Brain death determination controversy

Courtesy of my son

Annelise Camp, a 2-year-old girl whose parents sued to stop Texas Children’s Hospital from testing if she’s brain dead, died Monday after her breathing tube was removed.

In social media posts, Annelise’s family confirmed her death, ending a months-long legal dispute over whether hospitals need a family’s consent to test a patient for brain death. The New York Times first reported her death.

“Annelise is now with Jesus,” wrote her parents, Johnston Camp and Joy Camp, on the family’s GoFundMe page. “We pray that her legacy continues to inspire compassion, encourage meaningful change, and bring hope to families for years to come.”

                                   https://www.instagram.com/p/Dby1T05HxBT/

Rep. Steve Toth, R-The Woodlands, who has been in contact with Annelise’s father, said the family just told Annelise’s two siblings of her death.

“It’s been traumatic for the family,” said Toth in an interview with the Texas Tribune.

The Camps’ lawsuit, filed at the end of May, was part of a larger debate supported by anti-abortion advocates that challenged the use of brain death testing. The Camps had hoped that by preventing brain death testing and a determination of whether their daughter was brain dead, hospitals would be forced to keep Annelise on life-supporting services for as long as possible.

Under Texas law, brain death is the irreversible cessation of all brain function and hospitals are not required to obtain family consent before conducting the tests. Once a patient is declared brain dead, hospitals can withdraw life sustaining measures.

It is unclear why Annelise was extubated. According to a Facebook post from Steven Camp, her grandfather, Annelise passed shortly after the breathing tube was removed. The Camp family has not responded to requests for comment.

The family said in court filings that the testing conflicted with their religious beliefs. Texas Right to Life, who worked with the family, argued that a patient is alive as long as their heart is beating, even when breathing is sustained by a ventilator.

On Memorial Day, Annelise was pulled from a hotel swimming pool and taken to Texas Children’s Hospital, where she was placed on a ventilator. After three days, doctors said they had exhausted treatment options and recommended evaluating her for brain death to which her parents began legal action to block testing.

Annelise was transferred from Texas Children’s Hospital in Houston to Ochsner Medical Center in New Orleans, but was transferred back to a Texas hospital, Christus Mother Frances Hospital in Tyler, about a week ago, Toth said.

Toth hopes Annelise’s story will influence change by giving families in Texas and across the country more time on life-support services.

“Life is fragile, it shouldn’t be disposable,” Toth said.

Disclosure: Texas Children’s Hospital and The New York Times have been financial supporters of The Texas Tribune, a nonprofit, nonpartisan news organization that is funded in part by donations from members, foundations and corporate sponsors. Financial supporters play no role in The Texas Tribune’s journalism. Find a complete list of them here.

Katlyn Ma

https://www.texastribune.org/2026/08/07/texas-brain-death-testing-annelise-camp/

What happens when medical students rely on AI

Courtesy of my son

What happens when medical students rely on AI – and never develop their own judgment?

AI’s danger isn’t just in experts losing the ability to reason. It’s that trainees may never learn how to do so in the first place

In healthcare, there’s growing concern over doctors becoming less clinically adept as they increasingly rely on AI tools. But what about the trainees – medical students, residents and fellows – who are using these tools before they have built their own clinical judgment? The idea of deskilling implies that someone possessed an ability and then lost it. Here, the danger is not just deskilling but never-skilling. Although a doctor who has forgotten how to reason is recoverable, one who never learned how may not be.

OpenEvidence, essentially an AI chatbot for clinicians, has given this concern its most concrete form. About two-thirds of US doctors actively use OpenEvidence, asking about puzzling symptoms, drug interactions and clinical guidelines, getting responses within seconds, anchored in the latest research. Trainees, unsurprisingly, have also begun to use this AI tool in many of the same ways – but at a far more formative stage.

For example, trainees once asked to build a list of potential diagnoses might struggle and offer an incomplete set, learning what they missed, sometimes painfully. Now, trainees can simply ask OpenEvidence and get a nearly perfect answer, complete with possibilities they might have never considered and none of the embarrassment of having overlooked them. Repeating this answer on the wards may make the trainee look prepared and even impress the supervising doctor.

