Influenza-Associated Acute Necrotizing Encephalopathy (IA-ANE) Working Group; Silverman A, Walsh R, Santoro JD, Thomas K, Ballinger E, Fisher KS, Thomas AX, Appavu B, Kruer MC, Neilson D, Knoll J, Sharp AN, Edelman HE, Otallah S, Morgan A, Grzezulkowska A, Nguyen J, Rao LM, Hecht SM, Catalano L, Daigle H, Kronfol C, Wharton J, Adams D, Kalawi AZ, Kung M, Arellano JL, Smith L, Segal D, Feja K, Broomall E, Jayakar A, Arnold SR, Retallack H, Press CA, Gombolay G, McLaughlin MH, Kannan V, Thakkar K, Rezwan T, Hulfish E, Eid D, Meylor J, Peng D, Hurtado R, Nickerson T, Mandell I, Carbonell AU, Kerner-Rossi M, Jayaraman D, Davis M, Olivero R, Shah N, Osborne CM, Zhang B, Cortina C, Randolph AG, Rao S, LaRocca T, Van Haren KP, Wilson-Murphy M. Influenza-Associated Acute Necrotizing Encephalopathy in US Children. JAMA. 2025 Jul 30. doi: 10.1001/jama.2025.11534. Epub ahead of print. PMID: 40736730.
Abstract
Importance: Acute necrotizing encephalopathy (ANE) is a rare, but severe, neurologic condition for which epidemiologic and management data remain limited. During the 2024-2025 US influenza season, clinicians at large pediatric centers anecdotally reported an increased number of children with influenza-associated ANE, prompting this national investigation.
Objective: To understand the clinical presentation, interventions, and outcomes among US children diagnosed with influenza-associated ANE.
Design, setting, and participants: This study was a multicenter case series of children diagnosed with ANE with longitudinal follow-up. A call for cases was issued via academic societies, public health agencies, and by directly contacting pediatric specialists at 76 US academic centers, requesting cases between October 1, 2023, and May 30, 2025. Inclusion criteria required acute encephalopathy with radiologic evidence of acute thalamic injury and laboratory confirmation of influenza infection in individuals aged 21 years or younger.
Exposure: Influenza-associated ANE.
Main outcomes and measures: Presenting symptoms, vaccination history, laboratory and genetic findings, interventions, and clinical outcomes, including modified Rankin Scale score (0: no symptoms; 1-2: mild disability; 3-5: moderate to severe disability; 6: death), length of stay, and functional outcomes.
Results: Of 58 submitted cases, 41 cases (23 females; median age, 5 years [IQR, 2-8]) from 23 US hospitals met inclusion criteria. Thirty-one cases (76%) had no significant medical history; 5 (12%) were medically complex. Clinical presentation included fever in 38 patients (93%), encephalopathy in 41 (100%), and seizures in 28 (68%). Thirty-nine patients (95%) had influenza A (14 with A/H1pdm/2009, 7 with A/H3N2, and 18 with no subtype) and 2 had influenza B. Laboratory deviations included elevated liver enzymes (78%), thrombocytopenia (63%), and elevated cerebrospinal fluid protein (63%). Among 32 patients (78%) with genetic testing, 15 (47%) had genetic risk alleles potentially related to risk of ANE including 11 (34%) with RANBP2 variants. Among 38 patients with available vaccination history, only 6 (16%) had received age-appropriate seasonal influenza vaccination. Most patients received multiple immunomodulatory treatments, including methylprednisolone (95%), intravenous immunoglobulin (66%), tocilizumab (51%), plasmapheresis (32%), anakinra (5%), and intrathecal methylprednisolone (5%). Median intensive care unit and hospital lengths of stay were 11 days (IQR, 4-19) and 22 days (IQR, 7-36), respectively. Eleven patients (27%) died a median of 3 days (IQR, 2-4) from symptom onset, primarily from cerebral herniation (91%). Among the 27 survivors with 90-day follow-up, 63% had at least moderate disability (modified Rankin Scale score ≥3).
Conclusions and relevance: In this case series of children with influenza-associated ANE from the 2 most recent influenza seasons in the US, the condition was associated with high morbidity and mortality in this cohort of predominantly young and previously healthy children. The findings emphasize the need for prevention, early recognition, intensive treatment, and standardized management protocols.
Uyeki TM. Pediatric Influenza-Associated Acute Necrotizing Encephalopathy-Gaps Need to Be Addressed. JAMA. 2025 Jul 30. doi: 10.1001/jama.2025.13003. Epub ahead of print. PMID: 40737115.
Influenza is associated with a wide spectrum of respiratory and nonrespiratory complications, including neurologic manifestations, of variable disease severity. Influenza-associated encephalopathy (IAE) encompasses several clinical syndromes in which impaired consciousness and/or altered mental status and brain dysfunction may range from brief, mild, and self-limited to rapid progression to coma and death. The most severe clinical syndrome of IAE is acute necrotizing encephalopathy (ANE). Although thought to be rare, ANE has been associated with high mortality and high frequency of neurologic sequelae in survivors. Recently, consensus case definitions for ANE were proposed that include acute neurologic deterioration with neuroimaging findings of bilateral symmetric thalamic lesions and may also involve other areas of the brain such as the brainstem, cerebellum, and cerebral white matter. ANE can be triggered by multiple pathogens and has been described since the late 1970s in Japan, with some ANE cases identified during influenza epidemics. In the United States, pediatric deaths with IAE, and influenza-associated ANE (IANE) cases, have been reported, but no national surveillance exists for IAE or IANE.
Thursday, July 31, 2025
Wednesday, July 30, 2025
Hypomyelinating leukodystrophies
Takanashi JI. Magnetic resonance imaging and spectroscopy in hypomyelinating leukodystrophy. Brain Dev. 2025 Jun;47(3):104345. doi: 10.1016/j.braindev.2025.104345. Epub 2025 Apr 1. PMID: 40174481.
Abstract
Recent advancements in molecular biology and radiology have led to the identification of several new leukodystrophies. A key diagnostic feature of leukodystrophies is the increased white matter signal intensity observed on T2-weighted magnetic resonance (MR) images. Leukodystrophies are typically classified into two main categories: hypomyelinating leukodystrophies (HLD) and other forms, including demyelinating leukodystrophies. HLD is characterized by a primary defect in myelin due to genetic variants that affect structural myelin proteins, oligodendrocyte transcription factors, RNA translation, and lysosomal proteins. Radiologically, HLD tends to show less pronounced white matter hyperintensity on T2-weighted images than demyelinating leukodystrophies. A definitive diagnosis can often be made by identifying abnormalities in regions beyond the white matter, such as the basal ganglia or cerebellum, or through the presence of characteristic clinical symptoms. N-acetylaspartate, a neuroaxonal marker observed on MR spectroscopy, is typically reduced in many neurological conditions, but N-acetylaspartate levels often remain normal in HLD, which is considered a distinctive feature of this disorder. This article provides an overview of the latest imaging findings and clinical features associated with HLD.
Sharma S, Sundaram S, Kesavadas C, Thomas B. An Algorithmic Approach to MR Imaging of Hypomyelinating Leukodystrophies. J Magn Reson Imaging. 2025 Apr;61(4):1531-1551. doi: 10.1002/jmri.29558. Epub 2024 Aug 20. PMID: 39165110.
Abstract
Hypomyelinating leukodystrophies (HLDs) are a heterogeneous group of white matter diseases characterized by permanent deficiency of myelin deposition in brain. MRI is instrumental in the diagnosis and recommending genetic analysis, and is especially useful as many patients have a considerable clinical overlap, with the primary presenting complains being global developmental delay with psychomotor regression. Hypomyelination is defined as deficient myelination on two successive MR scans, taken at least 6 months apart, one of which should have been obtained after 1 year of age. Due to subtle differences in MRI features, the need for a systematic imaging approach to diagnose and classify hypomyelinating disorders is reiterated. The presented article provides an explicit review of imaging features of a myriad of primary and secondary HLDs, using state of the art genetically proven MR cases. A systematic pattern-based approach using MR features and specific clinical clues is illustrated for a quick yet optimal diagnosis of common as well as rare hypomyelinating disorders. The major MR features helping to narrow the differential diagnosis include extent of involvement like diffuse or patchy hypomyelination with selective involvement or sparing of certain white matter structures like optic radiations, median lemniscus, posterior limb of internal capsule and periventricular white matter; cerebellar atrophy; brainstem, corpus callosal or basal ganglia involvement; T2 hypointense signal of the thalami; and presence of calcifications. The authors also discuss the genetic and pathophysiologic basis of HLDs and recent methods to quantify myelin in vivo using advanced neuroradiology tools. The proposed algorithmic approach provides an improved understanding of these rare yet important disorders, enhancing diagnostic precision and improving patient outcomes. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 5.
Yan H, Ji H, Kubisiak T, Wu Y, Xiao J, Gu Q, Yang Y, Xie H, Ji T, Gao K, Li D, Xiong H, Shi Z, Li M, Zhang Y, Duan R, Bao X, Jiang Y, Burmeister M, Wang J. Genetic analysis of 20 patients with hypomyelinating leukodystrophy by trio-based whole-exome sequencing. J Hum Genet. 2021 Aug;66(8):761-768. doi: 10.1038/s10038-020-00896-5. Epub 2021 Feb 18. PMID: 33597727; PMCID: PMC8310791.
Abstract
Hypomyelinating leukodystrophies (HLDs) are a rare group of disorders characterized by myelin deficit of the brain-based on MRI. Here, we studied 20 patients with unexplained HLD to uncover their genetic etiology through whole-exome sequencing (WES). Trio-based WES was performed for 20 unresolved HLDs families after genetic tests for the PLP1 duplication and a panel of 115 known leukodystrophy-related genes. Variants in both known genes that related to HLDs and promising candidate genes were analyzed. Minigene splicing assay was conducted to confirm the effect of splice region variant. All 20 patients were diagnosed with HLDs clinically based on myelin deficit on MRI and impaired motor ability. Through WES, in 11 of 20 trios, 15 causative variants were detected in seven genes TUBB4A, POLR1C, POLR3A, SOX10, TMEM106B, DEGS1, and TMEM63A. The last three genes have just been discovered. Of 15 variants, six were novel. Using minigene splicing assay, splice variant POLR3A c.1770 + 5 G > C was proved to disrupt the normal splicing of intron 13 and led to a premature stop codon at position 618 (p.(P591Vfs*28)). Our analysis determined the molecular diagnosis of 11 HLDs patients. It emphasizes the heterogenicity of HLDs, the diagnostic power of trio-based WES for HLDs. Comprehensive analysis including a focus on candidate genes helps to discover novel disease-causing genes, determine the diagnosis for the first time, and improve the yield of WES. Moreover, novel mutations identified in TUBB4A, POLR3A, and POLR1C expand the mutation spectrum of these genes.
Abstract
Recent advancements in molecular biology and radiology have led to the identification of several new leukodystrophies. A key diagnostic feature of leukodystrophies is the increased white matter signal intensity observed on T2-weighted magnetic resonance (MR) images. Leukodystrophies are typically classified into two main categories: hypomyelinating leukodystrophies (HLD) and other forms, including demyelinating leukodystrophies. HLD is characterized by a primary defect in myelin due to genetic variants that affect structural myelin proteins, oligodendrocyte transcription factors, RNA translation, and lysosomal proteins. Radiologically, HLD tends to show less pronounced white matter hyperintensity on T2-weighted images than demyelinating leukodystrophies. A definitive diagnosis can often be made by identifying abnormalities in regions beyond the white matter, such as the basal ganglia or cerebellum, or through the presence of characteristic clinical symptoms. N-acetylaspartate, a neuroaxonal marker observed on MR spectroscopy, is typically reduced in many neurological conditions, but N-acetylaspartate levels often remain normal in HLD, which is considered a distinctive feature of this disorder. This article provides an overview of the latest imaging findings and clinical features associated with HLD.
Sharma S, Sundaram S, Kesavadas C, Thomas B. An Algorithmic Approach to MR Imaging of Hypomyelinating Leukodystrophies. J Magn Reson Imaging. 2025 Apr;61(4):1531-1551. doi: 10.1002/jmri.29558. Epub 2024 Aug 20. PMID: 39165110.
Abstract
Hypomyelinating leukodystrophies (HLDs) are a heterogeneous group of white matter diseases characterized by permanent deficiency of myelin deposition in brain. MRI is instrumental in the diagnosis and recommending genetic analysis, and is especially useful as many patients have a considerable clinical overlap, with the primary presenting complains being global developmental delay with psychomotor regression. Hypomyelination is defined as deficient myelination on two successive MR scans, taken at least 6 months apart, one of which should have been obtained after 1 year of age. Due to subtle differences in MRI features, the need for a systematic imaging approach to diagnose and classify hypomyelinating disorders is reiterated. The presented article provides an explicit review of imaging features of a myriad of primary and secondary HLDs, using state of the art genetically proven MR cases. A systematic pattern-based approach using MR features and specific clinical clues is illustrated for a quick yet optimal diagnosis of common as well as rare hypomyelinating disorders. The major MR features helping to narrow the differential diagnosis include extent of involvement like diffuse or patchy hypomyelination with selective involvement or sparing of certain white matter structures like optic radiations, median lemniscus, posterior limb of internal capsule and periventricular white matter; cerebellar atrophy; brainstem, corpus callosal or basal ganglia involvement; T2 hypointense signal of the thalami; and presence of calcifications. The authors also discuss the genetic and pathophysiologic basis of HLDs and recent methods to quantify myelin in vivo using advanced neuroradiology tools. The proposed algorithmic approach provides an improved understanding of these rare yet important disorders, enhancing diagnostic precision and improving patient outcomes. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 5.
Yan H, Ji H, Kubisiak T, Wu Y, Xiao J, Gu Q, Yang Y, Xie H, Ji T, Gao K, Li D, Xiong H, Shi Z, Li M, Zhang Y, Duan R, Bao X, Jiang Y, Burmeister M, Wang J. Genetic analysis of 20 patients with hypomyelinating leukodystrophy by trio-based whole-exome sequencing. J Hum Genet. 2021 Aug;66(8):761-768. doi: 10.1038/s10038-020-00896-5. Epub 2021 Feb 18. PMID: 33597727; PMCID: PMC8310791.
Abstract
Hypomyelinating leukodystrophies (HLDs) are a rare group of disorders characterized by myelin deficit of the brain-based on MRI. Here, we studied 20 patients with unexplained HLD to uncover their genetic etiology through whole-exome sequencing (WES). Trio-based WES was performed for 20 unresolved HLDs families after genetic tests for the PLP1 duplication and a panel of 115 known leukodystrophy-related genes. Variants in both known genes that related to HLDs and promising candidate genes were analyzed. Minigene splicing assay was conducted to confirm the effect of splice region variant. All 20 patients were diagnosed with HLDs clinically based on myelin deficit on MRI and impaired motor ability. Through WES, in 11 of 20 trios, 15 causative variants were detected in seven genes TUBB4A, POLR1C, POLR3A, SOX10, TMEM106B, DEGS1, and TMEM63A. The last three genes have just been discovered. Of 15 variants, six were novel. Using minigene splicing assay, splice variant POLR3A c.1770 + 5 G > C was proved to disrupt the normal splicing of intron 13 and led to a premature stop codon at position 618 (p.(P591Vfs*28)). Our analysis determined the molecular diagnosis of 11 HLDs patients. It emphasizes the heterogenicity of HLDs, the diagnostic power of trio-based WES for HLDs. Comprehensive analysis including a focus on candidate genes helps to discover novel disease-causing genes, determine the diagnosis for the first time, and improve the yield of WES. Moreover, novel mutations identified in TUBB4A, POLR3A, and POLR1C expand the mutation spectrum of these genes.
Locked in syndrome 2
Gareth Bayley had a stroke in his brain stem when he was 38 — triggering locked-in syndrome, a devastating condition that his wife Karen explains as being "trapped in his own body”
Those with locked-in syndrome are fully mentally present but usually can’t move or speak; Gareth has regained limited movement
Karen is now raising money for an innovative stationary bike that could help him progress even further: “The goal is to have him back home again,” she says
A young father of two’s devastating stroke led to locked-in syndrome — a heartbreaking condition where you’re conscious, but can’t move — but his wife says there may be a treatment that can help him regain his “independence and dignity.”
Gareth Bayley was just 38 when, in April 2022, he began to struggle with headaches every day for a week. The construction professional, who hails from the London suburb of Bexley, chalked it up to stress — but then he called his wife, Karen, to share that he didn’t feel well. She hurried to his job, where she’d learned he’d collapsed and had a seizure, according to Daily Mail.
Gareth continued to have seizures on the way to the hospital, where the next day, doctors confirmed he’d had a stroke in his brain stem. It triggered locked-in syndrome, a devastating condition where someone is fully conscious, but cannot move or speak. It’s rare, but as the Stroke Association explains, it’s usually caused by a stroke in the brain stem.
“He is still him — he's fully there and remembers everything. It's just he can't speak or move. It's like he's trapped in his own body. Doctors told us he would likely never move again, apart from slight eye movements,” Karen said.
“Gareth is a fighter," she continued. "Over the past three years, he has regained some movement: he smiles, he laughs, and his expressions have returned in ways we were told might never happen."
That progress has been encouraging, Karen explains, and inspired them to raise money for a functional electrical stimulation (FES) bike. It’s a personalized stationary bike that sends electrical impulses to paralyzed muscles to help them regain function, per the Christopher and Dana Reeve Foundation.
“We did try to get it funded as he is in a care home, but because it was so expensive, the funding got refused as it wasn't deemed an 'essential piece of equipment.' But to us, it is essential. If I can get him this bike, it will be amazing,” said Karen, who is raising money to purchase the bike via GoFundMe. On the fundraiser, she explains, “Gareth is a fighter. He has regained some head movement, he smiles, he laughs, and his expressions have returned in ways we were told might never happen. Every small step forward has given us hope that more recovery is possible … Every day, Gareth wakes up determined to keep fighting.”
Karen, who shares children Brooke and Jesse with Gareth, explained further that “It would help increase his muscle strength, prevent pressure sores, improve the movement range with his arms and legs, help his joint mobility, and help his muscle spasms,” per Daily Mail. “It could give Gareth the best possible chance at further recovery, independence, and dignity.”
Although he’s currently in a care home, “My husband has expressed that he wants to come home and be with me and the children again,” she said. “The goal is to have him back home again.”
