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
Retinoblastoma
It was September 2025, about a month after her daughter Miley turned 2, when she began noticing brief signs of what looked like a lazy eye. After contacting her pediatrician, she was referred to an ophthalmologist, with an appointment scheduled for December.
Because strabismus — commonly known as a “lazy eye” — affects about 2 to 4 percent of young children, according to the American Association for Pediatric Ophthalmology and Strabismus, there was no immediate concern.
Still, as the weeks passed, something didn't sit right.
Then one night in November, while giving Miley a bath, Kristen noticed something she couldn't brush off.
“I noticed she had a white pupil in the bathtub when she looked at me in the light. It looked like a glow in her eye,” the mom tells PEOPLE exclusively. “I panicked and started googling but was trying not to freak myself out.”
Even then, she tried to keep her fears in check.
But later that night, after Miley had gone to sleep, Kristen kept searching — until she came across a story that changed everything.
“I ended up researching after she went to bed and saw an article of a mom that found out her daughter had a tumor on a baby monitor because her daughter's eye was just black,” she says. “I then looked at the monitor and Miley's eye was black.”
In that moment, everything shifted.
Although her husband tried to reassure her, Kristen couldn't shake the feeling something wasn't right.
The next morning, on Nov. 9, the family drove to the emergency room, where her fears were confirmed. There, her daughter was diagnosed with retinoblastoma.
“It was dreadful. I felt alone," Kristen says. "I didn't know anyone with a child with cancer personally. I didn't know anyone with one eye. It was truly scary and I felt so scared for her future.”
Retinoblastoma is a rare type of eye cancer that typically begins in the retina — the light-sensitive tissue at the back of the eye — and most often affects young children, according to the Mayo Clinic. One of the most common warning signs is a white reflection in the pupil, sometimes noticeable in certain lighting or photos.
Just days earlier, life for Kristen and her family had felt steady and full. The 29-year-old, who lives near Cleveland, Ohio, shares a blended household with her husband — whom she met while they were both serving in the Air Force — along with his 13-year-old daughter, their 2½-year-old Miley and their 7-month-old baby. With a master's degree in social work, she was used to being the one helping others.
Less than two weeks later, the next step was clear. On Nov. 21, Miley underwent surgery to remove her eye.
“Her tumor ended up being grade E. Which typically means that the eye needs removed. They don't believe she had vision for a few months. It was hard to process this because she didn't even act like she had vision from one eye.”
In the days that followed, Kristen found herself looking back — wondering if there had been signs she missed.
But there weren't.
“My family and I are very attentive and we had no idea. it's amazing to me how well she adapted.”
And in many ways, Miley never stopped being Miley.
Now 2½, she still fills their home with energy and personality.
“She is so funny and loves to make us laugh, she loves to dance, she is empathetic and feels everyone's emotions around her. She loves princess dresses, painting her nails, all the girl things. But she also loves dinosaurs and helping her dad work with his tools.”
Still, the journey didn't end with surgery.
After doctors performed a biopsy, they determined the cancer had entered a high-risk area — meaning Miley would need chemotherapy.
“They told us she needs 6 rounds of chemo. She has her last round of chemo next month.”
Since then, their lives have revolved around treatment schedules and hospital stays.
“So far, she has needed 2 days of chemo a month. Three days total at the hospital with the last day being de-accessing her port and giving her a shot that helps raise her white blood cell count to help her fight infection during her treatment.”
But for Kristen, the hardest part has been the emotional toll.
“The most challenging part has been watching her be poked and prodded. Having her ask us to ‘just go home.'”
At home, a new routine brought its own challenges.
“We also have had to take out her prosthetic eye and clean it. Put it back in. This has been a hard adjustment for our whole family.”
And yet, through every step, Miley has led the way.
“Miley has blown us away. She has been so positive. She's been resilient. She has truly lead the way with her positivity. She is the strongest person that I know.”
In the midst of it all, Kristen found herself searching for connection — which ultimately led her to start sharing Miley's journey on TikTok.
“I am someone who really thrives having a community when I am going through something. I wanted to share Miley's story to help others who are facing hard times. I also want to give Miley a sense of purpose. So she can see that her hardship has helped others. I also wanted to give Miley a sense of community.”
What started as a way to cope quickly turned into something much bigger.
“Since posting Miley's journey, I have met SO many amazing men and women; girls and boys; with one eye. Miley now has so many people I can connect her with in her life so she never feels alone!”
The response, she says, has helped reshape how she sees the future.
“I have had people share their personal testimonies how having one eye has never stopped them. It has truly helped to give me positivity in something that seemed so so dreadful. The response from everyone else has also been so positive. There has been so much love and support. It's truly helped me to keep going and to be strong.”
At first, going viral came with complicated emotions.
“I felt guilty when she went viral at first. But as I stated, if I didn't, she wouldn't have this huge community of people.”
Now, she sees the impact more clearly.
“I have friends now with kids who have one eye who are her age and I can connect with. She has friends now who can relate with her. I have also had others reach out to me who are just now entering the journey who I have been able to help.”
Looking back, Kristen hopes sharing Miley's story will encourage other parents to trust their instincts.
“I hope people are just aware of the signs. Please, if you see a glow in your child's pupil. Go to the ER. In general, advocate for your kids. You as a parent know best!”
And for parents facing similar situations, she has one message.
“I would say - you are amazing. It's not your fault. Try not to carry guilt because we don't know what we don't know. I, myself, carry guilt for somehow not just KNOWING about this possibly diagnosis and getting her in sooner. But, we can only do what we can with the information we have.”
Jordan Greene
https://people.com/alarming-detail-baby-monitor-days-later-daughter-rare-diagnosis-exclusive-11954332
Because strabismus — commonly known as a “lazy eye” — affects about 2 to 4 percent of young children, according to the American Association for Pediatric Ophthalmology and Strabismus, there was no immediate concern.
Still, as the weeks passed, something didn't sit right.
Then one night in November, while giving Miley a bath, Kristen noticed something she couldn't brush off.
“I noticed she had a white pupil in the bathtub when she looked at me in the light. It looked like a glow in her eye,” the mom tells PEOPLE exclusively. “I panicked and started googling but was trying not to freak myself out.”
Even then, she tried to keep her fears in check.
But later that night, after Miley had gone to sleep, Kristen kept searching — until she came across a story that changed everything.
“I ended up researching after she went to bed and saw an article of a mom that found out her daughter had a tumor on a baby monitor because her daughter's eye was just black,” she says. “I then looked at the monitor and Miley's eye was black.”
In that moment, everything shifted.
Although her husband tried to reassure her, Kristen couldn't shake the feeling something wasn't right.
The next morning, on Nov. 9, the family drove to the emergency room, where her fears were confirmed. There, her daughter was diagnosed with retinoblastoma.
“It was dreadful. I felt alone," Kristen says. "I didn't know anyone with a child with cancer personally. I didn't know anyone with one eye. It was truly scary and I felt so scared for her future.”
Retinoblastoma is a rare type of eye cancer that typically begins in the retina — the light-sensitive tissue at the back of the eye — and most often affects young children, according to the Mayo Clinic. One of the most common warning signs is a white reflection in the pupil, sometimes noticeable in certain lighting or photos.
Just days earlier, life for Kristen and her family had felt steady and full. The 29-year-old, who lives near Cleveland, Ohio, shares a blended household with her husband — whom she met while they were both serving in the Air Force — along with his 13-year-old daughter, their 2½-year-old Miley and their 7-month-old baby. With a master's degree in social work, she was used to being the one helping others.
Less than two weeks later, the next step was clear. On Nov. 21, Miley underwent surgery to remove her eye.
“Her tumor ended up being grade E. Which typically means that the eye needs removed. They don't believe she had vision for a few months. It was hard to process this because she didn't even act like she had vision from one eye.”
In the days that followed, Kristen found herself looking back — wondering if there had been signs she missed.
But there weren't.
“My family and I are very attentive and we had no idea. it's amazing to me how well she adapted.”
And in many ways, Miley never stopped being Miley.
Now 2½, she still fills their home with energy and personality.
“She is so funny and loves to make us laugh, she loves to dance, she is empathetic and feels everyone's emotions around her. She loves princess dresses, painting her nails, all the girl things. But she also loves dinosaurs and helping her dad work with his tools.”
Still, the journey didn't end with surgery.
After doctors performed a biopsy, they determined the cancer had entered a high-risk area — meaning Miley would need chemotherapy.
“They told us she needs 6 rounds of chemo. She has her last round of chemo next month.”
Since then, their lives have revolved around treatment schedules and hospital stays.
“So far, she has needed 2 days of chemo a month. Three days total at the hospital with the last day being de-accessing her port and giving her a shot that helps raise her white blood cell count to help her fight infection during her treatment.”
But for Kristen, the hardest part has been the emotional toll.
“The most challenging part has been watching her be poked and prodded. Having her ask us to ‘just go home.'”
At home, a new routine brought its own challenges.
“We also have had to take out her prosthetic eye and clean it. Put it back in. This has been a hard adjustment for our whole family.”
And yet, through every step, Miley has led the way.
“Miley has blown us away. She has been so positive. She's been resilient. She has truly lead the way with her positivity. She is the strongest person that I know.”
In the midst of it all, Kristen found herself searching for connection — which ultimately led her to start sharing Miley's journey on TikTok.
“I am someone who really thrives having a community when I am going through something. I wanted to share Miley's story to help others who are facing hard times. I also want to give Miley a sense of purpose. So she can see that her hardship has helped others. I also wanted to give Miley a sense of community.”
What started as a way to cope quickly turned into something much bigger.
“Since posting Miley's journey, I have met SO many amazing men and women; girls and boys; with one eye. Miley now has so many people I can connect her with in her life so she never feels alone!”
The response, she says, has helped reshape how she sees the future.
“I have had people share their personal testimonies how having one eye has never stopped them. It has truly helped to give me positivity in something that seemed so so dreadful. The response from everyone else has also been so positive. There has been so much love and support. It's truly helped me to keep going and to be strong.”
At first, going viral came with complicated emotions.
“I felt guilty when she went viral at first. But as I stated, if I didn't, she wouldn't have this huge community of people.”
Now, she sees the impact more clearly.
“I have friends now with kids who have one eye who are her age and I can connect with. She has friends now who can relate with her. I have also had others reach out to me who are just now entering the journey who I have been able to help.”