However, this performance can also conceal the very deficit that training is meant to reveal: that the struggle is the point. Medical training, more than most professions, is an apprenticeship. A student becomes a resident, a resident becomes a fellow, and a fellow becomes an attending – every step shaped by failure, uncertainty and increasing responsibility. With years of repetition and watchful supervision, the habits of clinical reasoning slowly become part of the physician’s inner architecture.

Technology has long shifted how people learn medicine, from advanced imaging to electronic medical records. But AI is different, not just expanding what doctors can see but inserting itself into the cognitive machinery that training is meant to build. As these tools become more capable and the physician’s role increasingly involves supervising them, experienced clinicians may have enough intuition and independent judgment to critically evaluate the machine’s answers. But for trainees whose understanding of medicine is being formed alongside AI, the relationship is more fraught. Can they really question the reasoning that shaped their own? What happens when the generation trained by AI becomes the generation responsible for catching its mistakes? With unchecked use among trainees, we risk creating supervisors of reasoning before we create reasoners.

The stakes of that question are growing: a recent study in Nature Medicine found that tools pulling from the latest medical literature, like OpenEvidence does, can be less reliable than they appear and, in some cases, less accurate than general-purpose AI chatbots. The problem of misplaced trust is already embedded in the AI that trainees are using today.

To be clear, many trainees sense the trap, telling us they know that tools such as OpenEvidence can become a crutch. But these trainees also feel stuck in an arms race: if everyone else is using AI to sound more prepared, opting out feels like unilateral disarmament. The solution, then, cannot rest on individual restraint. It has to be structural.

That is why medical schools and residency programs need to shape not just whether trainees use AI, but when. No one can police every search on every phone, nor should they. But supervising doctors can build a simple expectation – reason first, consult AI second – and assess accordingly. Trainees should have to make their unaided first pass visible, committing to a leading diagnosis, naming the dangerous possibilities to rule out, and explaining what to do next. In practice, that might mean a resident who admits a patient overnight first writes a brief “pre-AI assessment” after the history and physical exam. On rounds, when a new lab result or symptom changes the case, the attending might need to pause the team – before anyone can consult AI – to ask how this changes the diagnosis or treatment plan.

As AI becomes more deeply integrated into medicine, this will feel cumbersome and inefficient. But such friction is purposeful: the learning scientists Elizabeth and Robert Bjork describe how “desirable difficulties” slow performance in the moment but improve retention and transfer of skills over time. In fact, used after an independent attempt, AI could actually serve as a powerful tutor, showing trainees what they missed and what they overemphasized.

Sequencing, however, may not be enough on its own. Aviation thus offers a useful precedent: pilots in training are not taught to avoid autopilot but to preserve their manual competence. The Federal Aviation Administration even advises pilots to maintain manual flying skills by periodically disengaging automation and hand-flying. Medicine needs similar discipline, with trainees required to periodically work through no-AI cases and assessed on their unaided reasoning to reveal potential drift.

Finally, trainees should be taught to interrogate AI itself. Programs could run the medical equivalent of flight simulator drills, built from real clinical cases: for example, a polished AI-generated assessment with a subtle flaw. Afterward, attendings could debrief not only whether the trainee reached the right answer but also when they trusted the tool, when they questioned it, and when they found the flaw. Just as important, attendings should mix in AI outputs that are perfectly accurate, so students learn not reflexive skepticism but disciplined judgment.

None of this is an argument for making medical training harder for its own sake or romanticizing humiliation as pedagogy. In every generation of medicine, there is a temptation to confuse difficulty with virtue, but the struggle to independently reason through a patient’s case is not hazing but a core competency.

AI is here to stay, and patients stand to benefit from its speed and reach. But patients will also need doctors who can stand apart from the machine long enough to know when it is wrong, incomplete, or right for the wrong reason – doctors whose reasoning is not subordinated to it. Although AI can reason over the facts it is given, a trainee who has seen pneumonia that looks like pneumonia, then pneumonia that looks like heart failure, then heart failure that looks like pneumonia, develops a richer bedside judgment: what to notice, what to question, and when a familiar pattern should be distrusted. That is what medical training is trying to produce. AI should help augment this, not replace it.

