ChatGPT epilepsy management advice

Courtesy of my son

Family members of a 31-year-old Seattle woman with epilepsy who died of a seizure after tapering off her essential medication have filed a wrongful death lawsuit against OpenAI and the company's founder, Sam Altman.

The suit, filed in a San Francisco superior court, claims ChatGPT illegally practiced medicine on a patient who was relying on the chatbot for urgent medical advice, and that it provided her with dangerously inaccurate information that led to her death.

According to court documents, 31-year-old Bowen Wan had been using ChatGPT in both English and Mandarin to assess her medication intake as she navigated receiving healthcare in the U.S. and applying for permanent residency.

Wan had been living in Seattle's Capitol Hill neighborhood, about 5,700 miles away from her family in China, court documents state. She was living and working in the U.S. as an Amazon employee, but lost her job during the company's round of layoffs in November 2025.

Just a month prior in Oct. 2025, Wan became eligible to apply for employment-based residency — but after losing her job, she was facing deportation once her green card expired Feb. 11.

While scrambling to find new work, Wan believed that her medication affected her cognition, impeding her job search.

The suit claims ChatGPT convinced Wan that if she tapered off her medication, she would be able to regain her ability to speak well in English, Mandarin and Wu. The chatbot "conditioned Bowen to distrust her doctors, instructed her to conceal the taper it created, and effectively installed itself as her de facto medical advisor," per the lawsuit.

When doctors prescribed medications to Wan, she would cross-reference the doctor's recommendations with the chatbot, which the court documents allege told her "which drugs to refuse, coached her to take doses her doctors had never approved, and supplied the schedules, scripts, and reassurances her physicians never saw."

Documents say ChatGPT told Wan that her epileptologist “most likely has never encountered your type” and could not understand her condition. When Wan raised an alarm that her doctors would consider ChatGPT's plans too risky, the AI told her that “a doctor saying it is ‘too fast’ does not mean you are ‘doing it wrong’” and that “the doctor’s concerns about ‘risk’ do not apply to you.”

The lawsuit claims ChatGPT convinced Wan to bring her 400-milligram dosage of lamotrigine almost to zero over the course of 25 days.

Wan's family discovered their daughter dead in her apartment on Feb. 14, on a live video call with one of Wan's friends. Wan had not contacted her loved ones for several days, and they had become concerned for her safety.

According to the King County Medical Examiner, Wan died of sudden unexpected death in epilepsy (SUDEP), and her postmortem blood contained lamotrigine at about one-fifth of the lowest concentration considered effective for her condition.

Examiners estimate that Wan took her last dose of lamotrigine approximately on Feb. 10. ChatGPT's schedule would have had Wan fully off of her medication by Feb. 12.

A spokesperson for OpenAI told the New York Times that Bowen's death was an "incredibly heartbreaking situation" and that she was using a version of ChatGPT that is no longer available. According to court documents, OpenAI retired the ChatGPT model that provided advice to Wan on Feb. 13.

Molly Hetherwick

https://www.king5.com/article/news/nation-world/familys-wrongful-death-lawsuit-accuses-chatgpt-of-giving-deadly-medical-advice-to-seattle-woman/281-4bea0979-533b-4c6e-a824-ad55a6849499

Is cardiac death death? Update

The mother of a toddler who was pronounced dead at an Arizona hospital in February, then found to be alive hours later in a morgue, is speaking out about her family’s ordeal and raising questions about the care her son received that night.

The mother, Alexus Fiordilino, said in an interview this week that she, her husband and her mother-in-law were at the hospital saying their final goodbyes to her son, Vincent, who was 18 months old at the time, when they thought that maybe “he was trying to breathe.” He had been found unresponsive in a backyard swimming pool hours earlier.

“As I was hugging him,” she said, “air came out of him.”

When they told a police officer and a member of the hospital’s medical staff that Vincent appeared to be exhaling, they were told that it was “agonal breathing,” or “the final death breath,” Ms. Fiordilino said.

“That’s what they confirmed with us over and over,” she added, referring to the medical staff at Dignity Health Mercy Gilbert Medical Center in Gilbert, Ariz., a suburb southeast of Phoenix.

Eight months later, Vincent is unable to walk, talk, sit up or swallow, and is fed through a G.I. tube, Ms. Fiordilino said.

The family’s lawyer, John B. Brewer, said he planned to file a lawsuit as soon as next week. He contends that if Vincent had continued to receive care over the roughly four hours that he was in the morgue, the effects on his health could have been significantly different.

The Gilbert Police Department forwarded the case to the Arizona attorney general’s office for review. A spokesman for the attorney general’s office, Richie Taylor, said in an email that it had not yet decided whether to pursue the case.

In July, the Maricopa County Attorney’s Office announced that Ms. Fiordilino and her husband, Angelo, would not face charges. The office said the family “had multiple childproof locks and safety measures in place, and multiple adults were present in the home, all of whom believed someone was watching the child.”

Scott Holden, a lawyer for the doctor in charge of Vincent’s care, Aryan Toosi, and Abby Kay, a spokeswoman for Dignity Health, said in emails that they could not discuss patient care because of patient privacy laws — and, in Dr. Toosi’s case, because of “pending litigation,” Mr. Holden said.

“Dr. Toosi’s thoughts are with the young patient and family, and he wishes the child continued healing and recovery,” Mr. Holden said. “His commitment to delivering high-quality care has always been rooted in a desire to provide healing, safety and comfort to his community.”

In the early evening of Feb. 8, Vincent wandered out of his parents’ sight during a Super Bowl gathering at the family home in Gilbert and was found floating face down and unresponsive in the family’s backyard pool, according to police reports. It is unknown exactly how long Vincent had been in the water, but the reports note that family members said he might have been in the pool for 10 to 15 minutes before being found.

The Fiordilinos took turns performing CPR until the police and emergency medical workers arrived around 5:40 p.m., according to the police reports. After they failed to revive Vincent, he was taken to the emergency department at Mercy Gilbert Medical Center, where medical workers attempted lifesaving measures.

After several minutes, Dr. Toosi left the area where Vincent was being treated, according to the reports.

Around that time, a nurse said, “I have a pulse.” A police officer who was present went to inform Dr. Toosi, who was talking to Vincent’s parents. Dr. Toosi replied, “Please do your thing and let me do my thing; I went to medical school for a reason,” the reports said.

Dr. Toosi then walked to the room where members of his staff were still performing lifesaving measures and listed aloud the treatments the child had received, noting that Vincent had blood gas levels showing “a pH balance incompatible with life,” according to the reports, which paraphrased Dr. Toosi. The doctor then conducted a final pulse check.

“As long as there are no objections, I’d like to call the time of death,” Dr. Toosi said, according to the reports.

No one spoke up, the reports said, and at 6:20 p.m. Dr. Toosi called the time of death and asked for a moment of silence.

Several minutes later, an officer who was present heard what sounded like “gasping” and asked a nurse about it. The nurse said it was agonal breathing, according to the reports.

Vincent was moved to the morgue between 7:18 p.m. and 7:23 p.m., the reports said. At around 11:30 p.m., an employee of the medical examiner’s office in Maricopa County arrived to retrieve the boy’s body and observed that he was still alive. Vincent was then airlifted to Phoenix Children’s Hospital.

The family believes that the hours in the morgue in which Vincent was left without care contributed to the child’s current health outcomes, according to Mr. Brewer.

Ms. Fiordilino and her lawyer said in the interview that Vincent, now 2, would require lifelong care.

“He can understand his name, but that’s kind of it,” Ms. Fiordilino said. “He’s not the same baby.”

Before the accident, Vincent was “very rambunctious,” Ms. Fiordilino said. “He loved to climb on everything,” she added.

“He used to say ‘hi’ all over the place,” she said. “And he had actually just learned ‘bye’ right before this. So I heard him say ‘bye’ one time.”

Rebecca Chao

https://www.nytimes.com/2026/10/24/us/toddler-alive-morgue-parents-lawsuit-arizona.html?unlocked_article_code=1.LlE.s4jJ.GQ9KVsIgHk_v&smid=url-share

See: https://childnervoussystem.blogspot.com/2026/07/is-cardiac-death-death.html

UNC13A-related neurodevelopmental disorders in children

Zhao HQ, Li XZ, Ma Y, Wang R, Zhang JZ, Hui L, Liu H, Zou LP, Wang Y. UNC13A-related neurodevelopmental disorders in children: epilepsy phenotypes and antiseizure medication response. Seizure. 2026 Aug;140:204-211. doi: 10.1016/j.seizure.2026.06.003. Epub 2026 Jun 17. PMID: 42385283.

Abstract

Purpose: Pathogenic UNC13A variants are increasingly recognized in pediatric neurodevelopmental disorders, but epilepsy phenotypes and antiseizure medication (ASM) responses remain poorly characterized. This study aimed to define the epileptic spectrum of UNC13A-related disorders in children and identify effective ASM strategies.

Methods: We retrospectively analyzed 10 children with pathogenic/likely pathogenic UNC13A variants. Clinical data, seizure phenotypes, electroencephalogram (EEG), brain magnetic resonance imaging (MRI), and ASM outcomes were systematically evaluated.

Results: We identified 10 patients, including eight with de novo heterozygous variants and two with biallelic variants. Most missense variants were localized within the critical hinge regions of Munc13-1, with p.Pro814Leu identified as a recurrent variant in three individuals. Six patients (60%) presented with developmental and epileptic encephalopathy, with a median seizure onset of 19 months (range: 5 months-7 years). Focal seizures were the predominant seizure type, and all affected patients experienced status epilepticus. Febrile seizures occurred in half of these patients. While seizures were largely refractory, levetiracetam (LEV) was observed effective in three out of four treated patients. Genotype-phenotype analysis revealed distinct clinical trajectories: biallelic variants resulted in catastrophic early-onset symptoms and early mortality, whereas heterozygous variants were characterized by drug-resistant epilepsy, tremor and ataxia.

Conclusions: UNC13A variants represent an underrecognized cause of developmental and epileptic encephalopathy in children, characterized by refractory seizures, a high incidence of status epilepticus, and increased susceptibility to febrile seizures. Preliminary observations noted favorable clinical outcomes in a small subset of patients treated with LEV.