Looking back, Kristen hopes sharing Miley's story will encourage other parents to trust their instincts.
“I hope people are just aware of the signs. Please, if you see a glow in your child's pupil. Go to the ER. In general, advocate for your kids. You as a parent know best!”
And for parents facing similar situations, she has one message.
“I would say - you are amazing. It's not your fault. Try not to carry guilt because we don't know what we don't know. I, myself, carry guilt for somehow not just KNOWING about this possibly diagnosis and getting her in sooner. But, we can only do what we can with the information we have.”
Jordan Greene
https://people.com/alarming-detail-baby-monitor-days-later-daughter-rare-diagnosis-exclusive-11954332
Wednesday, April 15, 2026
Genetic etiologies of epilepsies with status epilepticus
Marini C, Rosati A, Fusco L, Mastrangelo M, Izzo F, Olivotto S, Siliquini S, Cordelli DM, Mondardini MC, Vittorini R, Conio A, Battaglia DID, Pulitanò SM, Striano P, Riva A, Sartori S, Tona C, Darra F, Proietti J, Zanus C, Costa P, Parrini E, Guerrini R, Vigevano F, Bartolotta P; Italian Pediatric Status Epilepticus (IPSE) Group. Genetic Etiologies of Epilepsies With Status Epilepticus: Insights From the Italian Pediatric Status Epilepticus Group Cohort. Neurology. 2026 Apr 28;106(8):e214791. doi: 10.1212/WNL.0000000000214791. Epub 2026 Mar 31. PMID: 41915870.
Abstract
Background and objectives: Genetic factors are major contributors to pediatric epilepsy, but their role in status epilepticus (SE) remains incompletely defined. We aimed to characterize the clinical and genetic landscape of pediatric epilepsy complicated by SE in a large cohort, and to identify clinical features associated with genetic etiologies.
Methods: We conducted a retrospective, multicenter, exploratory cohort study by selecting patients aged 1 month-18 years who experienced SE from the Italian Pediatric Status Epilepticus (IPSE) group database (2010-2022). SE and epilepsy syndromes were defined according to International League Against Epilepsy criteria. From the IPSE dataset, we included only patients with epilepsy whose etiology was classified as genetic (confirmed or presumed) or nongenetic (lesional, autoimmune, metabolic-acquired, infectious, or unknown). Clinical data were collected using standardized electronic case report forms.
Results: Of 1,071 children in the IPSE cohort, 790 with SE and epilepsy were included (median age at SE onset 3.9 years, interquartile range 1.3-8.1; 44% female). A genetic etiology was confirmed or presumed in 519 (66%). Compared with those with nongenetic etiologies (n = 271), patients with genetic epilepsies presented with SE at a younger age (median 3.4 vs 4.8 years, q = 0.003) and more often had epilepsy with both focal and generalized seizures (31% vs 13%, q < 0.001). The underlying genetic abnormality was identified in 222 patients (42.7%) including 179 with confirmed single-gene pathogenic variants and 43 chromosomal alterations. Ion channel genes were most frequent (38%), with SCN1A variants accounting for 18% of confirmed single-gene cases. Neurodevelopmental and mTOR pathway genes were also frequent contributors. Logistic regression showed that younger age at SE (odds ratio [OR] 0.92, 95% CI 0.85-0.98, p = 0.020) and epilepsy with both focal and generalized seizures (OR 4.00, 95% CI 2.09-7.85, p < 0.001) were independently associated with channelopathies.
Discussion: In this large real-world cohort, two-thirds of children with epilepsy and SE had a genetic etiology, most commonly channelopathies. Younger age at SE and epilepsy with both focal and generalized seizure were linked to genetic causes. Despite limitations in testing strategies and retrospective design, these findings highlight the importance of systematic genetic investigation in pediatric epilepsies presenting SE.
Abstract
Background and objectives: Genetic factors are major contributors to pediatric epilepsy, but their role in status epilepticus (SE) remains incompletely defined. We aimed to characterize the clinical and genetic landscape of pediatric epilepsy complicated by SE in a large cohort, and to identify clinical features associated with genetic etiologies.
Methods: We conducted a retrospective, multicenter, exploratory cohort study by selecting patients aged 1 month-18 years who experienced SE from the Italian Pediatric Status Epilepticus (IPSE) group database (2010-2022). SE and epilepsy syndromes were defined according to International League Against Epilepsy criteria. From the IPSE dataset, we included only patients with epilepsy whose etiology was classified as genetic (confirmed or presumed) or nongenetic (lesional, autoimmune, metabolic-acquired, infectious, or unknown). Clinical data were collected using standardized electronic case report forms.
Results: Of 1,071 children in the IPSE cohort, 790 with SE and epilepsy were included (median age at SE onset 3.9 years, interquartile range 1.3-8.1; 44% female). A genetic etiology was confirmed or presumed in 519 (66%). Compared with those with nongenetic etiologies (n = 271), patients with genetic epilepsies presented with SE at a younger age (median 3.4 vs 4.8 years, q = 0.003) and more often had epilepsy with both focal and generalized seizures (31% vs 13%, q < 0.001). The underlying genetic abnormality was identified in 222 patients (42.7%) including 179 with confirmed single-gene pathogenic variants and 43 chromosomal alterations. Ion channel genes were most frequent (38%), with SCN1A variants accounting for 18% of confirmed single-gene cases. Neurodevelopmental and mTOR pathway genes were also frequent contributors. Logistic regression showed that younger age at SE (odds ratio [OR] 0.92, 95% CI 0.85-0.98, p = 0.020) and epilepsy with both focal and generalized seizures (OR 4.00, 95% CI 2.09-7.85, p < 0.001) were independently associated with channelopathies.
Discussion: In this large real-world cohort, two-thirds of children with epilepsy and SE had a genetic etiology, most commonly channelopathies. Younger age at SE and epilepsy with both focal and generalized seizure were linked to genetic causes. Despite limitations in testing strategies and retrospective design, these findings highlight the importance of systematic genetic investigation in pediatric epilepsies presenting SE.
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Doctors Thought This Mother Had Everything From Ringworm to Leukemia. After 19 Years She Was Finally Diagnosed with Lupus
"I always knew something was wrong with me," says Nyobie Gordon-Ricks, a mom of two
By Wendy Grossman Kantor Published on April 15, 2026 09:15AM EDT
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Doctors Thought it was Ringworm or Leukemia: After 19 Years She Was Diagnosed with Lupus
Nyobie Gordon-Ricks.
Credit : courtesy of Nyobie Gordon-Ricks
Nyobie Gordon-Ricks spent 19 years having her symptoms dismissed or misdiagnosed with everything from ringworm to leukemia before she was diagnosed with lupus in 2010.
“For years, I went to doctors and nobody listened to me,” says Nyobie Gordon-Ricks, 48 of Gilbert, Arizona, who works as a pharmacy technician. “I felt like no one understood and no one believed that there was really something wrong with me.”
Her long path to diagnosis isn’t unusual, says Dr. George Tsokos, a member of the Lupus Foundation of America Medical-Scientific Advisory Council, who has spent years educating healthcare professionals about the symptoms and signs of lupus, an autoimmune disease which attacks the body's own tissue. Because lupus can present in many different ways, symptoms can range from headaches and fatigue to joint paint to hair loss to seizures, which means that no two people might experience it the same way — and thus it can often be overlooked as a diagnosis.
“A big problem is, even in great medical centers, sometimes it takes a lot of time to diagnose,” says Tsokos, who is also chief of rheumatology and clinical immunology at Beth Israel Deconess Medical Center and professor at Harvard Medical School. “If there are symptoms that are not explained, insist on getting more expert opinions and find people who can treat early and treat aggressively.”
Now an ambassador for the Lupus Foundation of America, Gordon-Ricks shares her story urging others to advocate for themselves and to know they are not alone as they battle lupus, a misunderstood and often invisible illness.
“I want people to know that you have to look beyond what's visible. This disease is a disease that nobody can see,” she says.
Gordon-Ricks says her symptoms started when she was 13. Her knees and ankles were swollen, her back hurt and she had a rash on her face.
Her mother took her to a doctor who dismissed it as hormonal changes from puberty.
A year later, she started having episodes of partial paralysis. “I would go numb from my waist down,” she recalls. “I told my mom and she thought I was being lazy and I didn't want to go to school. I would literally lay on our living room floor for hours, waiting for the feeling to come back.”
The second time the paralysis happened, her mother called an ambulance. At the hospital, she was categorized as having a “mental episode,” she says. She was hospitalized for two days, then released: “After that I was like, “I'm just not going to tell anybody anything anymore because nobody's believing me."
She experienced partial paralysis throughout high school, she says, and would wait out the episodes with a heating pad and pain medications.
“There were days where I felt well, and then there were days where I wasn't,” she says. “I didn't know what was going on with me."
In 2009, she got a rash on her back, arms and legs; the first dermatologist she saw said she had ringworm. The second doctor thought it didn’t look like ringworm, but didn't have a better suggestion. Steroid cream helped and the rash went away, but Gordon-Ricks wanted to know what was wrong. She was, 32, engaged and planning her wedding.
In May 2010, she told her gynecologist about her symptoms; bloodwork showed her platelets and red and white blood cells were all low. She saw a series of doctors who thought she might have leukemia, multiple sclerosis or rheumatoid arthritis. The sixth specialist she visited asked if anyone in her family had lupus. She said no.
On December 11, 2010, she learned she tested positive for lupus. It was five days before her 33rd birthday.
“I'm feeling a little bit of relief because now I know what's wrong with me, but now I'm scared because I don't know what this means for me,” she says.
Her fiancé told her she would be fine. His aunt had lupus, and she always seemed fine, he said.
“I said, ‘From what I understand, a person can look fine but still be sick. Right now, I know physically I look good. But I feel like crap. Everything is sore. Everything hurts. When I move, it hurts,’ ” she recalls.
The unpredictability also meant she needed help caring for her then-3-year-old daughter and 8-year-old son.
“I went from wrestling with my kids to it hurting just for one of them to hug me,” she says. “I was in bed for days because the furthest I could go was from my bedroom to my bathroom. I couldn't comb my hair. I could barely brush my teeth. It was a hard adjustment because you're looking at somebody who on the outside looks healthy, but the inside their body is falling apart.”