Simar Bajaj and Joseph Sakran

Simar Bajaj is a medical student and Knight-Hennessy Scholar at Stanford University School of Medicine, as well as an award-winning journalist

Dr Joseph V Sakran is a trauma surgeon and public health expert who serves as executive vice-chair of surgery at Johns Hopkins Medicine

https://www.theguardian.com/commentisfree/2026/aug/10/ai-medical-students-judgment

Xia-Gibbs syndrome

Inspired by a patient

Shirai H, Oitani Y, Nishi E, Haraguchi K, Nakamura T, Ichinose F, Sanefuji M, Hattori A, Yanagi K, Shimojima Yamamoto K, Okamoto N, Matsuo M, Saitoh S, Yoshiura KI, Kaname T, Yamamoto T. Clinical and molecular profiles of patients with Xia-Gibbs syndrome: a cohort in Japan. Brain Dev. 2026 Apr;48(2):104509. doi: 10.1016/j.braindev.2026.104509. Epub 2026 Feb 6. PMID: 41653504.

Abstract

Background: Xia-Gibbs syndrome (XGS) is a rare neurodevelopmental disorder caused by pathogenic variants in the AT-hook DNA binding motif containing 1 (AHDC1) gene. More than 100 patients with XGS have been reported. In this study, we describe the findings from a Japanese cohort of patients with XGS. To enhance understanding, we also conducted a systematic literature review of XGS.

Methods: We collected clinical and genetic information from seven new Japanese patients with XGS which were diagnosed through comprehensive genetic analysis. A systematic literature review was also conducted using PubMed.

Results: All Japanese patients carried premature truncation variants or deletions. The core clinical features were global developmental delay and hypotonia, which were consistent with those observed in the 106 previously reported patients identified in our literature review. In one patient with a frameshift variant, escape from nonsense-mediated mRNA decay was confirmed using the patient's sample.

Conclusion: The clinical and molecular profiles of Japanese patients with XGS were analyzed and compared with those of previously reported patients from other countries, confirming the consistent characteristics of XGS. This study provides direct evidence of nonsense-mediated mRNA decay escape. A comprehensive understanding of this expanding phenotype is crucial for accurate diagnosis and management.

Jiang N, Zhang L, Zheng Z, Du H, Chen S, Pan H. Phenotypic subtypes of Xia-Gibbs syndrome: a latent class analysis. Eur J Hum Genet. 2025 Dec;33(12):1558-1566. doi: 10.1038/s41431-024-01754-0. Epub 2024 Dec 9. Erratum in: Eur J Hum Genet. 2026 Jun;34(6):886-892. doi: 10.1038/s41431-025-01825-w. PMID: 39648204; PMCID: PMC12669642.

Abstract

Xia-Gibbs syndrome (XGS) is a rare neurodevelopmental disorder with considerable clinical heterogeneity. To further characterize the syndrome's heterogeneity, we applied latent class analysis (LCA) on reported cases to identify phenotypic subtypes. By searching PubMed, Embase, China National Knowledge Infrastructure and Wanfang databases from inception to February 2024, we enrolled 97 cases with nonsense, frameshift or missense variants in the AHDC1 gene. LCA was based on the following 6 phenotypes with moderate occurrence and low missingness: ataxia, seizure, autism, sleep apnea, short stature and scoliosis. After excluding cases with missing data on all LCA variables or with unmatched phenotype-genotype information, a total of 85 cases were selected for LCA. Models with 1-5 classes were compared based on Akaike Information Criterion, Bayesian Information Criterion, Sample-Size Adjusted BIC and entropy. We used multinomial logistic regression (MLR) analyses to investigate the phenotype-genotype association and potential predictors for class membership. LCA revealed 3 distinct classes labeled as Ataxia subtype (n = 11 [12.9%]), Sleep apnea & short stature subtype (n = 23 [27.1%]) and Neuropsychological subtype (n = 51 [60.0%]). The commonest Neuropsychological subtype was characterized by high estimated probabilities of seizure, ataxia and autism. By adjusting for sex, age and variant type, MLR showed no significant association between phenotypic subtype and variant position. Age and variant type were identified as predictors of class membership. The findings of this review offer novel insights for different presentations of XGS. It is possible to deliver targeted monitoring and treatment for each subtype in the early stage.