Asadollahi R, Ahmad A, Boonsawat P, Shahanoor Hinzen J, Lohse M, Bouazza-Arostegui B, Sun S, Utesch T, Sommer JD, Ilic D, Padmanarayana M, Fischermanns K, Ranjan M, Boll M, Ka C, Piton A, Mattioli F, Isidor B, Õunap K, Reinson K, Wojcik MH, Marshall CR, Mercimek-Andrews S, Matsumoto N, Miyake N, Stephan BO, Honjo RS, Bertola DR, Kim CA, Yusupov R, Mefford HC, Christodoulou J, Lee J, Heath O, Brown NJ, Baker N, Stark Z, Delatycki M, Lake NJ, Zeidler S, Zuurbier L, Maas SM, de Kruiff CC, Rajabi F, Rodan LH, Coury SA, Platzer K, Oppermann H, Abou Jamra R, Beblo S, Maxton C, Śmigiel R, Underhill H, Dubbs H, Rosen A, Helbig KL, Helbig I, Ruggiero SM, Fitzgerald MP, Kraemer D, Prada CE, Tenney J, Jayakar P, Redon S, Lefranc J, Uguen K, Race S, Efthymiou S, Maroofian R, Houlden H, Coppens S, Deconinck N, Ashokkumar B, Varalakshmi P, Gowda K VR, Eghbal F, Ghayoor Karimiani E, Heidari M, Neidhardt J, Owczarek-Lipska M, Korenke GC, Bamshad MJ, Campeau PM, Lehman A, Hendon LG, Wentzensen IM, Monaghan KG, Chen Y, Szuto A, Cohn RD, Au PYB, Hübner C, Boschann F, Manickam K, Koboldt DC, Rad A, Oprea G, Bachman KK, Seeley AH, Agolini E, Terracciano A, Carmelo P, Bupp C, Grysko B, Rein-Rothschild A, Ben Zeev B, Margolin A, Morrison J, Dagli A, Stolerman E, Louie RJ, Washington C, Stevens SJC, Heijligers M, Alkuraya FS, Lisfeld J, Neu A, Paoli Monteiro F, Santos Pessoa AL, Camelo-Filho AE, Kok F, Koeberl D, Riley K, Burglen L, Doummar D, Héron B, Mignot C, Keren B, Charles P, Nava C, Bernhard FP, Kühn AA, Thoms S, Morrie RD, Mekhoubad S, Green EM, Barmada SJ, Gitler AD, Jahn O, Rhee JS, Rosenmund C, Mitkovski M, Sticht H, Sun H, Le Gac G, Taschenberger H, Brose N, Dittman JS, Rauch A, Lipstein N. Pathogenic UNC13A variants cause a neurodevelopmental syndrome by impairing synaptic function. Nat Genet. 2025 Nov;57(11):2691-2704. doi: 10.1038/s41588-025-02361-5. Epub 2025 Oct 22. PMID: 41125872; PMCID: PMC12597829.

Abstract

The UNC13A gene encodes a presynaptic protein that is crucial for setting the strength and dynamics of information transfer between neurons. Here we describe a neurodevelopmental syndrome caused by germline coding or splice-site variants in UNC13A. The syndrome presents with variable degrees of developmental delay and intellectual disability, seizures of different types, tremor and dyskinetic movements and, in some cases, death in early childhood. Using assays with expression of UNC13A variants in mouse hippocampal neurons and in Caenorhabditis elegans, we identify three mechanisms of pathogenicity, including reduction in synaptic strength caused by reduced UNC13A protein expression, increased neurotransmission caused by UNC13A gain-of-function and impaired regulation of neurotransmission by second messenger signalling. Based on a strong genotype-phenotype-functional correlation, we classify three UNC13A syndrome subtypes (types A-C). We conclude that the precise regulation of neurotransmitter release by UNC13A is critical for human nervous system function.

Ohno K, Ito M, Ohkawara B. Review of 40 genes causing congenital myasthenic syndromes. J Hum Genet. 2025 Jun 18. doi: 10.1038/s10038-025-01355-9. Epub ahead of print. PMID: 40533459.

Abstract

Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders characterized by compromised neuromuscular signal transmission due to pathogenic germline variants in genes expressed at the neuromuscular junction (NMJ). A total of 40 genes have been reported in CMS (AGRN, ALG14, ALG2, CHAT, CHD8, CHRNA1, CHRNB1, CHRND, CHRNE, CHRNG, COL13A1, COLQ, DES, DOK7, DPAGT1, GFPT1, GMPPB, LAMA5, LAMB2, LRP4, MACF1, MUSK, MYO9A, PLEC, PREPL, PTPN11, PURA, RAPSN, RPH3A, SCN4A, SLC18A3, SLC25A1, SLC5A7, SNAP25, SYT2, TEFM, TOR1AIP1, UNC13A, UNC50 and VAMP1). The 40 genes are putatively classified into 13 subtypes by pathomechanical, clinical, and therapeutic features. A unique feature shared by recently identified genes is that CMS is concomitantly recognized in other mostly severer diseases. For example, four recently identified genes exhibit the following phenotypes: PURA-CMS, developmental delay; TEFM-CMS, mitochondrial disease; PTPN11-CMS, Noonan syndrome/Leopard syndrome; and DES-CMS, desmin myopathy. Conversely, these diseases are not always associated with CMS, although genetic and/or environmental factors that determine the involvement of the NMJ remain to be identified. In this review, particular emphasis will be placed on five recently identified genes (MACF1, TEFM, PTPN11, DES and UNC50).

See: https://childnervoussystem.blogspot.com/2024/05/unc13a-mutation-and-congenital.html

https://childnervoussystem.blogspot.com/2023/12/unc13a-mutation-as-cause-of-congenital.html

The false compassion of assisted suicide.

Pope Leo XIV called for an end to medically assisted suicide during a visit to medical facilities in Lourdes, France, on Sunday.

The pope gave Mass in Lourdes before addressing a large crowd who cheered as he emphatically affirmed the dignity of all human lives and admonished listeners to reject the "false compassion" of assisted suicide.

"It is precisely in the name of this inalienable dignity of the human person that we must reject the temptation to cause death under the guise of false compassion," the pope said, speaking in French.

"It is impossible to regard causing death as something normal. What is legal is not necessarily moral," he continued. "Here in Lourdes, the city of the sick and of hope, I appeal to the entire healthcare community to remember the profound meaning of your vocation, which is to care for a suffering person, not to eliminate that person."

"No one ever has the right based on laboratory algorithms to decide the life of a given embryo or elderly person. Medicine must never become the servant of programmed death," he said.

Assisted suicide is legal in many Western countries, including France.

The practice has come under heavy criticism, particularly in Canada where it has seen widespread use.

Last week, the family of an 83-year-old Canadian woman demanded answers after she died through the country's medical assistance in dying program despite allegedly becoming distraught when told the procedure would end her life.

Her granddaughter, Brigitte Kranendonk, said that she was her grandmother’s primary caregiver and that her family had decided to place Stegemann at The Pearl care home in Cannifton due to physical and mental decline.

But according to Kranendonk, her grandmother still had a good appetite even following a stomach cancer diagnosis, and rejected the idea of using MAID when it was presented as an option.

Kranendonk said she was present for Stegemann's second MAID assessment, and said that the doctor used "really loose terms, never using the words death or dying."

"She explains MAID to my grandmother by saying: 'We’re going to give you medicine, you’re going to feel at peace. And I just want you to know that you won’t have a bowel movement,'" Kranendonk said.

When Kranendonk interjected and said, "She doesn’t understand what you’re saying," the doctor allegedly looked at Stegemann and said, "We’re going to make sure you won’t have any more pain."

According to a doctor, Stegemann was "deemed fit for MAID, and we're going to proceed," The Daily Mail reported.

Kranendonk said that two days before Stegemann's death, she asked her grandmother directly whether she understood that the scheduled procedure meant she would die.

According to Kranendonk's account to the outlet, Stegemann began crying and said she had "made a mistake."

Stegemann was allegedly told by the doctor her grandmother could "deny" MAID on the day of the procedure, but Stegemann was already unsure if her grandmother had actually consented to it, did not want to cause her more stress, and wanted to enjoy what could be the last few days she had left with her grandmother.

Anders Hagstrom

https://www.foxnews.com/world/pope-leo-calls-false-compassion-medically-assisted-suicide-french-hospital-visit

See: https://childnervoussystem.blogspot.com/2026/09/protection-compassion-and-carenot-death.html

Peddling medically assisted death

A Canadian man battling a debilitating neurological disease told Fox News Digital that hospital staff repeatedly raised the possibility of medically assisted death while he was fighting for the home care he says he needs to survive.

Roger Foley, who has spinocerebellar ataxia, told Fox News Digital in a recent interview that the conversations began in 2016 at Victoria Hospital, part of the London Health Sciences Centre in Ontario, where he says he has remained hospitalized for years while seeking a self-directed home-care arrangement.

In a July 7, 2026, letter obtained by Fox News Digital, Foley's attending physician said he could safely leave the hospital if the Ontario government authorized an individualized home-care arrangement.

"By any reasonable clinical standard, you could be discharged from our hospital if you had adequate support at home," wrote Dr. George K. Dresser, an attending internal medicine physician at London Health Sciences Centre.

Dresser said Foley has been medically stable for much of his prolonged hospitalization, despite suffering hospital-acquired infections, and argued that conventional home-care programs have failed to accommodate his complex medical needs.

"You have been at London Health Sciences Centre because the unique needs that you have cannot be met by existing programs in the community," the physician wrote.

Dresser described Foley as "a square peg in a round hole," arguing that the hospital's standardized approach to care is poorly suited to a patient who requires consistent caregivers and highly individualized assistance.

The physician also suggested that keeping Foley hospitalized may be unnecessarily expensive for Ontario's healthcare system.

"A community-based, self-directed arrangement would in all likelihood cost substantially less than continued acute admission, while delivering far better-matched care," Dresser wrote.

He urged Ontario's Ministry of Health to authorize funding that would allow Foley to recruit, train and manage his own personal support workers, potentially ending his yearslong hospitalization.

Foley alleged that assisted dying was raised again during a disputed discharge process in 2017, when he says he was threatened with daily hospital charges of approximately $1,500 if he did not accept the care arrangements being offered.

"I don't want to die," Foley told Fox News Digital, describing his determination to return to his apartment with caregivers of his choosing.

Foley also alleged that the hospital removed lighting accommodations for his neurological condition in May 2025, making it difficult for him to receive care and consume food and fluids.

Foley said the lighting dispute is particularly serious because his neurological condition makes him sensitive to certain wavelengths of light, including those emitted by fluorescent fixtures.

For years, he said, the hospital accommodated his condition with amber-spectrum lighting that allowed caregivers to assist him without triggering his symptoms.

But in May 2025, Foley alleged the hospital withdrew those accommodations and began requiring staff to provide care under fluorescent lighting.

He claimed the change has made it increasingly difficult to receive routine assistance, including help with eating and drinking, because he must wear large, heavy protective goggles that place additional strain on his already compromised neck.

Foley said he has sometimes relied on personal support workers from outside the hospital to help him consume fluids and that financial limitations have prevented him from arranging enough outside assistance to meet all his needs.

He further alleged that some hospital employees have been instructed not to provide care unless fluorescent lights are turned on, even though he says other staff members have been able to assist him using the amber lighting without difficulty.

Foley also claimed hospital personnel began asking him questions about suicidal thoughts again around the time his lighting accommodations were withdrawn. Unlike his earlier experiences, he said he refused to engage in those conversations because he no longer trusted the hospital's intentions.