She took her mother or her fiancé with her when she went to the doctor, because she had trouble remembering what the doctor told her.
“I was really spacey,” she says. “I could be in the middle of a conversation and I'll just stop talking because I lose train of thought.”
Plus she was having terrible headaches. “It felt like I can feel a heartbeat in my skull, all like the thump. I don't know what's going on,” she says.
https://people.com/lupus-diagnosis-after-years-of-misdiagnosis-exclusive-11919604
Her doctor ordered a full body scan. “He said, ‘You have inflammation from your brain to your toes. There is some type of swelling in every single part of your body,' " she recalls. The diagnosis: Lupus cerebritis, which affects the brain.
“I was scared for my life,” she recalls: “Can I die from this? Is this something that's fatal? How treatable is it?”
In March 2012, she started 12 rounds of monthly chemotherapy, which was effective.
And when she returned to the gynecologist who first took her symptoms seriously, Gordon-Ricks was emotional. "I told her, 'You literally saved my life. It's in my kidneys, it’s attacking my joints, and it's in my brain.’ She just hugged me and I cried like a baby. I was like, 'I don't think that I would be here if you didn't listen to me.' "
When Gordon-Ricks finished chemo, she and her fiancé moved to Arizona and got married in March 2014. “He’s been a big support. He goes to the doctor with me. He asks questions that I may not ask. He recognizes when I'm not feeling well, even when I pretend that I'm okay. He's even helped me facilitate lupus support groups. He was able to step in and help me the way that I needed help,” she says.
Her lupus nephritis went into remission in 2017. Because the lupus attacked her ovaries, cervix, and fallopian tubes, she had a full hysterectomy in September 2018.
Today, her lupus is still active, but is controlled by medication. She actively volunteers with the Lupus Foundation as an ambassador, speaking at health fairs and spreading awareness. She shares her story in hopes it will help other people get diagnosed more quickly than she did. She runs her own lupus awareness website, the Arizona Butterfly Warriors, and is active on social media.
“The biggest advice I can give is: Never give up. Learn how to be an advocate for yourself. Learn how to ask for a second opinion. Never take no for an answer. If you feel like you're not being heard, if you feel like your doctor isn't listening, find a new doctor,” she says. “If you know in your heart something's wrong with you, you need to keep going until you get the answers that you deserve. There is hope: There are people that are willing to listen. You just have to find them.”
A lupus diagnosis, she says, is not a death sentence.
“We can survive this,” she says.
https://people.com/lupus-diagnosis-after-years-of-misdiagnosis-exclusive-11919604
Sunday, April 12, 2026
Why only boys or girls sometimes runs in the family
Women who have had multiple children of the same sex are more likely to have another baby of the same sex, a new study has found.
Maternal age and genetics could be ‘weighting the coin toss’ for some couples, rather than every child having a truly random 50/50 chance of being a boy or a girl.
The study also showed that older mothers were more likely to have children of the same sex, and revealed two genes that could increase the likelihood of having all female or all male children, respectively.
A child’s sex at conception is determined by whether the sperm carries an X or Y chromosome, which should mean it’s a perfect coin flip over whether a child will be a boy or a girl.
However, PhD student Siwen Wang from Harvard University noticed this didn’t always seem to be the case.
“This project actually began with casual conversations among co-authors and friends about families we knew who had all boys or all girls,” said Wang to BBC Science Focus.
“It came up often enough that we started wondering: is it really just chance? Or is there a biological reason some families keep having children of the same sex?”
Wang and her colleagues drew on information from more than 58,007 women who had given birth to two or more children, checking if there were more families with siblings of all the same sex than you might expect due to random chance.
They found that if a couple had already had three boys, they had a 61 per cent chance of having another boy. Similarly, there was a 58 per cent chance of having another girl after having three girls.
The study identified a few factors that potentially tipped the scales in favour of all girl or all boy families.
“Women who had their first child after age 28 had about a 10 per cent higher chance of having only boys or only girls, compared to those who started before age 23,” said Wang. “So it’s not a huge shift, but it’s statistically significant.”
Though the study didn’t look into what might be causing this link, Wang did speculate on a few theories.
“As women age, they experience physiological changes such as shorter follicular phase and lower vaginal pH,” she said.
The follicular phase is the first stage of the menstrual cycle and tends to favour the survival of Y-chromosome sperm. Lower vaginal pH, however, favours X-chromosome sperm.
“These effects may differ from woman to woman, so ageing may tip the balance toward one sex or the other, depending on their specific biology,” said Wang.
Wang also suggested another possible connection.
“Older maternal age is usually highly associated with older paternal age. But unfortunately, we did not have paternal data to explore this aspect in our study," said Wang.
The researchers were also able to obtain genetic information for 7,530 women included in the study, looking for any relevant genetic markers. They found two – SNP NSUN6, which was associated with all female offspring; and SNP TSHZ1, which correlated to all male.
Wang also looked into whether behavioural factors could be creating such runs of single-sex children, such as couples who keep having boys continuing to have children until they have a girl, and vice versa.
“We ran analyses where we excluded the last birth in each family, which is the one most likely to be influenced by parents stopping once they’ve had both a boy and a girl. Even after doing that, we still see strong same-sex clustering,” said Wang.
About our expert
Siwen Wang is a PhD student in Nutritional Epidemiology at Harvard T.H. Chan School of Public Health. She investigates how nutrition, lifestyle, and psychosocial factors affect maternal and child health.
https://www.sciencefocus.com/news/boys-girls-birth
Maternal age and genetics could be ‘weighting the coin toss’ for some couples, rather than every child having a truly random 50/50 chance of being a boy or a girl.
The study also showed that older mothers were more likely to have children of the same sex, and revealed two genes that could increase the likelihood of having all female or all male children, respectively.
A child’s sex at conception is determined by whether the sperm carries an X or Y chromosome, which should mean it’s a perfect coin flip over whether a child will be a boy or a girl.
However, PhD student Siwen Wang from Harvard University noticed this didn’t always seem to be the case.
“This project actually began with casual conversations among co-authors and friends about families we knew who had all boys or all girls,” said Wang to BBC Science Focus.
“It came up often enough that we started wondering: is it really just chance? Or is there a biological reason some families keep having children of the same sex?”
Wang and her colleagues drew on information from more than 58,007 women who had given birth to two or more children, checking if there were more families with siblings of all the same sex than you might expect due to random chance.
They found that if a couple had already had three boys, they had a 61 per cent chance of having another boy. Similarly, there was a 58 per cent chance of having another girl after having three girls.
The study identified a few factors that potentially tipped the scales in favour of all girl or all boy families.
“Women who had their first child after age 28 had about a 10 per cent higher chance of having only boys or only girls, compared to those who started before age 23,” said Wang. “So it’s not a huge shift, but it’s statistically significant.”
Though the study didn’t look into what might be causing this link, Wang did speculate on a few theories.
“As women age, they experience physiological changes such as shorter follicular phase and lower vaginal pH,” she said.
The follicular phase is the first stage of the menstrual cycle and tends to favour the survival of Y-chromosome sperm. Lower vaginal pH, however, favours X-chromosome sperm.
“These effects may differ from woman to woman, so ageing may tip the balance toward one sex or the other, depending on their specific biology,” said Wang.
Wang also suggested another possible connection.
“Older maternal age is usually highly associated with older paternal age. But unfortunately, we did not have paternal data to explore this aspect in our study," said Wang.
The researchers were also able to obtain genetic information for 7,530 women included in the study, looking for any relevant genetic markers. They found two – SNP NSUN6, which was associated with all female offspring; and SNP TSHZ1, which correlated to all male.
Wang also looked into whether behavioural factors could be creating such runs of single-sex children, such as couples who keep having boys continuing to have children until they have a girl, and vice versa.
“We ran analyses where we excluded the last birth in each family, which is the one most likely to be influenced by parents stopping once they’ve had both a boy and a girl. Even after doing that, we still see strong same-sex clustering,” said Wang.
About our expert
Siwen Wang is a PhD student in Nutritional Epidemiology at Harvard T.H. Chan School of Public Health. She investigates how nutrition, lifestyle, and psychosocial factors affect maternal and child health.
https://www.sciencefocus.com/news/boys-girls-birth
Tuesday, April 7, 2026
CACNA1E mutation
Kayleigh and Ryan Dunn’s 11-month-old daughter, Lorelei, was diagnosed with CACNA1E. Due to this neurological condition, she lives with mobility challenges, experiences frequent seizures and requires a feeding tube.
Patrick Lawlor, Lorelei's neurologist in Michigan, described the severity of CACNA1E to local news outlet WXYZ, saying, “The lack of progress is something that really signals how severe her disorder is. Probably one of the most severe children I’ve taken care of. She has clusters of brief seizures. Sometimes 10 or 20 times per day.”
The Michigan mom explained that it's “even harder” because Lorelei has “no head control or upper body control.” Kayleigh added, "Even though we’re desensitized. It breaks my heart to see her like this."
Kayleigh has been documenting Lorelei's health journey on TikTok, inciting an outpouring of love and support, including when she had a G-tube surgery in January.
"She took it like a champ, and I could not be prouder of her," Kayleigh captioned the TikTok video. "I cannot wait to get her home and comfortable in her own bed. But for now, I’m going to enjoy this quiet moment alone in our little hospital room, just the two of us."
Kayleigh told WXYZ that Lorelei, who enjoys bath time, is nonverbal, adding, “For someone who is nonverbal, she is very vocal.”
The mother is hopeful that their family’s story encourages other people to get tested for neurological conditions.
Angela Munaco, one of the family’s close friends set up a GoFundMe to help the family cover Lorelei's medical bills and other costs.
“Shortly after her diagnosis, Kayleigh’s husband [Ryan] suffered a serious back injury at work, leaving him unable to work for several months,” the GoFundMe said. “Between his recovery, endless doctor appointments, and the long wait for state approval of Lorelei’s special needs insurance, Kayleigh had no choice but to step back from full-time work. She now works part-time when she can, balancing her career with being Lorelei’s full-time caregiver.”
Kayleigh told WXYZ, “I just want [Lorelei] to know I tried everything I can to make her better.”