Cara Lynn Shultz
https://people.com/dad-38-stroke-locked-in-syndrome-trapped-in-his-own-body-11780042
Jake Haendel had “everything going for him.” He was newly married and working as a head executive chef in Boston when he received a devastating and life-changing diagnosis.
In May 2017, Haendel noticed that his voice started to become higher pitched than normal. Initially brushing it off, it wasn’t until he started having balance issues that he decided to visit the emergency room on Memorial Day weekend.
Doctors believed he was having stroke-like symptoms, so he was admitted and given IV fluids. Haendel, now 36, had been to the hospital many times before and expected to be monitored for a few hours and then simply sent home with antibiotics. And he was right.
“They were actually about to discharge me when my wife came in and said, ‘You cannot discharge him. This is not my husband.’ She played an old voicemail for them. My voice and the voice I had been using were completely different,” he tells PEOPLE. “So the doctors and nurses and emergency room staff were like, ‘Whoa,’ and ordered an emergency MRI.”
One day later, Haendel was diagnosed with acute toxic leukoencephalopathy (ATL), a rare and often fatal brain disease caused by exposure to toxic substances. He was given six months to live.
“I woke up and there was a whole team of people in the room,” he recalls. “A doctor was sitting on the foot of my bed, put his hand on my knee and was like, ‘Jacob, we're extremely sorry. You have a rare terminal and progressive brain illness.'”
Haendel immediately thought about his late mother, who died of breast cancer when he was 19. He remembered watching her struggle to fight the disease for 10 years before her death, a time where he struggled mentally and turned to drugs to cope.
Doctors told Haendel that in his case, the ATL was attributed to that past substance abuse. “I literally said out loud, ‘I am f—ed.’ My first thought was how disappointed my mom would be in me,” he says. “There were very powerful emotions all at once.”
“I told my wife, ‘I watched my mom die. You shouldn't have to watch me die,’” he adds.
After revealing his diagnosis, doctors pulled out a whiteboard and broke down exactly how Haendel’s disease was expected to progress. The first month he wouldn’t be able to walk, even with the help of assistive devices. Month two, he would be confined to a wheelchair until he’s unable to tolerate it due to chronic pain. By month three, he would be bedridden and lose the ability to eat, swallow and talk. In the fourth and final stage of the disease, he would slip into a coma and eventually die.
“And no one had ever survived stage four,” Haendel says.
Unfortunately, Haendel’s doctors were “right on the money with that timeframe,” and his health took a turn for the worst. “I underestimated the amount of pain I would be in,” he admits, comparing his body to a car that’s gone haywire.
By November, Haendel’s speech was fully gone. He was admitted to the neuro ICU at Massachusetts General Hospital as he continued to deteriorate. Around this time, he slipped into what doctors believed was a coma, which was consistent with the natural progression of the disease.
December 1, 2017 was the first time he heard someone refer to him as brain dead.
“One of the doctors told my wife, ‘We're really sorry Mrs. Haendel, but your husband will not make it to Christmas.’ In my head, I was bummed because I had no illusion that I was going to die. But I'm in so much pain that it was also a relief that this constant struggle was going to be over,” he explains.
“But then I heard them say I was brain dead and it's time to start considering withdrawing life support. I was contemplating, am I brain dead? How can I think, how do I have memories?” he continues. “So even though I was having those thoughts that this is going to be over soon, I was like, ‘Oh, don't do that, I'm still in here.’”
Haendel appeared to be in a vegetative state. However, unknown to his doctors, his disease triggered locked-in syndrome, a rare and serious neurological disorder where damage to the brain stem leads to complete paralysis over all voluntary muscles except for the ones that control the eyes, according to the National Organization for Rare Disorders (NORD). While he can still feel touch, pain, an itch and other sensations, and he is entirely aware of his environment and surroundings, Haendel is “locked” inside his body, as the name of the syndrome implies.
“It was the worst you can imagine,” he explains. “It was like being a prisoner in solitary confinement, but worse. You're totally paralyzed, you can't move, talk or signal. I was just talking to myself in my head. It was more of survival to keep my brain going and kind of talk myself out of a full panic attack.”
“Everything in my body was failing and the one thing that seemed to be fully intact was my brain, which is always strange to me considering I had a brain illness and the damage was really catastrophic,” he adds.
Haendel remained in this state for 10 months, which he recalls being a brutal time. He was transferred to hospice care; however, he was eventually admitted back to the hospital because insurance only covered six months of care.
“I wasn't dying, but I wasn't getting better, which was a frightening thought,” he shares. “I kept overhearing them say I wouldn't make it out of this state. And I was like, ‘Oh my god. I could be stuck like this forever,’ which was actually more terrifying than dying.”
In June 2018, Haendel was transferred from hospice care back to Mass Gen’s neuro ICU. While there, he experienced the first glimpse of hope that he’d come out of locked-in syndrome.
“Around 4th of July, I heard the familiar voice of Dr. Levinson, who was in charge of my complex care. He was like, ‘You guys see that? He's moving something.’ And the other doctors were like, ‘No, that's involuntary.’”
“It was the first time medical staff had talked to me directly in a while. He just said, ‘Hey, I don't know if you can hear me, but if you can, do that again.’ I kind of had this rush go through me and I was like, ‘Wow, this is my one and only shot. I don't even know what I moved, but just do something,’” he recalls. “I tensed up my entire body and I didn't think it was working, but then I heard, ‘Wow, he is actually doing it.’”
Haendel’s doctors immediately brought in a specialist in nonverbal augmented speech therapy, who started working with him regularly to relearn how to blink. Over the next two weeks, he was able to blink. Medical staff then created a system where he was able to communicate yes and no by blinking and sticking out his tongue, which eventually progressed to him using a letter board to create sentences. “The first thing I spelled out was, ‘I can hear you,’” he says.
One day, Haendel recalls overhearing a conversation about moving him to a rehabilitation facility.
“I heard crosstalk of how I wouldn't be accepted because I can't participate in the mandatory three hours of physical, occupational and speech therapy. I could only participate in speech. I started freaking out. I heard my heart machine going off.”
“They were like, ‘Calm down, calm down. Do you want to use the letter board?’ And I just spelled out ‘I can do three hours.’ I heard them say, ‘Oh my God, he's actually tracking our conversations.’ And that was really the moment they realized how intact I was. And that was when I first felt like, okay, they actually know I'm in here.”
Days later Haendel was transferred to Spaulding Rehabilitation Hospital in Boston. “It was very motivating for me and at that point I was like, I am going to do everything in my power to get out of this.”
The next few years were a “very grueling, slow process,” as Haendel went through intense therapy retraining his brain to communicate with his body at Western Massachusetts Hospital.
“I thought I'd been through the worst. Not that it was any worse than being locked in, but it was a new type of pain that I hadn't experienced,” he explains on his recovery. “It was quite bad, but I kept telling myself if you want to get out of the hospital, if you want to have a life again, this is what it takes.”
By 2019, Haendel started coming out of his paralysis and making baby sounds. The following year, he started talking in sentences and was able to get out of bed and into a wheelchair for the first time.
In December 2020, he officially returned home and has since been doing outpatient therapy, which he will continue as his recovery remains ongoing.
“Now, I'm walking with a walker at home. I can also transfer in and out of cars. I navigate my community on a scooter, but in therapy I'm using a cane. I can also feed myself and hydrate myself,” he says. “In 2021, I was still not able to take care of myself whatsoever. And in the last year I've been able to take care of myself.”
Haendel, who is now divorced, says it’s unbelievable that he’s come so far in his recovery. He’s been sharing his journey on social media to help others understand the importance of determination when things get tough. The 36-year-old also co-founded an accessibility-focused app, Ahoi, which helps users find places that meet their specific needs like accessible parking, entry ramps, elevators, automatic doors, etc.
“I have such a different perspective on what's important in life. And going through what I went through has definitely made me stronger,” he tells PEOPLE. “It feels amazing and a big part of why I'm telling my story and have this company is to help people and help the world.”
“I want people to not give up in recovery when they hear they have terminal disease,” Haendel says. “That's a lot of what I want to do with my life now is just help and motivate people.”
Vanessa Etienne
https://people.com/man-declared-brain-dead-talks-locked-in-syndrome-recovery-exclusive-8740104
Mike Dils’ slurred words and weakness that led his wife, Cheryl, to take him to the urgent care clinic on Feb. 4, 2012, gave them no hint of what was to come.
In the waiting room he passed out. After EMTs revived him, he flatlined at the hospital. Within hours the vibrant realtor, then 64, was unable to move, breathe or speak on his own. He became the paralyzed victim of a stroke. In the days that followed, Cheryl says she struggled with whether to sign a do-not-resuscitate order: “The doctors told me there was zero hope,” she tells PEOPLE.
Mike heard it all, including his family wrestling over what to do with him. “You can’t imagine how desperate that is, being 100 percent of sound mind and not being able to convey that—while outside, people are telling you you’re a goner,” he says. “I was a prisoner in my own body.”
Then, after a doctor confirmed the dire diagnosis, Mike’s daughter Cheyenne, then 20, noticed tears in her father’s eyes.
“Can you understand us?” Cheyenne suddenly asked Mike. Abruptly she proposed going through the alphabet letter by letter, telling her dad to blink on the letters he needed to get his message out. In the breathless minutes that followed, he spelled out “NO HOPE.”
Watch People Features: Mike Dils – I Was A Prisoner Inside My Body, available now, on PeopleTV. Go to PeopleTV.com, or download the PeopleTV app on your favorite mobile or connected TV device.
That turned the startled family around. “There’s always hope,” Cheyenne told him. “If you want to get through this, we’ll help you.
Mike and his medical team now believe the stroke had caused locked-in syndrome, a rare condition where damage to the brain stem prevents it from being able to direct the body’s movements. “The reason [the diagnosis] is missed is because patients look for all the world like they’re in a coma,” says Dr. Karen Hirsch, a neurocritical care specialist. “If no one tests their vertical eye movement and responsiveness to commands, there aren’t a lot of other ways to know that they’re conscious.”
Five years later—following months of painstakingly blinking out messages, intensive physical therapy and Mike’s own determination to retrain his brain to communicate with his body— he has regained his ability to talk, walk and even drive on his own.
“When you hear about recovery, what it usually means is that the person was able to take the surviving circuits and squeeze some new behaviors out of them,” says Dr. Steve Cramer, a University of California-Irvine neurologist, who attributes Mike’s rebound to the brain’s innate ability to find work-arounds—and also to Mike’s optimism, strong social support and Type-A drive. (At one point, Mike had Cheryl buy him hundreds of tennis balls that he tossed for hours on end into a trash can, to improve his hand-eye coordination.) “He was able to cross a goal line few others have,” Cramer says.
Adds Cheryl, 50, a hairdresser: “It’s just amazing, that’s all I can say.”
Mike, 70, who returned home six months after his stroke and now moves easily with a walker, works out daily on exercise equipment and spends hours in his garage wood shop, looks ahead to the day he believes he will walk unassisted. He holds no animosity for doctors who told his family he was unlikely to recover.
“I know in their own minds they thought I couldn’t feel anything, that I was frozen in time and that’s the way I was going to die,” he says. He wants to encourage others “not to throw in the towel.”
“He has an incredible message to share,” says Cheryl. “He’s certainly made an incredible difference in my life.”
Those with locked-in syndrome are fully mentally present but usually can’t move or speak; Gareth has regained limited movement
Karen is now raising money for an innovative stationary bike that could help him progress even further: “The goal is to have him back home again,” she says
A young father of two’s devastating stroke led to locked-in syndrome — a heartbreaking condition where you’re conscious, but can’t move — but his wife says there may be a treatment that can help him regain his “independence and dignity.”
Gareth Bayley was just 38 when, in April 2022, he began to struggle with headaches every day for a week. The construction professional, who hails from the London suburb of Bexley, chalked it up to stress — but then he called his wife, Karen, to share that he didn’t feel well. She hurried to his job, where she’d learned he’d collapsed and had a seizure, according to Daily Mail.
Gareth continued to have seizures on the way to the hospital, where the next day, doctors confirmed he’d had a stroke in his brain stem. It triggered locked-in syndrome, a devastating condition where someone is fully conscious, but cannot move or speak. It’s rare, but as the Stroke Association explains, it’s usually caused by a stroke in the brain stem.
“He is still him — he's fully there and remembers everything. It's just he can't speak or move. It's like he's trapped in his own body. Doctors told us he would likely never move again, apart from slight eye movements,” Karen said.
“Gareth is a fighter," she continued. "Over the past three years, he has regained some movement: he smiles, he laughs, and his expressions have returned in ways we were told might never happen."
That progress has been encouraging, Karen explains, and inspired them to raise money for a functional electrical stimulation (FES) bike. It’s a personalized stationary bike that sends electrical impulses to paralyzed muscles to help them regain function, per the Christopher and Dana Reeve Foundation.
“We did try to get it funded as he is in a care home, but because it was so expensive, the funding got refused as it wasn't deemed an 'essential piece of equipment.' But to us, it is essential. If I can get him this bike, it will be amazing,” said Karen, who is raising money to purchase the bike via GoFundMe. On the fundraiser, she explains, “Gareth is a fighter. He has regained some head movement, he smiles, he laughs, and his expressions have returned in ways we were told might never happen. Every small step forward has given us hope that more recovery is possible … Every day, Gareth wakes up determined to keep fighting.”
Karen, who shares children Brooke and Jesse with Gareth, explained further that “It would help increase his muscle strength, prevent pressure sores, improve the movement range with his arms and legs, help his joint mobility, and help his muscle spasms,” per Daily Mail. “It could give Gareth the best possible chance at further recovery, independence, and dignity.”
Although he’s currently in a care home, “My husband has expressed that he wants to come home and be with me and the children again,” she said. “The goal is to have him back home again.”
Cara Lynn Shultz
https://people.com/dad-38-stroke-locked-in-syndrome-trapped-in-his-own-body-11780042
Jake Haendel had “everything going for him.” He was newly married and working as a head executive chef in Boston when he received a devastating and life-changing diagnosis.
In May 2017, Haendel noticed that his voice started to become higher pitched than normal. Initially brushing it off, it wasn’t until he started having balance issues that he decided to visit the emergency room on Memorial Day weekend.
Doctors believed he was having stroke-like symptoms, so he was admitted and given IV fluids. Haendel, now 36, had been to the hospital many times before and expected to be monitored for a few hours and then simply sent home with antibiotics. And he was right.
“They were actually about to discharge me when my wife came in and said, ‘You cannot discharge him. This is not my husband.’ She played an old voicemail for them. My voice and the voice I had been using were completely different,” he tells PEOPLE. “So the doctors and nurses and emergency room staff were like, ‘Whoa,’ and ordered an emergency MRI.”
One day later, Haendel was diagnosed with acute toxic leukoencephalopathy (ATL), a rare and often fatal brain disease caused by exposure to toxic substances. He was given six months to live.
“I woke up and there was a whole team of people in the room,” he recalls. “A doctor was sitting on the foot of my bed, put his hand on my knee and was like, ‘Jacob, we're extremely sorry. You have a rare terminal and progressive brain illness.'”
Haendel immediately thought about his late mother, who died of breast cancer when he was 19. He remembered watching her struggle to fight the disease for 10 years before her death, a time where he struggled mentally and turned to drugs to cope.
Doctors told Haendel that in his case, the ATL was attributed to that past substance abuse. “I literally said out loud, ‘I am f—ed.’ My first thought was how disappointed my mom would be in me,” he says. “There were very powerful emotions all at once.”
“I told my wife, ‘I watched my mom die. You shouldn't have to watch me die,’” he adds.
After revealing his diagnosis, doctors pulled out a whiteboard and broke down exactly how Haendel’s disease was expected to progress. The first month he wouldn’t be able to walk, even with the help of assistive devices. Month two, he would be confined to a wheelchair until he’s unable to tolerate it due to chronic pain. By month three, he would be bedridden and lose the ability to eat, swallow and talk. In the fourth and final stage of the disease, he would slip into a coma and eventually die.
“And no one had ever survived stage four,” Haendel says.
Unfortunately, Haendel’s doctors were “right on the money with that timeframe,” and his health took a turn for the worst. “I underestimated the amount of pain I would be in,” he admits, comparing his body to a car that’s gone haywire.
By November, Haendel’s speech was fully gone. He was admitted to the neuro ICU at Massachusetts General Hospital as he continued to deteriorate. Around this time, he slipped into what doctors believed was a coma, which was consistent with the natural progression of the disease.
December 1, 2017 was the first time he heard someone refer to him as brain dead.
“One of the doctors told my wife, ‘We're really sorry Mrs. Haendel, but your husband will not make it to Christmas.’ In my head, I was bummed because I had no illusion that I was going to die. But I'm in so much pain that it was also a relief that this constant struggle was going to be over,” he explains.
“But then I heard them say I was brain dead and it's time to start considering withdrawing life support. I was contemplating, am I brain dead? How can I think, how do I have memories?” he continues. “So even though I was having those thoughts that this is going to be over soon, I was like, ‘Oh, don't do that, I'm still in here.’”
Haendel appeared to be in a vegetative state. However, unknown to his doctors, his disease triggered locked-in syndrome, a rare and serious neurological disorder where damage to the brain stem leads to complete paralysis over all voluntary muscles except for the ones that control the eyes, according to the National Organization for Rare Disorders (NORD). While he can still feel touch, pain, an itch and other sensations, and he is entirely aware of his environment and surroundings, Haendel is “locked” inside his body, as the name of the syndrome implies.
“It was the worst you can imagine,” he explains. “It was like being a prisoner in solitary confinement, but worse. You're totally paralyzed, you can't move, talk or signal. I was just talking to myself in my head. It was more of survival to keep my brain going and kind of talk myself out of a full panic attack.”
“Everything in my body was failing and the one thing that seemed to be fully intact was my brain, which is always strange to me considering I had a brain illness and the damage was really catastrophic,” he adds.
Haendel remained in this state for 10 months, which he recalls being a brutal time. He was transferred to hospice care; however, he was eventually admitted back to the hospital because insurance only covered six months of care.
“I wasn't dying, but I wasn't getting better, which was a frightening thought,” he shares. “I kept overhearing them say I wouldn't make it out of this state. And I was like, ‘Oh my god. I could be stuck like this forever,’ which was actually more terrifying than dying.”
