FLNA mutations

Inspired by a patient

Pai V, Shinar S, Krishnan P, Shannon P, Chitayat D, Fisher Y, Blaser S, Miller E. Periventricular Nodular Heterotopia, Cerebellar Hypodysgenesis, and Mesial Temporal Malformation Detected on Fetal MRI: An Underrecognized Association. AJNR Am J Neuroradiol. 2026 Jul 1;47(7):1953-1959. doi: 10.3174/ajnr.A9173. PMID: 41565358; PMCID: PMC13322346.

Abstract

Periventricular nodular heterotopia (PNH) is a neuronal migrational anomaly frequently associated with filamin-A (FLNA) gene variants. However, in the absence of a pathogenic FLNA gene or in the context of other genetic mutations, PNH may demonstrate a distinct pattern of distribution, often accompanied by a variety of brain abnormalities. PNH associated with cerebellar hypodysgenesis (CHD) and malformation of cortical development (MCD) involving the mesial temporal lobes, without detectable FLNA variants, is a known but under-reported association. PNH in this context demonstrates a phenotypically distinct distribution (ie, along the infrasylvian lateral ventricles). In this review, we report the prenatal MRI finding of this unusual association and provide key insights into this abnormality.

Yang L, Wu G, Yin H, Pan M, Zhu Y. Periventricular nodular heterotopias is associated with mutation at the FLNA locus-a case history and a literature review. BMC Pediatr. 2023 Jul 8;23(1):346. doi: 10.1186/s12887-023-04161-4. PMID: 37422633; PMCID: PMC10329368.

Abstract

Background: Periventricular nodular heterotopia (PNH), associated with FLNA mutations, is a rare clinical condition potentially associated with multiple systemic conditions, including cardiac, pulmonary, skeletal, and cutaneous diseases. However, due to a paucity of information in the literature, accurate prognostic advice cannot be provided to patients with the disease.

Case presentation: We report a 2-year-old female whose PNH was associated with a nonsense mutation in the q28 region of the X chromosome, in exon 31 of FLNA (c.5159dupA). The patient is currently seizure-free and has no congenital heart disease, lung disease or skeletal or joint issues, and her development is normal.

Conclusions: FLNA-associated PNH is a genetically-heterogeneous disease, and the FLNA mutation, c.5159dupA (p.Tyr1720*) is a newly identified pathogenic variant. FLNA characterization will help the clinical diagnosis and treatment of PNH and provide individualized genetic counseling for patients.

Loft Nagel J, Jønch AE, Nguyen NTTN, Bygum A. Phenotypic manifestations in FLNA-related periventricular nodular heterotopia: a case report and review of the literature. BMJ Case Rep. 2022 Apr 12;15(4):e247268. doi: 10.1136/bcr-2021-247268. PMID: 35414575; PMCID: PMC9006829.

Abstract

Periventricular nodular heterotopia (PVNH) is an X-linked disease caused by loss-of-function variants in the filamin A (FLNA) gene. FLNA-PVNH is a heterogeneous disorder, and the phenotype is associated with neurological and non-neurological features including cardiovascular, gastrointestinal, pulmonary, haematological, cutaneous and skeletal manifestations. No clear definition of the FLNA-PVNH phenotype has been established, but the patients are predominantly females with seizures, cardiovascular manifestations, and normal intelligence or mild intellectual disability. Herein, we describe a PVNH patient diagnosed with a novel heterozygous missense variant in FLNA after an atypical presentation of deep vein thrombosis and thrombocytopenia. Clinical evaluation found hypermobility, cardiovascular and skin manifestations. Moreover, we conducted a literature review of 186 FLNA-PVNH patients to describe the phenotypic spectrum. In conclusion, our patient highlights the importance of thorough clinical evaluation to identify manifestations in this very heterogeneous disorder. The phenotypic review may guide clinicians in the assessment and follow-up of FLNA-PVNH patients.

Lu YT, Hsu CY, Liu YT, Chan CK, Chuang YC, Lin CH, Chang KP, Ho CJ, Ng CC, Lim KS, Tsai MH. The clinical and imaging features of FLNA positive and negative periventricular nodular heterotopia. Biomed J. 2022 Jun;45(3):542-548. doi: 10.1016/j.bj.2021.05.003. Epub 2021 May 20. PMID: 35660364; PMCID: PMC9421925.

Abstract

Background: Periventricular nodular heterotopia (PVNH) is caused by abnormal neuronal migration, resulting in the neurons accumulate as nodules along the surface of the lateral ventricles. PVNH often cause epilepsy, psychomotor development or cognition problem. Mutations in FLNA (Filamin A) is the most common underlying genetic etiology. Our purpose is to delineate the clinical and imaging spectrum that differentiates FLNA-positive and FLNA-negative PVNH patients.