Lexi Lane
https://people.com/michigan-girl-diagnosed-with-rare-genetic-disorder-cacna1e-11940319
Di Micco V, Affronte L, Khinchi MS, Rønde G, Miranda MJ, Hammer TB, Specchio N, Beniczky S, Olofsson K, Møller RS, Gardella E. Seizure and movement disorder in CACNA1E developmental and epileptic encephalopathy: Two sides of the same coin or same side of two different coins? Epileptic Disord. 2024 Aug;26(4):520-526. doi: 10.1002/epd2.20242. Epub 2024 May 23. PMID: 38780451.
Abstract
Pathogenic variants in CACNA1E are associated with early-onset epileptic and developmental encephalopathy (DEE). Severe to profound global developmental delay, early-onset refractory seizures, severe hypotonia, and macrocephaly are the main clinical features. Patients harboring the recurrent CACNA1E variant p.(Gly352Arg) typically present with the combination of early-onset DEE, dystonia/dyskinesia, and contractures. We describe a 2-year-and-11-month-old girl carrying the p.(Gly352Arg) CACNA1E variant. She has a severe DEE with very frequent drug-resistant seizures, profound hypotonia, and episodes of dystonia and dyskinesia. Long-term video-EEG-monitoring documented subsequent tonic asymmetric seizures during wakefulness and mild paroxysmal dyskinesias of the trunk out of sleep which were thought to be a movement disorder and instead turned out to be focal hyperkinetic seizures. This is the first documented description of the EEG findings in this disorder. Our report highlights a possible overlap between cortical and subcortical phenomena in CACNA1E-DEE. We also underline how a careful electro-clinical evaluation might be necessary for a correct discernment between the two disorders, playing a fundamental role in the clinical assessment and proper management of children with CACNA1E-DEE.
Ortiz Cabrera NV, Duat Rodríguez A, Fernández Garoz B, Bernardino Cuesta B, Jiménez Legido M, Cantarín Extremera V, García Peñas JJ. Dystonia and Contractures are Potential Early Signs of CACNA1E-Related Epileptic Encephalopathy. Mol Syndromol. 2021 Mar;12(1):25-32. doi: 10.1159/000511926. Epub 2020 Dec 10. PMID: 33776624; PMCID: PMC7983621.
Abstract
Epileptic encephalopathy related to CACNA1E has been described as a severe neurodevelopmental disorder presenting with early-onset refractory seizures, hypotonia, macrocephaly, hyperkinetic movements, and contractures and is associated with an autosomal dominant inheritance pattern. Most pathogenic variants described to date are missense variants with a gain of function effect, and the role of haploinsufficiency has yet to be clarified. We describe 2 cases of CACNA1E encephalopathy. Notable findings include congenital contractures and movement disorders predating onset of epilepsy, particularly dystonia. We further compared the key phenotypic features depending on variant location. In conclusion, the appearance of congenital contractures, areflexia, and movement disorders before the onset of epilepsy may provide key guidance in the diagnosis of epileptic CACNA1E encephalopathy. A genotype-phenotype correlation was found between the presence of movement disorders and severe intellectual disability and the location of the variant in the CACNA1E gene.
Helbig KL, Lauerer RJ, Bahr JC, Souza IA, Myers CT, Uysal B, Schwarz N, Gandini MA, Huang S, Keren B, Mignot C, Afenjar A, Billette de Villemeur T, Héron D, Nava C, Valence S, Buratti J, Fagerberg CR, Soerensen KP, Kibaek M, Kamsteeg EJ, Koolen DA, Gunning B, Schelhaas HJ, Kruer MC, Fox J, Bakhtiari S, Jarrar R, Padilla-Lopez S, Lindstrom K, Jin SC, Zeng X, Bilguvar K, Papavasileiou A, Xing Q, Zhu C, Boysen K, Vairo F, Lanpher BC, Klee EW, Tillema JM, Payne ET, Cousin MA, Kruisselbrink TM, Wick MJ, Baker J, Haan E, Smith N, Sadeghpour A, Davis EE, Katsanis N; Task Force for Neonatal Genomics; Corbett MA, MacLennan AH, Gecz J, Biskup S, Goldmann E, Rodan LH, Kichula E, Segal E, Jackson KE, Asamoah A, Dimmock D, McCarrier J, Botto LD, Filloux F, Tvrdik T, Cascino GD, Klingerman S, Neumann C, Wang R, Jacobsen JC, Nolan MA, Snell RG, Lehnert K, Sadleir LG, Anderlid BM, Kvarnung M, Guerrini R, Friez MJ, Lyons MJ, Leonhard J, Kringlen G, Casas K, El Achkar CM, Smith LA, Rotenberg A, Poduri A, Sanchis-Juan A, Carss KJ, Rankin J, Zeman A, Raymond FL, Blyth M, Kerr B, Ruiz K, Urquhart J, Hughes I, Banka S; Deciphering Developmental Disorders Study; Hedrich UBS, Scheffer IE, Helbig I, Zamponi GW, Lerche H, Mefford HC. De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias. Am J Hum Genet. 2018 Nov 1;103(5):666-678. doi: 10.1016/j.ajhg.2018.09.006. Epub 2018 Oct 18. Erratum in: Am J Hum Genet. 2019 Mar 7;104(3):562. doi: 10.1016/j.ajhg.2019.02.015. PMID: 30343943; PMCID: PMC6216110.
Abstract
Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the α1-subunit of the voltage-gated CaV2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed CaV2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.
Patrick Lawlor, Lorelei's neurologist in Michigan, described the severity of CACNA1E to local news outlet WXYZ, saying, “The lack of progress is something that really signals how severe her disorder is. Probably one of the most severe children I’ve taken care of. She has clusters of brief seizures. Sometimes 10 or 20 times per day.”
The Michigan mom explained that it's “even harder” because Lorelei has “no head control or upper body control.” Kayleigh added, "Even though we’re desensitized. It breaks my heart to see her like this."
Kayleigh has been documenting Lorelei's health journey on TikTok, inciting an outpouring of love and support, including when she had a G-tube surgery in January.
"She took it like a champ, and I could not be prouder of her," Kayleigh captioned the TikTok video. "I cannot wait to get her home and comfortable in her own bed. But for now, I’m going to enjoy this quiet moment alone in our little hospital room, just the two of us."
Kayleigh told WXYZ that Lorelei, who enjoys bath time, is nonverbal, adding, “For someone who is nonverbal, she is very vocal.”
The mother is hopeful that their family’s story encourages other people to get tested for neurological conditions.
Angela Munaco, one of the family’s close friends set up a GoFundMe to help the family cover Lorelei's medical bills and other costs.
“Shortly after her diagnosis, Kayleigh’s husband [Ryan] suffered a serious back injury at work, leaving him unable to work for several months,” the GoFundMe said. “Between his recovery, endless doctor appointments, and the long wait for state approval of Lorelei’s special needs insurance, Kayleigh had no choice but to step back from full-time work. She now works part-time when she can, balancing her career with being Lorelei’s full-time caregiver.”
Kayleigh told WXYZ, “I just want [Lorelei] to know I tried everything I can to make her better.”
Lexi Lane
https://people.com/michigan-girl-diagnosed-with-rare-genetic-disorder-cacna1e-11940319
Di Micco V, Affronte L, Khinchi MS, Rønde G, Miranda MJ, Hammer TB, Specchio N, Beniczky S, Olofsson K, Møller RS, Gardella E. Seizure and movement disorder in CACNA1E developmental and epileptic encephalopathy: Two sides of the same coin or same side of two different coins? Epileptic Disord. 2024 Aug;26(4):520-526. doi: 10.1002/epd2.20242. Epub 2024 May 23. PMID: 38780451.
Abstract
Pathogenic variants in CACNA1E are associated with early-onset epileptic and developmental encephalopathy (DEE). Severe to profound global developmental delay, early-onset refractory seizures, severe hypotonia, and macrocephaly are the main clinical features. Patients harboring the recurrent CACNA1E variant p.(Gly352Arg) typically present with the combination of early-onset DEE, dystonia/dyskinesia, and contractures. We describe a 2-year-and-11-month-old girl carrying the p.(Gly352Arg) CACNA1E variant. She has a severe DEE with very frequent drug-resistant seizures, profound hypotonia, and episodes of dystonia and dyskinesia. Long-term video-EEG-monitoring documented subsequent tonic asymmetric seizures during wakefulness and mild paroxysmal dyskinesias of the trunk out of sleep which were thought to be a movement disorder and instead turned out to be focal hyperkinetic seizures. This is the first documented description of the EEG findings in this disorder. Our report highlights a possible overlap between cortical and subcortical phenomena in CACNA1E-DEE. We also underline how a careful electro-clinical evaluation might be necessary for a correct discernment between the two disorders, playing a fundamental role in the clinical assessment and proper management of children with CACNA1E-DEE.
Ortiz Cabrera NV, Duat Rodríguez A, Fernández Garoz B, Bernardino Cuesta B, Jiménez Legido M, Cantarín Extremera V, García Peñas JJ. Dystonia and Contractures are Potential Early Signs of CACNA1E-Related Epileptic Encephalopathy. Mol Syndromol. 2021 Mar;12(1):25-32. doi: 10.1159/000511926. Epub 2020 Dec 10. PMID: 33776624; PMCID: PMC7983621.
Abstract
Epileptic encephalopathy related to CACNA1E has been described as a severe neurodevelopmental disorder presenting with early-onset refractory seizures, hypotonia, macrocephaly, hyperkinetic movements, and contractures and is associated with an autosomal dominant inheritance pattern. Most pathogenic variants described to date are missense variants with a gain of function effect, and the role of haploinsufficiency has yet to be clarified. We describe 2 cases of CACNA1E encephalopathy. Notable findings include congenital contractures and movement disorders predating onset of epilepsy, particularly dystonia. We further compared the key phenotypic features depending on variant location. In conclusion, the appearance of congenital contractures, areflexia, and movement disorders before the onset of epilepsy may provide key guidance in the diagnosis of epileptic CACNA1E encephalopathy. A genotype-phenotype correlation was found between the presence of movement disorders and severe intellectual disability and the location of the variant in the CACNA1E gene.
