When the White House announced it was exploring leucovorin as a treatment for autism, the calls from families started pouring in: "Can you prescribe leucovorin for my child?"
We experience versions of this frequently: an unproven treatment gains momentum on social media, and we as physicians must become informed enough to counsel families who are counting on us for answers. Not surprisingly, a recent analysis published in The Lancet showed a 71% increase in outpatient leucovorin prescriptions for a few months after the White House suggested the drug as a potential autism treatment.
The White House's promotion of leucovorin suggested that millions of people with autism have an ultra-rare condition called cerebral folate deficiency (CFD). The Lancet report captures exactly what concerned me when I heard the announcement: that physicians would feel compelled to prescribe an unproven treatment, predicated on an underlying diagnosis that most children with autism almost certainly do not have.
In reality, FOLR1-CFD -- for which leucovorin is an appropriate off-label treatment -- is so rare that less than 100 cases total have been reported worldwide. For people with this condition, mutations in the folate transporter gene FOLR1 prevent folate from being transported into the brain. Low cerebral folate levels cause people with untreated CFD to have more than just autism. They also have severe cognitive impairments, developmental regression, epilepsy, and movement disorders. This kind of CFD can be treated with leucovorin, a folate derivative that enters the brain through a different mechanism that doesn't require the FOLR1 transporter. The diagnosis of FOLR1-CFD is confirmed with a combination of genetic testing and a spinal tap to measure folate levels in the brain.
In addition to asking about leucovorin, families are also inquiring about testing their children for autoantibodies against the folate transporter. The premise is that autoantibodies inhibit the FOLR1 transporter, which leads to CFD and autism. This is an interesting idea, but that doesn't make it true. The blood test, which is only available from one commercial lab, has a cute name (Folate Receptor Autoantibody Test or FRAT), costs hundreds of dollars, and is not covered by insurance. Not only does the test have a high false positive rate, but the presence of an autoantibody alone does not equate to having an autoimmune disease. Using a positive folate receptor antibody test to diagnose a child with CFD would be like using a positive antinuclear antibody (ANA) test to diagnose lupus.
In the months since the White House announcement, one of the largest randomized, placebo-controlled studies on the use of leucovorin to treat autism was retracted for data inconsistencies. In addition, the American Academy of Pediatrics, the Society for Developmental and Behavioral Pediatrics, and the Child Neurology Society released guidelines recommending against leucovorin for autism treatment and recommending against folate receptor autoantibody testing for people with autism. And even though the White House reversed its stance on leucovorin for autism and acknowledged that there is insufficient evidence of its efficacy, the damage was already done.
What Do We Tell Families?
When I step back, it's clear that families are asking about leucovorin the same way they inquire about gluten-free diets, stem-cell tourism, and broccoli extract. I take every one of these conversations seriously, because the underlying question -- is there something treatable? -- is the one I'm also asking.
I educate families that profound autism is a symptom of 1,000 rare neurogenetic diseases. I now routinely offer genome sequencing to families to understand if their child has one of these conditions. It's a noninvasive test (just a cheek swab) -- no lumbar puncture required. I tell families that doing a "spellcheck on the DNA" is the first step in their diagnostic and treatment journey.
Identifying the cause of each child's disability is becoming increasingly important because we are entering the era of precision medicine for neurodevelopmental disorders. A growing number of autism-associated conditions already have treatments available or treatments being tested in clinical trials.
I tell families that getting the right diagnosis is what puts their child in line for when treatments become available for their condition. If testing reveals a treatable cause for their child's disability, we can act on it immediately. If their condition isn't treatable today, rapid advances in precision medicine mean it may be tomorrow. And if current testing does not provide an answer, we can retest in a few years once technology and our understanding of neurogenetics have advanced.
For families who aren't able to obtain genetic testing clinically, I recommend they enroll in a study to obtain testing on a research basis.
Families of autistic children are navigating long wait times with a limited number of neurodevelopmental specialists and real gaps in treatment for core features of autism. They deserve the best that science and medicine have to offer. That doesn't include prescribing drugs without scientific evidence, which are unlikely to help and could even cause harm.
Audrey C. Brumback, MD, PhD, is a pediatric neurologist specializing in autism spectrum disorder at Dell Medical School at The University of Texas at Austin.
https://www.medpagetoday.com/opinion/second-opinions/120530
Monday, July 27, 2026
Overlooked form of adversity can reveal hidden mental health risks
For years, pediatricians have relied on a widely used checklist to identify children who have experienced traumatic events such as abuse, neglect or household violence. But a new UC Irvine-led study suggests that another, less visible form of adversity may be shaping children’s mental health, and it often goes undetected.
Researchers found that growing up in an unpredictable environment, where daily life lacks consistency and children are unsure what comes next, is strongly associated with depression, anxiety, sleep disorders and other mental health challenges. The findings, published in Nature Mental Health, are based on nearly 30,000 children receiving care through Rady Children’s Health pediatric clinics in Orange County.
The study also shows that asking children and families a handful of questions about unpredictability can identify many at-risk young people who would not have been recognized through traditional Adverse Childhood Experiences, or ACEs, screenings alone.
The work represents years of neuroscience research translated into a practical tool that could help pediatricians identify vulnerable children earlier and give families opportunities to intervene before problems become more severe.
From the neuroscience lab to the doctor’s office
The project brings together neuroscientists, psychologists, pediatricians and data scientists from UC Irvine, Chapman University and Rady Children’s Health, demonstrating how discoveries about the developing brain can move beyond the laboratory and into everyday clinical care.
At the center of the research is Dr. Tallie Z. Baram, UC Irvine Donald Bren Professor and Distinguished Professor of pediatrics, neurology, and anatomy and neurobiology, as well as Danette Shepard Chair in Neurological Studies. For decades, Baram has studied how early-life experiences influence brain development.
Her laboratory research revealed that developing brains rely on predictable patterns to build healthy neural connections – findings that now appear to extend to children’s everyday lives.
“What we discovered in the laboratory mice is that optimal development of the brain depends on consistent patterns, which enable the maturation of brain connections,” said Baram, the study’s senior author and co-corresponding author. “Like mice, children’s brain connections involved in happiness, threat and safety benefit from repeated, predictable experiences. This study shows that those principles matter not only in neuroscience research but also in the lives of children and families from a broad range of wealth and backgrounds.”
Looking beyond traditional measures of adversity
Traditional ACEs screenings focus on experiences such as abuse, neglect and family dysfunction. While those tools have transformed the understanding of childhood trauma, they do not capture every child who may be struggling.
The new study evaluated whether adding a simple five-question measure of childhood unpredictability could improve screening.
Researchers found that both traditional adversity and unpredictability were linked to higher rates of depression, anxiety, behavioral concerns, sleep disorders and physical symptoms including headaches and abdominal pain.
But unpredictability revealed something more.
Children who reported highly unpredictable lives – even when they had no traditional ACEs – were substantially more likely to experience depression than children who scored low on both measures. The screening also proved especially useful in identifying children at risk for sleep disorders.
When researchers combined both screening methods, the relationship to mental health outcomes was often stronger than either tool alone.
“Traditional ACEs screening has helped our understanding of childhood adversity, but it fails to identify many children who are at risk for mental health problems,” said Laura M. Glynn, Ph.D., professor of psychology at Chapman University and co-corresponding author of the study. “Our findings suggest that unpredictability is a distinct and meaningful form of adversity that contributes to risk in ways that existing screening tools do not detect, thus increasing our ability to target individual children.”