Methods: We included 21 patients with confirmed PVNH. The detailed clinical information, electroencephalography, and other clinical findings were recorded. Detailed brain MR imaging was assessed. Mutation analysis of the FLNA gene was used Sanger sequencing or a next generation sequencing based assay.

Results: FLNA mutations were identified in 9 patients (7 females and 2 males), including two nonsense, two splice site, three frameshift, and two missense mutations. In FLNA-positive group, 8 patients had anterior predominant bilateral symmetric presentation and only one had asymmetrical distribution and dilated ventricles. Extra-cerebral features were more often observed in FLNA-positive group than FLNA-negative group.

Conclusion: Genetics of PVNH is heterogenous, and mutations in FLNA gene account for less than half of the patients in our cohort. Our finding between FLNA-positive and FLNA-negative patients could guide the clinicians to select relevant genetic testing.

Treatment of TUBB4A-related leukodystrophy with antisense oligonucleotide

Connor Gooley is the first patient ever treated with an n-Lorem ASO for TUBB4A-Related Leukodystrophy, a condition that severely disrupts his nervous system, slows nerve impulses, and impairs his fine motor skills. As a result, Connor cannot speak, walk, sit up on his own, or chew well. Still, he manages to army crawl, propel himself in his wheelchair, and use a gait trainer. He’s also remarkably resilient—rarely crying or complaining despite the daily challenges he faces. In this episode of the Patient Empowerment Program, Connor’s parents, Diana and Mike, share their family’s journey from diagnosis to treatment and reflect on their observations of Connor after more than six months on an n-Lorem discovered and developed treatment. This episode is proudly sponsored by Hongene Biotech.

On This Episode We Discuss:
1:33 Shaking eyes were the first sign of Connor’s rare disease
4:10 An MRI revealed little to no myelin, leading to whole genome sequencing and an eventual TUBB4A genetic mutation diagnosis
7:10 Connecting with another family with the same mutation 10:00 Finding n-Lorem through a ‘seeking patient candidates’ advertisement in a Global Genes annual report
12:26 Contextualizing Connor’s TUBB4A mutation in simple terms
21:19 How rare diseases affect families and creating a new normal
27:41 Receiving treatment in Boston and contemplating the decision to agree to an experimental treatment for their son
32:00 Observations after 6 months on treatment
35:45 n-Lorem has given the Gooley family hope for a better future for Connor

https://www.nlorem.org/connor-gooleys-story-a-first-for-tubb4a-treatment/

Sase S, Hacker JL, Napit PR, Bhagavatula A, Woidill S, D'Alessandro A, Jeffries MA, Almad A, Takanohashi A, Padiath QS, Grinspan JB, Marsh ED, Vanderver A. Therapeutic suppression of Tubb4a rescues H-ABC leukodystrophy. Mol Ther. 2026 May 6;34(5):2923-2943. doi: 10.1016/j.ymthe.2026.01.016. Epub 2026 Jan 20. PMID: 41566774; PMCID: PMC13154311.

Abstract

Hypomyelination and atrophy of basal ganglia and cerebellum (H-ABC) is a rare leukodystrophy associated with causal variants in β-tubulin 4A (TUBB4A). The recurring variant p.Asp249Asn (D249N) presents in infancy with dystonia, communication deficits, and loss of ambulation during the first decade of life. In this study, we characterized a genetic murine series (Tubb4aKO/KO, Tubb4aD249N/+, Tubb4aD249N/KO, and Tubb4aD249N/D249N) to demonstrate that disease severity correlates with the expression of mutant Tubb4a and relative preservation of wild-type tubulin. To further evaluate the translational potential of Tubb4a suppression as a therapy in H-ABC, we identified a well-tolerated Tubb4a-targeted antisense oligonucleotide (ASO) candidate that selectively reduces Tubb4a. Notably, single intracerebroventricular administration of ASO in postnatal Tubb4aD249N/KO mice drastically extends its lifespan, improves motor phenotypes, and reduces seizures. Neuropathologically, treating ASO Tubb4aD249N/KO mice prevents myelin and oligodendrocyte (OL) loss and recovers visual evoked potential latencies in vivo. Furthermore, the microtubule function of Mbp mRNA transport from the OL soma to the myelin sheath is retained. A major limitation we noted is that ASOs fail to target cerebellar granule neurons even with multiple routes of administration in the brain. This is the first preclinical proof-of-concept for Tubb4a suppression via ASO as a disease-modifying therapy for H-ABC.

When a child needs neurology care, fear is not the whole story

In child neurology, there is a moment when a parent’s face changes.