Helbig KL, Lauerer RJ, Bahr JC, Souza IA, Myers CT, Uysal B, Schwarz N, Gandini MA, Huang S, Keren B, Mignot C, Afenjar A, Billette de Villemeur T, Héron D, Nava C, Valence S, Buratti J, Fagerberg CR, Soerensen KP, Kibaek M, Kamsteeg EJ, Koolen DA, Gunning B, Schelhaas HJ, Kruer MC, Fox J, Bakhtiari S, Jarrar R, Padilla-Lopez S, Lindstrom K, Jin SC, Zeng X, Bilguvar K, Papavasileiou A, Xing Q, Zhu C, Boysen K, Vairo F, Lanpher BC, Klee EW, Tillema JM, Payne ET, Cousin MA, Kruisselbrink TM, Wick MJ, Baker J, Haan E, Smith N, Sadeghpour A, Davis EE, Katsanis N; Task Force for Neonatal Genomics; Corbett MA, MacLennan AH, Gecz J, Biskup S, Goldmann E, Rodan LH, Kichula E, Segal E, Jackson KE, Asamoah A, Dimmock D, McCarrier J, Botto LD, Filloux F, Tvrdik T, Cascino GD, Klingerman S, Neumann C, Wang R, Jacobsen JC, Nolan MA, Snell RG, Lehnert K, Sadleir LG, Anderlid BM, Kvarnung M, Guerrini R, Friez MJ, Lyons MJ, Leonhard J, Kringlen G, Casas K, El Achkar CM, Smith LA, Rotenberg A, Poduri A, Sanchis-Juan A, Carss KJ, Rankin J, Zeman A, Raymond FL, Blyth M, Kerr B, Ruiz K, Urquhart J, Hughes I, Banka S; Deciphering Developmental Disorders Study; Hedrich UBS, Scheffer IE, Helbig I, Zamponi GW, Lerche H, Mefford HC. De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias. Am J Hum Genet. 2018 Nov 1;103(5):666-678. doi: 10.1016/j.ajhg.2018.09.006. Epub 2018 Oct 18. Erratum in: Am J Hum Genet. 2019 Mar 7;104(3):562. doi: 10.1016/j.ajhg.2019.02.015. PMID: 30343943; PMCID: PMC6216110.
Abstract
Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the α1-subunit of the voltage-gated CaV2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed CaV2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.
Monday, April 6, 2026
Cardiac disease burden in DDX3X syndrome
Carlos Gallego-Navarro, Jeanne L. Theis, Radhika Dhamija et al. Under-recognized Cardiac Disease Burden in DDX3X Syndrome: Spectrum of Cardiovascular Abnormalities and Longitudinal Outcomes, 01 April 2026, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-9059706/v1]
Abstract
Background
DDX3X-syndrome is a rare neurodevelopmental disorder characterized by varying degrees of intellectual disability, predominantly affecting females. We present an institutional cohort supplemented by a systematic literature review, expanding the cardiovascular phenotype of DDX3X-syndrome.
Methods
We conducted a retrospective chart review of patients diagnosed with DDX3X-syndrome at Mayo Clinic. Additionally, we performed a systematic literature review to identify studies reporting cardiovascular abnormalities in patients with DDX3X-syndrome.
Results
A total of 200 patients with DDX3X-syndrome were analyzed, comprising 14 patients from our institutional cohort and 186 patients identified through a systematic review of 9 published studies. Our institutional cohort included 14 patients (12 females and 2 males) from 13 unrelated families diagnosed with DDX3X-syndrome, at a median age of 4.5 years (IQR 1.2–9.5). Echocardiogram was performed on nine patients, and cardiovascular abnormalities were found in 7 out of 9 patients who underwent echocardiography (78%), two of whom had major congenital heart defect (CHD) requiring surgical intervention. At the time of assessment, 13 individuals were still alive, while one had died at age six due to extracardiac complications. The systematic review included 9 studies involving 186 patients, of whom 32 (17.4%, 25 females and 7 males) had reported cardiovascular abnormalities, ranging from simple CHDs to more complex defects.
Conclusion
DDX3X-syndrome carries a significant cardiovascular burden, which is possibly higher than previously reported, including complex congenital heart disease requiring surgical repair. A thorough cardiovascular assessment, including an electrocardiogram and echocardiogram, should be universally recommended for all patients at the time of diagnosis.
Abstract
Background
DDX3X-syndrome is a rare neurodevelopmental disorder characterized by varying degrees of intellectual disability, predominantly affecting females. We present an institutional cohort supplemented by a systematic literature review, expanding the cardiovascular phenotype of DDX3X-syndrome.
Methods
We conducted a retrospective chart review of patients diagnosed with DDX3X-syndrome at Mayo Clinic. Additionally, we performed a systematic literature review to identify studies reporting cardiovascular abnormalities in patients with DDX3X-syndrome.
Results
A total of 200 patients with DDX3X-syndrome were analyzed, comprising 14 patients from our institutional cohort and 186 patients identified through a systematic review of 9 published studies. Our institutional cohort included 14 patients (12 females and 2 males) from 13 unrelated families diagnosed with DDX3X-syndrome, at a median age of 4.5 years (IQR 1.2–9.5). Echocardiogram was performed on nine patients, and cardiovascular abnormalities were found in 7 out of 9 patients who underwent echocardiography (78%), two of whom had major congenital heart defect (CHD) requiring surgical intervention. At the time of assessment, 13 individuals were still alive, while one had died at age six due to extracardiac complications. The systematic review included 9 studies involving 186 patients, of whom 32 (17.4%, 25 females and 7 males) had reported cardiovascular abnormalities, ranging from simple CHDs to more complex defects.
Conclusion
DDX3X-syndrome carries a significant cardiovascular burden, which is possibly higher than previously reported, including complex congenital heart disease requiring surgical repair. A thorough cardiovascular assessment, including an electrocardiogram and echocardiogram, should be universally recommended for all patients at the time of diagnosis.
Thursday, March 26, 2026
More on ARHGEF9 mutations
Wang JY, Zhou P, Wang J, Tang B, Su T, Liu XR, Li BM, Meng H, Shi YW, Yi YH, He N, Liao WP. ARHGEF9 mutations in epileptic encephalopathy/intellectual disability: toward understanding the mechanism underlying phenotypic variation. Neurogenetics. 2018 Jan;19(1):9-16. doi: 10.1007/s10048-017-0528-2. Epub 2017 Nov 13. PMID: 29130122.
Abstract
ARHGEF9 resides on Xq11.1 and encodes collybistin, which is crucial in gephyrin clustering and GABAA receptor localization. ARHGEF9 mutations have been identified in patients with heterogeneous phenotypes, including epilepsy of variable severity and intellectual disability. However, the mechanism underlying phenotype variation is unknown. Using next-generation sequencing, we identified a novel mutation, c.868C > T/p.R290C, which co-segregated with epileptic encephalopathy, and validated its association with epileptic encephalopathy. Further analysis revealed that all ARHGEF9 mutations were associated with intellectual disability, suggesting its critical role in psychomotor development. Three missense mutations in the PH domain were not associated with epilepsy, suggesting that the co-occurrence of epilepsy depends on the affected functional domains. Missense mutations with severe molecular alteration in the DH domain, or located in the DH-gephyrin binding region, or adjacent to the SH3-NL2 binding site were associated with severe epilepsy, implying that the clinical severity was potentially determined by alteration of molecular structure and location of mutations. Male patients with ARHGEF9 mutations presented more severe phenotypes than female patients, which suggests a gene-dose effect and supports the pathogenic role of ARHGEF9 mutations. This study highlights the role of molecular alteration in phenotype expression and facilitates evaluation of the pathogenicity of ARHGEF9 mutations in clinical practice.
Ghesh L, Besnard T, Nizon M, Trochu E, Landeau-Trottier G, Breheret F, Thauvin-Robinet C, Bruel AL, Kuentz P, Coubes C, Cuisset L, Mignot C, Keren B, Bézieau S, Cogné B. Loss-of-function variants in ARHGEF9 are associated with an X-linked intellectual disability dominant disorder. Hum Mutat. 2021 May;42(5):498-505. doi: 10.1002/humu.24188. Epub 2021 Mar 14. PMID: 33600053.
Abstract
ARHGEF9 defects lead to an X-linked intellectual disability disorder related to inhibitory synaptic dysfunction. This condition is more frequent in males, with a few affected females reported. Up to now, sequence variants and gross deletions have been identified in males, while only chromosomal aberrations have been reported in affected females who showed a skewed pattern of X-chromosome inactivation (XCI), suggesting an X-linked recessive (XLR) disorder. We report three novel loss-of-function (LoF) variants in ARHGEF9: A de novo synonymous variant affecting splicing (NM_015185.2: c.1056G>A, p.(Lys352=)) in one female; a nonsense variant in another female (c.865C>T, p.(Arg289*)), that is, also present as a somatically mosaic variant in her father, and a de novo nonsense variant in a boy (c.899G>A; p.(Trp300*)). Both females showed a random XCI. Thus, we suggest that missense variants are responsible for an XLR disorder affecting males and that LoF variants, mainly occurring de novo, may be responsible for an X-linked dominant disorder affecting males and females.
Aarabi M, Kessler E, Madan-Khetarpal S, Surti U, Bellissimo D, Rajkovic A, Yatsenko SA. Autism spectrum disorder in females with ARHGEF9 alterations and a random pattern of X chromosome inactivation. Eur J Med Genet. 2019 Apr;62(4):239-242. doi: 10.1016/j.ejmg.2018.07.021. Epub 2018 Jul 23. PMID: 30048823.
Abstract
Proper function of GABAergic synapses depends upon the postsynaptic compartment anchoring of neurotransmitter receptors to the membrane by gephyrin and collybistin (Cb). In humans, Cb is encoded by ARHGEF9 on Xq11.1. ARHGEF9 alterations, some inherited from unaffected mothers, have been reported in males with autism, seizures and severe neurodevelopmental abnormalities. In females, a spectrum of mild to moderate phenotype has been detected. We report two unrelated females with autism and mild intellectual disability. High resolution X-chromosome microarray analysis revealed de novo intragenic deletions in ARHGEF9 of 24 kb and 56 kb involving exons 5-8 and exons 3-8 and leading to truncated forms of collybistin. Peripheral blood samples revealed random X-chromosome inactivation in both patients. To explain phenotypic variability in female patients, we propose a model for disruption of collybistin and various irregular interactions in post-synaptic neurons based on X inactivation patterns. Our findings highlight the importance of ARHGEF9 integrity and suggest further research on its correlation with autism and neurobehavioral problems.