A statewide effort with national implications
The study grew out of a $2.9 million grant awarded in 2021 by the California Initiative to Advance Precision Medicine. Between 2021 and 2024, researchers incorporated the unpredictability questionnaire into routine pediatric visits at 19 Rady-affiliated clinics across Orange County.
California’s statewide ACEs screening initiative – already the first publicly supported program of its kind in the nation, created a unique opportunity to test whether expanding childhood adversity screenings could improve care for families from diverse socioeconomic, ethnic and cultural backgrounds.
Nearly 30,000 children under age 18 participated, making the project one of the largest real-world studies examining how different forms of adversity affect children’s mental health.
Small routines can make a difference
Unlike many forms of childhood adversity, unpredictability is often something families and communities can influence.
Consistent bedtime routines, reliable caregiving, predictable schedules and stable daily patterns may all help create environments that support healthy brain development. Previous research by members of the team also found that predictable home environments helped buffer children from stress during the COVID-19 pandemic.
Baram emphasizes that the findings are not about perfection.
“For parents, this isn’t about creating a perfect home,” Baram said. “It’s about recognizing that consistency matters. Small routines and predictable patterns in daily life can support healthy development.”
As pediatricians increasingly look for ways to identify children before mental health problems escalate, the researchers say measuring unpredictability could become an important addition to routine care – providing families with another opportunity to support healthy development during the years when the brain is growing fastest.
https://news.uci.edu/2026/07/21/when-childhood-feels-unpredictable-the-brain-remembers/
Glynn, L.M., Liu, S.R., Golden, C. et al. Unpredictability is a childhood adversity that contributes to mental health problems. Nat. Mental Health (2026). https://doi.org/10.1038/s44220-026-00681-x
Abstract
Although adverse childhood experiences (ACEs) increase risk for mental illness at the population level, existing ACEs screens are less helpful in forecasting individual outcomes, suggesting they may not capture significant elements of childhood adversity. We have previously identified unpredictable parental and household experiences as an ACE that portends poorer cognitive and mental health. However, the contribution of unpredictability to established ACEs in real-world settings is unknown. Here, leveraging existing ACEs screening in California, we added the five-item Questionnaire on Unpredictability in Childhood (QUIC-5) in 19 pediatric clinics spanning broad sociodemographic constituencies and compared in ~30,000 children the link of each screen with mental health diagnoses. Scores on either the ACEs or QUIC-5 associated with probabilities of depression, externalizing symptoms, sleep disorders, anxiety and somatic symptoms. Each screen provided unique contributions and combining them often doubled the strength of associations. For depression and sleep disorders, the QUIC-5 identified vulnerable individuals missed by ACEs screen, improving risk detection and facilitating future interventions.
Researchers found that growing up in an unpredictable environment, where daily life lacks consistency and children are unsure what comes next, is strongly associated with depression, anxiety, sleep disorders and other mental health challenges. The findings, published in Nature Mental Health, are based on nearly 30,000 children receiving care through Rady Children’s Health pediatric clinics in Orange County.
The study also shows that asking children and families a handful of questions about unpredictability can identify many at-risk young people who would not have been recognized through traditional Adverse Childhood Experiences, or ACEs, screenings alone.
The work represents years of neuroscience research translated into a practical tool that could help pediatricians identify vulnerable children earlier and give families opportunities to intervene before problems become more severe.
From the neuroscience lab to the doctor’s office
The project brings together neuroscientists, psychologists, pediatricians and data scientists from UC Irvine, Chapman University and Rady Children’s Health, demonstrating how discoveries about the developing brain can move beyond the laboratory and into everyday clinical care.
At the center of the research is Dr. Tallie Z. Baram, UC Irvine Donald Bren Professor and Distinguished Professor of pediatrics, neurology, and anatomy and neurobiology, as well as Danette Shepard Chair in Neurological Studies. For decades, Baram has studied how early-life experiences influence brain development.
Her laboratory research revealed that developing brains rely on predictable patterns to build healthy neural connections – findings that now appear to extend to children’s everyday lives.
“What we discovered in the laboratory mice is that optimal development of the brain depends on consistent patterns, which enable the maturation of brain connections,” said Baram, the study’s senior author and co-corresponding author. “Like mice, children’s brain connections involved in happiness, threat and safety benefit from repeated, predictable experiences. This study shows that those principles matter not only in neuroscience research but also in the lives of children and families from a broad range of wealth and backgrounds.”
Looking beyond traditional measures of adversity
Traditional ACEs screenings focus on experiences such as abuse, neglect and family dysfunction. While those tools have transformed the understanding of childhood trauma, they do not capture every child who may be struggling.
The new study evaluated whether adding a simple five-question measure of childhood unpredictability could improve screening.
Researchers found that both traditional adversity and unpredictability were linked to higher rates of depression, anxiety, behavioral concerns, sleep disorders and physical symptoms including headaches and abdominal pain.
But unpredictability revealed something more.
Children who reported highly unpredictable lives – even when they had no traditional ACEs – were substantially more likely to experience depression than children who scored low on both measures. The screening also proved especially useful in identifying children at risk for sleep disorders.
When researchers combined both screening methods, the relationship to mental health outcomes was often stronger than either tool alone.
“Traditional ACEs screening has helped our understanding of childhood adversity, but it fails to identify many children who are at risk for mental health problems,” said Laura M. Glynn, Ph.D., professor of psychology at Chapman University and co-corresponding author of the study. “Our findings suggest that unpredictability is a distinct and meaningful form of adversity that contributes to risk in ways that existing screening tools do not detect, thus increasing our ability to target individual children.”
A statewide effort with national implications
The study grew out of a $2.9 million grant awarded in 2021 by the California Initiative to Advance Precision Medicine. Between 2021 and 2024, researchers incorporated the unpredictability questionnaire into routine pediatric visits at 19 Rady-affiliated clinics across Orange County.
California’s statewide ACEs screening initiative – already the first publicly supported program of its kind in the nation, created a unique opportunity to test whether expanding childhood adversity screenings could improve care for families from diverse socioeconomic, ethnic and cultural backgrounds.
Nearly 30,000 children under age 18 participated, making the project one of the largest real-world studies examining how different forms of adversity affect children’s mental health.
Small routines can make a difference
Unlike many forms of childhood adversity, unpredictability is often something families and communities can influence.
Consistent bedtime routines, reliable caregiving, predictable schedules and stable daily patterns may all help create environments that support healthy brain development. Previous research by members of the team also found that predictable home environments helped buffer children from stress during the COVID-19 pandemic.
Baram emphasizes that the findings are not about perfection.
“For parents, this isn’t about creating a perfect home,” Baram said. “It’s about recognizing that consistency matters. Small routines and predictable patterns in daily life can support healthy development.”
As pediatricians increasingly look for ways to identify children before mental health problems escalate, the researchers say measuring unpredictability could become an important addition to routine care – providing families with another opportunity to support healthy development during the years when the brain is growing fastest.
https://news.uci.edu/2026/07/21/when-childhood-feels-unpredictable-the-brain-remembers/
Glynn, L.M., Liu, S.R., Golden, C. et al. Unpredictability is a childhood adversity that contributes to mental health problems. Nat. Mental Health (2026). https://doi.org/10.1038/s44220-026-00681-x
Abstract
Although adverse childhood experiences (ACEs) increase risk for mental illness at the population level, existing ACEs screens are less helpful in forecasting individual outcomes, suggesting they may not capture significant elements of childhood adversity. We have previously identified unpredictable parental and household experiences as an ACE that portends poorer cognitive and mental health. However, the contribution of unpredictability to established ACEs in real-world settings is unknown. Here, leveraging existing ACEs screening in California, we added the five-item Questionnaire on Unpredictability in Childhood (QUIC-5) in 19 pediatric clinics spanning broad sociodemographic constituencies and compared in ~30,000 children the link of each screen with mental health diagnoses. Scores on either the ACEs or QUIC-5 associated with probabilities of depression, externalizing symptoms, sleep disorders, anxiety and somatic symptoms. Each screen provided unique contributions and combining them often doubled the strength of associations. For depression and sleep disorders, the QUIC-5 identified vulnerable individuals missed by ACEs screen, improving risk detection and facilitating future interventions.