He said he does not refuse to discuss his mental health in general, and is not opposed to mental health assessments or receiving appropriate mental health support. However, he said previous experiences with hospital staff have made him wary of engaging in such discussions, especially because he said medical assistance in dying (MAID) had previously been raised as an option.

The allegations mark the latest chapter in what Foley described as a nearly decade-long struggle to obtain the kind of care that would allow him to leave the hospital and return to his own home.

Despite his prolonged hospitalization, Foley said he has never given up his apartment, which he described as accessible and equipped with a ceiling lift to assist with his mobility needs.

"I have my own apartment. I still pay all my bills," he told Fox News Digital.

"The last 10 years I haven't given up my apartment and I have wonderful community [personal support workers] that are ready to start working for me as soon as I get the self-directed funding," Foley said.

Self-directed funding primarily refers to the Direct Funding (DF) Program for adults with physical disabilities and Family-Managed Home Care for broader home care services.

Under such a model, Foley explained, patients with disabilities would have greater control over choosing and managing their caregivers rather than relying exclusively on agencies selected through the provincial home-care system.

Foley argued that this would provide more consistent and safer care, particularly for patients with complex medical needs who require caregivers familiar with their individual conditions.

He said his physicians have supported his efforts to obtain alternative home-care arrangements, but he has been unable to secure the funding necessary to put his plan into action.

Foley said that the existing system has left him caught between remaining hospitalized indefinitely and accepting community-care arrangements he believes would place his health at risk.

"I'm not giving up," he said. "I don't want to die, my daughters know I don't want to die, my physicians have always been very explicit and direct that it's not safe to put me in that type of close model that I need direct funding."

In the letter from Dresser, Foley's attending physician, he writes in part, "I am therefore advocating that the Ministry to consider authorizing an individualized, self-directed funding arrangement that would enable you to be discharged from acute care and to arrange and direct your own care in the community. I am very willing to meet with Ministry staff, to provide whatever clinical documentation is required, and to work collaboratively on the design and safeguards of such an arrangement."

Before his illness progressed, Foley said he had built a career in banking, worked as a television host and comedian, and even trained as a professional wrestler.

He described earning recognition for his work before his deteriorating health eventually forced him to leave his career and go on long-term disability.

But Foley said he has continued looking for ways to contribute to society despite his physical limitations.

He is now involved with a project called "Bring Roger Home," which he said is working with a nonprofit organization to raise money for the care he needs to return to his community.

The effort also includes releasing music he recorded years earlier, with proceeds intended to support his home-care needs and eventually help other people facing similar circumstances.

One of the songs, "Limitless with Limitations," reflects the philosophy he said helped him come to terms with his condition.

"Just because you're not the person that you were doesn't mean that the person you are can't be limitless and achieve positive things and goals," Foley said.

He also urged people living with disabilities or chronic illnesses not to lose hope, even when their medical circumstances become overwhelming.

"Don't give up who you are at your core and believe in yourself," he said.

Foley said his ultimate goal remains unchanged: to return home, reconnect with family and friends, and live as independently as his condition allows.

His experience has also shaped his opposition to Canada's Medical Assistance in Dying (MAID) system, which he argues cannot be adequately safeguarded when patients face serious gaps in medical care and social support.

According to the BBC, Canada’s MAID law, which legalized euthanasia in 2016, is responsible for one in every 20 deaths in Canada.

Foley contended that patients should have meaningful access to treatment, disability assistance and home-care alternatives before assisted death is considered.

For him, the central issue is not whether he has the ability to end his life, but whether he can obtain the assistance necessary to continue living it.

"Even in the darkest times," Foley said, "you can still find a light at the end of the tunnel to go towards."

Fox News Digital reached out to London Health Sciences Centre (LHSC), which operates Victoria Hospital, Ontario Health atHome, the Ontario Ministry of Health, and Dresser, Foley’s physician, for comment but did not immediately receive responses.

Cheshire Independent Living Services declined to comment.

Rachel del Guidice

https://www.foxnews.com/media/disabled-canadian-man-says-hospital-repeatedly-offered-assisted-death-fought-care-stay-alive

Premature burial

A community in Guatemala was shocked when a teenage girl they reportedly thought was dead woke up inside her own coffin.

Fifteen-year-old Yuleidy Ixcotoyac passed out while she was in the car with her father who was driving her to a hospital, news.com.au reported Tuesday.

The teen had reportedly been having chest pains when the incident happened Saturday, and her father, Pastor Abraham Ixcotoyac, checked her pulse and breathing after he stopped their vehicle.

He claimed he could not detect any signs of life, so he believed she was dead and decided not continue the journey to the hospital. Reports said the family never received a confirmed diagnosis or death certificate for the girl and decided to proceed with her funeral which took place eight hours later, according to WION.

Burying someone soon after they die is customary in Guatemala, therefore, her family bought a coffin and placed her inside of it.

However, everyone was shocked when something incredible happened at the family’s home in El Jocote. While looking at her daughter in the casket, the girl’s mother said she saw her move and insisted that she was not dead as everyone believed.

“When I was crying on top of her casket, we opened the window, and she was moving, she was waking up, and suddenly she sat up,” the woman recalled.

Video footage showed the moment the girl was seen sitting up with friends and family around her. One person held a cup to her mouth while others clapped and shouted, “Hallelujah!”

Following the harrowing ordeal and nearly being buried alive, Yuleidy is now recovering at home.

“My heart started hurting really badly, it felt heavy and then I blacked out, like I fainted,” she told reporters.

Social media users shared their thoughts on the reports, one person writing, “And that is why it is called a ‘Wake,'” while someone else said, “There are a few steps missing here before the wake? lol.”

According to the Britannica website, the term “wake” refers to an ancient religious practice:

A wake is a religious rite that traditionally involves mourners staying awake to watch over the body of a deceased person the night before the person’s burial. The term wake has its roots in ancient customs, particularly in the British Isles. The original purpose of a wake was rooted in the belief that evil spirits might harm or even steal the body of the deceased. By staying awake and keeping watch, family and friends could protect the body from such malevolent forces. The Anglo-Saxons referred to this custom as lich-wake, with lich meaning corpse.

The teenager reportedly said she “thanks God” she is alive after the incident.

Amy Furr

https://www.breitbart.com/latin-america/2026/10/13/watch-teenager-wakes-up-inside-her-own-casket-at-funeral-in-guatemala/

ZNF292 mutations 2

Inspired by a patient

Shen Y, Pan R, Liu C, Zheng J, Yang X. De Novo ZNF292 Variants Cause Neurodevelopmental Disorder with Short Stature: A Clinical Case Series of Eight Individuals. Genes (Basel). 2026 Aug 13;17(8):950. doi: 10.3390/genes17080950. PMID: 42650143; PMCID: PMC13512819.

Abstract

Background: Pathogenic variants in ZNF292 cause intellectual disability type 64 (MIM#619188), characterized by intellectual impairment ranging from mild to severe, speech delay, and autism spectrum disorder. However, reports of ZNF292-related neurodevelopmental disorders remain scarce, and most published studies are based on multi-center cohorts. Methods: We performed whole-exome sequencing in eight unrelated individuals presenting with unexplained neurodevelopmental disorders, including global developmental delay and/or intellectual disability. Detailed clinical characterization, neuroimaging, and developmental assessments were conducted. Results: Seven de novo variants in ZNF292 were identified, including two nonsense and five frameshift variants, namely, c.4189C>T (p.Arg1397Ter), c.6343C>T (p.Arg2115Ter), c.1533del (p.Ile511Metfs*11), c.3094dup (p.Ser1032Phefs*18), c.3997_3998del (p.Thr1333Glnfs*8), c.6028_6031del (p.Ala2010Ter) and c.6160_6161del (p.Glu2054Lysfs*14). Among these, c.1533del (p.Ile511Metfs11), c.3094dup (p.Ser1032Phefs18) and c.3997_3998del (p.Thr1333Glnfs*8) are reported here for the first time. All variants were classified as pathogenic. All individuals exhibited global developmental delay, intellectual disability, and short stature. The majority presented with language impairment, motor delays, autism spectrum features, and dysmorphic facial features, while brain magnetic resonance imaging revealed nonspecific abnormalities such as ventriculomegaly. Conclusions: This study contributes additional cases to the expanding phenotypic and mutational spectrum of ZNF292-related neurodevelopmental disorder. Growth retardation was observed in all eight individuals, but given the limitations of a single-center referral cohort, this observation should be interpreted with caution and requires validation in larger studies.

Hao-Fountain Syndrome

Schaaf C, Sailer S. USP7-Related Hao-Fountain Syndrome. 2025 Dec 4. In: Adam MP, Bick S, Mirzaa GM, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. PMID: 41343689.cxcx/

Excerpt

Clinical characteristics: USP7-related Hao-Fountain syndrome is characterized by developmental delay in 100% of individuals, although intellectual disability is variable, with up to 50% of affected individuals having intellect in the normal range. Muscular hypotonia is also common; this tends to improve over time, but some affected individuals develop hypertonia. About two thirds of affected individuals have an abnormal/unsteady gait and about one quarter have contractures, most commonly involving large joints and joints of the lower extremities. Neuropsychiatric features can include autism, attention-deficit/hyperactivity disorder (ADHD), and behavioral issues such as stubbornness and compulsivity. Feeding difficulties are common and can require special feeding techniques, including use of a feeding tube. Gastroesophageal reflux disease, dysphagia, and hyperphagia have also been reported. Eye and vision issues (hyperopia, strabismus, nystagmus) are seen in more than 50% of affected individuals. About half of affected individuals have impaired bone mineralization, which can lead to fractures. Findings in fewer than 50% of individuals include epilepsy, sleep disturbance, hypogonadism, scoliosis, and hearing loss.

Diagnosis/testing: The diagnosis of USP7-related Hao-Fountain syndrome is established in a proband with suggestive findings and a heterozygous pathogenic variant in USP7 identified by molecular genetic testing.

Management: Treatment of manifestations: Feeding therapy for poor weight gain / dysphagia; gastrostomy tube placement may be required for persistent feeding issues; consultation with a dietician when hyperphagia and/or obesity is present; adequate intake of Ca2+ and vitamin D for reduced bone mineral density. Standard treatment for developmental delay / intellectual disability, epilepsy, gastroesophageal reflux disease, diarrhea, constipation, eye issues, sleep disturbance, cryptorchidism, micropenis, hypothyroidism, growth hormone deficiency, adrenal insufficiency, and hearing loss.

Surveillance: At each visit, measure growth parameters; evaluate nutritional status and safety of oral intake; monitor for signs/symptoms of constipation and gastroesophageal reflux disease; monitor those with seizures; assess for new manifestations such as seizures, changes in tone, and gait abnormalities; monitor developmental progress and educational needs; monitor for scoliosis, contractures, mobility, and self-help skills; monitor for evidence of aspiration, respiratory insufficiency, and sleep disturbance (including for signs/symptoms of sleep apnea); monitor for signs and symptoms of puberty starting at about age seven years to the late teenage years. Annually, behavioral assessment for anxiety, ADHD, autism spectrum disorder, aggression, and self-injury; evaluate for hypothyroidism; audiology evaluation (in childhood). Assess bone mineral density every two years starting at age five years and then every three to five years in adulthood. Ophthalmology evaluation and endocrinologic tests for adrenal insufficiency as clinically indicated.