See: https://childnervoussystem.blogspot.com/2026/03/arhgef9-mutations.html
Abstract
ARHGEF9 resides on Xq11.1 and encodes collybistin, which is crucial in gephyrin clustering and GABAA receptor localization. ARHGEF9 mutations have been identified in patients with heterogeneous phenotypes, including epilepsy of variable severity and intellectual disability. However, the mechanism underlying phenotype variation is unknown. Using next-generation sequencing, we identified a novel mutation, c.868C > T/p.R290C, which co-segregated with epileptic encephalopathy, and validated its association with epileptic encephalopathy. Further analysis revealed that all ARHGEF9 mutations were associated with intellectual disability, suggesting its critical role in psychomotor development. Three missense mutations in the PH domain were not associated with epilepsy, suggesting that the co-occurrence of epilepsy depends on the affected functional domains. Missense mutations with severe molecular alteration in the DH domain, or located in the DH-gephyrin binding region, or adjacent to the SH3-NL2 binding site were associated with severe epilepsy, implying that the clinical severity was potentially determined by alteration of molecular structure and location of mutations. Male patients with ARHGEF9 mutations presented more severe phenotypes than female patients, which suggests a gene-dose effect and supports the pathogenic role of ARHGEF9 mutations. This study highlights the role of molecular alteration in phenotype expression and facilitates evaluation of the pathogenicity of ARHGEF9 mutations in clinical practice.
Ghesh L, Besnard T, Nizon M, Trochu E, Landeau-Trottier G, Breheret F, Thauvin-Robinet C, Bruel AL, Kuentz P, Coubes C, Cuisset L, Mignot C, Keren B, Bézieau S, Cogné B. Loss-of-function variants in ARHGEF9 are associated with an X-linked intellectual disability dominant disorder. Hum Mutat. 2021 May;42(5):498-505. doi: 10.1002/humu.24188. Epub 2021 Mar 14. PMID: 33600053.
Abstract
ARHGEF9 defects lead to an X-linked intellectual disability disorder related to inhibitory synaptic dysfunction. This condition is more frequent in males, with a few affected females reported. Up to now, sequence variants and gross deletions have been identified in males, while only chromosomal aberrations have been reported in affected females who showed a skewed pattern of X-chromosome inactivation (XCI), suggesting an X-linked recessive (XLR) disorder. We report three novel loss-of-function (LoF) variants in ARHGEF9: A de novo synonymous variant affecting splicing (NM_015185.2: c.1056G>A, p.(Lys352=)) in one female; a nonsense variant in another female (c.865C>T, p.(Arg289*)), that is, also present as a somatically mosaic variant in her father, and a de novo nonsense variant in a boy (c.899G>A; p.(Trp300*)). Both females showed a random XCI. Thus, we suggest that missense variants are responsible for an XLR disorder affecting males and that LoF variants, mainly occurring de novo, may be responsible for an X-linked dominant disorder affecting males and females.
Aarabi M, Kessler E, Madan-Khetarpal S, Surti U, Bellissimo D, Rajkovic A, Yatsenko SA. Autism spectrum disorder in females with ARHGEF9 alterations and a random pattern of X chromosome inactivation. Eur J Med Genet. 2019 Apr;62(4):239-242. doi: 10.1016/j.ejmg.2018.07.021. Epub 2018 Jul 23. PMID: 30048823.
Abstract
Proper function of GABAergic synapses depends upon the postsynaptic compartment anchoring of neurotransmitter receptors to the membrane by gephyrin and collybistin (Cb). In humans, Cb is encoded by ARHGEF9 on Xq11.1. ARHGEF9 alterations, some inherited from unaffected mothers, have been reported in males with autism, seizures and severe neurodevelopmental abnormalities. In females, a spectrum of mild to moderate phenotype has been detected. We report two unrelated females with autism and mild intellectual disability. High resolution X-chromosome microarray analysis revealed de novo intragenic deletions in ARHGEF9 of 24 kb and 56 kb involving exons 5-8 and exons 3-8 and leading to truncated forms of collybistin. Peripheral blood samples revealed random X-chromosome inactivation in both patients. To explain phenotypic variability in female patients, we propose a model for disruption of collybistin and various irregular interactions in post-synaptic neurons based on X inactivation patterns. Our findings highlight the importance of ARHGEF9 integrity and suggest further research on its correlation with autism and neurobehavioral problems.
See: https://childnervoussystem.blogspot.com/2026/03/arhgef9-mutations.html
Wednesday, March 25, 2026
KDM2B-related neurodevelopmental disorder
Inspired by a patient
Abstract
The KDM2B-related neurodevelopmental disorder is a recently identified Mendelian disorder of the epigenetic machinery associated with pathogenic variants in KDM2B. Global developmental delay, intellectual disability, congenital anomalies, and systemic manifestations characterize the disorder. Variants in KDM2B that primarily affect the CxxC DNA-binding domain are strongly linked to a specific epigenetic signature. We present three children with KDM2B-related neurodevelopmental disorder, each with a heterozygous variant in the CxxC domain of KDM2B. Patient 1 is a 2-year-old boy with developmental delay, solitary kidney, atrial septal defect, feeding difficulties, hemangiomas, and myopic astigmatism. Patient 2 is a 2-year-old girl with global developmental delay, hip dysplasia, feeding difficulties, hemangiomas, and myopic astigmatism. Patient 3 is a 5-year-old girl with autism, developmental delay, atrial septal defect, and ventricular septal defect, hypertrichosis, atopic dermatitis, and myopic astigmatism. Genetic analysis revealed a variant in KDM2B in each patient. Targeted methylation analysis for the epigenetic signature associated with the KDM2B-related syndrome revealed an abnormal methylation pattern consistent with a positive epigenetic signature of the disorder in individuals 2 and 3. These results provided supportive functional evidence for KDM2B-related neurodevelopmental disorder in the context of the clinical findings and KDM2B variants. Our findings emphasize the value of integrating genomic and epigenomic analyses for variant interpretation. This case series reinforces the consistent phenotype of KDM2B-related neurodevelopmental disorder and highlights ocular and dermatologic manifestations as recurring features in affected individuals.
van Jaarsveld RH, Reilly J, Cornips MC, Hadders MA, Agolini E, Ahimaz P, Anyane-Yeboa K, Bellanger SA, van Binsbergen E, van den Boogaard MJ, Brischoux-Boucher E, Caylor RC, Ciolfi A, van Essen TAJ, Fontana P, Hopman S, Iascone M, Javier MM, Kamsteeg EJ, Kerkhof J, Kido J, Kim HG, Kleefstra T, Lonardo F, Lai A, Lev D, Levy MA, Lewis MES, Lichty A, Mannens MMAM, Matsumoto N, Maya I, McConkey H, Megarbane A, Michaud V, Miele E, Niceta M, Novelli A, Onesimo R, Pfundt R, Popp B, Prijoles E, Relator R, Redon S, Rots D, Rouault K, Saida K, Schieving J, Tartaglia M, Tenconi R, Uguen K, Verbeek N, Walsh CA, Yosovich K, Yuskaitis CJ, Zampino G, Sadikovic B, Alders M, Oegema R. Delineation of a KDM2B-related neurodevelopmental disorder and its associated DNA methylation signature. Genet Med. 2023 Jan;25(1):49-62. doi: 10.1016/j.gim.2022.09.006. Epub 2022 Nov 1. PMID: 36322151; PMCID: PMC9825659.
Abstract
Purpose: Pathogenic variants in genes involved in the epigenetic machinery are an emerging cause of neurodevelopment disorders (NDDs). Lysine-demethylase 2B (KDM2B) encodes an epigenetic regulator and mouse models suggest an important role during development. We set out to determine whether KDM2B variants are associated with NDD.
Methods: Through international collaborations, we collected data on individuals with heterozygous KDM2B variants. We applied methylation arrays on peripheral blood DNA samples to determine a KDM2B associated epigenetic signature.
Results: We recruited a total of 27 individuals with heterozygous variants in KDM2B. We present evidence, including a shared epigenetic signature, to support a pathogenic classification of 15 KDM2B variants and identify the CxxC domain as a mutational hotspot. Both loss-of-function and CxxC-domain missense variants present with a specific subepisignature. Moreover, the KDM2B episignature was identified in the context of a dual molecular diagnosis in multiple individuals. Our efforts resulted in a cohort of 21 individuals with heterozygous (likely) pathogenic variants. Individuals in this cohort present with developmental delay and/or intellectual disability; autism; attention deficit disorder/attention deficit hyperactivity disorder; congenital organ anomalies mainly of the heart, eyes, and urogenital system; and subtle facial dysmorphism.
Conclusion: Pathogenic heterozygous variants in KDM2B are associated with NDD and a specific epigenetic signature detectable in peripheral blood.
van Oirsouw ASE, Hadders MA, Koetsier M, Peters EDJ, Assia Batzir N, Barakat TS, Baralle D, Beil A, Bonnet-Dupeyron MN, Boone PM, Bouman A, Carere DA, Cogne B, Dunnington L, Farach LS, Genetti CA, Isidor B, Januel L, Joshi A, Lahiri N, Lee KN, Maya I, McEntagart M, Northrup H, Pujalte M, Richardson K, Walker S, Koeleman BPC, Alders M, van Jaarsveld RH, Oegema R. KDM2B variants in the CxxC domain impair its DNA-binding ability and cause a distinct neurodevelopmental syndrome. Hum Mol Genet. 2025 Aug 16;34(16):1353-1367. doi: 10.1093/hmg/ddaf082. PMID: 40420380; PMCID: PMC12361114.