Friday, July 24, 2026
Death with gene editing therapy of CHD3 mutation
Courtesy of a colleague
The girl was slipping behind her peers in kindergarten. She still spoke in simple sentences and ate with training chopsticks. Underneath it all was a single mutated DNA base, a T that should have been a C.
“Your ‘book’ has a small mistake, which has caused you to have a disease that affects your growth,” read the children’s version of the informed consent form from the hospital. “Over time, it can get more serious.”
Doctors hoped to repair that mistake while her brain was still building itself. It would be a clinical trial of one, funded in part by $860,000 the parents had scraped together from their own savings and from relatives.
The parents felt they were in good hands. Xinhua Hospital, which is affiliated with the Shanghai Jiao Tong University School of Medicine, was acclaimed for its pediatrics department. It was the first Chinese institution to perform open heart surgery on infants, and the first in the country to separate conjoined twins. If all went well, the girl would be the first person in the world to receive a gene-editing therapy directed at the brain. It would rewrite the mutated gene in her neurons, restoring the needed DNA base so she could make a vital protein.
Leading the effort was Zilong Qiu, a neuroscientist at the university’s brain center, the Songjiang Research Institute. At the time, in late March 2025, Qiu was one of several researchers around the world vying to push base editors — a more precise form of the powerful gene editor CRISPR — into custom treatments for children with rare diseases. One month earlier, KJ Muldoon, an infant with a life-threatening metabolic disorder, had quietly received his first intravenous infusion of one such treatment at the Children’s Hospital of Philadelphia.
Although news that base editing saved “Baby KJ” would soon rocket around the world — Science named the feat one of the runners-up for its 2025 Breakthrough of the Year — the story of what happened at Xinhua Hospital has remained hidden. An entry for the study posted to ClinicalTrials.gov has not been updated for more than a year. And when Qiu and his colleagues published proof-of-concept animal studies related to the trial in Nature early this year, they stripped the paper of references to the family and its financial contributions, noting only that “bridging the gap between preclinical research and clinical translation remains a significant challenge.”
That vague language glossed over tragedy: Seven days after the girl’s medical team infused trillions of viruses carrying the recipe for the base editor into her spinal fluid, she died of a severe immune reaction linked to the therapy, Science and Retraction Watch can now reveal.
According to official documents and accounts provided by the girl’s parents, the hospital had allowed Qiu’s experimental treatment to proceed under a regulatory provision that does not require approval from national regulators. The lax oversight of this recent trial and the failure to publicly report the fatality “shows the gap between what is intended and what has been put in place,” says Joy Zhang, a sociologist at the University of Kent who has written about the pervasive culture of secrecy in Chinese scientific institutions.
Seven experts in fields including genetics, virology, and bioethics who reviewed details of the Nature study and the clinical trial for Science and Retraction Watch expressed concern that Qiu and his team downplayed the trial’s risks in describing them to the parents, overlooked safety signals in animal studies, and proceeded even though success was unlikely. “This shouldn’t have gone to trial,” says Steven Gray of the University of Texas Southwestern Medical Center, who develops viruses for gene therapy.
Gray and several of the other experts are calling for a full review of the images and other data in submitted and published versions of the Nature paper and full disclosure of the study’s funding. Some of the issues might warrant a retraction, they say. Neither Qiu nor his university or the hospital responded to multiple requests for comment for this story, and Nature says it was not aware of the issues surrounding the clinical trial before it published the group’s paper.
The girl’s parents have decided to tell her story now because they are angry about what they feel is a lack of accountability by the researchers and the institutions. “Learning the reality of these missing safeguards has fundamentally changed how we now view the entire project,” says the father, a software engineer. “We did not realize how unusual and dangerous many of the arrangements were.”
https://retractionwatch.com/2026/07/23/exclusive-death-gene-editing-trial-china-nature-science-investigation/#more-135456
See: https://www.science.org/content/article/exclusive-death-girl-chinese-gene-editing-trial-was-never-made-public
Yang K, Li WK, Geng YX, Zhang SQ, Wu SH, Cheng YB, Wang JW, Xu ZK, Wang WX, Zhang TY, Wang PY, Yuan YT, Fan J, Wu J, Xu RC, Zhang YF, Tao GJ, Li ZH, Lin CX, Li TS, Zhang XY, Li J, Zhang R, Yang WX, Wen JS, Yang ZY, Gong L, Zeng W, Du AL, Li JS, Li F, Cheng TL, Qiu Z. In vivo base editing of Chd3 rescues behavioural abnormalities in mice. Nature. 2026 Mar;651(8106):785-795. doi: 10.1038/s41586-026-10113-6. Epub 2026 Feb 18. PMID: 41708849; PMCID: PMC12999480.
Abstract
Neurodevelopmental disorders that arise from de novo mutations in chromatin-remodelling genes lack targeted treatments. Snijders Blok-Campeau syndrome (SNIBCPS)1, which is caused by pathogenic variants in CHD3, manifests with intellectual disability, autistic-like behaviours and motor deficits2. Whether somatic gene correction can reverse such phenotypes in vivo remains unknown. Here we show that modelling the recurrent CHD3 variant p.R1025W in a humanized mouse model (Chd3hR1025W/+) recapitulates key features of SNIBCPS, including reduced CHD3 protein levels and abnormalities in social communication, cognition and motor coordination. We engineered a TadA-embedded adenine base editor (TeABE) and delivered it brain-wide using a dual adeno-associated virus (AAV) system and achieved efficient on-target A•T-to-G•C correction across multiple cortical and hippocampal regions with minimal bystander activity. This intervention restored CHD3 levels and ameliorated behavioural abnormalities in vivo. Furthermore, intrathecal dual AAV delivery in nonhuman primates resulted in widespread neuronal transduction and efficient TeABE reconstitution, a result that supports its translational feasibility. These findings establish in vivo base editing as a viable therapeutic approach for CHD3-related neurodevelopmental disease. More broadly, they demonstrate that precise single-base correction in the postnatal brain can restore protein dosage and function, thereby offering a framework for the treatment of monogenic neurodevelopmental disorders.
Carbamoyl phosphate synthetase 1 treated with a customized CRISPR gene editing therapy 2
In a historic medical breakthrough, a child diagnosed with a rare genetic disorder has been successfully treated with a customized CRISPR gene editing therapy by a team at Children’s Hospital of Philadelphia (CHOP) and Penn Medicine. The infant, KJ, was born with a rare metabolic disease known as severe carbamoyl phosphate synthetase 1 (CPS1) deficiency. After spending the first several months of his life in the hospital, on a very restrictive diet, KJ received the first dose of his bespoke therapy in February 2025 between six and seven months of age. The treatment was administered safely, and he is now growing well and thriving.
KJ was only days old when he was diagnosed with a rare metabolic disorder and transferred to Children's Hospital of Philadelphia where doctors were actively researching new cell and gene therapies.
The case is detailed today in a study published by The New England Journal of Medicine and was presented at the American Society of Gene & Cell Therapy Annual Meeting in New Orleans. This landmark finding could provide a pathway for gene editing technology to be successfully adapted to treat individuals with rare diseases for whom no medical treatments are available.
