Simulation-Based Training Closes Competency Gap in Brain Death Determination
Brain death determination is "the diagnosis we cannot get wrong,” warned Nicholas Morris, MD, associate professor of neurology and director of the neurocritical care fellowship program at the University of Maryland School of Medicine in Baltimore. “It’s literally a life-and-death mistake if you make an error.”
Yet an interim analysis of an ongoing, multicenter study presented in April at the AAN Annual Meeting in Chicago suggests that most neurology trainees arrive at the simulation lab woefully underprepared to perform it, and that a rigorous, simulation-based, mastery learning curriculum can reliably close that gap.
In preliminary results from the study, neurology residents and neurocritical care fellows scored a mean of just 51.4 percent on a pretest assessment of brain death/death by neurologic criteria (BD/DNC) determination skills, well below the curriculum's minimum passing score (MPS) of 89 percent. After completing an online didactic course offered through the Neurocritical Care Society (NCS), participants improved to a mean of 81.2 percent, but it was only after a session of mentored deliberate practice in the simulation center that scores reached a mean of 97.9 percent, with all but one of the 18 people who completed the curriculum achieving the MPS.
"What we really want to do is make sure that we are training our learners to the very highest standards so that when they get out into independent practice, we can be confident that they have mastered this skill,” said Dr. Morris, the study’s presenting author.
The study, which began enrolling participants in August 2025 and remains ongoing, uses a pretest-posttest design across more than a dozen institutions. Trainees are randomized to one of three simulated BD/DNC cases as a pretest and then complete the NCS online brain death determination course and undergo a second simulation assessment. Those who have not yet passed engage in deliberate practice with a facilitator until they achieve competency.
Performance is scored using a checklist developed through a Delphi process involving the authors of the 2023 AAN/AAP Brain Death/Death by Neurologic Criteria Consensus Guideline. Since the abstract was submitted, enrollment has grown substantially; Dr. Morris told Neurology Today that approximately 82 participants have now started the curriculum, and roughly 60 have completed post-testing.
The low pretest scores, while striking, did not surprise Dr. Morris, who noted that prior survey data published in Neurology have shown that even board-certified neurologists performing BD/DNC determinations in clinical practice sometimes skip critical steps, including the apnea test.
"There's a lot of intricacy to brain death determination, and our checklist reflects that," he said. "So many different things have to be done correctly and completely."
Gary Gronseth, MD, professor and chair of neurology at the University of Kansas Medical Center in Kansas City and a co-author of the 2023 BD/DNC guideline, agreed that the gap is both real and underappreciated.
"It's a very complex process,” said Dr. Gronseth, who was not involved in the study. “Conceptually, it seems straightforward, but it's extraordinarily detail-oriented. Many neurology residents rotate through neurocritical care, but there may not be a brain death case that comes to them, so they simply don't get exposed to it. That's the fundamental challenge for program directors."
The jump from post-didactic to post-deliberate practice scores—from 81 to nearly 98 percent—underscores a key distinction: knowledge and performance are not the same thing.
"There's always a difference between what you know and what you can actually do," Dr. Morris said. "The online course has a 100 percent multiple-choice test at the end, but passing a knowledge test doesn't prove you can perform the procedure. That's where the gap is."
"This isn't something we can address by having residents, or even board-certified neurologists, just take an online course and a test," Dr. Gronseth said. "It has serious implications not only for program directors, who need to be actively working to ensure residents get hands-on exposure, but for community-based neurologists in practice, who may encounter a brain death case only rarely and have no mechanism for maintaining competency. Do we need something analogous to ACLS, like a recertification program with simulation? That's a real and difficult question."
The simulation-based mastery learning model is resource-intensive, with each participant spending roughly three hours between the simulation assessments and the online course, plus additional time for deliberate practice and long-term follow-up. It may not be appropriate for all trainees equally, Dr. Morris acknowledged.
"If someone is going into neurocritical care and this will be a routine part of their practice, the investment is clearly worth it," he said. "If they're unlikely to ever be asked to do this, perhaps a less-intensive approach makes sense."
His group is exploring artificial intelligence-based feedback and virtual-reality platforms as potential lower-resource alternatives, though he believes some form of directly observed hands-on assessment will remain essential.
The study also served as the launching pad for CRESCENT, a new multicenter consortium focused on collaborative education research in neurology.
"What we've been able to achieve is a collaboration among multiple institutions to do education research in neurology, which I'm not sure has ever been done before at this scale," Dr. Morris said. He hopes it will provide the infrastructure to test other educational interventions across training programs nationwide.
"When this study is complete, I hope it will provide the impetus for all neurology programs to ensure that every resident receives formal training in brain death determination that includes hands-on experience, whether through supervised cases or simulation,” Dr. Gronseth said.
Disclosures: Dr. Morris’s institution has received research support from the National Institute of Neurological Disorders and Stroke and the American Academy of Neurology (AAN). Dr. Morris has received compensation for serving as a webinar speaker for Kreg Therapeutics and serves as a non-compensated editorial board member for the AAN and the Neurocritical Care Society.