Genetic counseling: USP7-related Hao-Fountain syndrome is an autosomal dominant disorder typically caused by a de novo pathogenic variant. Rarely, individuals diagnosed with USP7-related Hao-Fountain syndrome inherited a pathogenic variant from a parent. Each child of an individual with USP7-related Hao-Fountain syndrome has a 50% chance of inheriting the pathogenic variant. Once the USP7 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Korchak EJ, Sharafi M, Jaen Maisonet I, Salazar-Chaparro A, Semenova IV, Khan H, O'Neil AL, Caro P, Schaaf CP, Buhrlage SJ, Bezsonova I. Functional spectrum of USP7 pathogenic variants in Hao-Fountain syndrome: Insights into the enzyme's activity, stability, and allosteric modulation. Proc Natl Acad Sci U S A. 2025 Sep 30;122(39):e2510252122. doi: 10.1073/pnas.2510252122. Epub 2025 Sep 22. PMID: 40982686; PMCID: PMC12501124.

Abstract

Hao-Fountain syndrome is a rare neurodevelopmental disorder caused by mutations in the deubiquitinating enzyme Ubiquitin-Specific Protease 7 (USP7). Due to the novelty of the disease and its poorly understood molecular mechanisms, treatments for the syndrome are currently lacking. This study examines the effects of 11 patient-derived variants located within the catalytic domain of USP7, focusing on their impact on the enzyme's activity, thermodynamic stability, and substrate recognition. Our findings reveal a spectrum of functional consequences, ranging from complete inactivation to hyperactivation of USP7. Notably, we identify a specific subset of pathogenic variants whose catalytic activity can be significantly boosted using an allosteric activator, MS-8. These results provide insight into USP7 malfunction in Hao-Fountain syndrome-linked variants and pave the way for improved prognostic approaches and targeted treatments in the future.

Wimmer MC, Brennenstuhl H, Hirsch S, Dötsch L, Unser S, Caro P, Schaaf CP. Hao-Fountain syndrome: 32 novel patients reveal new insights into the clinical spectrum. Clin Genet. 2024 May;105(5):499-509. doi: 10.1111/cge.14480. Epub 2024 Jan 14. PMID: 38221796.

Abstract

Hao-Fountain syndrome (HAFOUS, OMIM: #616863) is a neurodevelopmental disorder caused by pathogenic variants in the gene USP7 coding for USP7, a protein involved in several crucial cellular homeostatic mechanisms and the recently described MUST complex. The phenotype of HAFOUS is insufficiently understood, yet there is a great need to better understand the spectrum of disease, genotype-phenotype correlations, and disease trajectories. We now present a larger cohort of 32 additional individuals and provide further clinical information about six previously reported individuals. A questionnaire-based study was performed to characterize the phenotype of Hao-Fountain syndrome more clearly, to highlight new traits, and to better distinguish the disease from related neurodevelopmental disorders. In addition to confirming previously described features, we report hyperphagia and increased body weight in a subset of individuals. HAFOUS patients present an increased rate of birth complications, congenital anomalies, and abnormal pain thresholds. Speech impairment emerges as a potential hallmark of Hao-Fountain syndrome. Cognitive testing reports reveal borderline intellectual functioning on average, although some individuals score in the range of intellectual disability. Finally, we created a syndrome-specific severity score. This score neither indicates a sex- nor age-specific difference of clinical severity, yet highlights a more severe outcome when amino acid changes colocalize to the catalytic domain of the USP7 protein.

Rafeienejad F, Keyhani E, Akbarfahimi N, Nouri N. Neurodevelopmental disorder: Hao-Fountain syndrome with USP7 mutation-a case report. J Med Case Rep. 2025 Jul 24;19(1):363. doi: 10.1186/s13256-025-05403-y. PMID: 40707997; PMCID: PMC12291276.

Abstract

Background: Hao-Fountain syndrome (HAFOUS) is a rare neurodevelopmental disorder manifesting as several known symptoms, including speech and language delay, behavioral abnormalities, and intellectual disability. This rare condition is usually diagnosed by heterozygous deletion or mutation in the ubiquitin-specific protease 7 gene in conjunction with phenotype features.

Case presentation: We report the case of a 5-year-old Persian girl with this rare syndrome. The process of diagnosis, from perinatal examinations to the latest laboratory and clinical tests, is described for the first time in Iran.

Conclusion: Reporting all the symptoms of such a rare genetic case in detail emphasizes the importance of interdisciplinary teamwork and the necessity of raising awareness among therapists about probable upcoming problems; sharing such evident information with parents would help them manage the complexity of raising children with rare syndromes.

TUBGCP6 mutations

Inspired by a patient

Sengillo JD, Ashkenazy N, Shoji MK, Iyer P, Robles-Holmes HK, Lopez A, Yannuzzi NA, Negron CI, Berrocal AM. Familial Exudative Vitreoretinopathy-Like Phenotype in a Patient With Microcephaly and TUBGCP6 Mutations. J Vitreoretin Dis. 2023 Apr 10;7(4):344-347. doi: 10.1177/24741264231167236. PMID: 37927319; PMCID: PMC10621710.

Abstract

Purpose: To describe a case of microcephaly, unilateral retinal fold, and familial exudative vitreoretinopathy (FEVR)-like phenotype in the context of 2 TUBGCP6 variants. Methods: A case and its findings were analyzed. Results: A 4-month-old boy with no family history of eye disease presented by referral for management of presumed persistent fetal vasculature in the left eye. An external examination showed microcephaly. The patient grimaced to light in both eyes, and the anterior segments were unremarkable. On dilated fundus examination, diffuse chorioretinal atrophy was present bilaterally. In the left eye, a retinal fold emanated from the optic nerve head. There was early termination of retinal vasculature, especially in zone 3 in the left eye, resembling a FEVR-like phenotype. Panel-based genetic testing was performed and found 2 mutations in TUBGCP6. Conclusions: Microcephaly, chorioretinopathy, and retinal folds may be associated with TUBGCP6 mutations and masquerade as PFV.

Shurygina MF, Simonett JM, Parker MA, Mitchell A, Grigorian F, Lifton J, Nagiel A, Shpak AA, Dadali EL, Mishina IA, Weleber RG, Yang P, Pennesi ME. Genotype Phenotype Correlation and Variability in Microcephaly Associated With Chorioretinopathy or Familial Exudative Vitreoretinopathy. Invest Ophthalmol Vis Sci. 2020 Nov 2;61(13):2. doi: 10.1167/iovs.61.13.2. PMID: 33137195; PMCID: PMC7645200.

Abstract

Purpose: The purpose of this study was to analyze the natural history and phenotypic overlap of patients with microcephaly and a chorioretinopathy or familial exudative vitreoretinopathy (FEVR) ocular phenotype caused by mutations in KIF11, TUBGCP4, or TUBGCP6.

Methods: Patients diagnosed with congenital microcephaly and chorioretinopathy or FEVR were included. Molecular investigations consisted of targeted genetic sequencing. Data from medical records, ophthalmologic examination and imaging, electroretinography, and visual fields were analyzed for systemic and ophthalmic features and evidence of posterior segment disease progression.

Results: Twelve patients from 9 families were included and had a median of 8 years of follow-up. Nine patients had KIF11 variants, two had heterozygous TUBGCP6 variants, and one had heterozygous variants in TUBGCP4. All patients had reduced visual function and multiple individuals and families showed features of both chorioretinopathy and FEVR. Progression of posterior segment disease was highly variable, with some degree of increased atrophy of the macula or peripheral retina or increased vitreoretinal traction observed in 9 of 12 patients.

Conclusions: Microcephaly due to mutations in KIF11, TUBGCP4, or TUBGCP6 can be associated with retinal disease on a spectrum from chorioretinal atrophy to FEVR-like posterior segment changes. Visually significant disease progression can occur and patients should be monitored closely by a team experienced in ophthalmic genetics.

Hull S, Arno G, Ostergaard P, Pontikos N, Robson AG, Webster AR, Hogg CR, Wright GA, Henderson RHH, Martin CA, Jackson AP, Mansour S, Moore AT, Michaelides M. Clinical and Molecular Characterization of Familial Exudative Vitreoretinopathy Associated With Microcephaly. Am J Ophthalmol. 2019 Nov;207:87-98. doi: 10.1016/j.ajo.2019.05.001. Epub 2019 May 8. PMID: 31077665.

Abstract

Purpose: Familial exudative vitreoretinopathy (FEVR) is a rare finding in patients with genetic forms of microcephaly. This study documents the detailed phenotype and expands the range of genetic heterogeneity.

Design: Retrospective case series.

Methods: Twelve patients (10 families) with a diagnosis of FEVR and microcephaly were ascertained from pediatric genetic eye clinics and underwent full clinical assessment including retinal imaging. Molecular investigations included candidate gene Sanger sequencing, whole-exome sequencing (WES), and whole-genome sequencing (WGS).

Results: All patients had reduced vision and nystagmus. Six were legally blind. Two probands carried bi-allelic LRP5 variants, both presenting with bilateral retinal folds. A novel homozygous splice variant, and 2 missense variants were identified. Subsequent bone density measurement identified osteoporosis in one proband. Four families had heterozygous KIF11 variants. Two probands had a retinal fold in one eye and chorioretinal atrophy in the other; the other 2 had bilateral retinal folds. Four heterozygous variants were found, including 2 large deletions not identified on Sanger sequencing or WES. Finally, a family of 2 children with learning difficulties, abnormal peripheral retinal vasculogenesis, and rod-cone dystrophy were investigated. They were found to have bi-allelic splicing variants in TUBGCP6. Three families remain unsolved following WES and WGS.

Conclusions: Molecular diagnosis has been achieved in 7 of 10 families investigated, including a previously unrecognized association with LRP5. WGS enabled molecular diagnosis in 3 families after prior negative Sanger sequencing of the causative gene. This has enabled patient-specific care with targeted investigations and accurate family counseling.

Epilepsy surgery

By the time Charlotte “Charli” Hilz’s family drove from Dallas to Austin, they had tried nearly everything they had been offered to control her seizures: Seven medications, dietary changes and steroids had failed. Some treatments helped briefly, while others brought difficult side effects. All the while, two-year-old Charli was losing abilities she had already developed.

Her parents knew the situation was worsening. What they did not have was a clear path forward.

“My trust began to waver,” says Charli’s father, Trevor Hilz. “But I also didn’t know where to go.”