“Years and years of progress in gene editing and collaboration between researchers and clinicians made this moment possible, and while KJ is just one patient, we hope he is the first of many to benefit from a methodology that can be scaled to fit an individual patient’s needs,” said Rebecca Ahrens-Nicklas, MD, PhD, director of the Gene Therapy for Inherited Metabolic Disorders Frontier Program (GTIMD) at Children’s Hospital of Philadelphia and an assistant professor of Pediatrics in the Perelman School of Medicine at the University of Pennsylvania.
CRISPR (clustered regularly interspaced short palindromic repeats)-based gene editing can precisely correct disease-causing variants in the human genome. Gene editing tools are incredibly complex and nuanced, and up to this point, researchers have built them to target more common diseases that affect tens or hundreds of thousands of patients, such as the two diseases for which there currently are U.S. Food and Drug Administration-approved therapies, sickle cell disease and beta thalassemia. However, relatively few diseases benefit from a “one-size-fits-all” gene editing approach since so many disease-causing variants exist. Even as the field advances, many patients with rare genetic diseases – collectively impacting millions of patients worldwide – have been left behind.
Researchers and clinicians at CHOP and Penn began collaborating to study the feasibility of creating customized gene editing therapies for individual patients in 2023.
A Collaborative Effort
Ahrens-Nicklas and Kiran Musunuru, MD, PhD, the Barry J. Gertz Professor for Translational Research in Penn’s Perelman School of Medicine, who are co-corresponding authors on the published report, began collaborating to study the feasibility of creating customized gene editing therapies for individual patients in 2023, building upon many years of research into rare metabolic disorders, as well as the feasibility of gene editing to treat patients. Both are members of the NIH funded Somatic Cell Genome Editing Consortium, which supports collaborative genome editing research.
Ahrens-Nicklas and Musunuru decided to focus on urea cycle disorders. During the normal breakdown of proteins in the body, ammonia is naturally produced. Typically, our bodies know to convert the ammonia to urea and then excrete that urea through urination. However, a child with a urea cycle disorder lacks an enzyme in the liver needed to convert ammonia to urea. Ammonia then builds up to a toxic level, which can cause organ damage, particularly in the brain and the liver.
After years of preclinical research with similar disease-causing variants, Ahrens-Nicklas and Musunuru targeted KJ’s specific variant of CPS1, identified soon after his birth. Within six months, their team designed and manufactured a base editing therapy delivered via lipid nanoparticles to the liver in order to correct KJ’s faulty enzyme. In late February 2025, KJ received his first infusion of this experimental therapy, and since then, he has received follow-up doses in March and April 2025. In the newly published New England Journal of Medicine paper, the researchers, along with their academic and industry collaborators, describe the customized CRISPR gene editing therapy that was rigorously yet speedily developed for administration to KJ.
As of April 2025, KJ had received three doses of the therapy with no serious side effects. In the short time since treatment, he has tolerated increased dietary protein and needed less nitrogen scavenger medication. He also has been able to recover from certain typical childhood illnesses like rhinovirus without ammonia building up in his body. Longer follow-up is needed to fully evaluate the benefits of the therapy.
“While KJ will need to be monitored carefully for the rest of his life, our initial findings are quite promising,” Ahrens-Nicklas said.
“We want each and every patient to have the potential to experience the same results we saw in this first patient, and we hope that other academic investigators will replicate this method for many rare diseases and give many patients a fair shot at living a healthy life,” Musunuru said. “The promise of gene therapy that we’ve heard about for decades is coming to fruition, and it’s going to utterly transform the way we approach medicine.”
A Future for KJ
Typically, patients with CPS1 deficiency, like KJ, are treated with a liver transplant. However, for patients to receive a liver transplant, they need to be medically stable and old enough to handle such a major procedure. During that time, episodes of increased ammonia can put patients at risk for ongoing, lifelong neurologic damage or even prove fatal. Because of these threats to lifelong health, the researchers knew that finding new ways to treat patients who are too young and small to receive liver transplants would be life-changing for families whose children faced this disorder.
“We would do anything for our kids, so with KJ, we wanted to figure out how we were going to support him and how we were going to get him to the point where he can do all the things a normal kid should be able to do,” his mother, Nicole Muldoon, said. “We thought it was our responsibility to help our child, so when the doctors came to us with their idea, we put our trust in them in the hopes that it could help not just KJ but other families in our position.”
“We’ve been in the thick of this since KJ was born, and our whole world’s been revolving around this little guy and his stay in the hospital,” his father, Kyle Muldoon, said. “We’re so excited to be able to finally be together at home so that KJ can be with his siblings, and we can finally take a deep breath.”
This study was supported by grants from the National Institutes of Health Somatic Cell Genome Editing Program (U01TR005355, U19NS132301), as well as additional National Institutes of Health grants (R35HL145203, U19NS132303, DP2CA281401, P01HL142494). In-kind contributions were made by Acuitas Therapeutics, Integrated DNA Technologies, Aldevron, and Danaher Corporation. Additional funding was provided by the CHOP Research Institute’s Gene Therapy for Inherited Metabolic Disorders Frontier Program.
https://www.chop.edu/news/worlds-first-patient-treated-personalized-crispr-gene-editing-therapy-childrens-hospital
Musunuru K, Grandinette SA, Wang X, Hudson TR, Briseno K, Berry AM, Hacker JL, Hsu A, Silverstein RA, Hille LT, Ogul AN, Robinson-Garvin NA, Small JC, McCague S, Burke SM, Wright CM, Bick S, Indurthi V, Sharma S, Jepperson M, Vakulskas CA, Collingwood M, Keogh K, Jacobi A, Sturgeon M, Brommel C, Schmaljohn E, Kurgan G, Osborne T, Zhang H, Kinney K, Rettig G, Barbosa CJ, Semple SC, Tam YK, Lutz C, George LA, Kleinstiver BP, Liu DR, Ng K, Kassim SH, Giannikopoulos P, Alameh MG, Urnov FD, Ahrens-Nicklas RC. Patient-Specific In Vivo Gene Editing to Treat a Rare Genetic Disease. N Engl J Med. 2025 Jun 12;392(22):2235-2243. doi: 10.1056/NEJMoa2504747. Epub 2025 May 15. PMID: 40373211; PMCID: PMC12713542.
Abstract
Base editors can correct disease-causing genetic variants. After a neonate had received a diagnosis of severe carbamoyl-phosphate synthetase 1 deficiency, a disease with an estimated 50% mortality in early infancy, we immediately began to develop a customized lipid nanoparticle-delivered base-editing therapy. After regulatory approval had been obtained for the therapy, the patient received two infusions at approximately 7 and 8 months of age. In the 7 weeks after the initial infusion, the patient was able to receive an increased amount of dietary protein and a reduced dose of a nitrogen-scavenger medication to half the starting dose, without unacceptable adverse events and despite viral illnesses. No serious adverse events occurred. Longer follow-up is warranted to assess safety and efficacy. (Funded by the National Institutes of Health and others.).
KJ was only days old when he was diagnosed with a rare metabolic disorder and transferred to Children's Hospital of Philadelphia where doctors were actively researching new cell and gene therapies.
The case is detailed today in a study published by The New England Journal of Medicine and was presented at the American Society of Gene & Cell Therapy Annual Meeting in New Orleans. This landmark finding could provide a pathway for gene editing technology to be successfully adapted to treat individuals with rare diseases for whom no medical treatments are available.