Gina Shaw
A Simulation-based Mastery Learning Curriculum to Assess and Ensure Competency in Brain Death/Death by Neurological Criteria Determination: Preliminary Results. Nicholas Morris, Amjad Elmashala, Matthew Bevers, Galina Gheihman, Jamie LaBuzetta, Tracey Fan, Shivani Ghoshal, Justine Cormier, Casey Albin, Brittany Lachance, Melissa Pergakis, Matthew Hoerth, Nina Massad, Jenna Ford, Jon Rosenberg, Hera Kamdar, Hannah Kirsch, Lauren Koffman, Xin Zhou1, Sarah Wahlster, Sean Marinelli, Stefanie Cappucci, Rachel Beekman, Reem El-Ghawanmeh, Ariane Lewis, David Greer, William McGaghie, Daniel Harrison. 2026 AAN Annual Meeting Abstract 4711
Objective:
To evaluate if simulation-based mastery learning (SBML) can achieve uniform competency among neurology trainees in brain death / death by neurological criteria (BD/DNC) determination.
Background:
The ACGME Milestones suggest that neurology trainees should be able to properly perform BD/DNC determination by graduation. Data on physician knowledge, comfort, and competency with performing BD/DNC determinations demonstrate opportunities for improvement. We hypothesized that SBML could close the gap between ACGME expectations and practice in BD/DNC determination.
Design/Methods:
In August 2025, we began enrolling in an ongoing multicenter pretest-posttest study of SBML. We randomized neurology trainees to one of three simulated cases of BD/DNC determination as a pretest, followed by didactic training (the Neurocritical Care Society online Brain Death Determination course). We assessed participants using a different randomly selected simulated case immediately after taking the course, and again after deliberate practice. We scored performance using a checklist derived from a Delphi process involving authors of 2023 BD/DNC Guidelines with a minimum passing score (MPS = 89%) derived from Angoff standard setting determined by members of UCNS and ACGME Neurocritical Care examination committees. We performed repeated measures ANOVA for comparison among those that completed the curriculum.
Results:
Thirty neurology residents (5 PGY-2, 14 PGY-3, 11 PGY-4) and five neurocritical care fellows have enrolled and 18 completed the curriculum (17 in progress). Eleven (31%) previously received training in BD/DNC determination, 24 (69%) previously observed a BD/DNC evaluation, and 14 (40%) previously performed a BD/DNC evaluation with supervision. Among the 18 that completed the curriculum, performance improved across assessments (pretest mean (SD) 51.4% (12.9%) vs. post-online course mean (SD) 81.2% (10.2%) vs post-deliberate practice mean (SD) 97.9% (3.5%), F (2,34) = 144.01, p < .001). All but one participant achieved the MPS.
Conclusions:
SBML achieved near uniform competency in BD/DNC determination skills among neurology trainees that completed the SBML curriculum.
Simulation-based Brain Death Determination Training for Neurology Residents (P5-5.025).Noelia Morales, Cesar Escamilla Ocanas, Gabriel Torrealba Acosta, Catherine Garcia, Lintu Ramachandran, and Mohammad Hirzallah. Neurology April 8, 2025 issue 104 (7_Supplement_1) 5569
https://doi.org/10.1212/WNL.0000000000212451
Abstract
Objective:
N/A
Background:
Brain death determination is an essential skill every neurologist should have. Despite the availability of clear guidelines for brain death determination, there is significant variability in practice both, within the United States and internationally. Previous studies have shown neurology residents have limited exposure to brain death examination and typically do not perform this task independently. However, they are expected to be proficient in determining brain death by the end of residency.
Design/Methods:
A simulation-based brain death determination workshop was generated for second year neurology residents, and conducted for three consecutive years from 2022 to 2024. Two questionaries (Form A and B) were generated, each with 14 premises that evaluated different educational competencies on brain death determination guidelines.
The workshop was divided in two parts. The first part consisted of a 60 minute lecture given covering the above-mentioned competencies, based on the 2023 pediatric and adult BD/DNC consensus guideline by a neurocritical care attending. followed by a questionnaire.
Residents then teamed up in groups of 2. High fidelity mannequins were used to simulate patients in five different clinical scenarios. We asked teams to take turns leading each encounter. A debriefing session was conducted after each case to provide immediate feedback. After completing the simulations, the residents received the second questionnaire, ensuring it was a different version from the initial one. Questionnaire results had no identifiable information.
Results:
19 neurology residents completed the brain death determination workshop. 18 out of 19 demonstrated an improvement in performance following the completion of the workshop. Mean pre-workshop score was 63.68 % ± 17.80, while the mean post-workshop score increased to 89.71 % ± 9.4 (p<0.0001).
Conclusions:
Conducting a simulation-based workshop early during neurology training might help increase the level of confidence and proficiency performing a comprehensive brain death examination prior to the completion of residency.
Wednesday, April 29, 2026
Tuesday, April 28, 2026
Preimplantation genetic testing for neurofibromatosis type 1:
Ironically, if the parents of the affected prospective parent had opted for preimplantation genetic testing the affected prospective parent would not have been born.
Vernimmen V, Paulussen ADC, Dreesen JCFM, van Golde RJ, Zamani Esteki M, Coonen E, van Buul-van Zwet ML, Homminga I, Derijck AAHA, Brandts L, Stumpel CTRM, de Die-Smulders CEM. Preimplantation genetic testing for Neurofibromatosis type 1: more than 20 years of clinical experience. Eur J Hum Genet. 2023 Aug;31(8):918-924. doi: 10.1038/s41431-023-01404-x. Epub 2023 Jun 19. PMID: 37337089; PMCID: PMC10400537.
