condition is the result of a complex health problem typical of neglected tropical diseases and socially determined diseases. a missed or late diagnosis with absent or incomplete treatment and follow up can transform this infection into a life threatening condition. about 6 7 million people worldwide are estimated to be infected with t. cruzi, leading to approximately 12 000 deaths every year. although a condition of increasing global presence, chagas disease is found mainly in endemic areas of 21 continental latin american countries (1), where transmission is largely related to the vector presence. today, approximately 75 million people are considered at risk of infection. chagas disease is named after carlos chagas, a brazilian physician and researcher who on 14 april 1909 diagnosed the disease in a person for the first time. today, 14 april marks world chagas disease day. chagas disease was once entirely confined to continental rural areas of the americas. due to increased population mobility, most infected people now live in urban settings and the infection has been detected in 44 countries (including canada, the united states of america, and many european and some western pacific, african and eastern mediterranean countries). in latin america, t. cruzi parasites are mainly transmitted by contact with faeces/urine of infected blood sucking triatomine bugs. these bugs typically live in the wall or roof cracks of homes and surrounding structures, such as chicken coops, pens and warehouses, in rural or suburban areas. normally they hide during the day and become active at night when they feed on animal and human blood. they usually bite an exposed area of skin such as the face, and defecate or urinate close to the bite. the parasites enter the body when the person instinctively smears the bug’s faeces or urine into the bite, other skin breaks, the eyes or the mouth. t. cruzi can also infect animals; common opossums are considered one of the most important wild reservoirs of infection. t. cruzi can also be transmitted: chagas disease presents in two phases. the initial acute phase lasts for about two months after infection. although a high number of parasites can circulate in the blood, in most cases symptoms are absent or mild and non specific (fever, headache, enlarged lymph glands, pallor, muscle pain, difficulty in breathing, swelling, and abdominal or chest pain). much less frequently people bitten by a triatomine bug show the characteristic first visible signs, which can be a skin lesion or a purplish swelling of the lids of one eye. during the chronic phase, the parasites are hidden mainly in the heart and digestive muscles. one to three decades after infection, up to a third of patients suffer from cardiac disorders and up to 1 in 10 suffer from digestive (typically enlargement of the oesophagus or colon), neurological or mixed alterations. in later years these patients may experience the destruction of the nervous system and heart muscle, consequent cardiac arrhythmias or progressive heart failure, and sudden death. chagas disease can be treated with benznidazole or nifurtimox. both medicines kill the parasite and are fully effective in curing the disease if given early in the acute phase, including in case of congenital transmission. their efficacy diminishes, however, the longer a person has been infected; also, adverse reactions are more frequent in older age. treatment is also indicated for patients in whom infection has been reactivated (for example, due to immunosuppression), and during the early chronic phase, including for girls and women of childbearing age (before or after pregnancy) to prevent congenital transmission. adults with infection, especially those with no symptoms, should be offered treatment because antiparasitic medicines can also prevent or curb disease progression. in other cases, the potential benefits in preventing or delaying the development of chagas disease should be weighed against the duration of treatment (up to 2 months) and possible adverse reactions (occurring in up to 40% of adults). benznidazole and nifurtimox should not be administered to pregnant women or people with kidney or liver failure. nifurtimox is also contraindicated for people with a background of neurological or psychiatric disorders. additionally, specific life lasting treatment and follow up for cardiac, digestive or neurological manifestations is required. the large reservoir of t. cruzi parasites in wild animals throughout the americas means that the infection cannot be eradicated. instead, the public health targets are elimination of the transmission to humans, early health care access and life long follow up of the infected people. there is no vaccine to prevent chagas disease. t. cruzi can infect many species of triatomine bugs, the majority of which are found in the americas. vector control has been the most effective method of prevention in latin america. blood screening is necessary to prevent infection through transfusion, organ transplantation, and congenital transmission, and to increase detection and care of the affected population all over the world. depending on the geographical area, who recommends the following approaches to prevention and control: the medical care cost of patients with chronic cardiac, digestive, neurologic or mixed forms of the disease has been calculated to be >80% higher than the cost of spraying residual insecticide to control vectors and prevent infection. health professionals working at the first level of care (primary health care) have a key role in strengthening detection, treatment, follow up and notification of cases. assessment of the available diagnostics (including rapid serologic or chemiluminescence tests, molecular biology tests) and the most cost effective algorithms is fundamental to increase early case detection. promotion of biomedical, psychosocial and environmental studies focused on the determinants and risk factors of chagas disease is essential to identify novel approaches for prevention and control. national information systems are essential to monitor the number of acute and chronic cases and the active transmission routes, but are in place only in 6 out of the 44 countries that have reported cases so far. since the 1990s there have been successful intergovernmental initiatives in the americas, leading to a substantial reduction in transmission and increased access to diagnosis and antiparasitic treatment for chagas disease. the risk of t. cruzi transmission by transfusion has decreased sharply following the universal screening in all blood banks of continental latin american countries, and progressively in other countries and continents. who recognized chagas disease as a neglected tropical disease (ntd) in 2005. this facilitated its greater recognition as a global public health problem and was instrumental to strengthen prevention, early diagnosis and treatment, comprehensive care, psychosocial follow up, as well as information, education and communication activities. it also promoted the fight against misinformation, the lack of social demand and the weak political commitment to face the burden of disease. in may 2019, the 72nd world health assembly established world chagas disease day, to be celebrated annually on 14 april. the ntd road map 2021 2030 includes chagas disease among the conditions targeted for elimination as a public health problem and proposes five targets: to attain the goal of elimination of chagas disease transmission to humans and provide health care for affected people worldwide, who aims to strengthen networking at the global level and reinforcing regional and national capacities. notes related news fact sheets
supported by diagnosis the woman’s disorder was diagnosed when she was a child. thirty years later, she decided to have more testing done. by lisa sanders, m.d. the 40 year old woman glared at the windows in her lower manhattan apartment. they were filthy. she wanted to wash them. god knows they needed it. but she couldn’t. she considered what it would take to do the job. first, she would have to be on her feet for maybe 20 minutes. impossible. after standing for more than a few minutes, her legs would tremble with fatigue. she might have the strength in her arms to clean the lower half of a window   maybe one or two of them   but the top? forget it. on her best day, she could lift her arms up over her head, but she couldn’t keep them up. her muscles tired too quickly. no, if she wanted clean windows, she would have to hire someone. the thought was depressing. but it was that frustration that eventually led her back to the office of dr. mary lynn chu. chu is the medical director of the pediatric muscular dystrophy association care center at n.y.u.