In June 2018, Haendel was transferred from hospice care back to Mass Gen’s neuro ICU. While there, he experienced the first glimpse of hope that he’d come out of locked-in syndrome.
“Around 4th of July, I heard the familiar voice of Dr. Levinson, who was in charge of my complex care. He was like, ‘You guys see that? He's moving something.’ And the other doctors were like, ‘No, that's involuntary.’”
“It was the first time medical staff had talked to me directly in a while. He just said, ‘Hey, I don't know if you can hear me, but if you can, do that again.’ I kind of had this rush go through me and I was like, ‘Wow, this is my one and only shot. I don't even know what I moved, but just do something,’” he recalls. “I tensed up my entire body and I didn't think it was working, but then I heard, ‘Wow, he is actually doing it.’”
Haendel’s doctors immediately brought in a specialist in nonverbal augmented speech therapy, who started working with him regularly to relearn how to blink. Over the next two weeks, he was able to blink. Medical staff then created a system where he was able to communicate yes and no by blinking and sticking out his tongue, which eventually progressed to him using a letter board to create sentences. “The first thing I spelled out was, ‘I can hear you,’” he says.
One day, Haendel recalls overhearing a conversation about moving him to a rehabilitation facility.
“I heard crosstalk of how I wouldn't be accepted because I can't participate in the mandatory three hours of physical, occupational and speech therapy. I could only participate in speech. I started freaking out. I heard my heart machine going off.”
“They were like, ‘Calm down, calm down. Do you want to use the letter board?’ And I just spelled out ‘I can do three hours.’ I heard them say, ‘Oh my God, he's actually tracking our conversations.’ And that was really the moment they realized how intact I was. And that was when I first felt like, okay, they actually know I'm in here.”
Days later Haendel was transferred to Spaulding Rehabilitation Hospital in Boston. “It was very motivating for me and at that point I was like, I am going to do everything in my power to get out of this.”
The next few years were a “very grueling, slow process,” as Haendel went through intense therapy retraining his brain to communicate with his body at Western Massachusetts Hospital.
“I thought I'd been through the worst. Not that it was any worse than being locked in, but it was a new type of pain that I hadn't experienced,” he explains on his recovery. “It was quite bad, but I kept telling myself if you want to get out of the hospital, if you want to have a life again, this is what it takes.”
By 2019, Haendel started coming out of his paralysis and making baby sounds. The following year, he started talking in sentences and was able to get out of bed and into a wheelchair for the first time.
In December 2020, he officially returned home and has since been doing outpatient therapy, which he will continue as his recovery remains ongoing.
“Now, I'm walking with a walker at home. I can also transfer in and out of cars. I navigate my community on a scooter, but in therapy I'm using a cane. I can also feed myself and hydrate myself,” he says. “In 2021, I was still not able to take care of myself whatsoever. And in the last year I've been able to take care of myself.”
Haendel, who is now divorced, says it’s unbelievable that he’s come so far in his recovery. He’s been sharing his journey on social media to help others understand the importance of determination when things get tough. The 36-year-old also co-founded an accessibility-focused app, Ahoi, which helps users find places that meet their specific needs like accessible parking, entry ramps, elevators, automatic doors, etc.
“I have such a different perspective on what's important in life. And going through what I went through has definitely made me stronger,” he tells PEOPLE. “It feels amazing and a big part of why I'm telling my story and have this company is to help people and help the world.”
“I want people to not give up in recovery when they hear they have terminal disease,” Haendel says. “That's a lot of what I want to do with my life now is just help and motivate people.”
Vanessa Etienne
https://people.com/man-declared-brain-dead-talks-locked-in-syndrome-recovery-exclusive-8740104
Mike Dils’ slurred words and weakness that led his wife, Cheryl, to take him to the urgent care clinic on Feb. 4, 2012, gave them no hint of what was to come.
In the waiting room he passed out. After EMTs revived him, he flatlined at the hospital. Within hours the vibrant realtor, then 64, was unable to move, breathe or speak on his own. He became the paralyzed victim of a stroke. In the days that followed, Cheryl says she struggled with whether to sign a do-not-resuscitate order: “The doctors told me there was zero hope,” she tells PEOPLE.
Mike heard it all, including his family wrestling over what to do with him. “You can’t imagine how desperate that is, being 100 percent of sound mind and not being able to convey that—while outside, people are telling you you’re a goner,” he says. “I was a prisoner in my own body.”
Then, after a doctor confirmed the dire diagnosis, Mike’s daughter Cheyenne, then 20, noticed tears in her father’s eyes.
“Can you understand us?” Cheyenne suddenly asked Mike. Abruptly she proposed going through the alphabet letter by letter, telling her dad to blink on the letters he needed to get his message out. In the breathless minutes that followed, he spelled out “NO HOPE.”
Watch People Features: Mike Dils – I Was A Prisoner Inside My Body, available now, on PeopleTV. Go to PeopleTV.com, or download the PeopleTV app on your favorite mobile or connected TV device.
That turned the startled family around. “There’s always hope,” Cheyenne told him. “If you want to get through this, we’ll help you.
Mike and his medical team now believe the stroke had caused locked-in syndrome, a rare condition where damage to the brain stem prevents it from being able to direct the body’s movements. “The reason [the diagnosis] is missed is because patients look for all the world like they’re in a coma,” says Dr. Karen Hirsch, a neurocritical care specialist. “If no one tests their vertical eye movement and responsiveness to commands, there aren’t a lot of other ways to know that they’re conscious.”
Five years later—following months of painstakingly blinking out messages, intensive physical therapy and Mike’s own determination to retrain his brain to communicate with his body— he has regained his ability to talk, walk and even drive on his own.
“When you hear about recovery, what it usually means is that the person was able to take the surviving circuits and squeeze some new behaviors out of them,” says Dr. Steve Cramer, a University of California-Irvine neurologist, who attributes Mike’s rebound to the brain’s innate ability to find work-arounds—and also to Mike’s optimism, strong social support and Type-A drive. (At one point, Mike had Cheryl buy him hundreds of tennis balls that he tossed for hours on end into a trash can, to improve his hand-eye coordination.) “He was able to cross a goal line few others have,” Cramer says.
Adds Cheryl, 50, a hairdresser: “It’s just amazing, that’s all I can say.”
Mike, 70, who returned home six months after his stroke and now moves easily with a walker, works out daily on exercise equipment and spends hours in his garage wood shop, looks ahead to the day he believes he will walk unassisted. He holds no animosity for doctors who told his family he was unlikely to recover.
“I know in their own minds they thought I couldn’t feel anything, that I was frozen in time and that’s the way I was going to die,” he says. He wants to encourage others “not to throw in the towel.”
“He has an incredible message to share,” says Cheryl. “He’s certainly made an incredible difference in my life.”
Jeff Truesdell
https://people.com/human-interest/one-mans-recovery-locked-in-syndrome/
https://people.com/human-interest/one-mans-recovery-locked-in-syndrome/
Monday, July 28, 2025
Extreme prematurity
Earlier this month, Nash — affectionately nicknamed "Nash Potato" — turned 1 year old, defying all odds.
When he was born at the University of Iowa Health Care Stead Family Children’s Hospital, Nash weighed just 285 grams (10 ounces) at birth — less than a grapefruit — and measured 24 centimeters long, according to a press release from the hospital.
Nash Keen is pictured at 1 month old with his mother, Mollie Keen. He was born 133 days early, at just 21 weeks gestation. (University of Iowa Health Care Stead Family Children’s Hospital)
Two years before Nash’s premature birth, the Keens lost a baby girl, McKinley, at 18 weeks gestation.
At that time, Mollie Keen was diagnosed with an incompetent cervix, which is when the lower part of the cervix begins to open (dilate) too early, typically in the second trimester, the release shared.
She also suffers from polycystic ovary syndrome (PCOS), a hormonal disorder that can cause fertility difficulties.
Six months after their loss, the Keens found out another baby was on the way.
"When we went to our local doctor’s office for the 20-week scan for Nash, I just had some concerns about how I was feeling, so I asked them to look at me closer — which they normally don’t do at that appointment — and they found I was already 2 centimeters dilated," Mollie Keen said.
A few days later, she began having contractions and was placed on bed rest.
"We were devastated," she said. "We thought we were going through the exact same thing — we thought we were going to lose this baby."
The medical team at Stead Family Children’s Hospital’s neonatal intensive care unit (NICU) provides life-saving care for babies born at 21 weeks gestation and later.
Fortunately, Mollie’s care team was able to delay labor until just 10 hours after Nash surpassed the 21-week mark.
"We want what is best for patients, so we really try to convey that we do not know what the outcomes will be for these extremely premature births," said Malinda Schaefer, M.D., Ph.D., the high-risk obstetrician who delivered Nash.
"It is important for parents to understand most survival rates are low, and if babies do survive, they have a very high risk of long-term complications, even at 22 weeks."
The team quickly provided medicine to Nash to support his organ development and to reduce the risk of complications, according to the release.
"Sometimes babies born at 21 weeks are just too small for even our tiniest breathing tubes and intravenous lines," said neonatologist Amy Stanford, who treated Nash. "Our NICU team assessed Nash, and I was able to place a breathing tube. Once we had the breathing tube in, his heart rate stabilized and his oxygen levels were good."
Even so, Nash’s chances were slim, as no baby that young had ever survived.
Before Nash's birth, the most premature baby to survive was Curtis Zy-Keith Means, born to Michelle Butler on July 5, 2020, at the University of Alabama at Birmingham Hospital, according to Guinness World Records. He was born at a gestational age of 21 weeks and 1 day, which was 132 days premature.
"We never want the parents to lose hope, but many of them are in an unreal situation, so we have to be very honest with them," said Patrick McNamara, M.D., division director of neonatology at Stead Family Children’s Hospital.
"I would have told his parents, ‘The chance is zero, but I hope I'm wrong, and we will do everything we can to help him.’"
"I want him to see his story as a source of strength."
Around the one-month mark, Stanford said, the team began to "breathe a little easier."
"While we knew Nash still had a long journey ahead, that was the point when we started to feel more confident that he had a real chance of going home."
"It was a subtle but powerful shift – from day-to-day survival to long-term hope."
Nash received ongoing care during his 198 days in the hospital, as the team monitored his heart function and brain health.
In addition to receiving many medications, he also underwent surgery for a perforated bowel, which has up to a 40% mortality rate.
"They were on top of it every step of the way. They really gave him a fighting chance," said Randall Keen. "They were really honest with us during the whole journey about what his chances looked like. They made sure we were well-informed and kept us involved in all the decision-making."
After more than six months in the hospital, Nash was finally able to go home in January 2025.
Although he has had some developmental delays, Nash is getting stronger and more interactive with the help of ongoing therapy sessions, according to his mother.
Stanford shared her ultimate goal for Nash — "that by the time he's 5 years old when he goes to kindergarten, no one will know that he was born so early."
"Nash’s remarkable outcome reflects the progress we've made by building on the experiences of those patients who came before him," she added.
Mollie Keen shared that she wants Nash to know how loved he is — and "how many people have cheered him on from the very beginning."
"I want him to grow up and be healthy, happy and confident in who he is. I want him to see his story as a source of strength."
Melissa Rudy
https://www.foxnews.com/health/worlds-most-premature-baby-defies-all-medical-odds-reach-1st-birthday
When he was born at the University of Iowa Health Care Stead Family Children’s Hospital, Nash weighed just 285 grams (10 ounces) at birth — less than a grapefruit — and measured 24 centimeters long, according to a press release from the hospital.
Nash Keen is pictured at 1 month old with his mother, Mollie Keen. He was born 133 days early, at just 21 weeks gestation. (University of Iowa Health Care Stead Family Children’s Hospital)
Two years before Nash’s premature birth, the Keens lost a baby girl, McKinley, at 18 weeks gestation.
At that time, Mollie Keen was diagnosed with an incompetent cervix, which is when the lower part of the cervix begins to open (dilate) too early, typically in the second trimester, the release shared.
She also suffers from polycystic ovary syndrome (PCOS), a hormonal disorder that can cause fertility difficulties.
Six months after their loss, the Keens found out another baby was on the way.
"When we went to our local doctor’s office for the 20-week scan for Nash, I just had some concerns about how I was feeling, so I asked them to look at me closer — which they normally don’t do at that appointment — and they found I was already 2 centimeters dilated," Mollie Keen said.
A few days later, she began having contractions and was placed on bed rest.
"We were devastated," she said. "We thought we were going through the exact same thing — we thought we were going to lose this baby."
The medical team at Stead Family Children’s Hospital’s neonatal intensive care unit (NICU) provides life-saving care for babies born at 21 weeks gestation and later.
Fortunately, Mollie’s care team was able to delay labor until just 10 hours after Nash surpassed the 21-week mark.
"We want what is best for patients, so we really try to convey that we do not know what the outcomes will be for these extremely premature births," said Malinda Schaefer, M.D., Ph.D., the high-risk obstetrician who delivered Nash.
"It is important for parents to understand most survival rates are low, and if babies do survive, they have a very high risk of long-term complications, even at 22 weeks."
The team quickly provided medicine to Nash to support his organ development and to reduce the risk of complications, according to the release.
"Sometimes babies born at 21 weeks are just too small for even our tiniest breathing tubes and intravenous lines," said neonatologist Amy Stanford, who treated Nash. "Our NICU team assessed Nash, and I was able to place a breathing tube. Once we had the breathing tube in, his heart rate stabilized and his oxygen levels were good."
Even so, Nash’s chances were slim, as no baby that young had ever survived.
Before Nash's birth, the most premature baby to survive was Curtis Zy-Keith Means, born to Michelle Butler on July 5, 2020, at the University of Alabama at Birmingham Hospital, according to Guinness World Records. He was born at a gestational age of 21 weeks and 1 day, which was 132 days premature.
"We never want the parents to lose hope, but many of them are in an unreal situation, so we have to be very honest with them," said Patrick McNamara, M.D., division director of neonatology at Stead Family Children’s Hospital.
"I would have told his parents, ‘The chance is zero, but I hope I'm wrong, and we will do everything we can to help him.’"
"I want him to see his story as a source of strength."
Around the one-month mark, Stanford said, the team began to "breathe a little easier."
"While we knew Nash still had a long journey ahead, that was the point when we started to feel more confident that he had a real chance of going home."
"It was a subtle but powerful shift – from day-to-day survival to long-term hope."
Nash received ongoing care during his 198 days in the hospital, as the team monitored his heart function and brain health.
In addition to receiving many medications, he also underwent surgery for a perforated bowel, which has up to a 40% mortality rate.
"They were on top of it every step of the way. They really gave him a fighting chance," said Randall Keen. "They were really honest with us during the whole journey about what his chances looked like. They made sure we were well-informed and kept us involved in all the decision-making."
After more than six months in the hospital, Nash was finally able to go home in January 2025.
Nash Keen is pictured at 2 weeks old (left) and at 11 months old (right). (University of Iowa Health Care Stead Family Children’s Hospital)
He will continue to be monitored for ongoing health issues, including a minor heart defect, and is currently being weaned from oxygen. Nash is still on a feeding tube and wears hearing aids.Although he has had some developmental delays, Nash is getting stronger and more interactive with the help of ongoing therapy sessions, according to his mother.
Stanford shared her ultimate goal for Nash — "that by the time he's 5 years old when he goes to kindergarten, no one will know that he was born so early."
"Nash’s remarkable outcome reflects the progress we've made by building on the experiences of those patients who came before him," she added.
Mollie Keen shared that she wants Nash to know how loved he is — and "how many people have cheered him on from the very beginning."
"I want him to grow up and be healthy, happy and confident in who he is. I want him to see his story as a source of strength."
Melissa Rudy
https://www.foxnews.com/health/worlds-most-premature-baby-defies-all-medical-odds-reach-1st-birthday
Sunday, July 27, 2025
Gene therapy for Fabry disease
A study evaluating a pioneering lentivirus (LV)-mediated gene therapy trial for classical Fabry disease showed promising results over five years, indicating a potential breakthrough in treatment for the genetic disorder.
The trial, known as the FACTs (Fabry Disease Clinical Research and Therapeutics) study, was carried out in Halifax, Toronto and Calgary and started in 2016 with five Canadian men who were treated with a novel gene therapy that enabled their bodies to produce the missing enzyme that causes Fabry disease. The findings were published in the journal Clinical and Translational Medicine.
Life-changing results
The results were life-changing: four of five patients showed significant biomarker improvements, and three were able to stop their enzyme replacement therapy (ERT) entirely, suggesting the possibility of a "one-and-done" treatment.
"This trial marks a critical step forward in demonstrating the safety and efficacy of LV-mediated gene therapy for Fabry disease," says Dr. Michael West, a Dal professor and nephrologist at the QEII Health Sciences Center, who was a co-investigator in the study that was the first gene therapy trial for Fabry.
"The continued therapy response over five years and the positive impact on patients' quality of life, particularly the ability to discontinue ERT, offers hope that gene therapy can significantly change the landscape of treatment options for individuals affected by this rare disease."
Fabry disease causes certain fat molecules to accumulate in the cells of various tissues, because the body is unable to produce the correct version of an enzyme that breaks down these fatty materials. It can cause some people to experience pain in their hands and feet, intestinal problems, chronic fatigue, kidney disease, heart failure and strokes.
A working copy
The therapy uses engineered patient blood stem cells to deliver a working copy of the faulty gene. Results showed lasting enzyme production and stabilized kidney function in one patient with advanced kidney disease. Researchers are excited by the therapy's safety profile, with only two temporary severe adverse events reported.
The study revealed that all five patients had sustained persistence of LV-marked blood cells and continual enzyme production. As a result, three patients could stop biweekly ERT (every two weeks), with a saving of roughly $3.7 million in costs for provincial health-care programs.
"I had about four years with no ERT, and I gained back all that time with my family," said 44-year-old Ryan Deveau of Dartmouth, who was one of the five patients treated with the LV therapy.
"At one point, my wife and I realized we were forgetting I had Fabry at all."
Dr. West said the goal now is to create a similar study with 25 to 30 patients, including women, over a two- to three-year period.
The trial, known as the FACTs (Fabry Disease Clinical Research and Therapeutics) study, was carried out in Halifax, Toronto and Calgary and started in 2016 with five Canadian men who were treated with a novel gene therapy that enabled their bodies to produce the missing enzyme that causes Fabry disease. The findings were published in the journal Clinical and Translational Medicine.