Abstract
Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder that affects the skin and the nervous system. The condition is completely penetrant with extreme clinical variability, resulting in unpredictable manifestations in affected offspring, complicating reproductive decision-making. One of the reproductive options to prevent the birth of affected offspring is preimplantation genetic testing (PGT). We performed a retrospective review of the medical files of all couples (n = 140) referred to the Dutch PGT expert center with the indication NF1 between January 1997 and January 2020. Of the couples considering PGT, 43 opted out and 15 were not eligible because of failure to identify the underlying genetic defect or unmet criteria for in vitro fertilization (IVF) treatment. The remaining 82 couples proceeded with PGT. Fertility assessment prior to IVF treatment showed a higher percentage of male infertility in males affected with NF1 compared to the partners of affected females. Cardiac evaluations in women with NF1 showed no contraindications for IVF treatment or pregnancy. For 67 couples, 143 PGT cycles were performed. Complications of IVF treatment were not more prevalent in affected females compared to partners of affected males. The transfer of 174 (out of 295) unaffected embryos led to 42 ongoing pregnancies with a pregnancy rate of 24.1% per embryo transfer. There are no documented cases of misdiagnosis following PGT in this cohort. With these results, we aim to provide an overview of PGT for NF1 with regard to success rate and safety, to optimize reproductive counseling and PGT treatment for NF1 patients.
Vernimmen V, De Rycke M, Moutou C, Dreesen J, Blok MJ, van Minkelen R, Lauer-Zillhardt J, Verdyck P, Keymolen K, van Uum C, Homminga I, Brandts L, Stumpel CTRM, Coonen E, Heijligers M, van Zelst-Stams W, Zamani Esteki M, van den Wijngaard A, de Die-Smulders CEM, Paulussen ADC. Preimplantation genetic testing for neurofibromatosis type 1: molecular genetic aspects and impact on reproductive counseling. Hum Reprod. 2026 Feb 1;41(2):285-295. doi: 10.1093/humrep/deaf224. PMID: 41289058; PMCID: PMC12864152.
Abstract
Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder that affects the skin and the nervous system. The condition is completely penetrant with extreme clinical variability, resulting in unpredictable manifestations in affected offspring, complicating reproductive decision-making. One of the reproductive options to prevent the birth of affected offspring is preimplantation genetic testing (PGT). We performed a retrospective review of the medical files of all couples (n = 140) referred to the Dutch PGT expert center with the indication NF1 between January 1997 and January 2020. Of the couples considering PGT, 43 opted out and 15 were not eligible because of failure to identify the underlying genetic defect or unmet criteria for in vitro fertilization (IVF) treatment. The remaining 82 couples proceeded with PGT. Fertility assessment prior to IVF treatment showed a higher percentage of male infertility in males affected with NF1 compared to the partners of affected females. Cardiac evaluations in women with NF1 showed no contraindications for IVF treatment or pregnancy. For 67 couples, 143 PGT cycles were performed. Complications of IVF treatment were not more prevalent in affected females compared to partners of affected males. The transfer of 174 (out of 295) unaffected embryos led to 42 ongoing pregnancies with a pregnancy rate of 24.1% per embryo transfer. There are no documented cases of misdiagnosis following PGT in this cohort. With these results, we aim to provide an overview of PGT for NF1 with regard to success rate and safety, to optimize reproductive counseling and PGT treatment for NF1 patients.
Zheng W, Yang C, Yang S, Sun S, Mu M, Rao M, Zu R, Yan J, Ren B, Yang R, Guan Y. Obstetric and neonatal outcomes of pregnancies resulting from preimplantation genetic testing: a systematic review and meta-analysis. Hum Reprod Update. 2021 Oct 18;27(6):989-1012. doi: 10.1093/humupd/dmab027. PMID: 34473268.
Abstract
Background: Preimplantation genetic testing (PGT) includes methods that allow embryos to be tested for severe inherited diseases or chromosomal abnormalities. In addition to IVF/ICSI and repeated freezing and thawing of the embryos, PGT requires a biopsy to obtain embryonic genetic material for analysis. However, the potential effects of PGT on obstetric and neonatal outcomes are currently uncertain.
Objective and rationale: This study aimed to investigate whether pregnancies conceived after PGT were associated with a higher risk of adverse obstetric and neonatal outcomes compared with spontaneously conceived (SC) pregnancies or pregnancies conceived after IVF/ICSI.
Search methods: PubMed, EMBASE, MEDLINE, Web of Science and The Cochrane Library entries from January 1990 to January 2021 were searched. The primary outcomes in this study were low birth weight (LBW) and congenital malformations (CMs), and the secondary outcomes included gestational age, preterm delivery (PTD), very preterm delivery (VPTD), birth weight (BW), very low birth weight (VLBW), neonatal intensive care unit (NICU) admission, hypertensive disorders of pregnancy (HDP), gestational diabetes, placenta previa and preterm premature rupture of membranes (PROM). We further pooled the results of PGT singleton pregnancies. Subgroup analyses included preimplantation genetic diagnosis (PGD), preimplantation genetic screening (PGS), cleavage-stage biopsy combined with fresh embryo transfer (CB-ET) and blastocyst biopsy combined with frozen-thawed embryo transfer (BB-FET).