Romano F, Falco M, Cappuccio G, Brunetti-Pierri N, Lonardo F, Torella A, Digilio MC, Dentici ML, Alfieri P, Agolini E, Novelli A, Garavelli L, Accogli A; TUDP; Striano P, Scarano G, Nigro V, Scala M, Capra V. Genotype-phenotype spectrum and correlations in Xia-Gibbs syndrome: Report of five novel cases and literature review. Birth Defects Res. 2022 Aug 1;114(13):759-767. doi: 10.1002/bdr2.2058. Epub 2022 Jun 18. PMID: 35716097; PMCID: PMC9545659.

Abstract

Background: Xia-Gibbs syndrome (XGS) is a rare neurodevelopmental disorder caused by pathogenic variants in the AT-hook DNA-binding motif-containing 1 gene (AHDC1), encoding a protein with a crucial role in transcription and epigenetic regulation, axonogenesis, brain function, and neurodevelopment. AHDC1 variants possibly act through a dominant-negative mechanism and may interfere with DNA repair processes, leading to genome instability and impaired DNA translesion repair. Variants affecting residues closer to the N-terminal are thought to determine a milder phenotype with better cognitive performances. However, clean-cut genotype-phenotype correlations are still lacking.

Cases: In this study, we investigated five subjects with XGS in whom exome sequencing led to the identification of five novel de novo pathogenic variants in AHDC1. All variants were extremely rare and predicted to cause a loss of protein function. The phenotype of the reported patients included developmental delay, hypotonia, and distinctive facial dysmorphisms. Additionally, uncommon clinical features were observed, including congenital hypothyroidism and peculiar skeletal abnormalities.

Conclusions: In this study, we report uncommon XGS features associated with five novel truncating variants in AHDC, thus expanding the genotype and phenotypic spectrum of this complex condition. We also compared our cases to previously reported cases, discussing the current status of genotype-phenotype correlations in XGS.

Cinelli G, Della Vecchia S, Bergonzini P, Caramaschi E, Spezia E, Parenti C, Madeo SF, Lucaccioni L, Francesca C, Pugliese M, Raviglione F, Colonna C, Calabrese O, Stanghellini I, Marongiu MC, Biagioni E, Ferrari AR, Battini R, Iughetti L. Clinical, Behavioral and Neuroradiological Phenotype in an Italian Cohort of Patients With Xia Gibbs Syndrome: A Multicenter Cross-Sectional Study and Systematic Literature Review. Am J Med Genet A. 2026 Sep;200(9):2067-2079. doi: 10.1002/ajmg.a.70163. Epub 2026 Apr 30. PMID: 42059486.

Abstract

Heterozygous variants in the AHDC1 gene are associated with Xia Gibbs Syndrome (XGS), a genetic disorder with a highly variable phenotype. Cognitive impairment, motor delay, language delay, neonatal hypotonia, and sleep apnea are considered "cardinal" signs of the disease. In a multicenter cross-sectional study, we analyzed the genetic, epileptological, behavioral, and neuroradiological features of 15 patients with XGS harboring heterozygous variants in AHDC1. The phenotype of our patient cohort is almost overlapping with that already reported in the literature. Seizures begin between 2 and 9 years, while EEG is generally characterized by normal background activity with paroxysmal abnormalities in the posterior areas increased by sleep. We systematically analyzed brain imaging findings as the most frequent brain alteration: the thinning of the corpus callosum, followed by posterior fossa malformation and lateral ventricle morphology abnormalities. Regarding psychiatric disorders, we observed neurodevelopmental disorders such as ID, language disorders, Autism spectrum disorders (ASD), and ADHD in preschoolers, followed by a prevalence of externalizing problems during childhood and adolescence. Our study showed that epilepsy and brain anomalies are very common among XGS individuals. MRI changes are nonspecific, but their association with other clinical features of the syndrome can guide early diagnosis. EEG abnormalities are present in all epileptic patients in the temporal-occipital regions with the same characteristics, so we could hypothesize that these abnormalities could represent a recognizable EEG pattern of XGS. Behavioral disorders represent an important problem, and longitudinal evaluations are needed to improve the classification of the psychopathological spectrum in XGS.

Juvenile-onset ALS

See: https://childnervoussystem.blogspot.com/2015/06/mystery-illness.html

Esther and Rivka Herzfeld are members of an inspirational and beloved family that are well-known in the Teaneck community. Active members at Congregation Beth Aaron, all four children in the Herzfeld family have been diagnosed with juvenile-onset ALS, a neuromuscular degenerative disease. Esther’s husband (Rivka’s father) also suffers from a version of this disease, which developed in adulthood. The story of the Herzfelds has been featured in The Jewish Link in the past, particularly in 2015 during their successful quest for a van to allow their family mobility (“Herzfeld Family Gets Their Van,” July 9, 2015, https://jewishlink.news/herzfeld-family-gets-their-van/).