“Years and years of progress in gene editing and collaboration between researchers and clinicians made this moment possible, and while KJ is just one patient, we hope he is the first of many to benefit from a methodology that can be scaled to fit an individual patient’s needs,” said Rebecca Ahrens-Nicklas, MD, PhD, director of the Gene Therapy for Inherited Metabolic Disorders Frontier Program (GTIMD) at Children’s Hospital of Philadelphia and an assistant professor of Pediatrics in the Perelman School of Medicine at the University of Pennsylvania.
CRISPR (clustered regularly interspaced short palindromic repeats)-based gene editing can precisely correct disease-causing variants in the human genome. Gene editing tools are incredibly complex and nuanced, and up to this point, researchers have built them to target more common diseases that affect tens or hundreds of thousands of patients, such as the two diseases for which there currently are U.S. Food and Drug Administration-approved therapies, sickle cell disease and beta thalassemia. However, relatively few diseases benefit from a “one-size-fits-all” gene editing approach since so many disease-causing variants exist. Even as the field advances, many patients with rare genetic diseases – collectively impacting millions of patients worldwide – have been left behind.
Researchers and clinicians at CHOP and Penn began collaborating to study the feasibility of creating customized gene editing therapies for individual patients in 2023.
A Collaborative Effort
Ahrens-Nicklas and Kiran Musunuru, MD, PhD, the Barry J. Gertz Professor for Translational Research in Penn’s Perelman School of Medicine, who are co-corresponding authors on the published report, began collaborating to study the feasibility of creating customized gene editing therapies for individual patients in 2023, building upon many years of research into rare metabolic disorders, as well as the feasibility of gene editing to treat patients. Both are members of the NIH funded Somatic Cell Genome Editing Consortium, which supports collaborative genome editing research.
Ahrens-Nicklas and Musunuru decided to focus on urea cycle disorders. During the normal breakdown of proteins in the body, ammonia is naturally produced. Typically, our bodies know to convert the ammonia to urea and then excrete that urea through urination. However, a child with a urea cycle disorder lacks an enzyme in the liver needed to convert ammonia to urea. Ammonia then builds up to a toxic level, which can cause organ damage, particularly in the brain and the liver.
After years of preclinical research with similar disease-causing variants, Ahrens-Nicklas and Musunuru targeted KJ’s specific variant of CPS1, identified soon after his birth. Within six months, their team designed and manufactured a base editing therapy delivered via lipid nanoparticles to the liver in order to correct KJ’s faulty enzyme. In late February 2025, KJ received his first infusion of this experimental therapy, and since then, he has received follow-up doses in March and April 2025. In the newly published New England Journal of Medicine paper, the researchers, along with their academic and industry collaborators, describe the customized CRISPR gene editing therapy that was rigorously yet speedily developed for administration to KJ.
As of April 2025, KJ had received three doses of the therapy with no serious side effects. In the short time since treatment, he has tolerated increased dietary protein and needed less nitrogen scavenger medication. He also has been able to recover from certain typical childhood illnesses like rhinovirus without ammonia building up in his body. Longer follow-up is needed to fully evaluate the benefits of the therapy.
“While KJ will need to be monitored carefully for the rest of his life, our initial findings are quite promising,” Ahrens-Nicklas said.
“We want each and every patient to have the potential to experience the same results we saw in this first patient, and we hope that other academic investigators will replicate this method for many rare diseases and give many patients a fair shot at living a healthy life,” Musunuru said. “The promise of gene therapy that we’ve heard about for decades is coming to fruition, and it’s going to utterly transform the way we approach medicine.”
A Future for KJ
Typically, patients with CPS1 deficiency, like KJ, are treated with a liver transplant. However, for patients to receive a liver transplant, they need to be medically stable and old enough to handle such a major procedure. During that time, episodes of increased ammonia can put patients at risk for ongoing, lifelong neurologic damage or even prove fatal. Because of these threats to lifelong health, the researchers knew that finding new ways to treat patients who are too young and small to receive liver transplants would be life-changing for families whose children faced this disorder.
“We would do anything for our kids, so with KJ, we wanted to figure out how we were going to support him and how we were going to get him to the point where he can do all the things a normal kid should be able to do,” his mother, Nicole Muldoon, said. “We thought it was our responsibility to help our child, so when the doctors came to us with their idea, we put our trust in them in the hopes that it could help not just KJ but other families in our position.”
“We’ve been in the thick of this since KJ was born, and our whole world’s been revolving around this little guy and his stay in the hospital,” his father, Kyle Muldoon, said. “We’re so excited to be able to finally be together at home so that KJ can be with his siblings, and we can finally take a deep breath.”
This study was supported by grants from the National Institutes of Health Somatic Cell Genome Editing Program (U01TR005355, U19NS132301), as well as additional National Institutes of Health grants (R35HL145203, U19NS132303, DP2CA281401, P01HL142494). In-kind contributions were made by Acuitas Therapeutics, Integrated DNA Technologies, Aldevron, and Danaher Corporation. Additional funding was provided by the CHOP Research Institute’s Gene Therapy for Inherited Metabolic Disorders Frontier Program.
https://www.chop.edu/news/worlds-first-patient-treated-personalized-crispr-gene-editing-therapy-childrens-hospital
Musunuru K, Grandinette SA, Wang X, Hudson TR, Briseno K, Berry AM, Hacker JL, Hsu A, Silverstein RA, Hille LT, Ogul AN, Robinson-Garvin NA, Small JC, McCague S, Burke SM, Wright CM, Bick S, Indurthi V, Sharma S, Jepperson M, Vakulskas CA, Collingwood M, Keogh K, Jacobi A, Sturgeon M, Brommel C, Schmaljohn E, Kurgan G, Osborne T, Zhang H, Kinney K, Rettig G, Barbosa CJ, Semple SC, Tam YK, Lutz C, George LA, Kleinstiver BP, Liu DR, Ng K, Kassim SH, Giannikopoulos P, Alameh MG, Urnov FD, Ahrens-Nicklas RC. Patient-Specific In Vivo Gene Editing to Treat a Rare Genetic Disease. N Engl J Med. 2025 Jun 12;392(22):2235-2243. doi: 10.1056/NEJMoa2504747. Epub 2025 May 15. PMID: 40373211; PMCID: PMC12713542.
Abstract
Base editors can correct disease-causing genetic variants. After a neonate had received a diagnosis of severe carbamoyl-phosphate synthetase 1 deficiency, a disease with an estimated 50% mortality in early infancy, we immediately began to develop a customized lipid nanoparticle-delivered base-editing therapy. After regulatory approval had been obtained for the therapy, the patient received two infusions at approximately 7 and 8 months of age. In the 7 weeks after the initial infusion, the patient was able to receive an increased amount of dietary protein and a reduced dose of a nitrogen-scavenger medication to half the starting dose, without unacceptable adverse events and despite viral illnesses. No serious adverse events occurred. Longer follow-up is warranted to assess safety and efficacy. (Funded by the National Institutes of Health and others.).
See: https://childnervoussystem.blogspot.com/2025/05/carbamoyl-phosphate-synthetase-1.html
Wednesday, July 22, 2026
Ehlers-Danlos syndrome and small fiber neuropathy
Dell'Aversana D, Provitera V, Trinchillo A, Masciarelli F, Tozza S, Caporaso G, Vitale F, Borreca I, Areniello AR, Ciccarelli G, Esposito G, Iodice R, Dubbioso R, Manganelli F, Santoro L, Castori M, Nolano M. Distinct sensory and autonomic involvement in hypermobile Ehlers-Danlos syndrome compared with idiopathic small fiber neuropathy: a multimodal study. Sci Rep. 2026 Jul 3. doi: 10.1038/s41598-026-60461-6. Epub ahead of print. PMID: 42399338.