Outcomes: This meta-analysis included 15 studies involving 3682 babies born from PGT pregnancies, 127 719 babies born from IVF/ICSI pregnancies and 915 222 babies born from SC pregnancies. The relative risk (RR) of LBW was higher in PGT pregnancies compared with SC pregnancies (RR = 3.95, 95% confidence interval [CI]: 2.32-6.72), but the risk of CMs was not different between the two groups. The pooled results for the risks of LBW and CMs were similar in PGT and IVF/ICSI pregnancies. The risks of PTD (RR = 3.12, 95% CI: 2.67-3.64) and HDP (RR = 3.12, 95% CI: 2.18-4.47) were significantly higher in PGT pregnancies compared with SC pregnancies. Lower gestational age (mean difference [MD] = -0.76 weeks, 95% CI -1.17 to -0.34) and BW (MD = -163.80 g, 95% CI: -299.35 to -28.24) were also noted for PGT pregnancies compared with SC pregnancies. Nevertheless, compared with IVF/ICSI pregnancies, the risks of VPTD and VLBW in PGT pregnancies were significantly decreased by 41% and 30%, respectively, although the risk of HDP was still significantly increased by 50% in PGT pregnancies compared with IVF/ICSI pregnancies. The combined results of obstetric and neonatal outcomes of PGT and IVF/ICSI singleton pregnancies were consistent with the overall results. Further subgroup analyses indicated that both PGD and PGS pregnancies were associated with a higher risk of PTD and a lower gestational age compared with SC pregnancies.
Wider implications: This meta-analysis showed that PGT pregnancies may be associated with increased risks of LBW, PTD and HDP compared with SC pregnancies. The overall obstetric and neonatal outcomes of PGT pregnancies are favourable compared with those of IVF/ICSI pregnancies, although PGT pregnancies were associated with a higher risk of HDP. However, because the number of studies that could be included was limited, more randomised controlled trials and prospective cohort studies are needed to confirm these conclusions.
Vernimmen V, Paulussen ADC, Dreesen JCFM, van Golde RJ, Zamani Esteki M, Coonen E, van Buul-van Zwet ML, Homminga I, Derijck AAHA, Brandts L, Stumpel CTRM, de Die-Smulders CEM. Preimplantation genetic testing for Neurofibromatosis type 1: more than 20 years of clinical experience. Eur J Hum Genet. 2023 Aug;31(8):918-924. doi: 10.1038/s41431-023-01404-x. Epub 2023 Jun 19. PMID: 37337089; PMCID: PMC10400537.
Abstract
Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder that affects the skin and the nervous system. The condition is completely penetrant with extreme clinical variability, resulting in unpredictable manifestations in affected offspring, complicating reproductive decision-making. One of the reproductive options to prevent the birth of affected offspring is preimplantation genetic testing (PGT). We performed a retrospective review of the medical files of all couples (n = 140) referred to the Dutch PGT expert center with the indication NF1 between January 1997 and January 2020. Of the couples considering PGT, 43 opted out and 15 were not eligible because of failure to identify the underlying genetic defect or unmet criteria for in vitro fertilization (IVF) treatment. The remaining 82 couples proceeded with PGT. Fertility assessment prior to IVF treatment showed a higher percentage of male infertility in males affected with NF1 compared to the partners of affected females. Cardiac evaluations in women with NF1 showed no contraindications for IVF treatment or pregnancy. For 67 couples, 143 PGT cycles were performed. Complications of IVF treatment were not more prevalent in affected females compared to partners of affected males. The transfer of 174 (out of 295) unaffected embryos led to 42 ongoing pregnancies with a pregnancy rate of 24.1% per embryo transfer. There are no documented cases of misdiagnosis following PGT in this cohort. With these results, we aim to provide an overview of PGT for NF1 with regard to success rate and safety, to optimize reproductive counseling and PGT treatment for NF1 patients.
Vernimmen V, De Rycke M, Moutou C, Dreesen J, Blok MJ, van Minkelen R, Lauer-Zillhardt J, Verdyck P, Keymolen K, van Uum C, Homminga I, Brandts L, Stumpel CTRM, Coonen E, Heijligers M, van Zelst-Stams W, Zamani Esteki M, van den Wijngaard A, de Die-Smulders CEM, Paulussen ADC. Preimplantation genetic testing for neurofibromatosis type 1: molecular genetic aspects and impact on reproductive counseling. Hum Reprod. 2026 Feb 1;41(2):285-295. doi: 10.1093/humrep/deaf224. PMID: 41289058; PMCID: PMC12864152.
Abstract
Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder that affects the skin and the nervous system. The condition is completely penetrant with extreme clinical variability, resulting in unpredictable manifestations in affected offspring, complicating reproductive decision-making. One of the reproductive options to prevent the birth of affected offspring is preimplantation genetic testing (PGT). We performed a retrospective review of the medical files of all couples (n = 140) referred to the Dutch PGT expert center with the indication NF1 between January 1997 and January 2020. Of the couples considering PGT, 43 opted out and 15 were not eligible because of failure to identify the underlying genetic defect or unmet criteria for in vitro fertilization (IVF) treatment. The remaining 82 couples proceeded with PGT. Fertility assessment prior to IVF treatment showed a higher percentage of male infertility in males affected with NF1 compared to the partners of affected females. Cardiac evaluations in women with NF1 showed no contraindications for IVF treatment or pregnancy. For 67 couples, 143 PGT cycles were performed. Complications of IVF treatment were not more prevalent in affected females compared to partners of affected males. The transfer of 174 (out of 295) unaffected embryos led to 42 ongoing pregnancies with a pregnancy rate of 24.1% per embryo transfer. There are no documented cases of misdiagnosis following PGT in this cohort. With these results, we aim to provide an overview of PGT for NF1 with regard to success rate and safety, to optimize reproductive counseling and PGT treatment for NF1 patients.