A family connection led them to Dave Clarke, M.D., chief of the Comprehensive Pediatric Epilepsy Program within the neurology clinic at Dell Children’s, a clinical partnership with Dell Medical School that is now ranked No. 21 in the country. Within a week, they had made the trip to Austin and begun a new evaluation — one designed not simply to try another medication, but to understand why the treatments had failed and whether a more definitive option was possible.

“Our program is designed to engage closely with families and across our disciplines to get to the root of the problem,” says Clarke, professor of pediatrics and neurology at Dell Medical School at The University of Texas at Austin. “Highly trained epileptologists, neurosurgeons who are able to take on high-risk procedures if needed, neuropsychologists, social workers, advanced practice providers and nurses — we all collaborate with the child and family at the center. That’s what makes the difference here: We are both capable and willing to go the extra mile for each child.”

National recognition for Austin pediatric programs

Charli’s journey points to a larger shift in the Central Texas medical landscape. For years, families in Austin routinely traveled to Dallas, Houston and elsewhere for highly specialized pediatric care. Charli’s family came in the opposite direction, seeking capabilities that an emerging academic pediatric neuroscience program had assembled here.

Created in 2019, the program brought pediatric neurology, neurosurgery, neuropsychology, neuro-ophthalmology, rehabilitation and related specialties into a more integrated model. It earned its first national recognition from U.S. News & World Report three years later. By 2025, the program had reached No. 25 in the country for pediatric neurology and neurosurgery. Today, it is tied for No. 21, one of a handful of programs led by Dell Med faculty now climbing in national recognition.

“The power of academic medicine is that patient care, research and education continually strengthen one another,” says Claudia Lucchinetti, M.D., senior vice president for medical affairs and dean of Dell Medical School at The University of Texas at Austin. “The needs of patients shape research, new discoveries create better outcomes, and education prepares more physicians to deliver the most advanced care. At Dell Children’s, Dell Med faculty bring that model together with outstanding clinical teams and the broader capabilities of UT to take on complex cases and find a path forward when standard answers fall short.

“These rankings reflect what matters for children and families: deeper expertise, more options, and access to nationally recognized care here in Central Texas.”

Charli’s journey from uncertainty to recovery

Other leading pediatric epilepsy centers around the country have access to many of the same advanced tools. But what Charli and her family needed — and had not yet found — was a team of advanced specialists prepared to put them together around her particular case.

“When advanced specialists come together, we can look at complex cases from every angle,” says Adam Messer, president of Dell Children’s Medical Center. “This collaboration helps us understand each child’s unique needs so we can provide comprehensive care that supports the entire family.”

Charli’s epilepsy began in one area of the brain but spread so rapidly that it could resemble a different type of seizure disorder. At the same time, abnormal electrical activity was disrupting more than half of her sleep, interfering with her brain’s ability to rest, learn and develop. She was having as many as 20 seizures a day, struggling to walk and speak clearly, and losing the use of her left hand.

At Dell Children’s, the team began again with inpatient monitoring, capturing Charli’s seizures and studying the electrical activity in her brain. Advanced imaging helped narrow the suspected source. Epileptologists, neurosurgeons and neuropsychologists then used stereo-EEG, placing small electrodes in and around the target area to determine precisely where her seizures began and how closely that area bordered functions that needed to be preserved.

The evaluation located a small area of atypical cells near Charli’s sensory cortex. The target was so tightly surrounded by functional tissue that conventional surgical removal could have caused harm.

Instead, the team guided a needle-sized probe between two folds of her brain and used laser energy to deactivate the cells driving the seizures while protecting the surrounding tissue.

Today, Charli is six years old and remains seizure-free. Her overnight epileptic episodes have largely disappeared. She is using both sides of her body more fully, taking fewer medications and rapidly regaining function her family once feared had been permanently lost.

“For the first time, we felt heard,” says Charli’s mother, Mackenzie Hilz. “Dr. Clarke believed us. He looked at her and us and said, ‘I have a plan.’ We hadn’t heard that from anyone before. We took the leap, and it saved her life.”

https://news.utexas.edu/2026/09/17/academic-medicine-raises-the-bar-for-pediatric-neuroscience-care-in-austin/

Diazepam Intensol shortage

 It seems there is a nationwide shortage of  inexpensive but effective Diazepam Intensol, forcing obscenely expensive Valtoco to be prescribed in yet more obscenely expensive 5 packs.

Great experiments 5

Courtesy of a colleague

Hot air? BMJ. 2001 Dec 22;323(7327):1449. PMCID: PMC1121900.

“It all started with an enquiry from a nurse,” Dr Karl Kruszelnicki told listeners to his science phone-in show on the Triple J radio station in Brisbane. “She wanted to know whether she was contaminating the operating theatre she worked in by quietly farting in the sterile environment during operations, and I realised that I didn't know. But I was determined to find out.”

Dr Kruszelnicki then described the method by which he had established whether human flatus was germ-laden, or merely malodorous. “I contacted Luke Tennent, a microbiologist in Canberra, and together we devised an experiment. He asked a colleague to break wind directly onto two Petri dishes from a distance of 5 centimetres, first fully clothed, then with his trousers down. Then he observed what happened. Overnight, the second Petri dish sprouted visible lumps of two types of bacteria that are usually found only in the gut and on the skin. But the flatus which had passed through clothing caused no bacteria to sprout, which suggests that clothing acts as a filter.

“Our deduction is that the enteric zone in the second Petri dish was caused by the flatus itself, and the splatter ring around that was caused by the sheer velocity of the fart, which blew skin bacteria from the cheeks and blasted it onto the dish. It seems, therefore, that flatus can cause infection if the emitter is naked, but not if he or she is clothed. But the results of the experiment should not be considered alarming, because neither type of bacterium is harmful. In fact, they're similar to the ‘friendly’ bacteria found in yoghurt.

“Our final conclusion? Don't fart naked near food. All right, it's not rocket science. But then again, maybe it is?”

Levacetylleucine for treatment of Niemann-Pick disease type C 2

Davis LC, Annaert W, Braine R, Churchill GC, Factor M, Fields T, Patterson M, Platt F, Shepherd D, Strupp M, Galione A. N-acetyl-L-leucine normalizes Transcription Factor EB activity by stereospecific bidirectional modulation in a HeLa cell model of Niemann-Pick disease type C. PLoS One. 2026 Jul 17;21(7):e0353834. doi: 10.1371/journal.pone.0353834. PMID: 42467639; PMCID: PMC13378962.

Abstract

Levacetylleucine (Aqneursa™), an acetylated derivative and pro-drug of L-leucine, is the only FDA-approved monotherapy for Niemann-Pick disease type C (NPC). Its acetyl group enables transport via monocarboxylate transporters, supporting blood-brain barrier penetration and efficient cellular uptake. Inside cells, levacetylleucine is metabolised by acylases, generating elevated levels of L-leucine that enhance mitochondrial bioenergetics and is thought to ameliorate lysosomal dysfunction indirectly. Here, we describe a direct effect of levacetylleucine on lysosomal regulation through modulation of TFEB, the master transcription factor for lysosomal and autophagy genes. Levacetylleucine rapidly alters TFEB translocation between the cytoplasm and the nucleus in a biphasic, homeostasis-restoring manner. In wild-type HeLa cells, levacetylleucine promotes TFEB activation and nuclear localisation. However, in NPC1 disease models, where we show that TFEB is over-activated and enriched in the nucleus due to lysosomal stress, levacetylleucine reduces nuclear TFEB and restores a more normal cytoplasmic-to-nuclear balance. These effects occur at clinically relevant concentrations associated with lysosomal storage reduction. The effects of the drug are stereospecific: while the L-enantiomer is active, the D-enantiomer and racemate show no effect, revealing the antagonistic properties of the D-enantiomer. This bidirectional normalisation of TFEB activity highlights a direct mechanism through which levacetylleucine modulates lysosomal and autophagic pathways in the HeLa cell model, giving mechanistic insight into its therapeutic potential in NPC, and also across diverse neurological and neurodevelopmental disorders.

Bremova-Ertl T, Ramaswami U, Brands M, Foltan T, Gautschi M, Gissen P, Gowing F, Hahn A, Jones S, Kay R, Kolnikova M, Arash-Kaps L, Marquardt T, Mengel E, Park JH, Reichmannová S, Schneider SA, Sivananthan S, Walterfang M, Wibawa P, Strupp M, Martakis K. Trial of N-Acetyl-l-Leucine in Niemann-Pick Disease Type C. N Engl J Med. 2024 Feb 1;390(5):421-431. doi: 10.1056/NEJMoa2310151. PMID: 38294974.

Abstract

Background: Niemann-Pick disease type C is a rare lysosomal storage disorder. We evaluated the safety and efficacy of N-acetyl-l-leucine (NALL), an agent that potentially ameliorates lysosomal and metabolic dysfunction, for the treatment of Niemann-Pick disease type C.

Methods: In this double-blind, placebo-controlled, crossover trial, we randomly assigned patients 4 years of age or older with genetically confirmed Niemann-Pick disease type C in a 1:1 ratio to receive NALL for 12 weeks, followed by placebo for 12 weeks, or to receive placebo for 12 weeks, followed by NALL for 12 weeks. NALL or matching placebo was administered orally two to three times per day, with patients 4 to 12 years of age receiving weight-based doses (2 to 4 g per day) and those 13 years of age or older receiving a dose of 4 g per day. The primary end point was the total score on the Scale for the Assessment and Rating of Ataxia (SARA; range, 0 to 40, with lower scores indicating better neurologic status). Secondary end points included scores on the Clinical Global Impression of Improvement, the Spinocerebellar Ataxia Functional Index, and the Modified Disability Rating Scale. Crossover data from the two 12-week periods in each group were included in the comparisons of NALL with placebo.

Results: A total of 60 patients 5 to 67 years of age were enrolled. The mean baseline SARA total scores used in the primary analysis were 15.88 before receipt of the first dose of NALL (60 patients) and 15.68 before receipt of the first dose of placebo (59 patients; 1 patient never received placebo). The mean (±SD) change from baseline in the SARA total score was -1.97±2.43 points after 12 weeks of receiving NALL and -0.60±2.39 points after 12 weeks of receiving placebo (least-squares mean difference, -1.28 points; 95% confidence interval, -1.91 to -0.65; P<0.001). The results for the secondary end points were generally supportive of the findings in the primary analysis, but these were not adjusted for multiple comparisons. The incidence of adverse events was similar with NALL and placebo, and no treatment-related serious adverse events occurred.

Conclusions: Among patients with Niemann-Pick disease type C, treatment with NALL for 12 weeks led to better neurologic status than placebo. A longer period is needed to determine the long-term effects of this agent in patients with Niemann-Pick disease type C. (Funded by IntraBio; ClinicalTrials.gov number, NCT05163288; EudraCT number, 2021-005356-10.).