Life-changing results
The results were life-changing: four of five patients showed significant biomarker improvements, and three were able to stop their enzyme replacement therapy (ERT) entirely, suggesting the possibility of a "one-and-done" treatment.
"This trial marks a critical step forward in demonstrating the safety and efficacy of LV-mediated gene therapy for Fabry disease," says Dr. Michael West, a Dal professor and nephrologist at the QEII Health Sciences Center, who was a co-investigator in the study that was the first gene therapy trial for Fabry.
"The continued therapy response over five years and the positive impact on patients' quality of life, particularly the ability to discontinue ERT, offers hope that gene therapy can significantly change the landscape of treatment options for individuals affected by this rare disease."
Fabry disease causes certain fat molecules to accumulate in the cells of various tissues, because the body is unable to produce the correct version of an enzyme that breaks down these fatty materials. It can cause some people to experience pain in their hands and feet, intestinal problems, chronic fatigue, kidney disease, heart failure and strokes.
A working copy
The therapy uses engineered patient blood stem cells to deliver a working copy of the faulty gene. Results showed lasting enzyme production and stabilized kidney function in one patient with advanced kidney disease. Researchers are excited by the therapy's safety profile, with only two temporary severe adverse events reported.
The study revealed that all five patients had sustained persistence of LV-marked blood cells and continual enzyme production. As a result, three patients could stop biweekly ERT (every two weeks), with a saving of roughly $3.7 million in costs for provincial health-care programs.
"I had about four years with no ERT, and I gained back all that time with my family," said 44-year-old Ryan Deveau of Dartmouth, who was one of the five patients treated with the LV therapy.
"At one point, my wife and I realized we were forgetting I had Fabry at all."
Dr. West said the goal now is to create a similar study with 25 to 30 patients, including women, over a two- to three-year period.
-----------------------------------------------------------------------------------------------------------------------
Khan A, Barber DL, McKillop WM, Rupar CA, Auray-Blais C, Fraser G, Fowler DH, Berger A, Foley R, Keating A, West ML, Medin JA. Lentivirus-mediated gene therapy for Fabry disease: 5-year End-of-Study results from the Canadian FACTs trial. Clin Transl Med. 2025 Jan;15(1):e70073. doi: 10.1002/ctm2.70073. PMID: 39794302; PMCID: PMC11726700.
Abstract
Background: Fabry disease is an X-linked lysosomal storage disorder due to a deficiency of α-galactosidase A (α-gal A) activity. Our goal was to correct the enzyme deficiency in Fabry patients by transferring the cDNA for α-gal A into their CD34+ hematopoietic stem/progenitor cells (HSPCs). Overexpression of α-gal A leads to secretion of the hydrolase; which can be taken up and used by uncorrected bystander cells. Gene-augmented HSPCs can circulate and thus provide sustained systemic correction. Interim results from this 'first-in-the-world' Canadian FACTs (Fabry Disease Clinical Research and Therapeutics) trial were published in 2021. Herein we report 5-year 'End-of-Study' results.
Methods: Five males with classical Fabry disease were treated. Their HSPCs were mobilized, enriched, and transduced with a recombinant lentivirus engineering expression of α-gal A. Autologous transduced cells were infused after conditioning with a nonmyeloablative, reduced dose, melphalan regimen. Safety monitoring was performed. α-Gal A activity was measured in plasma and peripheral blood (PB) leucocytes. Globotriaosylceramide (Gb3) and lyso-Gb3 levels in urine and plasma were assessed by mass spectrometry. qPCR assays measured vector copy number in PB leucocytes. Antibody titers were measured by ELISA. Body weight, blood pressure, urinary protein levels, eGFR, troponin levels, and LVMI were tracked.
Results: Four out of 5 patients went home the same day as their infusions; one was kept overnight for observation. Circulating α-gal A activity was observed at Day 6-8 in each patient following infusion and has remained durable for 5+ years. LV marking of peripheral blood cells has remained durable and polyclonal. All 5 patients were eligible to come off biweekly enzyme therapy; 3 patients did so. Plasma lyso-Gb3 was significantly lower in 4 of 5 patients. There was no sustained elevation of anti-α-gal A antibodies. Patient weight was stable in 4 of the 5 patients. All blood pressures were in the normal range. Kidney symptoms were stabilized in all patients.
Conclusions: This treatment was well tolerated as only two SAEs occurred (during the treatment phase) and only two AEs were reported since 2021. We demonstrate that this therapeutic approach has merit, is durable, and should be explored in a larger clinical trial.
Highlights: This was the first gene therapy clinical trial to be completed for Fabry disease. There were no adverse events of any grade attributable to the cellular gene therapy intervention or host conditioning throughout the follow-up interval of 5 years. After reduced-intensity melphalan treatment, all patients engrafted their autologous modified α-gal A expressing cells. All patients synthesized and secreted α-gal A throughout the course of the study. Expression of α-gal A resulted in a decrease in plasma lyso-Gb3 in four of five patients and stabilization of kidney symptoms in all patients.
Khan A, Barber DL, McKillop WM, Rupar CA, Auray-Blais C, Fraser G, Fowler DH, Berger A, Foley R, Keating A, West ML, Medin JA. Lentivirus-mediated gene therapy for Fabry disease: 5-year End-of-Study results from the Canadian FACTs trial. Clin Transl Med. 2025 Jan;15(1):e70073. doi: 10.1002/ctm2.70073. PMID: 39794302; PMCID: PMC11726700.
Abstract
Background: Fabry disease is an X-linked lysosomal storage disorder due to a deficiency of α-galactosidase A (α-gal A) activity. Our goal was to correct the enzyme deficiency in Fabry patients by transferring the cDNA for α-gal A into their CD34+ hematopoietic stem/progenitor cells (HSPCs). Overexpression of α-gal A leads to secretion of the hydrolase; which can be taken up and used by uncorrected bystander cells. Gene-augmented HSPCs can circulate and thus provide sustained systemic correction. Interim results from this 'first-in-the-world' Canadian FACTs (Fabry Disease Clinical Research and Therapeutics) trial were published in 2021. Herein we report 5-year 'End-of-Study' results.
Methods: Five males with classical Fabry disease were treated. Their HSPCs were mobilized, enriched, and transduced with a recombinant lentivirus engineering expression of α-gal A. Autologous transduced cells were infused after conditioning with a nonmyeloablative, reduced dose, melphalan regimen. Safety monitoring was performed. α-Gal A activity was measured in plasma and peripheral blood (PB) leucocytes. Globotriaosylceramide (Gb3) and lyso-Gb3 levels in urine and plasma were assessed by mass spectrometry. qPCR assays measured vector copy number in PB leucocytes. Antibody titers were measured by ELISA. Body weight, blood pressure, urinary protein levels, eGFR, troponin levels, and LVMI were tracked.
Results: Four out of 5 patients went home the same day as their infusions; one was kept overnight for observation. Circulating α-gal A activity was observed at Day 6-8 in each patient following infusion and has remained durable for 5+ years. LV marking of peripheral blood cells has remained durable and polyclonal. All 5 patients were eligible to come off biweekly enzyme therapy; 3 patients did so. Plasma lyso-Gb3 was significantly lower in 4 of 5 patients. There was no sustained elevation of anti-α-gal A antibodies. Patient weight was stable in 4 of the 5 patients. All blood pressures were in the normal range. Kidney symptoms were stabilized in all patients.
Conclusions: This treatment was well tolerated as only two SAEs occurred (during the treatment phase) and only two AEs were reported since 2021. We demonstrate that this therapeutic approach has merit, is durable, and should be explored in a larger clinical trial.
Highlights: This was the first gene therapy clinical trial to be completed for Fabry disease. There were no adverse events of any grade attributable to the cellular gene therapy intervention or host conditioning throughout the follow-up interval of 5 years. After reduced-intensity melphalan treatment, all patients engrafted their autologous modified α-gal A expressing cells. All patients synthesized and secreted α-gal A throughout the course of the study. Expression of α-gal A resulted in a decrease in plasma lyso-Gb3 in four of five patients and stabilization of kidney symptoms in all patients.
Wednesday, July 23, 2025
Chromosome 10 deletion treated with an antiseizure medication
Courtesy of a colleague
“Anything is possible, and she’s definitely got a second chance at life,” says Dave.
Dave is talking about their daughter Jorie. The Krauses spent a long time trying to get pregnant and ultimately were able to conceive Jorie through IVF. They thought they had cleared the hurdle. Getting pregnant was the hard part, right? The couple thought health issues were in the clear as genetic testing was done as part of the process.
“At our 20-week scan, they found out that she was a little bit small and they found an undefined heart issue. They didn't quite know what it was, and so we prayed for wisdom, and we went to Mayo for a second opinion,” says Joanie.
Joanie, we should note, was a long-time KARE 11 employee, managing our sales department until recently.
At 33 weeks, the doctors at Mayo decided a cesarean section (C-section) was the best option, and Jorie Kraus was welcomed into the world.
“They immediately ended up putting her into one of those incubator things and shipped her off over to St. Mary's campus where I met her over there and Joanie stayed at the Mayo side of the campus and I had both women in my life in two different buildings and trying to split time with both and keep them both ok,” Dave recalls.
Jorie went on to spend 73 days in the NICU. It turned out she had not one but five heart issues, among some other physical anomalies, but nothing that couldn't be overcome.
“How are we going to fix it, and how are we going to address it? And this wonderful surgeon said, 'Hey, don't worry about it. We're going to figure this all out. You just need to worry about who she's taking to prom,'" says Joanie.
Joanie and Dave allowed themselves to exhale. But it's not where their baby girl's story ends.
Genetic testing came back showing a problem. Jorie was missing part of her chromosome 10. A spontaneous deletion during pregnancy, meaning it was not inherited from either parent, which is why it wasn't caught during the IVF process. Jorie was diagnosed with DeSanto-Shinawi Syndrome, a rare genetic disorder that was the cause of her physical issues but would also cause low muscle tone, developmental delays and intellectual disabilities. At the time, just a couple dozen people in the world had the same diagnosis.
"Joanie was asking a little bit about what does that mean? And I just sort of piped up and said, 'That means it's permanent. There's nothing with this one. This one doesn't have a fix. This one doesn't have a surgery,' and that's when I had to get up and leave the room," Dave said.
With no cure, early interventions, like physical and speech therapies, were the only options. A year passed, and as Jorie fell behind with her milestones like crawling and talking, Joanie and Dave pushed forward, fighting for answers.
“We're at the best hospital in the world. Where's the groundbreaking genetic research? And she had this big smile. This big, big smile and she goes, 'Have you met Dr. Whitney Thompson?'”
They had, in fact, met Dr. Thompson. She was working in the NICU when they ordered the genetic testing or rapid genome sequencing for Jorie right after birth. And since that time, Thompson had started a new project with Dr. Laura Lambert called BabyForce.
"We can send this comprehensive genetic test Day One in the NICU and get a diagnosis within that first week of life, and it can really make a huge difference for patients, but often we get the diagnosis, but we don't have a treatment, and that's really where Babyforce comes in," says Thompson.
The doctors take a patient's skin cells and grow them in a lab. Using Artificial intelligence, they search for already FDA-approved drugs that could potentially help. Then they test them on the patient's lab-grown cells to see if it works.
“Taking a drug that is already approved, and already known to be safe, and known to have a safety profile in children, really circumvents all of those issues that the rare disease population faces. So, we don't have to have that major investment into running a clinical trial because it's off-label use,” says Lambert.
For Jorie, the top hit from AI was an inexpensive drug commonly used to treat seizures in children. In the lab, it worked like a charm, boosting the levels of her working chromosome to compensate for the deleted one. Since the concept is so new, they had to go through ethics and legal departments first. Jorie just started taking the medicine a few months ago. Turns out, it is working like a charm in real life, too. Within days, Jorie started walking with a walker, going up and down stairs, and even starting to say words.
"It's like she was getting the information and understanding it but just couldn't figure out what to do with it, and now she's starting to figure out what to do with it,” says Joanie.
A treatment for an ultra-rare disease would normally take years—if at all. The success in Jorie's case opens a door of hope for others in the future.
“We're focused on the NICU because, certainly, the earlier we intervene, potentially the more impact we can have on somebody's life, and the hope is we can move that timeline up even more, and start treating before symptoms even develop," says Thompson.
“We know this could benefit patients who are born with genetic differences, but it also has applications for cancer, for example, where we could sequence an individual's tumor and understand what's causing the cancer and look for drugs using AI to try to have an impact for those patients as well,” adds Lambert.
Endless possibilities. Which is also what these doctors have given Jorie.
"She's going to be the best Jorie she can be. The barriers have been lifted for her," says Dave.
“She's just such a joy, and you know, we just hope that out of all of the hardship that we went through and all that she has gone through, that it will be a beacon of hope to others,” says Joanie.
In fact, it’s the reason they are sharing their story, to pay it forward. None of this process was covered by insurance. It was all funding from Mayo and private donors. The Krauses have started both a GoFundme and a charity called The Jorie Effect to help other children with rare diseases have access to this kind of medical care.
Thompson and Lambert have already presented their findings at several medical gatherings and will publish their work and findings at the end of July.
Author: Rena Sarigianopoulos
https://www.kare11.com/article/news/local/kare11-extras/medical-breakthrough-using-ai-at-mayo-clinic-hope-rare-disease/89-76ef7169-21df-4934-b7f3-4a5c7dc7894a
Tuesday, July 22, 2025
Glioblastoma and ipilimumab-a series of one
A man with the deadliest form of brain cancer has no signs of the disease after taking an experimental drug.
Ben Trotman was 40 when he was diagnosed in 2022 with glioblastoma, the most aggressive cancerous brain tumor. Patients typically live an average of 15 months after diagnosis, and the five-year survival rate is just 6.9%.
Trotman was referred to The National Hospital for Neurology and Neurosurgery at University College London Hospitals (UCLH), where he was treated by consultant UCLH medical oncologist Dr. Paul Mulholland, as detailed in a press release.
As the only person enrolled in a trial that ultimately closed due to lack of patients, Trotman received a medication called ipilimumab, a targeted immunotherapy treatment.
Ipilimumab is an antibody that binds to a protein on immune cells (T cells). It keeps cancer cells from suppressing the immune system so it can then attack and kill the cancer, according to the National Cancer Institute.
Trotman also received radiation and chemotherapy.
More than two years later, his quarterly scans show no signs of cancer.
"It is very unusual to have a clear scan with glioblastoma, especially when he didn’t have the follow-up surgery that had been planned to remove all of the tumor that was initially visible on scans," his oncologist, Mulholland, said in the release.
"We felt we had a lucky break in an otherwise devastating situation."
"We hope that the immunotherapy and follow-up treatment Ben has had will hold his tumor at bay — and it has so far, which we are delighted to see."
Two months after receiving the ipilimumab, Trotman married his wife, Emily. In April 2025, they welcomed their daughter, Mabel.
"Getting this diagnosis was the most traumatic experience — we were grappling with the fact that Ben had gone from being apparently perfectly healthy to having months to live," Emily Trotman said in the release.
"Had we not met Dr. Mulholland, that would have been it for us. We felt we had a lucky break in an otherwise devastating situation."
Ben Trotman added, "We obviously don’t know what the future holds, but having had the immunotherapy treatment and getting these encouraging scan results has given [us] a bit of hope."
"We are focused on rebuilding the life we thought we had lost and enjoying being parents."
Mulholland and his team have now opened another clinical trial for patients who have been newly diagnosed with glioblastoma.
Sixteen patients will be recruited for the trial, which is sponsored by UCL.
The treatment will be administered at the NIHR UCLH’s Clinical Research Facility and the National Hospital for Neurology and Neurosurgery, according to the press release.
The patients will receive ipilimumab before proceeding to standard treatments that may include surgery, radiotherapy and chemotherapy.
"The crucial element of this trial is that patients will have their immune system boosted by the drug before they have any other treatment, when they are fit and well enough to tolerate the immunotherapy," Mulholland said in the release.
The Win-Glio trial — nicknamed "Margaret’s Trial" — is funded by the efforts of Dame Siobhain McDonagh, sister of Margaret McDonagh, a London woman who died of glioblastoma in 2023 and was treated by Mulholland.
Ben Trotman said he is "delighted" that the new trial is moving forward with the same immunotherapy drug he received.
"It will give people newly diagnosed with glioblastoma some hope."
Melissa Rudy
https://www.foxnews.com/health/mans-deadly-brain-cancer-tumor-disappears-after-experimental-drug-trial
"Had we not met Dr. Mulholland, that would have been it for us. We felt we had a lucky break in an otherwise devastating situation."
Ben Trotman added, "We obviously don’t know what the future holds, but having had the immunotherapy treatment and getting these encouraging scan results has given [us] a bit of hope."
"We are focused on rebuilding the life we thought we had lost and enjoying being parents."
Mulholland and his team have now opened another clinical trial for patients who have been newly diagnosed with glioblastoma.
Sixteen patients will be recruited for the trial, which is sponsored by UCL.
The treatment will be administered at the NIHR UCLH’s Clinical Research Facility and the National Hospital for Neurology and Neurosurgery, according to the press release.
The patients will receive ipilimumab before proceeding to standard treatments that may include surgery, radiotherapy and chemotherapy.
"The crucial element of this trial is that patients will have their immune system boosted by the drug before they have any other treatment, when they are fit and well enough to tolerate the immunotherapy," Mulholland said in the release.
The Win-Glio trial — nicknamed "Margaret’s Trial" — is funded by the efforts of Dame Siobhain McDonagh, sister of Margaret McDonagh, a London woman who died of glioblastoma in 2023 and was treated by Mulholland.
Ben Trotman said he is "delighted" that the new trial is moving forward with the same immunotherapy drug he received.
"It will give people newly diagnosed with glioblastoma some hope."
Melissa Rudy
https://www.foxnews.com/health/mans-deadly-brain-cancer-tumor-disappears-after-experimental-drug-trial
Monday, July 21, 2025
Postpartum depression-being sectioned
AU.K. mom captured a happy moment with her baby, not knowing that, days later, she would be sectioned.
Jade Lloyd (@jadealloyd) posted a reel on Instagram smiling and playing with her newborn daughter, but, behind the scenes, the 31-year-old was falling apart.
Lloyd told Newsweek that she had struggled mentally after giving birth. At her six-week checkup, she tried to speak out, but her doctor didn't take any notice.
"It got progressively worse, which then started to turn into suicidal thoughts," Lloyd said.