Zheng W, Yang C, Yang S, Sun S, Mu M, Rao M, Zu R, Yan J, Ren B, Yang R, Guan Y. Obstetric and neonatal outcomes of pregnancies resulting from preimplantation genetic testing: a systematic review and meta-analysis. Hum Reprod Update. 2021 Oct 18;27(6):989-1012. doi: 10.1093/humupd/dmab027. PMID: 34473268.
Abstract
Background: Preimplantation genetic testing (PGT) includes methods that allow embryos to be tested for severe inherited diseases or chromosomal abnormalities. In addition to IVF/ICSI and repeated freezing and thawing of the embryos, PGT requires a biopsy to obtain embryonic genetic material for analysis. However, the potential effects of PGT on obstetric and neonatal outcomes are currently uncertain.
Objective and rationale: This study aimed to investigate whether pregnancies conceived after PGT were associated with a higher risk of adverse obstetric and neonatal outcomes compared with spontaneously conceived (SC) pregnancies or pregnancies conceived after IVF/ICSI.
Search methods: PubMed, EMBASE, MEDLINE, Web of Science and The Cochrane Library entries from January 1990 to January 2021 were searched. The primary outcomes in this study were low birth weight (LBW) and congenital malformations (CMs), and the secondary outcomes included gestational age, preterm delivery (PTD), very preterm delivery (VPTD), birth weight (BW), very low birth weight (VLBW), neonatal intensive care unit (NICU) admission, hypertensive disorders of pregnancy (HDP), gestational diabetes, placenta previa and preterm premature rupture of membranes (PROM). We further pooled the results of PGT singleton pregnancies. Subgroup analyses included preimplantation genetic diagnosis (PGD), preimplantation genetic screening (PGS), cleavage-stage biopsy combined with fresh embryo transfer (CB-ET) and blastocyst biopsy combined with frozen-thawed embryo transfer (BB-FET).
Outcomes: This meta-analysis included 15 studies involving 3682 babies born from PGT pregnancies, 127 719 babies born from IVF/ICSI pregnancies and 915 222 babies born from SC pregnancies. The relative risk (RR) of LBW was higher in PGT pregnancies compared with SC pregnancies (RR = 3.95, 95% confidence interval [CI]: 2.32-6.72), but the risk of CMs was not different between the two groups. The pooled results for the risks of LBW and CMs were similar in PGT and IVF/ICSI pregnancies. The risks of PTD (RR = 3.12, 95% CI: 2.67-3.64) and HDP (RR = 3.12, 95% CI: 2.18-4.47) were significantly higher in PGT pregnancies compared with SC pregnancies. Lower gestational age (mean difference [MD] = -0.76 weeks, 95% CI -1.17 to -0.34) and BW (MD = -163.80 g, 95% CI: -299.35 to -28.24) were also noted for PGT pregnancies compared with SC pregnancies. Nevertheless, compared with IVF/ICSI pregnancies, the risks of VPTD and VLBW in PGT pregnancies were significantly decreased by 41% and 30%, respectively, although the risk of HDP was still significantly increased by 50% in PGT pregnancies compared with IVF/ICSI pregnancies. The combined results of obstetric and neonatal outcomes of PGT and IVF/ICSI singleton pregnancies were consistent with the overall results. Further subgroup analyses indicated that both PGD and PGS pregnancies were associated with a higher risk of PTD and a lower gestational age compared with SC pregnancies.
Wider implications: This meta-analysis showed that PGT pregnancies may be associated with increased risks of LBW, PTD and HDP compared with SC pregnancies. The overall obstetric and neonatal outcomes of PGT pregnancies are favourable compared with those of IVF/ICSI pregnancies, although PGT pregnancies were associated with a higher risk of HDP. However, because the number of studies that could be included was limited, more randomised controlled trials and prospective cohort studies are needed to confirm these conclusions.
Monday, April 27, 2026
Antenatal presentation of MRPS22-related mitochondrial disease confirmed with rapid proteomics
L. N.Semcesen, M.Ball, D. H.Hock, et al., “Antenatal Presentation of MRPS22-Related Mitochondrial Disease Confirmed With Rapid Proteomics,” JIMD Reports67, no. 3 (2026): e70092, https://doi.org/10.1002/jmd2.70092.
Abstract
MRPS22-related mitochondrial disease (MIM#611719) is a rare autosomal recessive disorder caused by defects in the mitochondrial ribosomal protein S22, a component of the small mitoribosomal subunit essential for mitochondrial translation. Of the few reported cases, most present antenatally with a severe phenotype, conveying a poor prognosis. We describe a fetus with severe antenatal-onset MRPS22-related mitochondrial disease and the use of multi-omics in the molecular diagnosis. A primigravida underwent termination of pregnancy following identification of multiple congenital anomalies (hydrops fetalis, microcephaly, corpus callosal agenesis, periventricular cysts and cardiac hypertrophy) on ultrasound at 20 + 2 weeks' gestation, confirmed on fetal magnetic resonance imaging. Trio genome sequencing revealed compound heterozygous variants in MRPS22 (NM_020191.4: c.509G>A; p.(Arg170His) and c.565C>G; p.(Arg189Gly)). Rapid proteomic analysis demonstrated destabilisation of the small mitoribosomal subunit and combined reduction of OXPHOS complexes, supporting the pathogenicity of the variants. This case consolidates the antenatal phenotype of severe MRPS22-related disease and highlights the importance of considering mitochondrial disease in the differential diagnosis of congenital anomalies, especially hydrops fetalis and corpus callosum anomalies. This study provides evidence for the utility of multi-omic approaches (trio genome sequencing, proteomics) in confirming variant pathogenicity following pregnancy loss, enabling accurate diagnosis, and informing reproductive counselling for affected families.