Abstract
Rare variants affecting the epigenetic regulator KDM2B cause a recently delineated neurodevelopmental disorder. Interestingly, we previously identified both a general KDM2B-associated episignature and a subsignature specific to variants in the DNA-binding CxxC domain. In light of the existence of a distinct subsignature, we set out to determine if KDM2B CxxC variants are associated with a unique phenotype and disease mechanism. We recruited individuals with heterozygous CxxC variants and assessed the variants' effect on protein expression and DNA-binding ability. We analyzed clinical data from 19 individuals, including ten previously undescribed individuals with seven novel CxxC variants. The core phenotype of the KDM2B-CxxC cohort is more extensive as compared to that of individuals with KDM2B haploinsufficiency. All individuals with CxxC variants presented with developmental delay, mainly in the speech and motor domain, in addition to variable intellectual disability and mild facial dysmorphism. Congenital heart defects were observed in up to 78% of individuals, with additional common findings including musculoskeletal, ophthalmological, and urogenital anomalies, as well as behavioral challenges and feeding difficulties. Functional assays revealed that while mutant KDM2B protein with CxxC variants can be expressed in vitro, its DNA-binding ability is significantly reduced compared to wildtype. This study shows that KDM2B CxxC variants cause a distinct neurodevelopmental syndrome, possibly through a molecular mechanism different from haploinsufficiency.
Antiseizure medication dosing strategy during pregnancy and early postpartum in women With epilepsy
A large, multicenter analysis of antiseizure medications used during pregnancy provides clinicians with clear guidance on how to adjust dosing across gestation and into the postpartum period to minimize seizures and risk to unborn babies.
New research provides medication-specific guidance for safely increasing antiseizure medication (ASM) doses during pregnancy, delivering real-world evidence the neurology community has long needed to inform care for pregnant women with epilepsy.
Earlier studies have shown that pregnancy profoundly alters the metabolism of ASMs, often necessitating dose increases two or three times over baseline pre-pregnancy levels to maintain therapeutic blood concentrations. Maintaining these levels is essential, as allowing them to fall below roughly 65 percent of baseline sharply increases the risk of breakthrough seizures.
Until recently, however, clinicians have relied largely on anecdotal experience to guide ASM dose adjustments during pregnancy. Findings from this new multicenter, prospective trial—published online Dec. 29 in Neurology—provide much-needed data to inform dosing strategies and support more systematic, evidence-based clinical decision-making, however.
This latest research was driven by a very simple question, said Page B. Pennell, MD, FAAN, chair of neurology at the University of Pittsburgh School of Medicine and the study's senior author: “How do we take what we know about drug clearance in pregnant women with epilepsy and provide guidance on medication dose adjustments based on real-world evidence that clinicians everywhere can actually adopt?”...
Frequent drug level monitoring proved essential in capturing the dynamic changes of pregnancy. Based on observed practice patterns, the study supports checking ASM levels approximately every four to six weeks, a schedule that may be more intensive than what many clinicians currently employ.
“This paper really reinforces that less-frequent monitoring, once per trimester, or only early and late in pregnancy, is probably insufficient,” Dr. Maturu said. “It gives us a much clearer sense of how often we should be checking levels and making adjustments.”
Importantly, metabolic changes begin early. Although women in MONEAD were enrolled up to 20 weeks' gestation, prior work by Dr. Pennell and colleagues has shown significant clearance changes as early as five weeks—prompting her to advise patients to contact their neurologist immediately after a positive pregnancy test...
The postpartum period has emerged as one of the most critical, and underappreciated, phases of ASM management. As pregnancy-related metabolic changes rapidly normalize, serum drug levels can rebound within days.
“In this study, the average time to dose reduction was about three days after delivery,” Dr. Maturu noted. “That's a very practical signal that we need to reassess medications almost immediately after childbirth.”
Dr. Pennell added that while doses often need to be reduced quickly, they may still remain slightly higher than pre-pregnancy levels to account for sleep deprivation, stress, and seizure vulnerability during early parenthood.
A key takeaway for Dr. Hopp was that monitoring must continue soon after birth, when ASM pharmacokinetics begin reverting toward baseline...
Both Drs. Pennell and Maturu stressed that these findings reinforce the need for routine, proactive pregnancy counseling for all patients of childbearing potential.
“About half of pregnancies in women with epilepsy are unplanned,” Dr. Maturu said. “That means these conversations can't wait until someone says they're trying to conceive.”
Preconception counseling should include establishing baseline ASM levels, explaining the likelihood of dose increases, and outlining a postpartum adjustment plan. Clear expectations improve adherence and reduce anxiety when changes become necessary, Dr. Pennell emphasized.
Dr. Hopp noted that counseling should help patients understand the rationale behind frequent monitoring and dose adjustments...
Data were also strongest for a limited number of commonly used ASMs, leaving many newer or less frequently prescribed agents understudied.
“Out of more than 30 antiseizure medications available, we have robust pregnancy safety data for only a handful of drug options,” Dr. Pennell said
https://neurologytoday.aan.com/doi/full/10.1097/01.wnt.0001189220.34776.35
Pennell PB, Li D, Kerr WT, Pack AM, French J, Gerard E, Birnbaum AK, McFarlane KN, Meador KJ; MONEAD Study Group. Antiseizure Medication Dosing Strategy During Pregnancy and Early Postpartum in Women With Epilepsy in MONEAD. Neurology. 2026 Jan 27;106(2):e214483. doi: 10.1212/WNL.0000000000214483. Epub 2025 Dec 29. PMID: 41461064.
Abstract
Background and objectives: Antiseizure medications (ASMs) undergo marked pharmacokinetic alterations during pregnancy and postpartum. Suboptimal ASM management can lead to adverse maternal and child outcomes. However, there is scant literature to guide how to adjust ASM dosing. This study analyzed how ASMs were dosed in a large observational cohort study of pregnant women with epilepsy (PWWE) who had favorable seizure outcomes.
Methods: Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) was a prospective, observational cohort study that enrolled PWWE 2012-2016 across 20 US epilepsy centers. Inclusion criteria were PWWE, ages 14-45 years, and <20 weeks' gestational age. Seizures and ASM type(s) and doses were documented in a daily diary. Our analysis included ASM doses in pregnancy through early postpartum (6 weeks post-delivery). For each ASM, we analyzed percent participants who underwent ≥1 dose change in pregnancy and postpartum, time of first dose change after enrollment, time to subsequent changes, amount of each dose adjustment, and percent of conception dose at delivery and 6-week postpartum.
Results: A total of 299 participants (median 31 [range 17-46] years) were eligible for analysis. Median enrollment was 14-weeks gestation. Dose increases were made in 246/363 (67.8%) of ASMs during pregnancy beginning median 32 days post-enrollment; dose decreases were made within 6 weeks post-delivery for 171/357 (47.9%) of ASMs beginning median 3 days postpartum. For lamotrigine, 128/146 (87.7%) participants had doses increased, by 100 mg/d (median), reaching 191% of conception dose (mean) by delivery. Postpartum, 103/146 (70.5%) had dose tapers, by 100 mg/d (median), to 116% of conception dose (mean) by 6 weeks. For levetiracetam, 70/125 (56.0%) participants had doses increased, by 500 mg/d (median), reaching 177% of conception dose (mean) by delivery. Postpartum, 43/125 (34.4%) had dose tapers, by 500 mg/d (median), to 136% of conception dose (mean) by 6 weeks. For other ASMs, 10/14 had doses increased in pregnancy and 8/14 were tapered early postpartum.
Discussion: Previous MONEAD analyses showed no difference in seizure control between pregnant and nonpregnant women with epilepsy. We detail how ASMs were managed in pregnancy and early postpartum to achieve this favorable outcome. These findings can be useful for the management of PWWE. Limitations of this study include limited data in the first trimester, enrollment from epilepsy centers, and limited number of participants on a wider variety of ASMs.
Maturu S, Long L. Navigating the Storm-A New Horizon: An Updated Guide for Managing Antiseizure Medications During Pregnancy and the Postpartum Period. Neurology. 2026 Jan 27;106(2):e214585. doi: 10.1212/WNL.0000000000214585. Epub 2025 Dec 29. PMID: 41461062.
Excerpt
This study by Pennell et al. offers a roadmap of guidance on increasing and decreasing ASMs during pregnancy and the postpartum period, respectively. This is particularly important considering new and updated national practice guidelines. As we move forward, it is important to confirm the benefit of medication adjustments during conception and the postpartum period and how we can use the pharmacokinetics and pharmacodynamics of all ASMs to improve outcomes for patients. Specifically, do patients that are pregnant who undergo ASM changes have better seizure control compared with those who maintain preconception doses? Is there a need to adjust ASMs in the first trimester, and if so, does earlier adjustment impact clinical outcomes? And finally, does a slightly higher dosing of ASMs in the postpartum period help with seizure burden?
New research provides medication-specific guidance for safely increasing antiseizure medication (ASM) doses during pregnancy, delivering real-world evidence the neurology community has long needed to inform care for pregnant women with epilepsy.
Earlier studies have shown that pregnancy profoundly alters the metabolism of ASMs, often necessitating dose increases two or three times over baseline pre-pregnancy levels to maintain therapeutic blood concentrations. Maintaining these levels is essential, as allowing them to fall below roughly 65 percent of baseline sharply increases the risk of breakthrough seizures.
Until recently, however, clinicians have relied largely on anecdotal experience to guide ASM dose adjustments during pregnancy. Findings from this new multicenter, prospective trial—published online Dec. 29 in Neurology—provide much-needed data to inform dosing strategies and support more systematic, evidence-based clinical decision-making, however.
This latest research was driven by a very simple question, said Page B. Pennell, MD, FAAN, chair of neurology at the University of Pittsburgh School of Medicine and the study's senior author: “How do we take what we know about drug clearance in pregnant women with epilepsy and provide guidance on medication dose adjustments based on real-world evidence that clinicians everywhere can actually adopt?”...
Frequent drug level monitoring proved essential in capturing the dynamic changes of pregnancy. Based on observed practice patterns, the study supports checking ASM levels approximately every four to six weeks, a schedule that may be more intensive than what many clinicians currently employ.
“This paper really reinforces that less-frequent monitoring, once per trimester, or only early and late in pregnancy, is probably insufficient,” Dr. Maturu said. “It gives us a much clearer sense of how often we should be checking levels and making adjustments.”
Importantly, metabolic changes begin early. Although women in MONEAD were enrolled up to 20 weeks' gestation, prior work by Dr. Pennell and colleagues has shown significant clearance changes as early as five weeks—prompting her to advise patients to contact their neurologist immediately after a positive pregnancy test...
The postpartum period has emerged as one of the most critical, and underappreciated, phases of ASM management. As pregnancy-related metabolic changes rapidly normalize, serum drug levels can rebound within days.