What always strikes people who get to know the Herzfelds is how they stubbornly refuse to allow their challenges to define them, or to hold them back. While one of the siblings, Rivka, works 40 hours a week, another, Racheli, is pursuing a master’s degree in social work. As they are all in their 20s and early 30s, they also have special interests, activities and friends. They are also highly intelligent critical thinkers who are focused on staying as active as possible so that when a cure is found for their condition, they will be ready to benefit from it.

However, as time has gone on, the needs of the family have increased manifold, even though they have their van and now live in a fully accessible house all on one floor. With communal assistance, they are putting together a fundraiser with the aim of allowing them to pay for an immense shortfall in their bills for the long term.

That’s why the mother and daughter are embarking on a speaking tour called “Life Rewritten,” planning to demonstrate their immense strength as a family and their hope for a better, more supportive future. As Esther explained: “I’m an English teacher, and storytelling is important to me. I emphasize the role of strong women and the role they play in the life cycle of a whole family, and I thought about the irony of my inability to control my own story.” She emphasized that this is the case for many families. “Many people plan a life, and their lives are then derailed. We’re not the only ones.”

Juvenile-onset ALS, an extremely rare condition, affects limb strength, breath support and swallowing, among other basic functions. “Everyone knows about ALS because of Lou Gehrig and Stephen Hawking, and that type of ALS shows up for people in their 50s, 60s, or even 70s. That type of ALS is fatal,” Esther explained. The type of ALS her children and husband have is different, and much less well-known, even among doctors. “My children were studied by neurologists for years and given multiple wrong diagnoses. Finally, right before COVID, they started honing in on what neurons were affected, and because it was similar to ALS, they decided to call it juvenile-onset ALS. Baruch Hashem, it’s not fatal, but it affects daily living.” Of about 100 known cases, the Herzfelds make up five.

Because the condition wasn’t identified until recently, it was a process of years to figure out why the Herzfeld children couldn’t live life as normal. “At first, they were just tripping and falling and dropping things. In retrospect, we realize this was the beginning of the degeneration of the muscles.”

Esther and Rivka recounted that each child developed symptoms at a different stage in their life. While Tzipora was the first to mention that something felt wrong at age 6, Rivka didn’t experience symptoms until her senior year of high school. “I remember saying to my parents, ‘Do you think I have what Tzipora has?’ and they sort of quietly chuckled and said, ‘Yeah, of course you have what Tzipora has.’”

To explain the mechanisms of the condition, Rivka analogized the story of Bavel. “Our sphingolipids, the messengers from the brain to the muscles, are being sent in English. But the muscles are reading the messages from the neurons in Sanskrit. Our muscles can sometimes do the actions, but more slowly, and sometimes can’t do them at all, because they don’t understand Sanskrit.” Rivka clarified, however, that “it doesn’t impact our intellectual capability and our thinking, which is such a bracha.” In her mother’s words, “You’re not fast in your legs, but you’re fast in your mind.”

At this point in time, all four Herzfeld children are wheelchair- or scooter-bound. In their first family house on Schley Place in Teaneck, which they lived in until recently, it was nearly impossible for everyone to fit in the house at a time. “It was like putting corks in a dam that was going to burst,” said Esther. “We got a stairlift, and a ramp, and another ramp, but it was brutally uncomfortable.”

A few years ago, thanks to a previous campaign, the Herzfelds were able to move into a house on Queen Anne Road, which “took the pressure out of the pressure cooker,” said Esther. “There was no need to be fighting over who could get the door or pass each other in the hallway.” According to Rivka, “It’s such a mechaye [relief] to not worry about the house being an obstacle.”

However, the obstacles of navigation within the home are only a small challenge to the Herzfeld family. Between the cost of the electricity, the medical equipment, therapy required that isn’t covered by insurance, and the staggering cost of having multiple aides for 22 hours a day, the family is struggling financially.