Key Points
MRPS22-related mitochondrial disease should be considered in the differential diagnosis of fetal hydrops and multiple congenital anomalies, particularly in the presence of corpus callosum agenesis.
Rapid proteomic analysis confirmed the pathogenicity of MRPS22 variants identified by genomic autopsy, demonstrating the utility of multi-omic diagnostics following pregnancy loss.
Abstract
MRPS22-related mitochondrial disease (MIM#611719) is a rare autosomal recessive disorder caused by defects in the mitochondrial ribosomal protein S22, a component of the small mitoribosomal subunit essential for mitochondrial translation. Of the few reported cases, most present antenatally with a severe phenotype, conveying a poor prognosis. We describe a fetus with severe antenatal-onset MRPS22-related mitochondrial disease and the use of multi-omics in the molecular diagnosis. A primigravida underwent termination of pregnancy following identification of multiple congenital anomalies (hydrops fetalis, microcephaly, corpus callosal agenesis, periventricular cysts and cardiac hypertrophy) on ultrasound at 20 + 2 weeks' gestation, confirmed on fetal magnetic resonance imaging. Trio genome sequencing revealed compound heterozygous variants in MRPS22 (NM_020191.4: c.509G>A; p.(Arg170His) and c.565C>G; p.(Arg189Gly)). Rapid proteomic analysis demonstrated destabilisation of the small mitoribosomal subunit and combined reduction of OXPHOS complexes, supporting the pathogenicity of the variants. This case consolidates the antenatal phenotype of severe MRPS22-related disease and highlights the importance of considering mitochondrial disease in the differential diagnosis of congenital anomalies, especially hydrops fetalis and corpus callosum anomalies. This study provides evidence for the utility of multi-omic approaches (trio genome sequencing, proteomics) in confirming variant pathogenicity following pregnancy loss, enabling accurate diagnosis, and informing reproductive counselling for affected families.
Key Points
MRPS22-related mitochondrial disease should be considered in the differential diagnosis of fetal hydrops and multiple congenital anomalies, particularly in the presence of corpus callosum agenesis.
Rapid proteomic analysis confirmed the pathogenicity of MRPS22 variants identified by genomic autopsy, demonstrating the utility of multi-omic diagnostics following pregnancy loss.
Friday, April 24, 2026
Treatment practices and outcomes in continuous spike and wave during slow wave sleep
Baumer FM, McNamara NA, Fine AL, Pestana-Knight E, Shellhaas RA, He Z, Arndt DH, Gaillard WD, Kelley SA, Nagan M, Ostendorf AP, Singhal NS, Speltz L, Chapman KE. Treatment Practices and Outcomes in Continuous Spike and Wave during Slow Wave Sleep: A Multicenter Collaboration. J Pediatr. 2021 May;232:220-228.e3. doi: 10.1016/j.jpeds.2021.01.032. Epub 2021 Jan 20. PMID: 33484700; PMCID: PMC8934740.
Abstract
Objectives: To determine how continuous spike and wave during slow wave sleep (CSWS) is currently managed and to compare the effectiveness of current treatment strategies using a database from 11 pediatric epilepsy centers in the US.
Study design: This retrospective study gathered information on baseline clinical characteristics, CSWS etiology, and treatment(s) in consecutive patients seen between 2014 and 2016 at 11 epilepsy referral centers. Treatments were categorized as benzodiazepines, steroids, other antiseizure medications (ASMs), or other therapies. Two measures of treatment response (clinical improvement as noted by the treating physician; and electroencephalography improvement) were compared across therapies, controlling for baseline variables.
Results: Eighty-one children underwent 153 treatment trials during the study period (68 trials of benzodiazepines, 25 of steroids, 45 of ASMs, 14 of other therapies). Children most frequently received benzodiazepines (62%) or ASMs (27%) as first line therapy. Treatment choice did not differ based on baseline clinical variables, nor did these variables correlate with outcome. After adjusting for baseline variables, children had a greater odds of clinical improvement with benzodiazepines (OR 3.32, 95%CI 1.57-7.04, P = .002) or steroids (OR 4.04, 95%CI 1.41-11.59, P = .01) than with ASMs and a greater odds of electroencephalography improvement after steroids (OR 3.36, 95% CI 1.09-10.33, P = .03) than after ASMs.
Conclusions: Benzodiazepines and ASMs are the most frequent initial therapy prescribed for CSWS in the US. Our data suggests that ASMs are inferior to benzodiazepines and steroids and support earlier use of these therapies. Multicenter prospective studies that rigorously assess treatment protocols and outcomes are needed.
Abstract
Objectives: To determine how continuous spike and wave during slow wave sleep (CSWS) is currently managed and to compare the effectiveness of current treatment strategies using a database from 11 pediatric epilepsy centers in the US.