They have just heard that their child may be having seizures, or that something may be affecting the brain, and suddenly an appointment becomes a fear about the future. Parents imagine what a diagnosis could mean for independence, friendships, school and family life before they understand what is known, what remains uncertain, and what kinds of care and support may be available.

This is not a rare experience in Rochester. At Golisano Children’s Hospital, the Division of Child Neurology serves nearly 13,000 patients each year from across Upstate New York. Some children come with seizures or headaches. Others come with movement concerns, muscle weakness, developmental questions, immune-related neurologic conditions, or rare genetic disorders.

But a referral to child neurology does not always mean the worst. All concerns are evaluated step by step, often beginning with pediatricians who know what to watch for and when a specialist should become involved. Some symptoms turn out to be common or manageable. Others require a closer look. Part of our work is helping families understand what is routine, what is uncertain, and what may be more complicated.

Child neurology has a wealth of tools to help make those distinctions. We begin by listening carefully to what families have noticed about a child’s symptoms, development, and daily life. A neurologic examination, imaging, genetic testing, EEG monitoring, blood work, developmental assessment, and ongoing follow-up can then help us better understand what is happening. When we know something may be serious, or when the answer is not yet clear, specialized child neurology care becomes especially important.

The goal is not only to treat a condition, but to help a child and family live as fully as possible. For one family, that may mean learning what to do if a seizure happens at school. For another, it may mean finding a medication plan that helps a child sleep through the night and feel more like themselves during the day. For another, it may mean understanding why a child tires easily, struggles with movement, or needs support that teachers and classmates cannot always see.

Families also need help with ordinary questions that become urgent when a child has a neurologic condition: What is safe? What should school know? When should we worry? How do we help our child keep learning, growing, and belonging?

A diagnosis can be an important turning point, but for many families, the medical plan becomes real in daily life. A diagnosis gives a name to symptoms a family has been watching for months or years. It can point toward treatment, therapies, school supports, genetic counseling, or what to watch for next. A diagnosis can help them to identify a community for guidance, support, and sharing of goals. But a diagnosis is a beginning, not an ending.

Child neurology is rarely limited to one appointment or decision. A child’s condition is lived out over time, often in places far from the exam room: at school, at home, with friends, in sports and activities, and later in the push toward independence. Good care has to follow the child into those settings, not simply name the condition and stop there.

That is why pediatric neurology is team-based. A child’s care may involve a physician adjusting medication, a neuropsychologist helping a family understand learning needs, a dietitian supporting dietary therapy for epilepsy, or a surgeon evaluating whether a procedure could help. Others may need coordination across school, therapy, genetics, and developmental services.

Rochester has a long history of leadership in neurology, clinical research, and care for rare neurological diseases. At University of Rochester Medicine, child neurology works closely with neurosurgery, developmental and behavioral pediatrics, behavioral health, genetics, and other specialties to support children whose needs do not fit neatly into one category. That kind of collaboration matters because families rarely experience a child’s condition in isolated pieces. They experience it as part of daily life.

The field is also changing rapidly. Research in rare diseases, neurogenetics, epilepsy, and gene-targeted therapies is opening new possibilities for diagnosis and treatment, especially for conditions where earlier recognition can change what options are available. These advances are promising, but they also make public understanding, research participation, and community support more important.

Families who participate in research help expand what we know about common and rare neurologic conditions and contribute to better diagnostic and treatment options for children in the future. But participation in research is only one way families and communities move this work forward. Advocacy, education, philanthropy, and broader public understanding all help support the mission of helping children with neurologic conditions live as fully as possible.

That engagement matters because child neurology does not happen only inside the clinic. It depends on families who share what they are seeing, pediatricians who know when to refer, schools that understand a child’s needs, researchers who ask better questions, and communities willing to support children whose challenges are not always visible.

A neurologic diagnosis should never define the whole of a child’s life. With the right diagnosis, support, treatment, and understanding, many children continue to learn, play, build friendships, and live lives marked not only by medical complexity, but by joy, growth, and possibility.

For families, the first referral to child neurology may begin with fear. Our responsibility as a community is to help ensure it does not end there.

Inna Hughes M.D.

https://rochesterbeacon.com/2026/07/28/when-a-child-needs-neurology-care-fear-is-not-the-whole-story/

"Can you prescribe leucovorin for my child?"

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

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.

Death with gene editing therapy of CHD3 mutation

Courtesy of a colleague

The 6-year-old girl tugged on her mother’s hand as they pressed through the doors of the hospital in Shanghai. Behind them, her father rolled a large suitcase with everything the child needed for the weeklong stay. She told her parents it felt like they were going on vacation. In fact, they brought her here for an experimental gene therapy.

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.).

See: https://childnervoussystem.blogspot.com/2025/05/carbamoyl-phosphate-synthetase-1.html