Unfortunately, government funding only pays for 40 hours a week for home care per person, which is not enough to cover the needs of the family, which has five members who require full care 22 hours each day. It means, they have to pay cash to their aides to the tune of close to $6,000 each week.

While many have asked the Herzfelds why the government can’t stretch more to help them, Rivka believes that her case specifically is confusing for a disability office to make space for, and possibly out of their comfort zone. For example: “I am a working person, but I have a full disability that is congenital, but didn’t occur until I was 17. All of those things make it extremely complicated for people to understand, especially the government. There’s a $25,000-a-month need, every single month. This is critical to the maintenance of our family.”

Beyond that, all family members take physical and other types of therapy with hand specialists and others at not-insignificant costs, which insurances can often limit or not cover because “they’re not getting better.”

With “Life Rewritten,” the Herzfelds are hoping to take their lives back into their own hands. Currently, they only have enough money for another few weeks of therapy. “I’m afraid to look at the fund total,” Esther said. “I’m just taking out the money. I’m hoping that December 28th will help.” Rivka added: “It’s Kislev, and it should be a month of light. It should be a month in which people can see the light that we can give and not just take. A month of miracles.”

Rabbi Daniel Fridman of the Jewish Center of Teaneck is helping to spearhead the campaign. He shared his thoughts on the importance of helping the Herzfelds. “Chazal describe the Jewish people as possessed of certain indelible characteristics. Amongst these are our status as rachmanim, merciful people, and gomlei chasadim, active purveyors of loving kindness. We invite the entire community to join us to learn about the story of the Herzfeld family, and in doing so, to express these two qualities.”

On Dec. 28, the “Life Rewritten” campaign begins. Please join at Jewish Center of Teaneck, where Esther and Rivka will tell their story and ask for help, allowing them to begin to rewrite their life story. They also recently appeared on The Jewish Link “Pitch Meeting” podcast: youtube.com/watch?v=tTQ7jRrreuw&t=4s. To donate to the campaign, visit thechesedfund.com/herzfeld/the-herzfeld-family.

Eliana Birman

https://jewishlink.news/herzfeld-family-launches-life-rewritten-speaking-tour-and-dec-28-fundraiser/

Gene replacement therapy for SURF1-related Leigh syndrome.

Ling Q, Rioux M, Hu Y, Lee M, Gray SJ. Adeno-associated viral vector serotype 9-based gene replacement therapy for SURF1-related Leigh syndrome. Mol Ther Methods Clin Dev. 2021 Sep 7;23:158-168. doi: 10.1016/j.omtm.2021.09.001. PMID: 34703839; PMCID: PMC8517205.

Abstract

SURF1 (surfeit locus protein 1)-related Leigh syndrome is an early-onset neurodegenerative disorder, characterized by reduction in complex IV activity, resulting in disrupted mitochondrial function. Currently, there are no treatment options available. To test our hypothesis that adeno-associated viral vector serotype 9 (AAV9)/human SURF1 (hSURF1) gene replacement therapy can provide a potentially meaningful and long-term therapeutic benefit, we conducted preclinical efficacy studies using SURF1 knockout mice and safety evaluations with wild-type (WT) mice. Our data indicate that with a single intrathecal (i.t.) administration, our treatment partially and significantly rescued complex IV activity in all tissues tested, including liver, brain, and muscle. Accordingly, complex IV content (examined via MT-CO1 protein expression level) also increased with our treatment. In a separate group of mice, AAV9/hSURF1 mitigated the blood lactic acidosis induced by exhaustive exercise at 9 months post-dosing. A toxicity study in WT mice showed no adverse effects in either the in-life portion or after microscopic examination of major tissues up to a year following the same treatment regimen. Taken together, our data suggest a single dose, i.t. administration of AAV9/hSURF1 is safe and effective in improving biochemical abnormalities induced by SURF1 deficiency with potential applicability for SURF1-related Leigh syndrome patients.