Study design: This retrospective study gathered information on baseline clinical characteristics, CSWS etiology, and treatment(s) in consecutive patients seen between 2014 and 2016 at 11 epilepsy referral centers. Treatments were categorized as benzodiazepines, steroids, other antiseizure medications (ASMs), or other therapies. Two measures of treatment response (clinical improvement as noted by the treating physician; and electroencephalography improvement) were compared across therapies, controlling for baseline variables.
Results: Eighty-one children underwent 153 treatment trials during the study period (68 trials of benzodiazepines, 25 of steroids, 45 of ASMs, 14 of other therapies). Children most frequently received benzodiazepines (62%) or ASMs (27%) as first line therapy. Treatment choice did not differ based on baseline clinical variables, nor did these variables correlate with outcome. After adjusting for baseline variables, children had a greater odds of clinical improvement with benzodiazepines (OR 3.32, 95%CI 1.57-7.04, P = .002) or steroids (OR 4.04, 95%CI 1.41-11.59, P = .01) than with ASMs and a greater odds of electroencephalography improvement after steroids (OR 3.36, 95% CI 1.09-10.33, P = .03) than after ASMs.
Conclusions: Benzodiazepines and ASMs are the most frequent initial therapy prescribed for CSWS in the US. Our data suggests that ASMs are inferior to benzodiazepines and steroids and support earlier use of these therapies. Multicenter prospective studies that rigorously assess treatment protocols and outcomes are needed.
Thursday, April 23, 2026
Euthanasia story
A physically healthy British woman heartbroken over the death of her only son is heading to Switzerland to end her own life at an assisted suicide clinic.
Wendy Duffy, 56, attempted to take her own life after her son died four years ago — but is soon bound for Switzerland, where assisted suicide is legal, after her application was accepted by a clinic, according to the London Times.
Duffy, a former care worker from the West Midlands, told the Daily Mail that she paid Pegasos, a Swiss assisted-dying nonprofit organization, $13,500 to euthanize herself under its care, saying suicide is the only way her “spirit can be free.”
“I could step off a motorway bridge or a tower block but that would leave anyone finding me dealing with that for the rest of their lives,” she said.
She said she’s been forced to travel to Switzerland as a hotly debated right-to-die bill has stalled in Parliament over the last year.
Duffy’s son, Marcus, died at the age of 23 after choking on a tomato that became lodged in his windpipe while he was sleeping.
Nine months later, she tried to kill herself by overdosing and had to be put on a ventilator for two weeks.
Ultimately, she said, no amount of medication or therapy can make her whole again and that she “can’t wait” to die.
She’s already chosen what she will wear on her deathbed and told the Daily Mail that Lady Gaga and Bruno Mars’ “Die With A Smile” will be playing as she passes on. Once she’s dead, she’s requested that all the belongings she brought with her be donated.
Duffy said her siblings, four sisters and two brothers, are understanding of her decision — but she knows it will be difficult to say goodbye to them forever.
“I will call them when I get to Switzerland. It will be a hard call where I’ll say goodbye and thank them,” she said. “But they will get it. They know. Honestly, 100%, they know that I’m not happy, that I don’t want to be here.”
Patrick Reilly
https://nypost.com/2026/04/23/world-news/physically-healthy-mom-to-end-life-by-euthanasia-at-swiss-clinic-after-death-of-her-son/
Wendy Duffy, 56, attempted to take her own life after her son died four years ago — but is soon bound for Switzerland, where assisted suicide is legal, after her application was accepted by a clinic, according to the London Times.
Duffy, a former care worker from the West Midlands, told the Daily Mail that she paid Pegasos, a Swiss assisted-dying nonprofit organization, $13,500 to euthanize herself under its care, saying suicide is the only way her “spirit can be free.”
“I could step off a motorway bridge or a tower block but that would leave anyone finding me dealing with that for the rest of their lives,” she said.
She said she’s been forced to travel to Switzerland as a hotly debated right-to-die bill has stalled in Parliament over the last year.
Duffy’s son, Marcus, died at the age of 23 after choking on a tomato that became lodged in his windpipe while he was sleeping.
Nine months later, she tried to kill herself by overdosing and had to be put on a ventilator for two weeks.
Ultimately, she said, no amount of medication or therapy can make her whole again and that she “can’t wait” to die.
She’s already chosen what she will wear on her deathbed and told the Daily Mail that Lady Gaga and Bruno Mars’ “Die With A Smile” will be playing as she passes on. Once she’s dead, she’s requested that all the belongings she brought with her be donated.
Duffy said her siblings, four sisters and two brothers, are understanding of her decision — but she knows it will be difficult to say goodbye to them forever.
“I will call them when I get to Switzerland. It will be a hard call where I’ll say goodbye and thank them,” she said. “But they will get it. They know. Honestly, 100%, they know that I’m not happy, that I don’t want to be here.”
Patrick Reilly
https://nypost.com/2026/04/23/world-news/physically-healthy-mom-to-end-life-by-euthanasia-at-swiss-clinic-after-death-of-her-son/
Digenic muscular dystrophy due to SRPK3 and TTN variants
Inspired by a patient
Abstract
In digenic inheritance, pathogenic variants in two genes must be inherited together to cause disease. Only very few examples of digenic inheritance have been described in the neuromuscular disease field. Here we show that predicted deleterious variants in SRPK3, encoding the X-linked serine/argenine protein kinase 3, lead to a progressive early onset skeletal muscle myopathy only when in combination with heterozygous variants in the TTN gene. The co-occurrence of predicted deleterious SRPK3/TTN variants was not seen among 76,702 healthy male individuals, and statistical modeling strongly supported digenic inheritance as the best-fitting model. Furthermore, double-mutant zebrafish (srpk3-/-; ttn.1+/-) replicated the myopathic phenotype and showed myofibrillar disorganization. Transcriptome data suggest that the interaction of srpk3 and ttn.1 in zebrafish occurs at a post-transcriptional level. We propose that digenic inheritance of deleterious changes impacting both the protein kinase SRPK3 and the giant muscle protein titin causes a skeletal myopathy and might serve as a model for other genetic diseases.