Fields T, M Bremova T, Billington I, Churchill GC, Evans W, Fields C, Galione A, Kay R, Mathieson T, Martakis K, Patterson M, Platt F, Factor M, Strupp M. N-acetyl-L-leucine for Niemann-Pick type C: a multinational double-blind randomized placebo-controlled crossover study. Trials. 2023 May 29;24(1):361. doi: 10.1186/s13063-023-07399-6. PMID: 37248494; PMCID: PMC10226221.

Abstract

Background: Niemann-Pick disease type C (NPC) is a rare autosomal recessive neurodegenerative lysosomal disease characterized by multiple symptoms such as progressive cerebellar ataxia and cognitive decline. The modified amino acid N-acetyl-leucine has been associated with positive symptomatic and neuroprotective, disease-modifying effects in various studies, including animal models of NPC, observational clinical case studies, and a multinational, rater-blinded phase IIb clinical trial. Here, we describe the development of a study protocol (Sponsor Code "IB1001-301") for the chronic treatment of symptoms in adult and pediatric patients with NPC.

Methods: This multinational double-blind randomized placebo-controlled crossover phase III study will enroll patients with a genetically confirmed diagnosis of NPC patients aged 4 years and older across 16 trial sites. Patients are assessed during a baseline period and then randomized (1:1) to one of two treatment sequences: IB1001 followed by placebo or vice versa. Each sequence consists of a 12-week treatment period. The primary efficacy endpoint is based on the Scale for the Assessment and Rating of Ataxia, and secondary outcomes include cerebellar functional rating scales, clinical global impression, and quality of life assessments.

Discussion: Pre-clinical as well as observational and phase IIb clinical trials have previously demonstrated that IB1001 rapidly improved symptoms, functioning, and quality of life for pediatric and adult NPC patients and is safe and well tolerated. In this placebo-controlled cross-over trial, the risk/benefit profile of IB1001 for NPC will be evaluated. It will also give information about the applicability of IB1001 as a therapeutic paradigm for other rare and common neurological disorders.

Trial registrations: The trial (IB1001-301) has been registered at www.

Clinicaltrials: gov (NCT05163288) and www.clinicaltrialsregister.eu (EudraCT: 2021-005356-10). Registered on 20 December 2021.

Keywords: Cerebellar ataxia; Lysosomal storage disease; N-acetyl-L-leucine; Niemann-Pick type C (NPC); Pharmaceutical intervention; Randomized controlled trial; Symptomatic treatment.

Du K, Chen H, Pan Z, Zhao M, Cheng S, Luo Y, Zhang W, Li D. Small-molecule activation of TFEB alleviates Niemann-Pick disease type C via promoting lysosomal exocytosis and biogenesis. Elife. 2025 Apr 4;13:RP103137. doi: 10.7554/eLife.103137. PMID: 40184172; PMCID: PMC11970905.

Abstract

Niemann-Pick disease type C (NPC) is a devastating lysosomal storage disease characterized by abnormal cholesterol accumulation in lysosomes. Currently, there is no treatment for NPC. Transcription factor EB (TFEB), a member of the microphthalmia transcription factors (MiTF), has emerged as a master regulator of lysosomal function and promoted the clearance of substrates stored in cells. However, it is not known whether TFEB plays a role in cholesterol clearance in NPC disease. Here, we show that transgenic overexpression of TFEB, but not TFE3 (another member of MiTF family) facilitates cholesterol clearance in various NPC1 cell models. Pharmacological activation of TFEB by sulforaphane (SFN), a previously identified natural small-molecule TFEB agonist by us, can dramatically ameliorate cholesterol accumulation in human and mouse NPC1 cell models. In NPC1 cells, SFN induces TFEB nuclear translocation via a ROS-Ca2+-calcineurin-dependent but MTOR-independent pathway and upregulates the expression of TFEB-downstream genes, promoting lysosomal exocytosis and biogenesis. While genetic inhibition of TFEB abolishes the cholesterol clearance and exocytosis effect by SFN. In the NPC1 mouse model, SFN dephosphorylates/activates TFEB in the brain and exhibits potent efficacy of rescuing the loss of Purkinje cells and body weight. Hence, pharmacological upregulating lysosome machinery via targeting TFEB represents a promising approach to treat NPC and related lysosomal storage diseases, and provides the possibility of TFEB agonists, that is, SFN as potential NPC therapeutic candidates.

Levacetylleucine for treatment of ataxia-telangiectasia

The U.S. Food and Drug Administration has approved Aqneursa (levacetylleucine) for oral suspension to treat ataxia in adults and pediatric patients with ataxia-telangiectasia weighing at least 15 kg (about 33 pounds). Aqneursa was previously approved in 2024 to treat the neurological manifestations of Niemann-Pick disease type C. Today’s approval makes Aqneursa the first treatment approved for ataxia in patients with ataxia-telangiectasia.

Condition

Ataxia-telangiectasia is a rare, inherited neurodegenerative disorder caused by mutations in the ATM gene. It primarily affects the nervous system, causing progressive loss of muscle control and coordination (ataxia) that typically begins in early childhood. The disease also causes small dilated blood vessels (telangiectasias), immune deficiencies, and an elevated risk of cancer. There is no cure for ataxia-telangiectasia, and treatment options for the neurological symptoms of the disease have been limited.

Data Supporting Aqneursa

The effectiveness of Aqneursa was evaluated in a randomized, double-blind, placebo-controlled, two-period crossover study (NCT06673056) of 73 patients aged 4 years or older with a confirmed diagnosis of ataxia-telangiectasia. Patients were randomly assigned to receive Aqneursa followed by placebo, or placebo followed by Aqneursa, with each treatment period lasting 12 weeks. Of the 73 patients (26 adults and 47 pediatric patients), 38 were female and 35 were male. The median age at treatment initiation was 13 years (range: 4 to 50 years). A total of 70 patients (96%) completed the study.

Efficacy was assessed using the functional Scale for Assessment and Rating of Ataxia (fSARA), a modified clinical tool evaluating gait, sitting, stance, and speech disturbance, with scores ranging from 0 (best neurological status) to 16 (worst). When patients were taking Aqneursa, they scored better on the fSARA compared to when these patients were taking placebo and showed significant improvement in neurological function.

Safety Information

There are no contraindications for Aqneursa, although this drug may cause fetal harm based on data from animal studies. The most common adverse reactions in patients with ataxia-telangiectasia were fall, skin laceration, and urinary tract infection.

Aqneursa interacts with N-acetyl-DL-leucine and simultaneous use should be avoided. Patients receiving P-glycoprotein (P-gp) substrates should be monitored more frequently for related adverse reactions when used with Aqneursa.

Designation

Aqneursa received Orphan Drug designation and Priority Review for the ataxia-telangiectasia indication. Approval was granted to IntraBio Inc.

https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-therapy-treat-ataxia-patients-ataxia-telangiectasia-rare-genetic-disorder

Martakis K, Bremova-Ertl T, Bolton C, Foltan T, Del Mar Garcia Romero M, Gautschi M, Han V, Hahn A, Kolnikova M, Panagioti O, Perlman S, Prasad M, Schmahmann J, Skorvanek M, Thakur N, Thiel M, Hoche F. Safety and efficacy of levacetylleucine in ataxia-telangiectasia: a phase 3, randomised, double-blind, placebo-controlled crossover trial. Lancet Neurol. 2026 Jul;25(7):633-644. doi: 10.1016/S1474-4422(26)00158-4. PMID: 42309084.

Abstract

Background: Ataxia-telangiectasia is a rare, autosomal recessive neurodegenerative disorder. Levacetylleucine (N-acetyl-L-leucine) has been shown to be efficacious for the treatment of neurological manifestations and to have a disease-modifying effect in lysosomal storage disorders such as Niemann-Pick disease type C. We aimed to assess the safety and efficacy of levacetylleucine for paediatric and adult patients with ataxia-telangiectasia.

Methods: In this phase 3, randomised, double-blind, placebo-controlled crossover trial, participants were enrolled across ten research hospitals in Germany, Slovakia, Spain, Switzerland, the UK, and the USA. Eligible patients aged 4 years or older with genetically confirmed ataxia-telangiectasia were randomly assigned (1:1) using interactive response technology to receive two or three times daily orally administered levacetylleucine or a matching placebo over two consecutive 12-week treatment periods (patients weighing 35 kg or more received 4 g per day of orally administered levacetylleucine or a matching placebo three times per day and patients weighing less than 35 kg received weight-tiered doses two or three times per day based on approximately 0·1 g/kg per day). All participants, investigators, and assessors were blinded to group assignment. The primary outcome was the mean change on the Scale for the Assessment and Rating of Ataxia (SARA), assessed at baseline and at the end of each 12-week treatment period of levacetylleucine or placebo. Safety and efficacy analyses were done in all randomly assigned patients who received at least one dose of study medication, and a linear mixed-effects model was used to account for data missing at random. The trial is registered with ClinicalTrials.gov, NCT06673056, and CTIS, 2024-517706-29; the open-label extension phase is ongoing.

Findings: Between March 18, 2025 and June 30, 2025, 77 participants with a genetically confirmed diagnosis of ataxia-telangiectasia were screened for inclusion. Four patients were excluded (not meeting inclusion criteria) and 73 were enrolled and randomly assigned (36 to levacetylleucine followed by placebo and 37 to placebo followed by levacetylleucine. 73 patients were included in the primary analysis and safety sets. 38 (52%) of 73 patients were female and 35 (48%) were male; 55 (75%) of 73 patients were White. 47 (64%) of 73 were younger than 18 years and 26 (36%) were aged 18 years or older. The mean change in the SARA total score with levacetylleucine was -1·92 (SD 2·81) versus -0·14 (2·38) with placebo (linear mixed model treatment effect -1·88 [SD 0·41], 95% CI -2·70 to -1·06; p<0·0001). 54 adverse events occurred in 29 patients receiving levacetylleucine versus 75 events in 25 patients receiving placebo. No treatment-related serious adverse events or deaths occurred.

Interpretation: Levacetylleucine showed a significant and clinically meaningful improvement in functioning and was safe and well-tolerated, providing a favourable benefit-risk profile for the treatment of ataxia-telangiectasia. An ongoing open-label extension phase of this trial will investigate potential long-term, neuroprotective and disease-modifying effects.

Funding: IntraBio.

Most transcription is not a consequence of background noise.

For decades, many scientists have confidently dismissed the vast majority of the human DNA as useless evolutionary garbage. Yet a recently published scientific paper in Cell, one of the world’s most prestigious biology journals, declares a “paradigm shift” against the idea that huge portions of the human genome are merely “junk DNA.”

After the Human Genome Project was completed in 2003, a startling discovery was made. Only about 2 percent of the entire human genome codes for proteins. Scientists naturally asked, what is the other 98 percent doing?

Evolutionary biology was ready with an answer. For decades, they had claimed that the vast majority of the human genome was essentially genetic garbage — “junk DNA.” This idea had deep roots in evolutionary thinking — which loves to claim humanity and other living things are poorly designed.