Mitochondrial transfer therapy

Nakai, R., Varnum, S., Field, R.L. et al. Mitochondria transfer-based therapies reduce the morbidity and mortality of Leigh syndrome. Nat Metab 6, 1886–1896 (2024). https://doi.org/10.1038/s42255-024-01125-5

Abstract

Mitochondria transfer is a recently described phenomenon in which donor cells deliver mitochondria to acceptor cells. One possible consequence of mitochondria transfer is energetic support of neighbouring cells; for example, exogenous healthy mitochondria can rescue cell-intrinsic defects in mitochondrial metabolism in cultured ρ0 cells or Ndufs4−/− peritoneal macrophages. Exposing haematopoietic stem cells to purified mitochondria before autologous haematopoietic stem cell transplantation allowed for treatment of anaemia in patients with large-scale mitochondrial DNA mutations, and mitochondria transplantation was shown to minimize ischaemic damage to the heart, brain and limbs. However, the therapeutic potential of using mitochondria transfer-based therapies to treat inherited mitochondrial diseases is unclear. Here we demonstrate improved morbidity and mortality of the Ndufs4−/− mouse model of Leigh syndrome (LS) in multiple treatment paradigms associated with mitochondria transfer. Transplantation of bone marrow from wild-type mice, which is associated with release of haematopoietic cell-derived extracellular mitochondria into circulation and transfer of mitochondria to host cells in multiple organs, ameliorates LS in mice. Furthermore, administering isolated mitochondria from wild-type mice extends lifespan, improves neurological function and increases energy expenditure of Ndufs4−/− mice, whereas mitochondria from Ndufs4−/− mice did not improve neurological function. Finally, we demonstrate that cross-species administration of human mitochondria to Ndufs4−/− mice also improves LS. These data suggest that mitochondria transfer-related approaches can be harnessed to treat mitochondrial diseases, such as LS.

15q26.3 deletions

Inspired by a patient

Sivakumaran TA, Grebe TA. 15q26.3 deletions distal to IGF1R cause growth retardation, congenital heart defect and skeletal anomalies: Case report and review of literature. Am J Med Genet A. 2023 Sep;191(9):2392-2397. doi: 10.1002/ajmg.a.63350. Epub 2023 Jul 12. PMID: 37434556.

Abstract

15q26 deletion is a rare genomic disorder characterized by intrauterine and postnatal growth retardation, microcephaly, intellectual disability, and congenital malformations. Here, we report a 4-month-old female with intrauterine growth retardation, short stature, pulmonary hypertension, atrial septal defect and congenital bowing of long bones of the legs. Chromosomal microarray analysis showed a de novo deletion of approximately 2.1 Mb at 15q26.3 region that does not include IGF1R. Our analysis of patients documented in the literature and the DECIPHER database with 15q26 deletions distal to IGF1R, including 10 patients with de novo pure deletions, allowed us to define the smallest region of overlap to 686 kb. This region includes ALDH1A3, LRRK1, CHSY1, SELENOS, SNRPA1, and PCSK6. We propose haploinsufficiency of one or more genes, besides IGF1R, within this region may contribute to the clinical findings in patients with 15q26.3 deletion.

Dincer BT, Ozdemir EM, Cetincelik U, Ucar A. Drayer Syndrome due to Chromosome 15q26.3 Deletion: Response to Growth Hormone Treatment. Sisli Etfal Hastan Tip Bul. 2024 Dec 24;58(4):521-523. doi: 10.14744/SEMB.2024.01879. PMID: 39816431; PMCID: PMC11729826.

Abstract

Chromosome 15q26 deletion is a rare condition that causes short stature and is associated with intrauterine growth restriction (IUGR), failure to thrive, congenital heart disease and many congenital malformations. The insulin growth factor receptor (IGF-1R) on chromosome 15 has many important roles, especially in growth regulation. Our case is an 18-month-old small for gestational age girl who presented with severe short stature, microcephaly and minor dysmorphic features. Chromosome microarray revealed 15q26 deletion including the IGF1R gene. Recombinant growth hormone (rGH) has been used in patients with IGF-1R defects with variable treatment responses. The reason for rGH unresponsiveness in some patients with terminal chromosome 15q deletion is still unclear. Herein we discuss the use of rGH in a patient with heterozygous IGF1R deletion and emphasize the need for further follow-up regarding other endocrine disorders.

Benbouchta Y, De Leeuw N, Amasdl S, Sbiti A, Smeets D, Sadki K, Sefiani A. 15q26 deletion in a patient with congenital heart defect, growth restriction and intellectual disability: case report and literature review. Ital J Pediatr. 2021 Sep 16;47(1):188. doi: 10.1186/s13052-021-01121-5. PMID: 34530895; PMCID: PMC8447573.