After finally receiving a diagnosis of postnatal depression and being prescribed antidepressants, Lloyd felt pressure to appear as if she were improving.
"[I] started putting on a front, although, inside, I was falling apart," Lloyd said. "I was trying to hold it together until my brain couldn't handle it anymore, and it turned into psychosis."
Sleep deprivation, she was later told by clinicians, likely contributed to the onset of acute psychosis. "Over the period of a week, I probably slept a total of 10 hours," Lloyd added.
Lloyd was sectioned under the U.K.'s Mental Health Act and was admitted to a Mother and Baby Unit—a specialist facility where mothers can receive psychiatric care while staying with their infants.
"Initially, [it] felt like a prison, and, when I was sectioned, it meant I was unable to leave," Lloyd said.
"My daughter and I were able to stay together, which was vital for my recovery, as I kept thinking I had killed her. I couldn't imagine what it would have been like if I wasn't able to be with her."
Despite facing challenges during her stay, Lloyd said that her experience was positive overall, and she praised the staff who worked there.
"They listened, cared for myself and my daughter, and gave me space to heal. I will be forever grateful for them," she said.
Following her release after a month, Lloyd struggled with depression and found it difficult even to get out of bed.
Given that she wasn't permitted to drive for three months, Lloyd felt isolated in her small town. Thankfully, friends and family rallied around to help her find a way forward.
"Now I would say I'm in the best place I've been," Lloyd said. "I go back and volunteer [at the Mother and Baby Unit] and do the moms' nails. It's healing and rewarding at the same time."
Lloyd has also built an online platform to raise awareness and support others.
"The response has been positive, and I hope to grow this and go on to do more advocacy work to help better maternal care for mental health," Lloyd said.
To mothers who might be struggling, Lloyd offered this message: "Whether you've just given birth, or you are three years into your motherhood journey, you are doing amazing.
"Even if you're struggling with your mental health and you're just scraping by every single day, know that you are enough for your baby, and nothing can change that.
"There is light out there, and if you are in the darkness, there is a way out. It takes time and work, but you've got this," Lloyd said.
Daniella Gray
https://www.newsweek.com/mom-captures-moment-newborn-not-knowing-sectioned-2099666
Jade Lloyd (@jadealloyd) posted a reel on Instagram smiling and playing with her newborn daughter, but, behind the scenes, the 31-year-old was falling apart.
Lloyd told Newsweek that she had struggled mentally after giving birth. At her six-week checkup, she tried to speak out, but her doctor didn't take any notice.
"It got progressively worse, which then started to turn into suicidal thoughts," Lloyd said.
After finally receiving a diagnosis of postnatal depression and being prescribed antidepressants, Lloyd felt pressure to appear as if she were improving.
"[I] started putting on a front, although, inside, I was falling apart," Lloyd said. "I was trying to hold it together until my brain couldn't handle it anymore, and it turned into psychosis."
Sleep deprivation, she was later told by clinicians, likely contributed to the onset of acute psychosis. "Over the period of a week, I probably slept a total of 10 hours," Lloyd added.
Lloyd was sectioned under the U.K.'s Mental Health Act and was admitted to a Mother and Baby Unit—a specialist facility where mothers can receive psychiatric care while staying with their infants.
"Initially, [it] felt like a prison, and, when I was sectioned, it meant I was unable to leave," Lloyd said.
"My daughter and I were able to stay together, which was vital for my recovery, as I kept thinking I had killed her. I couldn't imagine what it would have been like if I wasn't able to be with her."
Despite facing challenges during her stay, Lloyd said that her experience was positive overall, and she praised the staff who worked there.
"They listened, cared for myself and my daughter, and gave me space to heal. I will be forever grateful for them," she said.
Following her release after a month, Lloyd struggled with depression and found it difficult even to get out of bed.
Given that she wasn't permitted to drive for three months, Lloyd felt isolated in her small town. Thankfully, friends and family rallied around to help her find a way forward.
"Now I would say I'm in the best place I've been," Lloyd said. "I go back and volunteer [at the Mother and Baby Unit] and do the moms' nails. It's healing and rewarding at the same time."
Lloyd has also built an online platform to raise awareness and support others.
"The response has been positive, and I hope to grow this and go on to do more advocacy work to help better maternal care for mental health," Lloyd said.
To mothers who might be struggling, Lloyd offered this message: "Whether you've just given birth, or you are three years into your motherhood journey, you are doing amazing.
"Even if you're struggling with your mental health and you're just scraping by every single day, know that you are enough for your baby, and nothing can change that.
"There is light out there, and if you are in the darkness, there is a way out. It takes time and work, but you've got this," Lloyd said.
Daniella Gray
https://www.newsweek.com/mom-captures-moment-newborn-not-knowing-sectioned-2099666
Sunday, July 20, 2025
Treacher-Collins syndrome 2
She labored for nearly 17 hours before giving birth to her son.
You would expect her and her husband, Russel, to be overwhelmed with the joy of bringing a new life into the world?
It might be the best moment of their life, but at the same time, also the worst.
As her husband, Russel Newman, took a closer look at the baby, he screamed, “OMG! What happened? What's happening?” Chaos and alarms ensued as nurses took the baby away into the back room without letting Magda take a look.
That day, Magda Newman was left on the delivery table, because the doctors and nurses were working hard to save the baby's life.
The baby wasn't breathing or crying. The baby didn't look like any other babies. He didn't have ears, cheekbones, upper or lower eyelids or eyesockets. The only parts recognizable were a small jaw line and eyes that severely slanted downwards.
It was hours before the doctor reached a diagnosis which made Russel break down in tears. The baby was born with Treacher Collins Syndrome, a rare congenital craniofacial disorder caused by mutations in the POLR1C gene. It happens to 1 out of 50,000 newborn babies.
The Newmans' baby, named Nathaniel, was immediately transferred to the neonatal ICU at NYU Langone, where he lived for the entire first month of his life. It was in the ICU where Russel held the baby for the first time.
It took Russel and Magda a year before they could look at their son without flinching and acknowledge that this really happened to their own son.
But the appearance wasn't the worst part. It was functioning. Eating and hearing were almost impossible for Nathaniel. The doctors had a hard time trying to make him breathe. His nasal passageway was nearly solid bone, and his airway was very narrow.
The only comforting part was that Nathaniel's brain was unaffected.
Within the first year, Nathaniel underwent at least 10 surgeries in order to live. The first few surgical attempts to open his nasal passageway weren't successful. Then the doctors tried an emergency tracheotomy, which was a procedure to put an incision in the trachea creating a direct airway. Eventually, Nathaniel could finally breathe through a trach.
It was impossible to take Nathaniel out for a stroll, because they were living in New York City. As soon as others saw them with a stroller, they would take a look at the baby. While in other circumstances they would say, “Oh, he's so cute!” But in their case, they were horrified by what they saw.
Things were just as hard for Nathaniel.
He became aware of his looks at around 5 years old. Every time he went to a birthday party, kids would immediately run away, screaming in terror. He realized it was about him. Other kids would call him “monster” and insult him. Kids don't think twice before saying anything, and sometimes that could be very hurtful.
By the time he turned 11, Nathaniel had been through 54 surgeries, including a radical surgery which had only been performed once in history, a surgery that involved literally rearranging the bones in his face, and several surgeries that lasted longer than 10 hours.
One time after a 12-hour surgery of separating his skull from his face and moving it into the correct position, Nathaniel was left with a metal halo that had to remain attached to his head for three months and a wired jaw to shut the halo. Attached to the halo were tiny turning devices that need to be screwed three times a day.
It was never easy for a kid to lie on a metal table, surrounded by tools that were going to cut him open. But Nathaniel pulled through anyway. He had tackled more life-altering challenges than many old people on earth.
In 2012, a book titled Wonder was published, making Treacher Collins Syndrome better known to the world. The book was about an inspiring story of a 5th grade boy August (Auggie) Pullman, who was born with Treacher Collins Syndrome.
In 2015, the family moved to the West Coast and Nathaniel enrolled in a local middle school. His parents feared that he would be bullied and threatened because of his condition. To help his classmates understand his condition, Nathaniel wrote a letter before the first day of school.
This is Nathaniel with Jacob.
Hey,
How is your summer going? I want to take a second and introduce myself. My name is Nathaniel Newman and I am moving to Reno from Short Hills, New Jersey. I’m going to be a 5th grader.
My parents and I think it would be a good idea if I tell you a little about myself before you meet me for the first time. We think that might make it easier for us all to become friends. Why you ask? Well, I’m different than most kids you may have met before.
I know, I know… All Kids are different. But, I think you will agree I am a little different than most. I was born with a rare genetic birth defect called Treacher-Collins Syndrome (TCS). TCS causes a crazy thing to happen when you are growing in your momma’s belly. The bones and stuff in your face don’t grow properly. Then, when you are born, you look very different than most kids. Not only do you look different, it’s hard for you to do things most kids do pretty easily. I had a hard time eating, breathing and hearing when I was a baby. The good news though, thanks to some wicked awesome doctors I can eat, hear and breathe pretty well. But, I still look different and I don’t want you to be nervous when you meet me.
A few more details would help. I have had 54 surgeries in 10 years. You read that right. 54 surgeries. Many to reconstruct the bones in my face. NOT FUN AT ALL! Some to build new airways to breathe through. Some to build me a bone attached hearing aid. Too many to talk about. Surgery is NOT fun. But, the cool part is that I have been to some of the coolest cities in the world for my operations. NYC, Boston and Cincinnati just to name a few. Now, I still breathe with a tracheotomy which is a tube in your neck. Don’t be grossed out. It doesn’t bother me just try not to touch it. I also have a hearing aid in my skull. It’s cool cause I hear everything but dad worries cause if it gets wet or damaged it is MUCHO expensive.
Now the fun part. Other than all the stuff I just wrote I AM TOTALLY NORMAL!!! I am seriously smart… I love PIZZA and Meatballs and Spaghetti. I have a brother Jacob he is 8. (Totally annoying!!!) My dogs Smokey and Coco are totally BOSS! And of course I love my Mom & Dad. I have cool friends all over the country. And my absolute favorite fun thing… WAIT FOR IT… WAIT FOR IT!! MINECRAFT! I love MINECRAFT. Other video games too but especially MINECRAFT. Maybe we can play sometime if you like it as well. I also draw seriously funny cartoons.
Last thing… Kids like me sometimes have a hard time at new schools. Because I look so different kids stare and say mean things sometimes. If you wouldn’t mind, please don’t do that. It makes me sad and I’d much rather have fun with you than be sad. THANKS. If you want, you can read this awesome book called WONDER. My friend RJ Pallacio wrote it. It’s about a kid like me named Auggie when he goes to a new school. RJ calls me her real life Auggie. Check it out, I know you will like it.
If your Mom or Dad has any questions, tell them to shoot my dad an email.
Thanks. Always Choose to Be Kind.
Nathaniel
In 2016, after a series of groundbreaking surgeries, Nathaniel's trach was removed. He was capable of breathing through an unobstructed airway for the first time in his life.
Additionally, the book Wonder was made into a movie, starring Jacob Tremblay, Julia Roberts, and Owen Wilson.
Canadian actor Jacob Tremblay played Auggie. It is said that the makeup takes more than two hours to put on. No wonder it looks so real.
Currently, Nathaniel is living a normal life as a 15-year-old high school student. He has become accustomed to his condition and grown to sort of like it, as it makes him stand out from the crowd.
This is a picture of the family on the movie “Wonder” premiere — Russel, Magda, Nathaniel, and his younger brother Jacob.
They are working on a book called Normal: One Kid's Extraordinary Journey, which will be published next year.
https://www.quora.com/search?q=treacher-collins
All my childrenPosted by
Palwasha 5y
Treacher-Collins Syndrome.
Alex C. Lee
Updated 5y
What innocent-seeming picture is actually heartbreaking?
Dementia incidence higher for younger chronic back pain patients prescribed gabapentin
Eghrari NB, Yazji IH, Yavari B, et al. Risk of dementia following gabapentin prescription in chronic low back pain patients.
Regional Anesthesia & Pain Medicine Published Online First: 10 July 2025. doi: 10.1136/rapm-2025-106577
Abstract
Introduction Gabapentin is widely used to treat chronic pain, but its association with cognitive decline and dementia remains unclear. This study examined whether gabapentin prescription is associated with dementia in adults with chronic low back pain.
Methods We conducted a retrospective cohort study using the TriNetX national database of de-identified patient records from 2004 to 2024. Adults diagnosed with chronic low back pain were included; those with prior gabapentin use, dementia, epilepsy, stroke, or cancer were excluded. Propensity score matching controlled for demographics, comorbidities, and pain medications. Patients were stratified by age and gabapentin prescription frequency. Primary outcomes were dementia and mild cognitive impairment.
Results 26,416 adults we analyzed following propensity-score matching. Patients with six or more gabapentin prescriptions had an increased incidence of dementia (RR: 1.29; 95% CI: 1.18–1.40) and mild cognitive impairment (RR: 1.85; 95% CI: 1.63–2.10). When stratified by age, non-elderly adults (18–64) prescribed gabapentin had over twice the risk of dementia (RR: 2.10; 95% CI: 1.75–2.51) and mild cognitive impairment (RR: 2.50; 95% CI: 2.04–3.05) compared to those not prescribed gabapentin. Risk increased further with prescription frequency: patients with 12 or more prescriptions had a higher incidence of dementia (RR: 1.40; 95% CI: 1.25–1.57) and mild cognitive impairment (RR: 1.65; 95% CI: 1.42–1.91) than those prescribed gabapentin 3–11 times.
Conclusions Gabapentin prescription in adults with chronic low back pain is associated with increased risk of dementia and cognitive impairment, particularly in non-elderly adults. Physicians should monitor cognitive outcomes in patients prescribed gabapentin.
__________________________________________________________________
Gabapentin (Neurontin) prescriptions for chronic low back pain were linked with an increased risk of dementia and cognitive impairment, especially in younger people, an analysis of U.S. healthcare claims suggested.
Among more than 52,000 adults with chronic back pain who were followed for 10 years, those who had six or more gabapentin prescriptions had a higher incidence of dementia (risk ratio [RR] 1.29, 95% CI 1.18-1.40) and mild cognitive impairment (RR 1.85, 95% CI 1.63-2.10) than those not prescribed gabapentin, according to Chong Kim, MD, of MetroHealth Medical Center in Cleveland, Ohio, and co-authors.
Prescription frequency correlated with risk, Kim and colleagues reported in Regional Anesthesia & Pain Medicineopens in a new tab or window. People with 12 or more gabapentin prescriptions had a higher incidence of dementia (RR 1.40, 95% CI 1.25-1.57) and mild cognitive impairment (RR 1.65, 95% CI 1.42-1.91) than those prescribed gabapentin three to 11 times.
Among younger chronic back pain patients -- ages 18 to 64 -- those prescribed gabapentin had over twice the risk of dementia (RR 2.10, 95% CI 1.75-2.51) and mild cognitive impairment (RR 2.50, 95% CI 2.04-3.05) compared with their counterparts who didn't have gabapentin.
There was no heightened risk among people 18 to 34 years old who were prescribed the drug, but dementia risk was more than double and mild cognitive impairment risk more than triple among those ages 35 to 49. A similar pattern emerged among those 50 to 64 years old.
In people ages 65 and older, the gabapentin group had an increased incidence of both dementia (RR 1.28, 95% CI 1.15-1.42) and mild cognitive impairment (RR 1.53, 95% CI 1.28-1.83).
"This project highlights a potential concern for prescribing practitioners to consider, particularly with the increasing use of gabapentin for off-label conditions, as well as the need for continuing evaluation of efficacy and risks of any treatment," Kim told MedPage Today.
"Due to the design of the project, the results have limitations, and further studies are needed to validate the findings," he added.
Gabapentin is approved for seizures and post-herpetic neuralgia; gabapentin enacarbil is approved for restless legs syndrome. Despite limited indications, gabapentin and its cousin, pregabalin (Lyrica), are widely prescribed off-labelopens in a new tab or window for various other pain syndromes.
Common side effects of gabapentinoids include drowsiness, dizziness, blurry or double vision, and difficulty with coordination and concentration. In 2019, the FDA warned about serious breathing problemsopens in a new tab or window that may occur in patients using gabapentin or pregabalin who have respiratory risk factors. These factors included taking opioids or other drugs that depress the central nervous system, conditions like chronic obstructive pulmonary disease (COPD) that reduce lung function, and older age.
"While existing literature identifies several risks, there lacks a strong understanding of how gabapentin impacts cognitive function and whether it contributes to neurodegenerative processes," Kim and co-authors wrote.
"At the moment, there's not enough evidence to suggest pain medications are linked to higher dementia risk, but this research gives us interesting insights," observed Leah Mursaleen, PhD, of Alzheimer's Research U.K. in Cambridge, who wasn't involved with the study.
"Because this study only used health records of people with chronic pain, we cannot rule out other factors that might be influencing the findings," Mursaleen posted on the U.K. Science Media Center website. "And previous studies looking at people prescribed gabapentin for other conditions, like seizures, didn't show a link between the medication and higher dementia risk."
For this analysis, the researchers used the TriNetX national database of patient records from 2004 to 2024, including adults with chronic low back pain and following them for 10 years. People with prior gabapentin use, dementia, epilepsy, stroke, or cancer were excluded from the study.
Kim and colleagues used propensity score matching to control for demographics, medical diagnoses related to cognitive decline, and pain medications. After propensity score matching, 26,416 chronic back pain patients were in the gabapentin group, and 26,416 were in the no-gabapentin group.
Mean age in both groups was about 53 years. Approximately 58% were female, and 73% were white. In both groups, about 65% received opioid prescriptions, 39% received prescriptions for benzodiazepines, and 29% had skeletal muscle relaxants. Comorbidities -- including hypertension, diabetes, nicotine dependence, alcohol-related disorders, sleep disorders, and others -- were similar in each group.
The study was observational and could not generate causal conclusions, the researchers noted. Electronic medical record data may have been miscoded, and other variables may have influenced results. Neither dose nor duration of gabapentin use was controlled for.
"Our results support the need for close monitoring in adult patients prescribed gabapentin to assess for potential cognitive decline," Kim and colleagues wrote.
"We hope the current study promotes further research to delineate whether gabapentin plays a causal role in the development of dementia and the underlying mechanisms of this relationship."