Abstract
Hypermobile Ehlers-Danlos syndrome (hEDS), frequently presents with pain and autonomic symptoms suggestive of small fiber neuropathy (SFN). However, systematic comparisons between hEDS and idiopathic SFN (iSFN) using combined clinical, functional, and morphological approaches are lacking. We prospectively studied a population of SFN patients who also fulfilled the 2017 criteria for hEDS (hEDS/SFN) and compared them with a group of iSFN patients of similar age. All underwent SFN-Symptoms Inventory Questionnaire (SFN-SIQ), Douleur Neuropathique 4 (DN4), and the Composite Autonomic Symptom Score-31 (COMPASS-31) questionnaires, quantitative sensory testing (QST), autonomic testing (cardiovascular reflexes, sympathetic skin response, dynamic sweat test), and skin biopsy from leg, thigh, and fingertip. Clinical, morphological and functional data were compared with our normative dataset and between the two patient groups. 35 hEDS/SFN and 38 iSFN patients were included in the study. hEDS/SFN patients had earlier symptom onset (19.5 ± 5.9 years vs. 35.2 ± 8.7 years, p < 0.001), more generalized distribution, and higher COMPASS-31 scores (54.3 ± 16.9 vs. 33.9 ± 19.4 p < 0.01), particularly in orthostatic intolerance, gastrointestinal, and urinary domains. Postural Orthostatic Tachycardia Syndrome (POTS) was present in half of hEDS/SFN patients while it was not found in iSFN (51.5% vs. 0.0%). Skin biopsy revealed similar intraepidermal nerve fiber loss in both groups, but hEDS had greater autonomic fiber loss (p < 0.05). Small fiber involvement in hEDS is characterized by earlier onset, more generalized pain and severe autonomic symptoms, and higher autonomic morpho-functional impairment compared with iSFN. Systematic autonomic assessment and targeted management should be considered in this population.
Novak P, Systrom DM, Marciano SP, Witte A, Warren A, Felsenstein D, Giannetti MP, Hamilton MJ, Nicoloro-SantaBarbara J, Castells M, Farhad K, Pilgrim DM, Mullally WJ, Fishman MC, Milunsky JM, Milunsky A, Krier J. Hypermobile Ehlers-Danlos Syndrome: Cerebrovascular, Autonomic and Neuropathic Features. Am J Med Open. 2025 Jul 18;14:100111. doi: 10.1016/j.ajmo.2025.100111. PMID: 40843452; PMCID: PMC12365377.
Abstract
Background: Hypermobile Ehlers-Danlos syndrome (hEDS) affects multiple systems, but comprehensive evaluations of a larger sample of hEDS patients are lacking. The objective of this study was to describe cerebrovascular, autonomic, and neuropathic features of hEDS.
Methods: This retrospective case-control study was conducted at Brigham and Women's Faulkner Hospital between 2016-2023. Data from hEDS patients who completed autonomic testing and skin biopsies were analyzed. Outcome measures include validated surveys (Survey of Autonomic Functions, Neuropathy Total Symptom Score-6 (SAS)) and autonomic function testing (Valsalva maneuver, deep breathing, head-up tilt and sudomotor), cerebrovascular (cerebral blood flow velocity (CBFv) in the middle cerebral artery), respiratory (capnography), and neuropathic (skin biopsies for assessment of small fiber neuropathy) testing and inflammatory/ autoimmune markers.
Results: Total 270 hEDS patients were analyzed and compared to 29 healthy controls. Common hEDS complaints (prevalence > 90% ) were orthostatic sudomotor, vasomotor, gastrointestinal, and pain. Orthostatic cerebral blood flow velocity was reduced in 79% of hEDS and correlated with orthostatic dizziness. The head-up tilt test revealed postural tachycardia syndrome (prevalence 33%), hypocapnic cerebral hypoperfusion (22%), orthostatic cerebral hypoperfusion syndrome (18%), and neurogenic orthostatic hypotension (9%). Widespread but mild autonomic failure was present in 90% of hEDS patients on autonomic testing. Small fiber neuropathy using structural criteria was detected in 64%, and using combined structural and functional criteria in 82%.
Conclusions: This study provided evidence of cerebrovascular dysregulation with reduced orthostatic cerebral blood flow velocity associated with symptoms of cerebral hypoperfusion, frequent small fiber neuropathy, and widespread but mild autonomic failure in hEDS.
Igharo D, Thiel JC, Rolke R, Akkaya M, Weis J, Katona I, Schulz JB, Maier A. Skin biopsy reveals generalized small fibre neuropathy in hypermobile Ehlers-Danlos syndromes. Eur J Neurol. 2023 Mar;30(3):719-728. doi: 10.1111/ene.15649. Epub 2022 Dec 13. PMID: 36437696.
Abstract
Background and purpose: Ehlers-Danlos syndromes are hereditary disorders of connective tissue that are characterized by joint hypermobility, skin hyperextensibility and tissue fragility. The most common subtype is the hypermobile type. In addition to symptoms of small fibre neuropathy (SFN) due to damage to the small peripheral nerve fibres, with degeneration of the distal nerve endings, autonomic disorders such as postural tachycardia syndrome (PoTS) are frequently reported features in patients with hypermobile Ehlers-Danlos syndrome (hEDS). To date, the underlying pathophysiological mechanisms are still not completely understood.
Study purpose: To better understand pathophysiological mechanisms of small fiber neuropathy and autonomic neuropathy in hypermobile Ehlers-Danlos Syndromes.
Methods: We prospectively investigated 31 patients with hEDS compared to 31 healthy controls by using skin biopsy, quantitative sensory testing, tilt-table testing, the painDetect, Small Fibre Neuropathy Screening List and the COMPASS-31 (Composite Autonomic Symptom Score 31) questionnaire.
Results: Nineteen (61%) patients with hEDS were diagnosed with SFN, and 10 (32%) fulfilled the criteria for PoTS. Patients with hEDS had significantly higher heart rates than controls. According to quantitative sensory testing, these patients had generalized thermal and tactile hypesthesia. Skin biopsy revealed significantly reduced intraepithelial nerve fibre density proximally (thigh) and distally (lower leg) in patients compared to controls. This was consistent with various complaints of pain and sensory disturbances in both the proximal and distal body regions.
Conclusion: These results confirm histologically proven SFN as a common feature in patients with hEDS, revealing a generalized distribution of nerve fibre loss. Regarding the frequently reported autonomic and neuropathic dysfunctions, the findings support SFN as an important, but not the only, underlying pathomechanism.