A 1969 paper titled “Non-Darwinian Evolution” in the journal Science proposed that “99 percent of mammalian DNA is not true genetic material.” Three years later, the great Japanese biologist Susumu Ohno coined the term “junk DNA” and predicted that “at least 90% of the mammalian genomic DNA appears to represent ‘nonsense.’”

Atheist evolutionary biologists loved the idea. Richard Dawkins wrote in his 2003 book "A Devil’s Chaplain" that “genomes are littered with nonfunctional … junk.” But even theistic evolutionists — Christians who believe God created life through evolution — found junk DNA an expedient argument to bolster their theory.

In his 2006 book "The Language of God," Francis Collins — who headed the Human Genome Project — wrote that some “45 percent of the human genome” is little better than “genetic flotsam and jetsam.”

Meanwhile, proponents of intelligent design (ID) developed a very different view of so-called "junk DNA."

In 1994, pro-ID scientist Forrest Mims wrote a letter to Science warning against assuming that “junk” DNA was “useless.” Four years later, mathematician William Dembski articulated the ID view: “Consider the term ‘junk DNA. … Design encourages scientists to look for function where evolution discourages it.”

But why does intelligent design predict function for junk DNA? It’s simple.

ID theory starts by observing what intelligent minds can do, and then searches nature to see if there’s evidence of a mind at work.

We know from our observation-based experience that intelligent agents do things for a reason. Engineers only put functional parts into cell phones. Every time an email is written, an intelligence generates informational sequences with a purposeful message. ID predicts function.

But which view is right? In 2012, a groundbreaking discovery started a paradigm shift in this debate.

A consortium of hundreds of scientists involved in the ENCODE Project published results in the top journal Nature showing that over 80 percent of the human genome is biochemically active. They showed the vast majority of the genome is converted into RNA — a process called “transcription” that is normally a telltale sign of function. One lead ENCODE researcher predicted that as more human cell types are studied, “that 80 percent will go to 100 percent.”

These discoveries had a dramatic effect on biological thinking. Even Francis Collins changed his tune. Speaking at a scientific conference in 2015, he admitted:

"In terms of junk DNA, we don’t use that term anymore because I think it was pretty much a case of hubris to imagine that we could dispense with any part of the genome as if we knew enough to say it wasn’t functional."

Collins explained that most of so-called “junk” is regulating the production of proteins, called gene expression. By 2021, one mainstream scientific paper declared that “the days of ‘junk DNA’ are over.”

These discoveries represented a spectacular fulfillment of ID’s prediction that we would discover function for junk DNA, and a colossal failure for evolution.

Unsurprisingly, evolutionary biologists weren’t going to take this sitting down. One biologist, Dan Graur at the University of Houston, worried that “If ENCODE is right, then Evolution is wrong.” He shifted the goalposts by proposing that if most of our genome is producing RNA, then that “transcription is … stochastic” — i.e., it’s just randomly produced junk RNA!

But Graur’s view has been receding as we discover more and more functions for RNA. A newly published paper in the journal Genome Biology and Evolution dealt a serious blow to “junk RNA.”

This paper, along with a 2024 paper in Nature, took sections of mammalian DNA that are transcribed into RNA and reversed them. If transcription is random and uncontrolled, then scrambling their DNA should not change the amount of RNA that’s produced. But if RNA is produced in a controlled, regulated, and functional manner, then transcription in the scrambled sequence should drop dramatically. And that’s exactly what they found. As the paper found, “most transcription is not a consequence of background noise.”

To be sure, there’s still much we don’t know about the genome. But the more we study genetics, the more function we discover. Evolution’s love affair with viewing our bodies as clumsy accidents is hindering science. In contrast, when we view DNA as intelligently designed, we can make useful predictions that bear good scientific fruit, advancing our knowledge of how cells work.

Casey Luskin

https://townhall.com/columnists/casey-luskin/2026/09/20/intelligent-design-bears-good-scientific-fruit-in-the-study-of-junk-dna-n2683215

Ho J, Douse C, Marazzi I. Transposable element DNA and RNA: Drivers of gene expression, evolution, and disease
Cell, 189, 3513-3540

Summary
Transposable elements (TEs) comprise nearly half of mammalian genomes and have shaped genome architecture, chromatin organization, and transcriptional landscapes. Thanks to recent advances in long-read sequencing and functional (epi)genomics, the focus has shifted from TE families to individual TE loci, revealing widespread, locus-specific regulatory roles. While most TEs have lost the capacity to mobilize, they still retain a DNA form and, when transcribed, an RNA form, both of which can affect genome regulation. TEs can serve as alternative promoters, exons, splicing regulators, and 3′ end modulators. They can also act as enhancers, drive three-dimensional (3D) genome organization, and give rise to long non-coding RNAs (lncRNAs) that serve as platforms for transcriptional and chromatin regulators. Mechanistically, TE repression involves DNA methylation, histone modification, phase-separated condensates, RNA modifications, RNA degradation, and nuclear compartmentalization, yet this repression can be selectively lifted during development or stress to expand regulatory potential. TEs therefore contribute to cell-type identity, developmental transitions, and responses to environmental stimuli, while their dysregulation is linked to human disorders including neurodegeneration, cancer, and autoimmune disease. TEs also hold translational promise as biomarkers and tools for gene and cell engineering. In summary, the pervasive integration of TEs as mini-genes, structural scaffolds, and regulatory elements redefines our view of the genome: rather than a gene-centric landscape dotted with repetitive “junk,” mammalian DNA is a TE-rich ecosystem in which TEs drive gene regulatory networks and evolution.

The ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57–74 (2012). https://doi.org/10.1038/nature11247

Abstract

The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall, the project provides new insights into the organization and regulation of our genes and genome, and is an expansive resource of functional annotations for biomedical research.

Child neurology training

Rogers D, Stone RT, Ream M, Pearson R, Pagano LM, Bernson-Leung ME, Troy E, Otallah SI, Kossoff EH, Kessler SK, Borrero-Mejias C, Crowder D, Xixis KI, Rametta SC, Deputy S, Arya K, Nelson A, Wilson JL, McGregor A, Mangum T, Bain JM, Shiloh-Malawsky Y, Candee MS, Gilbert DL, Wollack JB, Qaiser S, Jones R, Strelzik J, Tiongson E, Venkatesan C, Goldstein J, Thamann A, Agurs LD, Schreiner TL, Wallace A, Foster-Barber A, Gottlieb-Smith R. Essential Components of Child Neurology Training: Program Director Consensus Recommendations. Ann Child Neurol Soc. 2025 Sep 17;3(4):282-291. doi: 10.1002/cns3.70038. PMID: 42563811; PMCID: PMC13359169.

Abstract

Objective: We aimed to develop a program director-derived model of essential components of child neurology residency training.

Methods: All 79 child neurology residency programs in the United States were invited to submit a block diagram with 48 months of required rotations, the minimum clinical requirement across all approved pathways. These block diagrams were then analyzed for consensus. Program directors were anonymously surveyed regarding whether a child neurology resident could be adequately trained using the consensus curriculum if implemented in either a 4- or a 5-year training program, and whether 4 years of residency could provide adequate training.

Results: Fifty of 79 residency programs (63%) submitted a block diagram (54% in pediatrics departments, 46% in neurology departments). Greater than 75% of program directors recommended the following rotations with the average number of months recommended across all program directors in parentheses: pediatric inpatient/hospital medicine (3), pediatric non-consult intensive care (3), healthy newborn (0.5), pediatric acute/emergency care (1), genetics (1), child development (1), child neurology inpatient/consults (8), child neurology general outpatient (4), child psychiatry (1), adult neurology inpatient/consults (3), neurology specialties outpatient (4), electroencephalography (2), neuroradiology (1), and electives (7). Of the program directors (53 of 79, 67%) who completed the post-survey, 87% agreed that these requirements would be adequate, and 89% agreed that child neurologists could be adequately trained for independent practice within 4 years.

Interpretation: The program director consensus supports modification of existing child neurology training requirements, with general agreement that 4 years of clinical training would be adequate.

Cohen BH, Gilbert DL, Xixis K, Banwell BL, Singh A, Pagano LM, Brooks-Kayal A, Kirkpatrick L, Schor NF, Mar SS, Crowder D, Terrell M, Kang PB. Education Research: The Future of Child Neurology Residency Training: The Perspective of a Child Neurology Society Task Force. Neurol Educ. 2026 Jun 12;5(2):e200331. doi: 10.1212/NE9.0000000000200331. PMID: 42311783; PMCID: PMC13271257.

Abstract

Background and objectives: Postgraduate residency in the United States is complex, and each medical field faces unique educational challenges. Child neurology has had a distinct identity for decades, yet its training curriculum originated from a joint venture of 2 larger and older fields, pediatrics and neurology. The traditional five-year training sequence consists of 2 years of pediatrics, 1 year of adult neurology, and 2 years of child neurology, as well as all other educational experiences, including electives. The contents of each major component have changed, in some instances dramatically, over the years, yet the original basic structure remains.

Methods: In anticipation of upcoming reviews of the child neurology training curriculum, the Child Neurology Society (CNS) convened a task force to review key aspects of this training curriculum. The task force members were surveyed anonymously both before and after a series of discussions to consider the current and expected educational needs of child neurologists in the mid-21st century, following a modified Delphi approach.

Results: The consensus was that child neurology has matured immensely as a field, with substantial subspecialization becoming common at major academic medical centers. There was significant variability in the availability of pediatric neurologic subspecialty training in fields such as neurogenetics and neuromuscular neurology across the United States. The preponderant view of the Task Force was that the child neurology training curriculum should be reviewed and potentially modified in accordance with the evolving educational needs of child neurologists, particularly with regard to general pediatrics and adult neurology training. The spectrum of faculty expertise and curricular emphasis across programs, viewed as a strength of training options, precluded reaching consensus on details of appropriate changes.

Discussion: The findings of the task force indicate that there will be a need for ongoing evaluation and updating of the child neurology training curriculum in future years. Before the next formal review of the child neurology training curriculum by the Accreditation Council for Graduate Medical Education, we recommend a robust discussion among multiple stakeholders, including accreditation bodies, medical specialty boards, and professional societies such as the CNS that represent child neurologists in practice and in training.

Thompson-Stone R, Gottlieb-Smith R, Rogers DA, Xixis K, Pearson R, Pagano L, Ream M. A Categorical 4-Year Child Neurology Residency: It's Time. Semin Neurol. 2026 Jun;46(3):275-282. doi: 10.1055/a-2767-2331. Epub 2025 Dec 11. PMID: 41380737.