Judy George
https://www.medpagetoday.com/neurology/painmanagement/116456
Regional Anesthesia & Pain Medicine Published Online First: 10 July 2025. doi: 10.1136/rapm-2025-106577
Abstract
Introduction Gabapentin is widely used to treat chronic pain, but its association with cognitive decline and dementia remains unclear. This study examined whether gabapentin prescription is associated with dementia in adults with chronic low back pain.
Methods We conducted a retrospective cohort study using the TriNetX national database of de-identified patient records from 2004 to 2024. Adults diagnosed with chronic low back pain were included; those with prior gabapentin use, dementia, epilepsy, stroke, or cancer were excluded. Propensity score matching controlled for demographics, comorbidities, and pain medications. Patients were stratified by age and gabapentin prescription frequency. Primary outcomes were dementia and mild cognitive impairment.
Results 26,416 adults we analyzed following propensity-score matching. Patients with six or more gabapentin prescriptions had an increased incidence of dementia (RR: 1.29; 95% CI: 1.18–1.40) and mild cognitive impairment (RR: 1.85; 95% CI: 1.63–2.10). When stratified by age, non-elderly adults (18–64) prescribed gabapentin had over twice the risk of dementia (RR: 2.10; 95% CI: 1.75–2.51) and mild cognitive impairment (RR: 2.50; 95% CI: 2.04–3.05) compared to those not prescribed gabapentin. Risk increased further with prescription frequency: patients with 12 or more prescriptions had a higher incidence of dementia (RR: 1.40; 95% CI: 1.25–1.57) and mild cognitive impairment (RR: 1.65; 95% CI: 1.42–1.91) than those prescribed gabapentin 3–11 times.
Conclusions Gabapentin prescription in adults with chronic low back pain is associated with increased risk of dementia and cognitive impairment, particularly in non-elderly adults. Physicians should monitor cognitive outcomes in patients prescribed gabapentin.
__________________________________________________________________
Gabapentin (Neurontin) prescriptions for chronic low back pain were linked with an increased risk of dementia and cognitive impairment, especially in younger people, an analysis of U.S. healthcare claims suggested.
Among more than 52,000 adults with chronic back pain who were followed for 10 years, those who had six or more gabapentin prescriptions had a higher incidence of dementia (risk ratio [RR] 1.29, 95% CI 1.18-1.40) and mild cognitive impairment (RR 1.85, 95% CI 1.63-2.10) than those not prescribed gabapentin, according to Chong Kim, MD, of MetroHealth Medical Center in Cleveland, Ohio, and co-authors.
Prescription frequency correlated with risk, Kim and colleagues reported in Regional Anesthesia & Pain Medicineopens in a new tab or window. People with 12 or more gabapentin prescriptions had a higher incidence of dementia (RR 1.40, 95% CI 1.25-1.57) and mild cognitive impairment (RR 1.65, 95% CI 1.42-1.91) than those prescribed gabapentin three to 11 times.
Among younger chronic back pain patients -- ages 18 to 64 -- those prescribed gabapentin had over twice the risk of dementia (RR 2.10, 95% CI 1.75-2.51) and mild cognitive impairment (RR 2.50, 95% CI 2.04-3.05) compared with their counterparts who didn't have gabapentin.
There was no heightened risk among people 18 to 34 years old who were prescribed the drug, but dementia risk was more than double and mild cognitive impairment risk more than triple among those ages 35 to 49. A similar pattern emerged among those 50 to 64 years old.
In people ages 65 and older, the gabapentin group had an increased incidence of both dementia (RR 1.28, 95% CI 1.15-1.42) and mild cognitive impairment (RR 1.53, 95% CI 1.28-1.83).
"This project highlights a potential concern for prescribing practitioners to consider, particularly with the increasing use of gabapentin for off-label conditions, as well as the need for continuing evaluation of efficacy and risks of any treatment," Kim told MedPage Today.
"Due to the design of the project, the results have limitations, and further studies are needed to validate the findings," he added.
Gabapentin is approved for seizures and post-herpetic neuralgia; gabapentin enacarbil is approved for restless legs syndrome. Despite limited indications, gabapentin and its cousin, pregabalin (Lyrica), are widely prescribed off-labelopens in a new tab or window for various other pain syndromes.
Common side effects of gabapentinoids include drowsiness, dizziness, blurry or double vision, and difficulty with coordination and concentration. In 2019, the FDA warned about serious breathing problemsopens in a new tab or window that may occur in patients using gabapentin or pregabalin who have respiratory risk factors. These factors included taking opioids or other drugs that depress the central nervous system, conditions like chronic obstructive pulmonary disease (COPD) that reduce lung function, and older age.
"While existing literature identifies several risks, there lacks a strong understanding of how gabapentin impacts cognitive function and whether it contributes to neurodegenerative processes," Kim and co-authors wrote.
"At the moment, there's not enough evidence to suggest pain medications are linked to higher dementia risk, but this research gives us interesting insights," observed Leah Mursaleen, PhD, of Alzheimer's Research U.K. in Cambridge, who wasn't involved with the study.
"Because this study only used health records of people with chronic pain, we cannot rule out other factors that might be influencing the findings," Mursaleen posted on the U.K. Science Media Center website. "And previous studies looking at people prescribed gabapentin for other conditions, like seizures, didn't show a link between the medication and higher dementia risk."
For this analysis, the researchers used the TriNetX national database of patient records from 2004 to 2024, including adults with chronic low back pain and following them for 10 years. People with prior gabapentin use, dementia, epilepsy, stroke, or cancer were excluded from the study.
Kim and colleagues used propensity score matching to control for demographics, medical diagnoses related to cognitive decline, and pain medications. After propensity score matching, 26,416 chronic back pain patients were in the gabapentin group, and 26,416 were in the no-gabapentin group.
Mean age in both groups was about 53 years. Approximately 58% were female, and 73% were white. In both groups, about 65% received opioid prescriptions, 39% received prescriptions for benzodiazepines, and 29% had skeletal muscle relaxants. Comorbidities -- including hypertension, diabetes, nicotine dependence, alcohol-related disorders, sleep disorders, and others -- were similar in each group.
The study was observational and could not generate causal conclusions, the researchers noted. Electronic medical record data may have been miscoded, and other variables may have influenced results. Neither dose nor duration of gabapentin use was controlled for.
"Our results support the need for close monitoring in adult patients prescribed gabapentin to assess for potential cognitive decline," Kim and colleagues wrote.
"We hope the current study promotes further research to delineate whether gabapentin plays a causal role in the development of dementia and the underlying mechanisms of this relationship."
Judy George
https://www.medpagetoday.com/neurology/painmanagement/116456
Computed tomography perfusion and angiography for death by neurologic criteria
Chassé M, Shankar JJS, Fergusson DA, et al. Computed Tomography Perfusion and Angiography for Death by Neurologic Criteria. JAMA Neurol. Published online June 13, 2025. doi:10.1001/jamaneurol.2025.2375
Abstract
Importance Accurate and timely confirmation of death by neurologic criteria (DNC) is essential for clinical decision-making and organ-donation processes, yet currently available ancillary tests have suboptimal diagnostic performance or limited validation.
Objectives To determine the diagnostic accuracy, interrater reliability, and safety of brain computed tomography (CT) perfusion and CT angiography as ancillary investigations for DNC.
Design, Setting, and Participants Between April 25, 2017, and March 10, 2021, a prospective, multicenter, blinded diagnostic accuracy cohort study was conducted in 15 adult intensive care units across Canada. Consecutive, critically ill adults (aged ≥18 years) with a Glasgow Coma Scale score of 3 and no confounding factors who were at high risk of DNC were included. Data collection and analysis were performed from April 2021 to July 2024.
Exposure Contrast-enhanced brain CT perfusion with CT angiography reconstructions performed within 2 hours of a blinded, standardized clinical DNC examination.
Main Outcomes and Measures The primary outcomes were the sensitivity and specificity of qualitative and quantitative brainstem CT perfusion for DNC determination, assessed by 2 independent neuroradiologists blinded to clinical findings; the prespecified validation threshold was greater than 98%. Secondary outcomes were the diagnostic accuracy of whole-brain CT perfusion and CT angiography, interrater reliability (Cohen κ), and adverse events associated with imaging.
Results A total of Results A total of 282 patients (mean [SD] age, 57.8 [15.4] years; 133 [47%] female) completed the study protocol and were included in the primary analysis; 204 (72%) of these were ultimately declared deceased by standardized clinical criteria. Qualitative brainstem CT perfusion showed a sensitivity of 98.5% (95% CI, 95.8%-99.7%) and a specificity of 74.4% (95% CI, 63.2%-83.6%); quantitative brainstem CT perfusion was not diagnostically accurate. Qualitative whole-brain CT perfusion yielded a sensitivity of 93.6% (95% CI, 89.3%-96.6%) and a specificity of 92.3% (95% CI, 84.0%-97.1%). CT angiography sensitivity ranged from 75.5% (95% CI, 69.0%-81.2%) to 87.3% (95% CI, 81.9%-91.5%), and its specificity ranged from 89.7% (95% CI, 80.8%-95.5%) to 91.0% (95% CI, 82.4%-96.3%). Interrater reliability was excellent for all ancillary tests (κ ranged from 0.81 [95% CI, 0.73-0.89] to 0.84 [95% CI, 0.78-0.91]). Fourteen patients (5%) experienced minor, self-limited adverse events; no serious adverse events occurred.
Conclusions and Relevance The observed sensitivity and specificity measures for CT perfusion and CT angiography as an ancillary test for DNC did not meet the prespecified validation threshold of greater than 98%. Clinical examination remains the cornerstone of DNC, and ancillary imaging should be interpreted cautiously within a comprehensive clinical assessment.282 patients (mean [SD] age, 57.8 [15.4] years; 133 [47%] female) completed the study protocol and were included in the primary analysis; 204 (72%) of these were ultimately declared deceased by standardized clinical criteria. Qualitative brainstem CT perfusion showed a sensitivity of 98.5% (95% CI, 95.8%-99.7%) and a specificity of 74.4% (95% CI, 63.2%-83.6%); quantitative brainstem CT perfusion was not diagnostically accurate. Qualitative whole-brain CT perfusion yielded a sensitivity of 93.6% (95% CI, 89.3%-96.6%) and a specificity of 92.3% (95% CI, 84.0%-97.1%). CT angiography sensitivity ranged from 75.5% (95% CI, 69.0%-81.2%) to 87.3% (95% CI, 81.9%-91.5%), and its specificity ranged from 89.7% (95% CI, 80.8%-95.5%) to 91.0% (95% CI, 82.4%-96.3%). Interrater reliability was excellent for all ancillary tests (κ ranged from 0.81 [95% CI, 0.73-0.89] to 0.84 [95% CI, 0.78-0.91]). Fourteen patients (5%) experienced minor, self-limited adverse events; no serious adverse events occurred.
Abstract
Importance Accurate and timely confirmation of death by neurologic criteria (DNC) is essential for clinical decision-making and organ-donation processes, yet currently available ancillary tests have suboptimal diagnostic performance or limited validation.
Objectives To determine the diagnostic accuracy, interrater reliability, and safety of brain computed tomography (CT) perfusion and CT angiography as ancillary investigations for DNC.
Design, Setting, and Participants Between April 25, 2017, and March 10, 2021, a prospective, multicenter, blinded diagnostic accuracy cohort study was conducted in 15 adult intensive care units across Canada. Consecutive, critically ill adults (aged ≥18 years) with a Glasgow Coma Scale score of 3 and no confounding factors who were at high risk of DNC were included. Data collection and analysis were performed from April 2021 to July 2024.
Exposure Contrast-enhanced brain CT perfusion with CT angiography reconstructions performed within 2 hours of a blinded, standardized clinical DNC examination.
Main Outcomes and Measures The primary outcomes were the sensitivity and specificity of qualitative and quantitative brainstem CT perfusion for DNC determination, assessed by 2 independent neuroradiologists blinded to clinical findings; the prespecified validation threshold was greater than 98%. Secondary outcomes were the diagnostic accuracy of whole-brain CT perfusion and CT angiography, interrater reliability (Cohen κ), and adverse events associated with imaging.
Results A total of Results A total of 282 patients (mean [SD] age, 57.8 [15.4] years; 133 [47%] female) completed the study protocol and were included in the primary analysis; 204 (72%) of these were ultimately declared deceased by standardized clinical criteria. Qualitative brainstem CT perfusion showed a sensitivity of 98.5% (95% CI, 95.8%-99.7%) and a specificity of 74.4% (95% CI, 63.2%-83.6%); quantitative brainstem CT perfusion was not diagnostically accurate. Qualitative whole-brain CT perfusion yielded a sensitivity of 93.6% (95% CI, 89.3%-96.6%) and a specificity of 92.3% (95% CI, 84.0%-97.1%). CT angiography sensitivity ranged from 75.5% (95% CI, 69.0%-81.2%) to 87.3% (95% CI, 81.9%-91.5%), and its specificity ranged from 89.7% (95% CI, 80.8%-95.5%) to 91.0% (95% CI, 82.4%-96.3%). Interrater reliability was excellent for all ancillary tests (κ ranged from 0.81 [95% CI, 0.73-0.89] to 0.84 [95% CI, 0.78-0.91]). Fourteen patients (5%) experienced minor, self-limited adverse events; no serious adverse events occurred.
Conclusions and Relevance The observed sensitivity and specificity measures for CT perfusion and CT angiography as an ancillary test for DNC did not meet the prespecified validation threshold of greater than 98%. Clinical examination remains the cornerstone of DNC, and ancillary imaging should be interpreted cautiously within a comprehensive clinical assessment.282 patients (mean [SD] age, 57.8 [15.4] years; 133 [47%] female) completed the study protocol and were included in the primary analysis; 204 (72%) of these were ultimately declared deceased by standardized clinical criteria. Qualitative brainstem CT perfusion showed a sensitivity of 98.5% (95% CI, 95.8%-99.7%) and a specificity of 74.4% (95% CI, 63.2%-83.6%); quantitative brainstem CT perfusion was not diagnostically accurate. Qualitative whole-brain CT perfusion yielded a sensitivity of 93.6% (95% CI, 89.3%-96.6%) and a specificity of 92.3% (95% CI, 84.0%-97.1%). CT angiography sensitivity ranged from 75.5% (95% CI, 69.0%-81.2%) to 87.3% (95% CI, 81.9%-91.5%), and its specificity ranged from 89.7% (95% CI, 80.8%-95.5%) to 91.0% (95% CI, 82.4%-96.3%). Interrater reliability was excellent for all ancillary tests (κ ranged from 0.81 [95% CI, 0.73-0.89] to 0.84 [95% CI, 0.78-0.91]). Fourteen patients (5%) experienced minor, self-limited adverse events; no serious adverse events occurred.
Friday, July 18, 2025
Heyn-Sproul-Jackson syndrome
Inspired by a patient
Heyn P, Logan CV, Fluteau A, Challis RC, Auchynnikava T, Martin CA, Marsh JA, Taglini F, Kilanowski F, Parry DA, Cormier-Daire V, Fong CT, Gibson K, Hwa V, Ibáñez L, Robertson SP, Sebastiani G, Rappsilber J, Allshire RC, Reijns MAM, Dauber A, Sproul D, Jackson AP. Gain-of-function DNMT3A mutations cause microcephalic dwarfism and hypermethylation of Polycomb-regulated regions. Nat Genet. 2019 Jan;51(1):96-105. doi: 10.1038/s41588-018-0274-x. Epub 2018 Nov 26. PMID: 30478443; PMCID: PMC6520989.
Abstract
DNA methylation and Polycomb are key factors in the establishment of vertebrate cellular identity and fate. Here we report de novo missense mutations in DNMT3A, which encodes the DNA methyltransferase DNMT3A. These mutations cause microcephalic dwarfism, a hypocellular disorder of extreme global growth failure. Substitutions in the PWWP domain abrogate binding to the histone modifications H3K36me2 and H3K36me3, and alter DNA methylation in patient cells. Polycomb-associated DNA methylation valleys, hypomethylated domains encompassing developmental genes, become methylated with concomitant depletion of H3K27me3 and H3K4me3 bivalent marks. Such de novo DNA methylation occurs during differentiation of Dnmt3aW326R pluripotent cells in vitro, and is also evident in Dnmt3aW326R/+ dwarf mice. We therefore propose that the interaction of the DNMT3A PWWP domain with H3K36me2 and H3K36me3 normally limits DNA methylation of Polycomb-marked regions. Our findings implicate the interplay between DNA methylation and Polycomb at key developmental regulators as a determinant of organism size in mammals.
Kim GH, Kim J, Lee J, Jang DH. A novel pathogenic variant of DNMT3A associated with craniosynostosis: a case report of Heyn-Sproul-Jackson syndrome. Front Pediatr. 2023 May 25;11:1165638. doi: 10.3389/fped.2023.1165638. PMID: 37303757; PMCID: PMC10248406.
Abstract
Pathogenic variants of DNMT3A have been implicated in Tatton-Brown-Rahman syndrome, an overgrowth disorder with macrocephaly and intellectual disability. However, there are recent reports of variants in the same gene giving rise to an opposing clinical phenotype presenting with microcephaly, growth failure, and impaired development-named Heyn-Sproul-Jackson syndrome (HESJAS). Here, we present a case of HESJAS caused by a novel pathogenic variant of DNMT3A. A five-year-old girl presented with severe developmental delay. Perinatal and family history were non-contributory. Physical exam showed microcephaly and facial dysmorphic features, and neurodevelopmental assessments revealed profound global developmental delay. Brain magnetic resonance imaging findings were normal; however, brain 3D computed tomography revealed craniosynostosis. Next generation sequencing revealed a novel heterozygous variant in DNMT3A (NM_175629.2: c.1012_1014 + 3del). The patient's parents did not carry the variant. In this report, a novel feature associated with HESJAS (craniosynostosis) is described, along with a more detailed account of clinical manifestations than those in the original report.
Heyn P, Logan CV, Fluteau A, Challis RC, Auchynnikava T, Martin CA, Marsh JA, Taglini F, Kilanowski F, Parry DA, Cormier-Daire V, Fong CT, Gibson K, Hwa V, Ibáñez L, Robertson SP, Sebastiani G, Rappsilber J, Allshire RC, Reijns MAM, Dauber A, Sproul D, Jackson AP. Gain-of-function DNMT3A mutations cause microcephalic dwarfism and hypermethylation of Polycomb-regulated regions. Nat Genet. 2019 Jan;51(1):96-105. doi: 10.1038/s41588-018-0274-x. Epub 2018 Nov 26. PMID: 30478443; PMCID: PMC6520989.