Abstract
Hypermobile Ehlers-Danlos syndrome (hEDS), frequently presents with pain and autonomic symptoms suggestive of small fiber neuropathy (SFN). However, systematic comparisons between hEDS and idiopathic SFN (iSFN) using combined clinical, functional, and morphological approaches are lacking. We prospectively studied a population of SFN patients who also fulfilled the 2017 criteria for hEDS (hEDS/SFN) and compared them with a group of iSFN patients of similar age. All underwent SFN-Symptoms Inventory Questionnaire (SFN-SIQ), Douleur Neuropathique 4 (DN4), and the Composite Autonomic Symptom Score-31 (COMPASS-31) questionnaires, quantitative sensory testing (QST), autonomic testing (cardiovascular reflexes, sympathetic skin response, dynamic sweat test), and skin biopsy from leg, thigh, and fingertip. Clinical, morphological and functional data were compared with our normative dataset and between the two patient groups. 35 hEDS/SFN and 38 iSFN patients were included in the study. hEDS/SFN patients had earlier symptom onset (19.5 ± 5.9 years vs. 35.2 ± 8.7 years, p < 0.001), more generalized distribution, and higher COMPASS-31 scores (54.3 ± 16.9 vs. 33.9 ± 19.4 p < 0.01), particularly in orthostatic intolerance, gastrointestinal, and urinary domains. Postural Orthostatic Tachycardia Syndrome (POTS) was present in half of hEDS/SFN patients while it was not found in iSFN (51.5% vs. 0.0%). Skin biopsy revealed similar intraepidermal nerve fiber loss in both groups, but hEDS had greater autonomic fiber loss (p < 0.05). Small fiber involvement in hEDS is characterized by earlier onset, more generalized pain and severe autonomic symptoms, and higher autonomic morpho-functional impairment compared with iSFN. Systematic autonomic assessment and targeted management should be considered in this population.
Novak P, Systrom DM, Marciano SP, Witte A, Warren A, Felsenstein D, Giannetti MP, Hamilton MJ, Nicoloro-SantaBarbara J, Castells M, Farhad K, Pilgrim DM, Mullally WJ, Fishman MC, Milunsky JM, Milunsky A, Krier J. Hypermobile Ehlers-Danlos Syndrome: Cerebrovascular, Autonomic and Neuropathic Features. Am J Med Open. 2025 Jul 18;14:100111. doi: 10.1016/j.ajmo.2025.100111. PMID: 40843452; PMCID: PMC12365377.
Abstract
Background: Hypermobile Ehlers-Danlos syndrome (hEDS) affects multiple systems, but comprehensive evaluations of a larger sample of hEDS patients are lacking. The objective of this study was to describe cerebrovascular, autonomic, and neuropathic features of hEDS.
Methods: This retrospective case-control study was conducted at Brigham and Women's Faulkner Hospital between 2016-2023. Data from hEDS patients who completed autonomic testing and skin biopsies were analyzed. Outcome measures include validated surveys (Survey of Autonomic Functions, Neuropathy Total Symptom Score-6 (SAS)) and autonomic function testing (Valsalva maneuver, deep breathing, head-up tilt and sudomotor), cerebrovascular (cerebral blood flow velocity (CBFv) in the middle cerebral artery), respiratory (capnography), and neuropathic (skin biopsies for assessment of small fiber neuropathy) testing and inflammatory/ autoimmune markers.
Results: Total 270 hEDS patients were analyzed and compared to 29 healthy controls. Common hEDS complaints (prevalence > 90% ) were orthostatic sudomotor, vasomotor, gastrointestinal, and pain. Orthostatic cerebral blood flow velocity was reduced in 79% of hEDS and correlated with orthostatic dizziness. The head-up tilt test revealed postural tachycardia syndrome (prevalence 33%), hypocapnic cerebral hypoperfusion (22%), orthostatic cerebral hypoperfusion syndrome (18%), and neurogenic orthostatic hypotension (9%). Widespread but mild autonomic failure was present in 90% of hEDS patients on autonomic testing. Small fiber neuropathy using structural criteria was detected in 64%, and using combined structural and functional criteria in 82%.
Conclusions: This study provided evidence of cerebrovascular dysregulation with reduced orthostatic cerebral blood flow velocity associated with symptoms of cerebral hypoperfusion, frequent small fiber neuropathy, and widespread but mild autonomic failure in hEDS.
Igharo D, Thiel JC, Rolke R, Akkaya M, Weis J, Katona I, Schulz JB, Maier A. Skin biopsy reveals generalized small fibre neuropathy in hypermobile Ehlers-Danlos syndromes. Eur J Neurol. 2023 Mar;30(3):719-728. doi: 10.1111/ene.15649. Epub 2022 Dec 13. PMID: 36437696.
Abstract
Background and purpose: Ehlers-Danlos syndromes are hereditary disorders of connective tissue that are characterized by joint hypermobility, skin hyperextensibility and tissue fragility. The most common subtype is the hypermobile type. In addition to symptoms of small fibre neuropathy (SFN) due to damage to the small peripheral nerve fibres, with degeneration of the distal nerve endings, autonomic disorders such as postural tachycardia syndrome (PoTS) are frequently reported features in patients with hypermobile Ehlers-Danlos syndrome (hEDS). To date, the underlying pathophysiological mechanisms are still not completely understood.
Study purpose: To better understand pathophysiological mechanisms of small fiber neuropathy and autonomic neuropathy in hypermobile Ehlers-Danlos Syndromes.
Methods: We prospectively investigated 31 patients with hEDS compared to 31 healthy controls by using skin biopsy, quantitative sensory testing, tilt-table testing, the painDetect, Small Fibre Neuropathy Screening List and the COMPASS-31 (Composite Autonomic Symptom Score 31) questionnaire.
Results: Nineteen (61%) patients with hEDS were diagnosed with SFN, and 10 (32%) fulfilled the criteria for PoTS. Patients with hEDS had significantly higher heart rates than controls. According to quantitative sensory testing, these patients had generalized thermal and tactile hypesthesia. Skin biopsy revealed significantly reduced intraepithelial nerve fibre density proximally (thigh) and distally (lower leg) in patients compared to controls. This was consistent with various complaints of pain and sensory disturbances in both the proximal and distal body regions.
Conclusion: These results confirm histologically proven SFN as a common feature in patients with hEDS, revealing a generalized distribution of nerve fibre loss. Regarding the frequently reported autonomic and neuropathic dysfunctions, the findings support SFN as an important, but not the only, underlying pathomechanism.
See: https://childnervoussystem.blogspot.com/2016/10/ehlers-danlos-syndrome-linked-to-small.html
Wednesday, July 15, 2026
Great experiments 3
Lee HF, Chi CS, Tsai CR, Chen CH, Wang CC. Electroencephalographic features of patients with SCN1A-positive Dravet syndrome. Brain Dev. 2015 Jun;37(6):599-611. doi: 10.1016/j.braindev.2014.10.003. Epub 2014 Oct 27. PMID: 25459968.
Video EEG recording during HWBT (hot water bathing test) was performed after obtaining informed consent from the patients’ parents. After a 20-min routine EEG recording, the patient was requested to remove his or her clothing and then sit in chest above the level of the water. The initial water temperature was around 35–37 C depending on the patient’s preference. Hot water at a temperature of around 55–60 C was collected in a stainless wash basin. The water temperature of the bath tub was increased gradually by means of alternately scooping water out of the bath tub and transferring hot water from the wash basin to the bath tub to raise the water temperature up to a maximum of around 40 C. Simultaneously, water from the bath tub was intermittently poured onto the patient’s shoulders with a small bowl in order to elevate the patient’s body temperature. The patient’s axillary temperature and the water temperature were recorded simultaneously every 10 min during the course of the test. The procedure was discontinued immediately after seizure initiation. In cases where the patient exhibited a seizure during the test, he or she was taken out of the water, placed on a bed, gently dried with a towel, and seizure patterns were then recorded. If no seizure developed, the HWBT was ended after 30 min, and the final axillary and water temperatures were recorded.
Mytinger JR, Weisleder P. E. Steve Roach: Reflections From the Editor-In-Chief of Pediatric Neurology. Pediatr Neurol. 2021 Dec;125:58-60. doi: 10.1016/j.pediatrneurol.2021.09.006. PMID: 34715988.
What is the most chillingly inappropriate manuscript that was submitted during your term as the journal's editor?