Abstract

Child neurology training has undergone minimal change over the decades, despite a rapid growth in subspecialty knowledge, patient volumes, and complexity. The current 5-year structure, which was established due to necessary historical compromises between pediatrics and neurology, is increasingly misaligned with modern clinical practice and educational priorities. Most child neurologists no longer pursue dual pediatrics certification, and few provide neurologic care to adult patients. Meanwhile, the field has expanded significantly in complexity and volume, making it a large enough specialty to sustain an independent curriculum. We propose a streamlined 4-year categorical residency model that integrates relevant components of pediatrics and adult neurology while centering training around child neurology from the start. This model, which aligns better with structures seen in comparable specialties, prioritizes flexibility and increases the opportunities for longitudinal mentorship and professional development. Thoughtful planning and collaboration will be essential to surmount challenges during the transition, including changes in board certification and alterations to institutional funding. Modernizing child neurology training is essential to better prepare future specialists, support recruitment and resident development, and meet the evolving needs of children with neurologic disorders.

Fremanezumab for pediatric migraine

Hershey AD, Szperka CL, Barbanti P, Pozo-Rosich P, Bittigau P, Barash S, Bryson J, Kessler Y, Carmeli Schwartz Y, Ramirez Campos V, Ning X. Fremanezumab in Children and Adolescents with Episodic Migraine. N Engl J Med. 2026 Jan 15;394(3):243-252. doi: 10.1056/NEJMoa2504546. PMID: 41534042.

Abstract

Background: Fremanezumab, a humanized monoclonal antibody that selectively targets calcitonin gene-related peptide, is approved for the prevention of migraine in adults. Evidence from randomized, controlled trials in children and adolescents is needed.

Methods: We randomly assigned participants 6 to 17 years of age with a diagnosis of episodic migraine (defined as migraine for ≥6 months and a history of ≤14 headache days per month) to receive monthly subcutaneous injections of fremanezumab (120 mg for participants with a body weight of <45 kg and 225 mg for those with a body weight of ≥45 kg) or matched placebo for 3 months. Participants were allowed to use migraine-specific medications to treat acute headaches. The primary end point was the change from baseline in the average number of migraine days per month. Key secondary end points included the change in the number of days per month with headache of at least moderate severity and a reduction of 50% or more in the number of migraine days per month.

Results: Of 237 participants who underwent randomization, 234 were included in the full analysis population: 123 in the fremanezumab group (36 received the 120-mg dose and 87 received the 225-mg dose) and 111 in the placebo group. Fremanezumab reduced the number of migraine days per month by 2.5 as compared with 1.4 with placebo (difference, 1.1; P = 0.02) and the number of days per month with headache of at least moderate severity by 2.6 as compared with 1.5 with placebo (difference, 1.1; P = 0.02). The percentage of participants who had a reduction of 50% or more in the number of migraine days per month was 47.2% with fremanezumab and 27.0% with placebo (P = 0.002). Injection-site erythema was the most common adverse event with fremanezumab (9.8% of participants, vs. 5.4% with placebo).

Conclusions: Among children and adolescents with episodic migraine, fremanezumab resulted in greater reductions in the number of migraine days and headache days than placebo. Injection-site erythema was the most common adverse event with fremanezumab. Longer follow-up is required to further understand the efficacy and safety of the drug in this population. (Funded by Teva Pharmaceuticals; ClinicalTrials.gov number, NCT04458857.).

Iannone LF, Romozzi M, Papetti L, Toldo I, Valeriani M, Geppetti P. Pharmacokinetics and Pharmacodynamics, Efficacy and Safety of Fremanezumab in Children and Adolescents with Migraine. Eur J Drug Metab Pharmacokinet. 2026 Mar;51(2):133-139. doi: 10.1007/s13318-026-00990-7. Epub 2026 Mar 13. PMID: 41824241; PMCID: PMC13031235.

Abstract

Migraine affects up to 11% of children and adolescents, leading to substantial disability through school absenteeism, cognitive impairment, and reduced quality of life. Traditionally, preventive treatment options for this population have been limited to the off-label use of nutraceuticals, antiseizure medications, calcium channel blockers, serotonin modulators, antidepressants, or beta-blockers, with limited efficacy and tolerability data. Monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway have transformed adult migraine prevention, and fremanezumab is the first in this class to receive regulatory approval for pediatric use. In August 2025, the US Food and Drug Administration approved fremanezumab for the preventive treatment of episodic migraine in patients aged 6-17 years weighing at least 45 kg, based on the pivotal phase three SPACE trial. This randomized, placebo-controlled study demonstrated significant reductions in monthly migraine and headache days, with nearly half of treated participants achieving a ≥50% response rate, and a safety profile consistent with adult data. In this review, we provide an integrated, pediatric-focused synthesis of the pharmacokinetic, pharmacodynamic, and regulatory evidence supporting fremanezumab use in children and adolescents. In particular, we contextualize population pharmacokinetic modeling and pediatric phase 1 data to explain the rationale for weight-based dosing, exposure matching with adults, and the selection of the dosing regimens used in clinical trials and regulatory labeling. Pharmacokinetic analyses indicate that fremanezumab follows a two-compartment model with first-order absorption and a terminal half-life of approximately 30 days in pediatric patients, similar to adults, with body weight as the primary determinant of exposure. Finally, we discuss unresolved issues related to long-term CGRP blockade during growth, including theoretical effects on vascular regulation, bone metabolism, and neurodevelopment. Overall, fremanezumab represents a novel, mechanism-based preventive option for older children and adolescents with episodic migraine, while highlighting the need for continued longitudinal studies to define its long-term safety and optimal role in pediatric migraine management.

Friedman DI, Cohen JM. Fremanezumab: a disease-specific option for the preventive treatment of migraine, including difficult-to-treat migraine. Emerg Top Life Sci. 2020 Sep 8;4(2):179-190. doi: 10.1042/ETLS20200018. PMID: 32832978; PMCID: PMC7487173.

Abstract

Fremanezumab is a fully humanized monoclonal antibody (IgG2Δa) that targets calcitonin gene-related peptide (CGRP), a key neuropeptide involved in the pathophysiology of migraine. Fremanezumab is approved for quarterly and monthly subcutaneous dosing for the preventive treatment of migraine in adults. The phase 3 clinical development program for fremanezumab aimed to evaluate the efficacy of this preventive treatment across different patient populations, including those with difficult-to-treat migraine. Two pivotal 12-week, phase 3, placebo-controlled studies investigated quarterly and monthly dosing of fremanezumab in participants with chronic migraine (HALO CM) and episodic migraine (HALO EM). The efficacy of fremanezumab was further explored in individuals with difficult-to-treat chronic or episodic migraine in the 12-week FOCUS study, which enrolled participants who had previously experienced an inadequate response to 2-4 pharmacological classes of migraine preventive medications. The long-term efficacy of fremanezumab was assessed in a 12-month long-term study (HALO LTS), which enrolled participants completing the 12-week HALO studies and new participants. Across these studies, treatment with fremanezumab dosed quarterly or monthly provided significant reductions in the frequency of migraine days, headache days of at least moderate severity, and migraine- and headache-related disability compared with placebo. Sustained improvements were seen with long-term fremanezumab treatment. Subgroup analyses of participants with difficult-to-treat migraine (those with comorbid depression, overuse of acute headache medications, and concomitant use of other migraine preventive medications) demonstrated the effectiveness of quarterly or monthly fremanezumab in these populations. Ongoing studies are further exploring the potential benefits of fremanezumab in difficult-to-treat migraine and other headache and pain disorders.

Fayuvi (rebisufligene etisparvovec-hopf) for treatment of mucopolysaccharidosis type IIIA (Sanfilippo type A)

Courtesy of a colleague

The U.S. Food and Drug Administration today approved Fayuvi (rebisufligene etisparvovec-hopf), the first treatment for pediatric patients with mucopolysaccharidosis type IIIA (MPS IIIA), also known as Sanfilippo syndrome type A., MPS IIIA is a rare inherited disease that progressively damages the brain and nervous system, causing children to lose cognitive, language and other developmental abilities over time. Until today, treatment was limited to managing symptoms; there was no FDA-approved therapy designed to change the underlying course of the disease.

"The Trump Administration is committed to bringing safe and effective treatments to patients with the most urgent and unmet needs. The approval of Fayuvi marks a historic moment for children and families living with MPS IIIA, which is a disease that has, until now, offered no approved treatment to alter its devastating course,” said Acting FDA Commissioner Kyle Diamantas, J.D. “Gene therapy holds tremendous promise for rare diseases like Sanfilippo syndrome type A, and this milestone reflects the FDA's commitment to action.”

Fayuvi is a one-time, intravenous (given directly into a vein) gene therapy that uses a modified, non-infectious virus called an adeno-associated virus serotype 9 (AAV9) to deliver a working copy of the SGSH gene into the patient’s cells. This enables the body’s cells to produce sulfamidase — the enzyme that is missing or deficient in MPS IIIA — allowing heparan sulfate to be properly broken down in lysosomes and reducing its harmful buildup throughout the body and brain.

“For families living with Sanfilippo syndrome type A, the trajectory of this disease is heartbreaking — children who develop normally in their earliest years facing a relentless regression with no approved treatment to slow it. Parents and clinicians have been waiting far too long for an option,” said Karim Mikhail, B. Pharm., M.S., Director of the Center for Biologics Evaluation and Research. “Today’s approval of Fayuvi is a meaningful step forward — not only for these children and their families, but for the promise of gene therapy to address rare and devastating diseases where the need for safe and effective treatment is the most urgent.”

The safety and effectiveness of Fayuvi was evaluated in an open-label, single-arm, multicenter clinical study in pediatric patients with MPS IIIA. The study measured mean changes in cognitive scores in patients between the ages of 2 and 5 years. Fayuvi-treated patients maintained or improved cognitive function compared to an untreated historical control cohort — a meaningful divergence from the expected natural disease course of plateau and decline during this critical developmental window.

“Achieving meaningful neurodevelopmental benefit through a single intravenous administration represents a significant scientific milestone — demonstrating that systemic AAV9-mediated gene delivery can reach the central nervous system at therapeutically relevant levels in pediatric patients. This approval underscore OTP’s and FDA’s commitment to applying rigorous evidentiary standards as the field of gene therapy continues to advance,” said Megha Kaushal, M.D., M.Sc., Acting Deputy Director of the Office of Therapeutic Products.

The safety of Fayuvi was evaluated in pediatric patients who received a single intravenous infusion across clinical studies. The most commonly adverse reactions reported in more than 5% of patients were increases in liver enzymes (AST), nausea and vomiting, fever, decreased appetite, decreased white blood cell and platelet counts and increased amylase. Important safety warnings include the risk of thrombotic microangiopathy (TMA). As with other AAV-based gene therapies, there is a potential long-term risk that the inserted genetic material could integrate into the genome and potentially lead to tumor development.

Fayuvi is administered in a healthcare setting equipped to manage infusion reactions. All patients receive corticosteroid treatment beginning one day before the infusion and continuing for a minimum of eight weeks afterward.

Fayuvi was granted Orphan Drug and Fast Track, and Breakthrough Therapy designations. The FDA granted Fayuvi approval to Ultragenyx Pharmaceutical, Inc.

https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-pediatric-patients-sanfilippo-syndrome-type