Abstract
DNA methylation and Polycomb are key factors in the establishment of vertebrate cellular identity and fate. Here we report de novo missense mutations in DNMT3A, which encodes the DNA methyltransferase DNMT3A. These mutations cause microcephalic dwarfism, a hypocellular disorder of extreme global growth failure. Substitutions in the PWWP domain abrogate binding to the histone modifications H3K36me2 and H3K36me3, and alter DNA methylation in patient cells. Polycomb-associated DNA methylation valleys, hypomethylated domains encompassing developmental genes, become methylated with concomitant depletion of H3K27me3 and H3K4me3 bivalent marks. Such de novo DNA methylation occurs during differentiation of Dnmt3aW326R pluripotent cells in vitro, and is also evident in Dnmt3aW326R/+ dwarf mice. We therefore propose that the interaction of the DNMT3A PWWP domain with H3K36me2 and H3K36me3 normally limits DNA methylation of Polycomb-marked regions. Our findings implicate the interplay between DNA methylation and Polycomb at key developmental regulators as a determinant of organism size in mammals.
Kim GH, Kim J, Lee J, Jang DH. A novel pathogenic variant of DNMT3A associated with craniosynostosis: a case report of Heyn-Sproul-Jackson syndrome. Front Pediatr. 2023 May 25;11:1165638. doi: 10.3389/fped.2023.1165638. PMID: 37303757; PMCID: PMC10248406.
Abstract
Pathogenic variants of DNMT3A have been implicated in Tatton-Brown-Rahman syndrome, an overgrowth disorder with macrocephaly and intellectual disability. However, there are recent reports of variants in the same gene giving rise to an opposing clinical phenotype presenting with microcephaly, growth failure, and impaired development-named Heyn-Sproul-Jackson syndrome (HESJAS). Here, we present a case of HESJAS caused by a novel pathogenic variant of DNMT3A. A five-year-old girl presented with severe developmental delay. Perinatal and family history were non-contributory. Physical exam showed microcephaly and facial dysmorphic features, and neurodevelopmental assessments revealed profound global developmental delay. Brain magnetic resonance imaging findings were normal; however, brain 3D computed tomography revealed craniosynostosis. Next generation sequencing revealed a novel heterozygous variant in DNMT3A (NM_175629.2: c.1012_1014 + 3del). The patient's parents did not carry the variant. In this report, a novel feature associated with HESJAS (craniosynostosis) is described, along with a more detailed account of clinical manifestations than those in the original report.
Thursday, July 17, 2025
3 parent children
Eight healthy babies have been born in the UK using a new IVF technique that successfully reduced their risk of inheriting genetic diseases from their mothers, the results of a world-first trial said Wednesday.
The findings were hailed as a breakthrough which raises hopes that women with mutations in their mitochondrial DNA could one day have children without passing debilitating or deadly diseases on to the children.
One out of every 5,000 births is affected by mitochondrial diseases, which cannot be treated, and include symptoms such as impaired vision, diabetes and muscle wasting.
In 2015, Britain became the first country to approve an in-vitro fertilisation (IVF) technique that uses a small amount of healthy mitochondrial DNA from the egg of a donor – along with the mother's egg and father's sperm.
Some have called the result of this process "three-parent babies", though researchers have pushed back at this term because only roughly 0.1 percent of the newborn's DNA comes from the donor.
The results of the much-awaited UK trial were published in several papers in the New England Journal of Medicine.
'Important reproductive option'
Out of 22 women to undergo the treatment at the Newcastle Fertility Centre in northeast England, eight babies were born. The four boys and four girls now range from under six months to over two years old.
The amount of mutated mitochondrial DNA – which causes disease – was reduced by 95-100 percent in six of the babies, according to the research.
For the other two newborns, the amount fell by 77-88 percent, which is below the range that causes disease.
This indicates the technique was "effective in reducing transmission" of diseases between mother and child, one of the studies said.
The eight children are currently healthy, though one had a disturbance of their heart's rhythm which was successfully treated, the researchers said.
Their health will be followed up over the coming years to see if problems arise.
Nils-Goran Larsson, a Swedish reproductive expert not involved in the research, hailed the "breakthrough".
The new technique offers a "very important reproductive option" for families affected by "devastating" mitochondrial diseases, he added.
Ethical review
Mitochondrial donation remains controversial and has not been approved in many countries, including the United States and France.
Religious leaders have opposed the procedure because it involves the destruction of human embryos. Other opponents have expressed fears it could pave the way for genetically engineered "designer babies".
An ethical review carried out by the UK's independent Nuffield Council on Bioethics was "instrumental" in conducting the new research, the council's director Danielle Hamm said Wednesday.
Peter Thompson, head of the UK's Human Fertilisation and Embryology Authority which approved the procedure, said only people with a "very high risk" of passing on a mitochondrial disease would be eligible for the treatment.
Ethical concerns have also been raised over the use of mitochondrial donation for infertility in Greece and Ukraine.
French mitochondrial disease specialist Julie Stefann told AFP that "it is a question of the risk-benefit ratio: for a mitochondrial disease, the benefit is obvious".
"In the context of infertility, it has not been proven," she added.
Oxford University reproductive genetics expert Dagan Wells observed that "some scientists will be a little disappointed that so much time and effort has, so far, only led to the birth of eight children".
Among the children being closely monitored are three that showed some signs of what is known as "reversal", which is still little understood.
It is "a phenomenon where the therapy initially succeeds in producing an embryo with very few defective mitochondria, but by the time the child is born the proportion of abnormal mitochondria in its cells has significantly increased," he explained.
https://www.sciencealert.com/8-babies-born-in-uk-using-radical-three-parent-ivf-technique
Louise A. Hyslop, Emma L. Blakely, Magomet Aushev, Jordan Marley, Yuko Takeda, Angela Pyle, Eilis Moody, et al. Mitochondrial Donation and Preimplantation Genetic Testing for mtDNA Disease. Published July 16, 2025 DOI: 10.1056/NEJMoa2415539
Abstract
Background
Children born to women who carry pathogenic variants in mitochondrial DNA (mtDNA) are at risk for a range of clinical syndromes collectively known as mtDNA disease. Mitochondrial donation by pronuclear transfer involves transplantation of nuclear genome from a fertilized egg from the affected woman to an enucleated fertilized egg donated by an unaffected woman. Thus, pronuclear transfer offers affected women the potential to have a genetically related child with a reduced risk of mtDNA disease.
Methods
We offered mitochondrial donation (by pronuclear transfer) or preimplantation genetic testing (PGT) to a series of women with pathogenic mtDNA variants who sought to reduce the transmission of these variants to their children. Patients with heteroplasmy (variants present in a proportion of copies of mtDNA) were offered PGT, and patients with homoplasmy (variants present in all copies of mtDNA) or elevated heteroplasmy were offered pronuclear transfer.
Results
Clinical pregnancies were confirmed in 8 of 22 patients (36%) and 16 of 39 patients (41%) who underwent an intracytoplasmic sperm injection procedure for pronuclear transfer or for PGT, respectively. Pronuclear transfer resulted in 8 live births and 1 ongoing pregnancy. PGT resulted in 18 live births. Heteroplasmy levels in the blood of the 8 infants whose mothers underwent pronuclear transfer ranged from undetectable to 16%. Levels of the maternal pathogenic mtDNA variant were 95 to 100% lower in 6 newborns and 77 to 88% lower in 2 newborns than in the corresponding enucleated zygotes. Heteroplasmy levels were known for 10 of the 18 infants whose mothers underwent PGT and ranged from undetectable to 7%.
Conclusions
We found that mitochondrial donation through pronuclear transfer was compatible with human embryo viability. An integrated program involving pronuclear transfer and PGT was effective in reducing the transmission of homoplasmic and heteroplasmic pathogenic mtDNA variants. (Funded by NHS England and others.)
Robert McFarland, Louise A. Hyslop, Catherine Feeney, Rekha N. Pillai, Emma L. Blakely, Eilis Moody, Matthew Prior, Ph.D., et al. Mitochondrial Donation in a Reproductive Care Pathway for mtDNA Disease Mitochondrial Donation in a Reproductive Care Pathway for mtDNA Disease. Published July 16, 2025. DOI: 10.1056/NEJMoa2503658
Summary
Pathogenic variants in mitochondrial DNA (mtDNA) are a common cause of severe, often fatal, inherited metabolic disease. A reproductive care pathway was implemented to provide women carrying pathogenic mtDNA variants with reproductive options. A total of 22 women with pathogenic mtDNA variants have commenced or completed pronuclear transfer (and thus receipt of a mitochondrial donation), and there have been 8 live births. All 8 children were healthy at birth, with no or low levels of mtDNA heteroplasmy in blood. Hyperlipidemia and cardiac arrhythmia developed in a child whose mother had hyperlipidemia during pregnancy; both of the child’s conditions responded to treatment. Infant myoclonic epilepsy developed in another child, with spontaneous remission. At the time of this report, all the children have made normal developmental progress. (Funded by the U.K. National Health Service and others.)
The findings were hailed as a breakthrough which raises hopes that women with mutations in their mitochondrial DNA could one day have children without passing debilitating or deadly diseases on to the children.
One out of every 5,000 births is affected by mitochondrial diseases, which cannot be treated, and include symptoms such as impaired vision, diabetes and muscle wasting.
In 2015, Britain became the first country to approve an in-vitro fertilisation (IVF) technique that uses a small amount of healthy mitochondrial DNA from the egg of a donor – along with the mother's egg and father's sperm.
Some have called the result of this process "three-parent babies", though researchers have pushed back at this term because only roughly 0.1 percent of the newborn's DNA comes from the donor.
The results of the much-awaited UK trial were published in several papers in the New England Journal of Medicine.
'Important reproductive option'
Out of 22 women to undergo the treatment at the Newcastle Fertility Centre in northeast England, eight babies were born. The four boys and four girls now range from under six months to over two years old.
The amount of mutated mitochondrial DNA – which causes disease – was reduced by 95-100 percent in six of the babies, according to the research.
For the other two newborns, the amount fell by 77-88 percent, which is below the range that causes disease.
This indicates the technique was "effective in reducing transmission" of diseases between mother and child, one of the studies said.
The eight children are currently healthy, though one had a disturbance of their heart's rhythm which was successfully treated, the researchers said.
Their health will be followed up over the coming years to see if problems arise.
Nils-Goran Larsson, a Swedish reproductive expert not involved in the research, hailed the "breakthrough".
The new technique offers a "very important reproductive option" for families affected by "devastating" mitochondrial diseases, he added.
Ethical review
Mitochondrial donation remains controversial and has not been approved in many countries, including the United States and France.
Religious leaders have opposed the procedure because it involves the destruction of human embryos. Other opponents have expressed fears it could pave the way for genetically engineered "designer babies".
An ethical review carried out by the UK's independent Nuffield Council on Bioethics was "instrumental" in conducting the new research, the council's director Danielle Hamm said Wednesday.
Peter Thompson, head of the UK's Human Fertilisation and Embryology Authority which approved the procedure, said only people with a "very high risk" of passing on a mitochondrial disease would be eligible for the treatment.
Ethical concerns have also been raised over the use of mitochondrial donation for infertility in Greece and Ukraine.
French mitochondrial disease specialist Julie Stefann told AFP that "it is a question of the risk-benefit ratio: for a mitochondrial disease, the benefit is obvious".
"In the context of infertility, it has not been proven," she added.
Oxford University reproductive genetics expert Dagan Wells observed that "some scientists will be a little disappointed that so much time and effort has, so far, only led to the birth of eight children".
Among the children being closely monitored are three that showed some signs of what is known as "reversal", which is still little understood.
It is "a phenomenon where the therapy initially succeeds in producing an embryo with very few defective mitochondria, but by the time the child is born the proportion of abnormal mitochondria in its cells has significantly increased," he explained.
https://www.sciencealert.com/8-babies-born-in-uk-using-radical-three-parent-ivf-technique
Louise A. Hyslop, Emma L. Blakely, Magomet Aushev, Jordan Marley, Yuko Takeda, Angela Pyle, Eilis Moody, et al. Mitochondrial Donation and Preimplantation Genetic Testing for mtDNA Disease. Published July 16, 2025 DOI: 10.1056/NEJMoa2415539
Abstract
Background
Children born to women who carry pathogenic variants in mitochondrial DNA (mtDNA) are at risk for a range of clinical syndromes collectively known as mtDNA disease. Mitochondrial donation by pronuclear transfer involves transplantation of nuclear genome from a fertilized egg from the affected woman to an enucleated fertilized egg donated by an unaffected woman. Thus, pronuclear transfer offers affected women the potential to have a genetically related child with a reduced risk of mtDNA disease.
Methods
We offered mitochondrial donation (by pronuclear transfer) or preimplantation genetic testing (PGT) to a series of women with pathogenic mtDNA variants who sought to reduce the transmission of these variants to their children. Patients with heteroplasmy (variants present in a proportion of copies of mtDNA) were offered PGT, and patients with homoplasmy (variants present in all copies of mtDNA) or elevated heteroplasmy were offered pronuclear transfer.
Results
Clinical pregnancies were confirmed in 8 of 22 patients (36%) and 16 of 39 patients (41%) who underwent an intracytoplasmic sperm injection procedure for pronuclear transfer or for PGT, respectively. Pronuclear transfer resulted in 8 live births and 1 ongoing pregnancy. PGT resulted in 18 live births. Heteroplasmy levels in the blood of the 8 infants whose mothers underwent pronuclear transfer ranged from undetectable to 16%. Levels of the maternal pathogenic mtDNA variant were 95 to 100% lower in 6 newborns and 77 to 88% lower in 2 newborns than in the corresponding enucleated zygotes. Heteroplasmy levels were known for 10 of the 18 infants whose mothers underwent PGT and ranged from undetectable to 7%.
Conclusions
We found that mitochondrial donation through pronuclear transfer was compatible with human embryo viability. An integrated program involving pronuclear transfer and PGT was effective in reducing the transmission of homoplasmic and heteroplasmic pathogenic mtDNA variants. (Funded by NHS England and others.)
Robert McFarland, Louise A. Hyslop, Catherine Feeney, Rekha N. Pillai, Emma L. Blakely, Eilis Moody, Matthew Prior, Ph.D., et al. Mitochondrial Donation in a Reproductive Care Pathway for mtDNA Disease Mitochondrial Donation in a Reproductive Care Pathway for mtDNA Disease. Published July 16, 2025. DOI: 10.1056/NEJMoa2503658
Summary
Pathogenic variants in mitochondrial DNA (mtDNA) are a common cause of severe, often fatal, inherited metabolic disease. A reproductive care pathway was implemented to provide women carrying pathogenic mtDNA variants with reproductive options. A total of 22 women with pathogenic mtDNA variants have commenced or completed pronuclear transfer (and thus receipt of a mitochondrial donation), and there have been 8 live births. All 8 children were healthy at birth, with no or low levels of mtDNA heteroplasmy in blood. Hyperlipidemia and cardiac arrhythmia developed in a child whose mother had hyperlipidemia during pregnancy; both of the child’s conditions responded to treatment. Infant myoclonic epilepsy developed in another child, with spontaneous remission. At the time of this report, all the children have made normal developmental progress. (Funded by the U.K. National Health Service and others.)
See: https://childnervoussystem.blogspot.com/2015/02/babies-with-3-genetic-parents.html
Wednesday, July 16, 2025
Diffuse intrinsic pontine glioma 6
Nonnenbroich LF, Bouchal SM, Millesi E, Rechberger JS, Khatua S, Daniels DJ. H3K27-Altered Diffuse Midline Glioma of the Brainstem: From Molecular Mechanisms to Targeted Interventions. Cells. 2024 Jun 28;13(13):1122. doi: 10.3390/cells13131122. PMID: 38994974; PMCID: PMC11240752.
Abstract
Pediatric high-grade gliomas are a devastating subset of brain tumors, characterized by their aggressive pathophysiology and limited treatment options. Among them, H3 K27-altered diffuse midline gliomas (DMG) of the brainstem stand out due to their distinct molecular features and dismal prognosis. Recent advances in molecular profiling techniques have unveiled the critical role of H3 K27 alterations, particularly a lysine-to-methionine mutation on position 27 (K27M) of the histone H3 tail, in the pathogenesis of DMG. These mutations result in epigenetic dysregulation, which leads to altered chromatin structure and gene expression patterns in DMG tumor cells, ultimately contributing to the aggressive phenotype of DMG. The exploration of targeted therapeutic avenues for DMG has gained momentum in recent years. Therapies, including epigenetic modifiers, kinase inhibitors, and immunotherapies, are under active investigation; these approaches aim to disrupt aberrant signaling cascades and overcome the various mechanisms of therapeutic resistance in DMG. Challenges, including blood-brain barrier penetration and DMG tumor heterogeneity, require innovative approaches to improve drug delivery and personalized treatment strategies. This review aims to provide a comprehensive overview of the evolving understanding of DMG, focusing on the intricate molecular mechanisms driving tumorigenesis/tumor progression and the current landscape of emerging targeted interventions.
Weisbrod LJ, Thiraviyam A, Vengoji R, Shonka N, Jain M, Ho W, Batra SK, Salehi A. Diffuse intrinsic pontine glioma (DIPG): A review of current and emerging treatment strategies. Cancer Lett. 2024 May 28;590:216876. doi: 10.1016/j.canlet.2024.216876. Epub 2024 Apr 10. PMID: 38609002; PMCID: PMC11231989.
Abstract
Diffuse intrinsic pontine glioma (DIPG) is a childhood malignancy of the brainstem with a dismal prognosis. Despite recent advances in its understanding at the molecular level, the prognosis of DIPG has remained unchanged. This article aims to review the current understanding of the genetic pathophysiology of DIPG and to highlight promising therapeutic targets. Various DIPG treatment strategies have been investigated in pre-clinical studies, several of which have shown promise and have been subsequently translated into ongoing clinical trials. Ultimately, a multifaceted therapeutic approach that targets cell-intrinsic alterations, the micro-environment, and augments the immune system will likely be necessary to eradicate DIPG.