One alarming manuscript summarized a study that attempted to verify the clinical observation that increased temperature can trigger seizures in children with Dravet syndrome by immersing children in a hot water bath designed to raise their body temperature to see if it would trigger a seizure. The children who experienced a seizure were then removed from the bath so the seizure could be filmed and characterized, with no stated plan for intervening should a prolonged seizure occur. All of this, naturally, without mention of an institutional review board approval!
Video EEG recording during HWBT (hot water bathing test) was performed after obtaining informed consent from the patients’ parents. After a 20-min routine EEG recording, the patient was requested to remove his or her clothing and then sit in chest above the level of the water. The initial water temperature was around 35–37 C depending on the patient’s preference. Hot water at a temperature of around 55–60 C was collected in a stainless wash basin. The water temperature of the bath tub was increased gradually by means of alternately scooping water out of the bath tub and transferring hot water from the wash basin to the bath tub to raise the water temperature up to a maximum of around 40 C. Simultaneously, water from the bath tub was intermittently poured onto the patient’s shoulders with a small bowl in order to elevate the patient’s body temperature. The patient’s axillary temperature and the water temperature were recorded simultaneously every 10 min during the course of the test. The procedure was discontinued immediately after seizure initiation. In cases where the patient exhibited a seizure during the test, he or she was taken out of the water, placed on a bed, gently dried with a towel, and seizure patterns were then recorded. If no seizure developed, the HWBT was ended after 30 min, and the final axillary and water temperatures were recorded.
Mytinger JR, Weisleder P. E. Steve Roach: Reflections From the Editor-In-Chief of Pediatric Neurology. Pediatr Neurol. 2021 Dec;125:58-60. doi: 10.1016/j.pediatrneurol.2021.09.006. PMID: 34715988.
What is the most chillingly inappropriate manuscript that was submitted during your term as the journal's editor?
One alarming manuscript summarized a study that attempted to verify the clinical observation that increased temperature can trigger seizures in children with Dravet syndrome by immersing children in a hot water bath designed to raise their body temperature to see if it would trigger a seizure. The children who experienced a seizure were then removed from the bath so the seizure could be filmed and characterized, with no stated plan for intervening should a prolonged seizure occur. All of this, naturally, without mention of an institutional review board approval!
(The Lee article is not necessarily the one referred to in the Mytinger article. I could not confirm.)
Pediatric headache: A comprehensive review
Wander A, Meena AK, Choudhary PK, Peer S, Singh R. Pediatric Headache: A Comprehensive Review. Ann Child Neurol. 2024;32(4):207-218.
Abstract
Pediatric headache is a common condition that often results in frequent outpatient visits. There are two broad etiological groups of headaches—primary and secondary headaches—with the former being more prevalent. Migraine, a type of primary headache, shares similarities with those experienced by adults, albeit with some variations in diagnostic criteria. The secondary causes of headache should be differentiated from the primary headaches with proper clinical evaluation and focussed investigations. The management of migraine focusses on lifestyle modifications, behavioral therapy, and pharmacotherapy for acute episodes and long-term preventive therapy. There are many novel promising treatment modalities. This review article provides an overview of pediatric headache epidemiology, classification, and pathophysiology and then elaborates on management and prevention strategies.
Abstract
Pediatric headache is a common condition that often results in frequent outpatient visits. There are two broad etiological groups of headaches—primary and secondary headaches—with the former being more prevalent. Migraine, a type of primary headache, shares similarities with those experienced by adults, albeit with some variations in diagnostic criteria. The secondary causes of headache should be differentiated from the primary headaches with proper clinical evaluation and focussed investigations. The management of migraine focusses on lifestyle modifications, behavioral therapy, and pharmacotherapy for acute episodes and long-term preventive therapy. There are many novel promising treatment modalities. This review article provides an overview of pediatric headache epidemiology, classification, and pathophysiology and then elaborates on management and prevention strategies.
From the article:
1. Etiology
Headaches in children can be categorized into primary, where pain is a result of the headache condition itself, and secondary, where pain serves as a symptom of an underlying condition. Migraine and tension-type headaches are the most frequently encountered types of primary headaches in children. Cluster headache, a type of primary headache in children, exhibits similar characteristics to headaches in adults but is rare among young children. Upper respiratory tract infections are the commonest cause of secondary headaches that prompt emergency visits. Meningitis, hydrocephalus, and intracranial tumours are common etiologies of life-threatening headache in children. Frequently, no diagnosis can be reached despite an extensive evaluation. In a study involving 48,575 children aged 5 to 17 years who had headache disorders, about 19% were identified with primary headaches, 1.1% were diagnosed with secondary headaches, and 79.7% did not receive a formal diagnosis.
2. Pathophysiology
The pathophysiology of headaches is intricate, with genetic and environmental factors playing crucial roles in the development of migraine, tension-type headache, and cluster headache. However, identifying the specific genes involved has proven to be a challenging task. Familial hemiplegic migraine, which is linked to mutations in the calcium voltage-gated channel subunit alpha1 A (CACNA1A), ATPase Na+/K+ transporting subunit alpha 2 (ATP1A2), and sodium voltage-gated channel alpha subunit 1 (SCN1A) genes, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which is associated with a notch receptor 3 (NOTCH3) gene mutation, stand out as the most extensively studied headache disorders with a genetic foundation.
The vascular theory of migraines, according to which migraine stems from blood vessel dilation and that the aura is a result of vasoconstriction, is now deemed invalid, as evidenced by magnetic resonance angiography studies. A typical migraine episode consists of four phases: the prodromal or premonitory phase, the aura phase, the headache phase, and the post-dromal phase. The premonitory phase is characterized by irritability, fatigue, difficulty in concentration, nausea, or pallor. Functional neuroimaging studies suggest involvement of the hypothalamus in the premonitory phase, as well as during the migraine attack phase. The migraine aura constitutes a reversible neurological phenomenon impacting approximately one-third of all migraine sufferers and occasionally overlapping with the headache phase. The underlying mechanism of this phase is thought to involve cortical spreading depolarization (CSD) across the cortex. CSD is marked by a brief excitation period, followed by a prolonged depression of cortical activity. Originating from the occipital lobes, it propagates anteriorly, dissipates at the central sulcus, and influences neurotransmitter levels, ionic balance, and blood flow. The headache phase is characterized by the activation of the trigeminocervical complex. Neuropeptides, particularly calcitonin gene-related peptide (CGRP), are involved in trigeminal activation and have emerged as a potential target for therapeutic interventions in migraine patients.
The development of cluster headaches involves interactions among the trigemino-vascular pathway, trigeminal autonomic reflex, hypothalamus, and the neuropeptides CGRP and pituitary adenylate cyclase-activating polypeptide. In tension-type headaches, the pain is thought to stem from myofascial structures and is heightened by central sensitization mechanisms. This central sensitization involves an imbalance in neurotransmitters such as CGRP, nitric oxide, neurokinin-A, glutamate, substance-P, serotonin, and endogenous peptide systems...
Conclusion
Pediatric headache is a prevalent condition in children, leading to substantial morbidity and frequent healthcare visits. The primary culprits are often primary headaches and acute viral infections. The initial assessment is essential for identifying potential warning signs, excluding secondary or life-threatening causes of headaches, and minimizing unnecessary investigations. Migraine is the most significant and common type of headache in children and adolescents. Prompt acute management of migraines involves supportive care and analgesics, but there is a lack of clear evidence-based recommendations for preventive therapy in children, highlighting a need for further research in this area. Newer modalities including non-invasive neuro-simulation botulinum toxin and CGRP antagonists are promising and emerging therapies.
Subscribe to:
Posts (Atom)