Abstract

Background: 15q26 deletion is a relatively rare chromosomal disorder, and it is described only in few cases. Patients with this aberration show many signs and symptoms, particularly pre- and postnatal growth restriction, developmental delay, microcephaly, intellectual disability and various congenital malformations.

Case presentation: We report on a girl, 4 years old, of consanguineous parents, with a 15q26 deletion. Clinical manifestations included failure to thrive, developmental delay, microcephaly, dysmorphic facies with broad forehead, hypertelorism, narrowed eyelid slits and protruding columella. The patient also showed skeletal abnormalities, especially clinodactyly of the 5th finger, varus equine right foot and left club foot. Additionally, she had teething delay and divergent strabismus. Heart ultrasound displayed two atrial septal defects with left-to-right shunt, enlarging the right cavities. Routine cytogenetic analysis revealed a shortened 15q chromosome. Subsequent array analysis disclosed a terminal 9.15 Mb deletion at subband 15q26.1-q26.3. Four candidate genes associated with 15q26 deletion phenotype were within the deleted region, i.e. IGF1R, NR2F2, CHD2 and MEF2A.

Poot M, Verrijn Stuart AA, van Daalen E, van Iperen A, van Binsbergen E, Hochstenbach R. Variable behavioural phenotypes of patients with monosomies of 15q26 and a review of 16 cases. Eur J Med Genet. 2013 Jul;56(7):346-50. doi: 10.1016/j.ejmg.2013.04.001. Epub 2013 Apr 16. PMID: 23603061.

Abstract

Patients with trisomy or tetrasomy of distal 15q show a recognizable overgrowth syndrome, whereas patients with a monosomy of 15q26 share some degree of pre- and postnatal growth retardation, but differ with respect to facial and skeletal dysmorphisms, congenital heart disease and intellectual development. By reviewing 16 cases with losses of 15q26 we found that the size of the deletion was also not a predictor of the breadth of the phenotypic spectrum, the severity of disease or prognosis of the patient. Although monosomies of 15q26 do not represent a classical contiguous gene syndrome, a few candidate genes for selected features such as proportional growth retardation and cardiac abnormalities have been identified. In 11 out of 16 patients with monosomy of distal 15q variable neurobehavioral phenotypes, including learning difficulties, seizures, attention-deficit-hyperactivity disorder, hearing loss and autism, have been found. We discuss clinical ramifications for cases with a loss of 15q26 detected by prenatal array-CGH.

O'Riordan AM, McGrath N, Sharif F, Murphy NP, Franklin O, Lynch SA, O'Grady MJ. Expanding the clinical spectrum of chromosome 15q26 terminal deletions associated with IGF-1 resistance. Eur J Pediatr. 2017 Jan;176(1):137-142. doi: 10.1007/s00431-016-2802-y. Epub 2016 Nov 8. PMID: 27826649.

Abstract

Haploinsufficiency of the insulin-like growth factor-1 receptor (IGF1R) gene on chromosome 15q26.3 is associated with impaired prenatal and postnatal growth, developmental delay, dysmorphic features and skeletal abnormalities. Terminal deletions of chromosome 15q26 arising more proximally may also be associated with congenital heart disease, epilepsy, diaphragmatic hernia and renal anomalies. We report three additional cases of 15q26 terminal deletions with novel features which may further expand the spectrum of this rarely reported contiguous gene syndrome. Phenotypic features including neonatal lymphedema, aplasia cutis congenita and aortic root dilatation have not been reported previously. Similarly, laboratory features of insulin-like growth factor 1 (IGF-1) resistance are described, including markedly elevated IGF-1 of up to +4.7 SDS. In one patient, the elevated IGF-1 declined over time and this coincided with a period of spontaneous growth acceleration.

Conclusion: Deletions of 15q26 are a potential risk factor for aortic root dilatation, neonatal lymphedema and aplasia cutis in addition to causing growth restriction. What is Known: • Terminal deletions of chromosome 15q26 are associated with impaired prenatal and postnatal growth, developmental delay, dysmorphic features and skeletal abnormalities. What is New: • Neonatal lymphedema, aplasia cutis congenita and aortic root dilatation have not been previously described in 15q26 terminal deletions and may represent novel features. • IGF-1 levels may be increased up to 4.7 SDS.