Damodharan S, Lara-Velazquez M, Williamsen BC, Helgager J, Dey M. Diffuse Intrinsic Pontine Glioma: Molecular Landscape, Evolving Treatment Strategies and Emerging Clinical Trials. J Pers Med. 2022 May 20;12(5):840. doi: 10.3390/jpm12050840. PMID: 35629262; PMCID: PMC9144327.
Abstract
Diffuse intrinsic pontine glioma (DIPG) is a type of intrinsic brainstem glial tumor that occurs primarily in the pediatric population. DIPG is initially diagnosed based on clinical symptoms and the characteristic location on imaging. Histologically, these tumors are characterized by a heterogenous population of cells with multiple genetic mutations and high infiltrative capacity. The most common mutation seen in this group is a lysine to methionine point mutation seen at position 27 (K27M) within histone 3 (H3). Tumors with the H3 K27M mutation, are considered grade 4 and are now categorized within the H3 K27-altered diffuse midline glioma category by World Health Organization classification. Due to its critical location and aggressive nature, DIPG is resistant to the most eradicative treatment and is universally fatal; however, modern advances in the surgical techniques resulting in safe biopsy of the lesion have significantly improved our understanding of this disease at the molecular level. Genomic analysis has shown several mutations that play a role in the pathophysiology of the disease and can be targeted therapeutically. In this review, we will elaborate on DIPG from general aspects and the evolving molecular landscape. We will also review innovative therapeutic options that have been trialed along with new promising treatments on the horizon.
Abstract
Pediatric high-grade gliomas are a devastating subset of brain tumors, characterized by their aggressive pathophysiology and limited treatment options. Among them, H3 K27-altered diffuse midline gliomas (DMG) of the brainstem stand out due to their distinct molecular features and dismal prognosis. Recent advances in molecular profiling techniques have unveiled the critical role of H3 K27 alterations, particularly a lysine-to-methionine mutation on position 27 (K27M) of the histone H3 tail, in the pathogenesis of DMG. These mutations result in epigenetic dysregulation, which leads to altered chromatin structure and gene expression patterns in DMG tumor cells, ultimately contributing to the aggressive phenotype of DMG. The exploration of targeted therapeutic avenues for DMG has gained momentum in recent years. Therapies, including epigenetic modifiers, kinase inhibitors, and immunotherapies, are under active investigation; these approaches aim to disrupt aberrant signaling cascades and overcome the various mechanisms of therapeutic resistance in DMG. Challenges, including blood-brain barrier penetration and DMG tumor heterogeneity, require innovative approaches to improve drug delivery and personalized treatment strategies. This review aims to provide a comprehensive overview of the evolving understanding of DMG, focusing on the intricate molecular mechanisms driving tumorigenesis/tumor progression and the current landscape of emerging targeted interventions.
Weisbrod LJ, Thiraviyam A, Vengoji R, Shonka N, Jain M, Ho W, Batra SK, Salehi A. Diffuse intrinsic pontine glioma (DIPG): A review of current and emerging treatment strategies. Cancer Lett. 2024 May 28;590:216876. doi: 10.1016/j.canlet.2024.216876. Epub 2024 Apr 10. PMID: 38609002; PMCID: PMC11231989.
Abstract
Diffuse intrinsic pontine glioma (DIPG) is a childhood malignancy of the brainstem with a dismal prognosis. Despite recent advances in its understanding at the molecular level, the prognosis of DIPG has remained unchanged. This article aims to review the current understanding of the genetic pathophysiology of DIPG and to highlight promising therapeutic targets. Various DIPG treatment strategies have been investigated in pre-clinical studies, several of which have shown promise and have been subsequently translated into ongoing clinical trials. Ultimately, a multifaceted therapeutic approach that targets cell-intrinsic alterations, the micro-environment, and augments the immune system will likely be necessary to eradicate DIPG.
Damodharan S, Lara-Velazquez M, Williamsen BC, Helgager J, Dey M. Diffuse Intrinsic Pontine Glioma: Molecular Landscape, Evolving Treatment Strategies and Emerging Clinical Trials. J Pers Med. 2022 May 20;12(5):840. doi: 10.3390/jpm12050840. PMID: 35629262; PMCID: PMC9144327.
Abstract
Diffuse intrinsic pontine glioma (DIPG) is a type of intrinsic brainstem glial tumor that occurs primarily in the pediatric population. DIPG is initially diagnosed based on clinical symptoms and the characteristic location on imaging. Histologically, these tumors are characterized by a heterogenous population of cells with multiple genetic mutations and high infiltrative capacity. The most common mutation seen in this group is a lysine to methionine point mutation seen at position 27 (K27M) within histone 3 (H3). Tumors with the H3 K27M mutation, are considered grade 4 and are now categorized within the H3 K27-altered diffuse midline glioma category by World Health Organization classification. Due to its critical location and aggressive nature, DIPG is resistant to the most eradicative treatment and is universally fatal; however, modern advances in the surgical techniques resulting in safe biopsy of the lesion have significantly improved our understanding of this disease at the molecular level. Genomic analysis has shown several mutations that play a role in the pathophysiology of the disease and can be targeted therapeutically. In this review, we will elaborate on DIPG from general aspects and the evolving molecular landscape. We will also review innovative therapeutic options that have been trialed along with new promising treatments on the horizon.
From the article:
Figure 1. DIPG Imaging Findings. MRI of the brain with and without gadolinium in a child with an H3 K27-altered, DIPG. The imaging demonstrates a sagittal T1 hypointense (A) and axial T2 hyperintense (B) lesion with homogeneous enhancement along with obstruction within the fourth ventricle of the brain occupying almost half of the axial diameter.
Perrone MG, Ruggiero A, Centonze A, Carrieri A, Ferorelli S, Scilimati A. Diffuse Intrinsic Pontine Glioma (DIPG): Breakthrough and Clinical Perspective. Curr Med Chem. 2021;28(17):3287-3317. doi: 10.2174/0929867327666200806110206. PMID: 32767913.
Abstract
Diffuse intrinsic pontine glioma (DIPG) mainly affects children with a median age of 6-7 years old. It accounts for 10% of all pediatric tumors. Unfortunately, DIPG has a poor prognosis, and the median survival is generally less than 16-24 months independently from the treatment received. Up to now, children with DIPG are treated with focal radiotherapy alone or in combination with antitumor agents. In the last decade, ONC201 known as dopamine receptor antagonist was uncovered, by a high throughput screening of public libraries of compounds, to be endowed with cytotoxic activity against several cancer cell lines. Efforts were made to identify the real ONC201 target, responsible for its antiproliferative effect. The hypothesized targets were the Tumor necrosis factor-Related Apoptosis-Inducing Ligand stimulation (TRAIL), two oncogenic kinases (ERK/AKT system) that target the same tumor-suppressor gene (FOXO3a), dopamine receptors (DRD2 and DRD3 subtypes) and finally the mitochondrial Caseynolitic Protease P (ClpP). ONC201 structure-activity relationship is extensively discussed in this review, together with other two classes of compounds, namely ADEPs and D9, already known for their antibiotic activity but noteworthy to be discussed and studied as potential "leads" for the development of new drugs to be used in the treatment of DIPG. In this review, a detailed and critical description of ONC201, ADEPs, and D9 pro-apoptotic activity is made, with particular attention to the specific interactions established with its targets that also are intimately described. Pubmed published patents and clinical trial reports of the last ten years were used as the bibliographic source.
________________________________________________________________________
If you search Facebook https://www.facebook.com/search/top/?q=H3K27%20%20Diffuse%20Intrinsic%20Pontine%20Glioma you will find heart-breaking story after story like the one below.
It is with a heavy heart that Lynn and I write this post.
Mackenzie Lynn Barron, our beautiful 3 year old daughter was just diagnosed with a super rare brain cancer.
Diffuse Intrinsic Pontine Glioma.
She fell about 8 weeks ago and hit her head hard enough that we had to take her to the emergency room. During a routine CT scan, they saw a bright spot on her brain. At the time they didn't know if it was something or just static. They ordered up and MRI that was finally performed on June 15th, 2018.
Lynn and I learned of the diagnoses Yesterday at the MRI reading with the doctor.
The Doctor was visibly shaken while trying to give us the news. As of now, there is no chemo therapy available, no cure, no treatments outside of radiation. Radiation therapy may reduce the tumor, thus prolonging the inevitable.
There are less then 300 children diagnosed with this cancer every year. We were informed that the average expected time is 18 mos.
We go see her Oncologist and radiologist this coming Monday to discuss all options available. We are requesting a second opinion be performed through St. Jude's Hospital.
Our hearts are broken and we need all the prayer and love our family and friends can give. We are so far away and feel so alone, it is unbearable.
Please ask God to look over our Mackenzie and move those mountains.
At this time we request that no phone calls or text messages until Monday evening. Allow us this weekend with our baby girl to make some memories and process this news.
Thank you everyone for your thoughts and prayers
Thomas, Lynn, Noah, Kayla and Mackenzie
_________________________________________________________________________
A 13-year-old named Lucas from Belgium has become the world's first known child cured of diffuse intrinsic pontine glioma (DIPG), a rare and aggressive brain cancer.
After a seven-year journey through treatments, there is no trace of the tumour remaining, according to Dr Jacques Grill, head of the brain tumour program at the Gustave Roussy Cancer Center in Paris.
DIPG, aka diffuse intrinsic pontine glioma, is known for its aggressive nature and lack of effective treatment options, with only around 300 children in the United States and 100 in France diagnosed each year.
This type of childhood cancer forms in the brainstem. It is very rare and almost always occurs in the paediatric population.
However, the outlook for DIPG remains bleak, with most children not surviving beyond a year post-diagnosis, and only 10 percent alive two years later, according to recent studies.
Lucas and his family participated in the BIOMEDE trial in France, testing potential new drugs for DIPG. Remarkably, Lucas responded positively to the cancer drug Everolimus, which he was randomly assigned, leading to the complete disappearance of the tumour.
Dr Grill, as per news agency AFP, noted that Lucas's case is unique globally. But the exact reasons for his full recovery and its potential implications for other children are yet to be fully understood.
While seven other children in the trial survived for years after diagnosis, Lucas's case is exceptional as his tumour vanished entirely.
Dr Grill suggested that the unique response could be linked to the "biological particularities" of each child's tumour, with Lucas having an extremely rare mutation that made his tumour cells highly sensitive to the drug.
https://www.indiatoday.in/health/story/13-year-old-becomes-worlds-first-child-to-beat-rare-brain-cancer-in-drug-trial-2502682-2024-02-15?fbclid=IwY2xjawLlWS5leHRuA2FlbQIxMQABHiytoD0GQ-rfRYL4nCcDi6ry2F2CE7toOqIOkRUJZRiRe_Ci0sEMfkQrfy9z_aem_F8rAkgaCw8LthjewUFYfHw
25 years. A quarter century. 25 years ago I was diagnosed with terminal brain cancer called Diffuse Intrinsic Pontine Glioma (DIPG). Like so many other parents, mine were told there was almost no hope and that they should go home and make memories while they could, because I probably wouldnt make it a year. 25 years of hospital visits, MRIs, PET scans, blood tests, and meeting with doctors from around the world. 25 years of worrying about what my next check up would show. 25 years of meeting new kids who have the same diagnosis, none of whom deserved it. I think the most frustrating thing is that 25 years later, the treatment options and survival rate have not changed.
Its pretty fitting that September, the month I celebrate making it another year, is childhood cancer awareness month. Childhood cancers are the leading cause of death by disease for children under the age of 19 yet only 4 percent of government cancer funding is devoted to researching childhood cancers. This is unacceptable. We need to do better. These kids deserve better. Even if kids survive their cancer, they are usually left with health problems down the line. I havent had any treatment since I was 12, but im still dealing with the effects of that treatment. I’m a lucky one though because im still able to live a normal life, many kids don’t get that chance. The first step in helping is awareness. Awareness is power. Awareness leads to funding. Funding leads to research, and research leads to a cure. As I’ve grown older, I've realized just how lucky I am. No one can explain why I've remained stable for so long. I was given a second chance and I will not stop using my voice to raise awareness and to help these families.
https://www.facebook.com/search/top/?q=H3K27%20%20Diffuse%20Intrinsic%20Pontine%20Glioma
Abstract
Diffuse intrinsic pontine glioma (DIPG) mainly affects children with a median age of 6-7 years old. It accounts for 10% of all pediatric tumors. Unfortunately, DIPG has a poor prognosis, and the median survival is generally less than 16-24 months independently from the treatment received. Up to now, children with DIPG are treated with focal radiotherapy alone or in combination with antitumor agents. In the last decade, ONC201 known as dopamine receptor antagonist was uncovered, by a high throughput screening of public libraries of compounds, to be endowed with cytotoxic activity against several cancer cell lines. Efforts were made to identify the real ONC201 target, responsible for its antiproliferative effect. The hypothesized targets were the Tumor necrosis factor-Related Apoptosis-Inducing Ligand stimulation (TRAIL), two oncogenic kinases (ERK/AKT system) that target the same tumor-suppressor gene (FOXO3a), dopamine receptors (DRD2 and DRD3 subtypes) and finally the mitochondrial Caseynolitic Protease P (ClpP). ONC201 structure-activity relationship is extensively discussed in this review, together with other two classes of compounds, namely ADEPs and D9, already known for their antibiotic activity but noteworthy to be discussed and studied as potential "leads" for the development of new drugs to be used in the treatment of DIPG. In this review, a detailed and critical description of ONC201, ADEPs, and D9 pro-apoptotic activity is made, with particular attention to the specific interactions established with its targets that also are intimately described. Pubmed published patents and clinical trial reports of the last ten years were used as the bibliographic source.
________________________________________________________________________
If you search Facebook https://www.facebook.com/search/top/?q=H3K27%20%20Diffuse%20Intrinsic%20Pontine%20Glioma you will find heart-breaking story after story like the one below.
It is with a heavy heart that Lynn and I write this post.
Mackenzie Lynn Barron, our beautiful 3 year old daughter was just diagnosed with a super rare brain cancer.
Diffuse Intrinsic Pontine Glioma.
She fell about 8 weeks ago and hit her head hard enough that we had to take her to the emergency room. During a routine CT scan, they saw a bright spot on her brain. At the time they didn't know if it was something or just static. They ordered up and MRI that was finally performed on June 15th, 2018.
Lynn and I learned of the diagnoses Yesterday at the MRI reading with the doctor.
The Doctor was visibly shaken while trying to give us the news. As of now, there is no chemo therapy available, no cure, no treatments outside of radiation. Radiation therapy may reduce the tumor, thus prolonging the inevitable.
There are less then 300 children diagnosed with this cancer every year. We were informed that the average expected time is 18 mos.
We go see her Oncologist and radiologist this coming Monday to discuss all options available. We are requesting a second opinion be performed through St. Jude's Hospital.
Our hearts are broken and we need all the prayer and love our family and friends can give. We are so far away and feel so alone, it is unbearable.
Please ask God to look over our Mackenzie and move those mountains.
At this time we request that no phone calls or text messages until Monday evening. Allow us this weekend with our baby girl to make some memories and process this news.
Thank you everyone for your thoughts and prayers
Thomas, Lynn, Noah, Kayla and Mackenzie
_________________________________________________________________________
A 13-year-old named Lucas from Belgium has become the world's first known child cured of diffuse intrinsic pontine glioma (DIPG), a rare and aggressive brain cancer.
After a seven-year journey through treatments, there is no trace of the tumour remaining, according to Dr Jacques Grill, head of the brain tumour program at the Gustave Roussy Cancer Center in Paris.
DIPG, aka diffuse intrinsic pontine glioma, is known for its aggressive nature and lack of effective treatment options, with only around 300 children in the United States and 100 in France diagnosed each year.
This type of childhood cancer forms in the brainstem. It is very rare and almost always occurs in the paediatric population.
However, the outlook for DIPG remains bleak, with most children not surviving beyond a year post-diagnosis, and only 10 percent alive two years later, according to recent studies.
Lucas and his family participated in the BIOMEDE trial in France, testing potential new drugs for DIPG. Remarkably, Lucas responded positively to the cancer drug Everolimus, which he was randomly assigned, leading to the complete disappearance of the tumour.
Dr Grill, as per news agency AFP, noted that Lucas's case is unique globally. But the exact reasons for his full recovery and its potential implications for other children are yet to be fully understood.
While seven other children in the trial survived for years after diagnosis, Lucas's case is exceptional as his tumour vanished entirely.
Dr Grill suggested that the unique response could be linked to the "biological particularities" of each child's tumour, with Lucas having an extremely rare mutation that made his tumour cells highly sensitive to the drug.
https://www.indiatoday.in/health/story/13-year-old-becomes-worlds-first-child-to-beat-rare-brain-cancer-in-drug-trial-2502682-2024-02-15?fbclid=IwY2xjawLlWS5leHRuA2FlbQIxMQABHiytoD0GQ-rfRYL4nCcDi6ry2F2CE7toOqIOkRUJZRiRe_Ci0sEMfkQrfy9z_aem_F8rAkgaCw8LthjewUFYfHw
25 years. A quarter century. 25 years ago I was diagnosed with terminal brain cancer called Diffuse Intrinsic Pontine Glioma (DIPG). Like so many other parents, mine were told there was almost no hope and that they should go home and make memories while they could, because I probably wouldnt make it a year. 25 years of hospital visits, MRIs, PET scans, blood tests, and meeting with doctors from around the world. 25 years of worrying about what my next check up would show. 25 years of meeting new kids who have the same diagnosis, none of whom deserved it. I think the most frustrating thing is that 25 years later, the treatment options and survival rate have not changed.
Its pretty fitting that September, the month I celebrate making it another year, is childhood cancer awareness month. Childhood cancers are the leading cause of death by disease for children under the age of 19 yet only 4 percent of government cancer funding is devoted to researching childhood cancers. This is unacceptable. We need to do better. These kids deserve better. Even if kids survive their cancer, they are usually left with health problems down the line. I havent had any treatment since I was 12, but im still dealing with the effects of that treatment. I’m a lucky one though because im still able to live a normal life, many kids don’t get that chance. The first step in helping is awareness. Awareness is power. Awareness leads to funding. Funding leads to research, and research leads to a cure. As I’ve grown older, I've realized just how lucky I am. No one can explain why I've remained stable for so long. I was given a second chance and I will not stop using my voice to raise awareness and to help these families.
https://www.facebook.com/search/top/?q=H3K27%20%20Diffuse%20Intrinsic%20Pontine%20Glioma
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