Sharkova I, Borovikov A, Konovalov F, Nefedova M, Shchagina O, Kutsev S, Murtazina A. Clinical and Genetic Analysis of Digenic Muscular Dystrophy due to SRPK3 and TTN Variants in Two Siblings. Clin Genet. 2025 May;107(5):547-551. doi: 10.1111/cge.14673. Epub 2024 Dec 12. PMID: 39667923.
Abstract
We present a family with two male siblings diagnosed with a newly described digenic myopathy, involving likely pathogenic loss-of-function variants in the SRPK3 and TTN genes: hemizygous p.(Pro68ArgfsTer55) and heterozygous p.(Trp14174Ter), respectively. Both siblings experienced prenatal disease onset, characterized by weak fetal movements, but showed significant clinical improvement over two last years of our follow-up. Key features included early onset, delayed motor development, and prominent axial and proximal weakness, while adult variants' carriers remained asymptomatic, without any myopathic or cardiac manifestations. Lower limb MRI revealed distinctive abnormalities, with different patterns between the siblings: the older brother showed more pronounced involvement of the thigh muscles, while the younger brother exhibited greater changes in the lower leg muscles. Given the early stage of the disease in our patients and the initial changes observed on MRI, we suggest that the semitendinosus and vastus lateralis muscles are primarily involved at the thigh level in SRPK3/TTN-myopathy. This case highlights the importance of considering digenic inheritance in neuromuscular disorders and underscores the necessity of comprehensive genetic analysis in similar cases.
Wednesday, April 22, 2026
Reproductive decision-making in individuals with neurofibromatosis type 1
Kowal K, Domaradzki J. "To have children or not?" Between desire, responsibility, luck, and guilt: reproductive decision-making in individuals with neurofibromatosis type 1. Orphanet J Rare Dis. 2025 Oct 21;20(1):531. doi: 10.1186/s13023-025-04061-z. PMID: 41121384; PMCID: PMC12542219.
Abstract
Background
Neurofibromatosis type 1 (NF1) is a rare autosomal dominant disorder with a 50% chance of being passed to offspring. Its hereditary nature presents individuals with complex reproductive dilemmas. This study explores the complexity of decision-making and reproductive choices faced by people with NF1 regarding parenthood.
Results
Genetic risk is a key factor shaping reproductive decisions. For some individuals, the decision not to have children is seen as a protective and morally responsible practice, aiming to spare potential offspring from the stigma and isolation they themselves experienced. Some women were also concerned for their own physical and emotional health, especially in relation to pregnancy and caregiving. Medical professionals’ opinions significantly influence choices, sometimes outweighing personal desires for parenthood and shaping perceptions of reproductive responsibility. Parents who were unaware of their diagnosis at the time of conception express guilt and regret. Despite the risks, many still wish to have children but struggle with the fear of passing on the NF1 mutation and potential difficulties in bonding with a child who may also be affected. Individuals who realized procreative plans despite severe NF1 treat parenthood as an important element of their non-disease identity and a source of emotional strength.
Conclusions
For individuals with NF1, reproductive decision-making is a complex dilemma, in which procreation anxiety intersects with hopes for parenthood, a sense of responsibility for the child’s future, and personal identity.
https://www.youtube.com/watch?v=056dMq2upWs
https://www.youtube.com/watch?v=hETXFdKOc6M
https://www.youtube.com/watch?v=toJsm1FL0RU
Abstract
Background
Neurofibromatosis type 1 (NF1) is a rare autosomal dominant disorder with a 50% chance of being passed to offspring. Its hereditary nature presents individuals with complex reproductive dilemmas. This study explores the complexity of decision-making and reproductive choices faced by people with NF1 regarding parenthood.
Results
Genetic risk is a key factor shaping reproductive decisions. For some individuals, the decision not to have children is seen as a protective and morally responsible practice, aiming to spare potential offspring from the stigma and isolation they themselves experienced. Some women were also concerned for their own physical and emotional health, especially in relation to pregnancy and caregiving. Medical professionals’ opinions significantly influence choices, sometimes outweighing personal desires for parenthood and shaping perceptions of reproductive responsibility. Parents who were unaware of their diagnosis at the time of conception express guilt and regret. Despite the risks, many still wish to have children but struggle with the fear of passing on the NF1 mutation and potential difficulties in bonding with a child who may also be affected. Individuals who realized procreative plans despite severe NF1 treat parenthood as an important element of their non-disease identity and a source of emotional strength.
Conclusions
For individuals with NF1, reproductive decision-making is a complex dilemma, in which procreation anxiety intersects with hopes for parenthood, a sense of responsibility for the child’s future, and personal identity.
https://www.youtube.com/watch?v=056dMq2upWs
https://www.youtube.com/watch?v=hETXFdKOc6M
https://www.youtube.com/watch?v=toJsm1FL0RU
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