“In this study, the average time to dose reduction was about three days after delivery,” Dr. Maturu noted. “That's a very practical signal that we need to reassess medications almost immediately after childbirth.”
Dr. Pennell added that while doses often need to be reduced quickly, they may still remain slightly higher than pre-pregnancy levels to account for sleep deprivation, stress, and seizure vulnerability during early parenthood.
A key takeaway for Dr. Hopp was that monitoring must continue soon after birth, when ASM pharmacokinetics begin reverting toward baseline...
Both Drs. Pennell and Maturu stressed that these findings reinforce the need for routine, proactive pregnancy counseling for all patients of childbearing potential.
“About half of pregnancies in women with epilepsy are unplanned,” Dr. Maturu said. “That means these conversations can't wait until someone says they're trying to conceive.”
Preconception counseling should include establishing baseline ASM levels, explaining the likelihood of dose increases, and outlining a postpartum adjustment plan. Clear expectations improve adherence and reduce anxiety when changes become necessary, Dr. Pennell emphasized.
Dr. Hopp noted that counseling should help patients understand the rationale behind frequent monitoring and dose adjustments...
Data were also strongest for a limited number of commonly used ASMs, leaving many newer or less frequently prescribed agents understudied.
“Out of more than 30 antiseizure medications available, we have robust pregnancy safety data for only a handful of drug options,” Dr. Pennell said
https://neurologytoday.aan.com/doi/full/10.1097/01.wnt.0001189220.34776.35
Pennell PB, Li D, Kerr WT, Pack AM, French J, Gerard E, Birnbaum AK, McFarlane KN, Meador KJ; MONEAD Study Group. Antiseizure Medication Dosing Strategy During Pregnancy and Early Postpartum in Women With Epilepsy in MONEAD. Neurology. 2026 Jan 27;106(2):e214483. doi: 10.1212/WNL.0000000000214483. Epub 2025 Dec 29. PMID: 41461064.
Abstract
Background and objectives: Antiseizure medications (ASMs) undergo marked pharmacokinetic alterations during pregnancy and postpartum. Suboptimal ASM management can lead to adverse maternal and child outcomes. However, there is scant literature to guide how to adjust ASM dosing. This study analyzed how ASMs were dosed in a large observational cohort study of pregnant women with epilepsy (PWWE) who had favorable seizure outcomes.
Methods: Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) was a prospective, observational cohort study that enrolled PWWE 2012-2016 across 20 US epilepsy centers. Inclusion criteria were PWWE, ages 14-45 years, and <20 weeks' gestational age. Seizures and ASM type(s) and doses were documented in a daily diary. Our analysis included ASM doses in pregnancy through early postpartum (6 weeks post-delivery). For each ASM, we analyzed percent participants who underwent ≥1 dose change in pregnancy and postpartum, time of first dose change after enrollment, time to subsequent changes, amount of each dose adjustment, and percent of conception dose at delivery and 6-week postpartum.
Results: A total of 299 participants (median 31 [range 17-46] years) were eligible for analysis. Median enrollment was 14-weeks gestation. Dose increases were made in 246/363 (67.8%) of ASMs during pregnancy beginning median 32 days post-enrollment; dose decreases were made within 6 weeks post-delivery for 171/357 (47.9%) of ASMs beginning median 3 days postpartum. For lamotrigine, 128/146 (87.7%) participants had doses increased, by 100 mg/d (median), reaching 191% of conception dose (mean) by delivery. Postpartum, 103/146 (70.5%) had dose tapers, by 100 mg/d (median), to 116% of conception dose (mean) by 6 weeks. For levetiracetam, 70/125 (56.0%) participants had doses increased, by 500 mg/d (median), reaching 177% of conception dose (mean) by delivery. Postpartum, 43/125 (34.4%) had dose tapers, by 500 mg/d (median), to 136% of conception dose (mean) by 6 weeks. For other ASMs, 10/14 had doses increased in pregnancy and 8/14 were tapered early postpartum.
Discussion: Previous MONEAD analyses showed no difference in seizure control between pregnant and nonpregnant women with epilepsy. We detail how ASMs were managed in pregnancy and early postpartum to achieve this favorable outcome. These findings can be useful for the management of PWWE. Limitations of this study include limited data in the first trimester, enrollment from epilepsy centers, and limited number of participants on a wider variety of ASMs.
Maturu S, Long L. Navigating the Storm-A New Horizon: An Updated Guide for Managing Antiseizure Medications During Pregnancy and the Postpartum Period. Neurology. 2026 Jan 27;106(2):e214585. doi: 10.1212/WNL.0000000000214585. Epub 2025 Dec 29. PMID: 41461062.
Excerpt
This study by Pennell et al. offers a roadmap of guidance on increasing and decreasing ASMs during pregnancy and the postpartum period, respectively. This is particularly important considering new and updated national practice guidelines. As we move forward, it is important to confirm the benefit of medication adjustments during conception and the postpartum period and how we can use the pharmacokinetics and pharmacodynamics of all ASMs to improve outcomes for patients. Specifically, do patients that are pregnant who undergo ASM changes have better seizure control compared with those who maintain preconception doses? Is there a need to adjust ASMs in the first trimester, and if so, does earlier adjustment impact clinical outcomes? And finally, does a slightly higher dosing of ASMs in the postpartum period help with seizure burden?
Wednesday, March 18, 2026
Prenatal glucose intolerance and child neurodevelopmental disorders
Grosvenor LP, Gunderson EP, Qian Y, Alexeeff S, Ames JL, Weiss LA, Sahagun E, Ashwood P, Yolken R, Zhu Y, Van de Water J, Croen LA. Prenatal Glucose Intolerance and Child Neurodevelopmental Disorders. JAMA Netw Open. 2025 Nov 3;8(11):e2541657. doi: 10.1001/jamanetworkopen.2025.41657. PMID: 41191356; PMCID: PMC12590297.
Abstract
Importance: Gestational diabetes has been associated with risk of neurodevelopmental disorders (NDD). An improved understanding of this association can inform prevention strategies and elucidate underlying mechanisms.
Objective: To determine associations between prenatal glucose intolerance and NDD and examine differences by gestational timing and child sex.
Design, setting, and participants: This population-based case-control study examined data from electronic health records from mother-child pairs in an integrated health system in northern California. Children born January 1, 2011, to December 31, 2018, and their mothers were eligible; children were followed up for outcomes through 2023. Data were analyzed from February 2024 to March 2025.
Exposures: Gestational diabetes was determined from routine prenatal test results and categorized as diagnosed early (less than 24 weeks), standard (24 to 28 weeks), or late (more than 28 weeks) in gestation. Prenatal subclinical impaired glucose tolerance (IGT) was defined by elevated glucose screening tests and neither GDM diagnosis nor treatment.
Main outcomes and measures: Autism spectrum disorder (ASD) and developmental delay were determined from medical records. Adjusted odds ratios (aOR) for associations between prenatal exposures and NDD were estimated using multivariable logistic regression models, adjusted for child sex, birth year, maternal age, race and ethnicity, education, parity, gestational age at prenatal care entry, and prepregnancy body mass index. Effect modification was evaluated by GDM diagnosis timing and sex.
Results: A total of 4546 mother-child pairs (median [IQR]) age of diagnosis: ASD, 3.0 [2.0-5.0] years; developmental delay, 2.0 [1.0-3.0] years; 2697 male children [59.3%]) were included in the study, of which 403 mothers (8.9%) had GDM and 64 (1.4%) had IGT; 683 children [15.0%] had ASD, 2054 [45.2%] had developmental delay, and 1809 [39.8%] were controls. GDM was not associated with increased odds of ASD (aOR, 1.15 [95% CI, 0.83-1.60]) or developmental delay (aOR, 1.24 [95% CI, 0.98-1.57]) overall. In sex-stratified analyses, GDM was associated with increased odds of ASD only among females (females: aOR, 2.05 [95% CI, 1.15-3.56]; males: aOR, 0.93 [95% CI, 0.62-1.37]; P for interaction = .04). When assessed by timing, early GDM was associated with increased odds of ASD among females (aOR, 3.23 [95% CI, 1.11-8.91]) but not among males (aOR, 0.78 [95% CI, 0.38-1.56]; P for interaction = .02). There were no associations between standard or late GDM and ASD in either sex. Prenatal IGT was associated with increased odds of developmental delay among females only (females: aOR, 3.25 [95% CI, 1.34-8.68]; males: aOR, 1.07 [95% CI, 0.50-2.39]; P for interaction = .08).
Conclusions and relevance: In this case-control study, GDM was associated with NDD in a gestational timing- and sex-specific manner. IGT associations with NDD were also sex-specific, adding to a body of research demonstrating influences of prenatal IGT on child outcomes.
Abstract
Importance: Gestational diabetes has been associated with risk of neurodevelopmental disorders (NDD). An improved understanding of this association can inform prevention strategies and elucidate underlying mechanisms.
Objective: To determine associations between prenatal glucose intolerance and NDD and examine differences by gestational timing and child sex.
Design, setting, and participants: This population-based case-control study examined data from electronic health records from mother-child pairs in an integrated health system in northern California. Children born January 1, 2011, to December 31, 2018, and their mothers were eligible; children were followed up for outcomes through 2023. Data were analyzed from February 2024 to March 2025.
Exposures: Gestational diabetes was determined from routine prenatal test results and categorized as diagnosed early (less than 24 weeks), standard (24 to 28 weeks), or late (more than 28 weeks) in gestation. Prenatal subclinical impaired glucose tolerance (IGT) was defined by elevated glucose screening tests and neither GDM diagnosis nor treatment.
Main outcomes and measures: Autism spectrum disorder (ASD) and developmental delay were determined from medical records. Adjusted odds ratios (aOR) for associations between prenatal exposures and NDD were estimated using multivariable logistic regression models, adjusted for child sex, birth year, maternal age, race and ethnicity, education, parity, gestational age at prenatal care entry, and prepregnancy body mass index. Effect modification was evaluated by GDM diagnosis timing and sex.
Results: A total of 4546 mother-child pairs (median [IQR]) age of diagnosis: ASD, 3.0 [2.0-5.0] years; developmental delay, 2.0 [1.0-3.0] years; 2697 male children [59.3%]) were included in the study, of which 403 mothers (8.9%) had GDM and 64 (1.4%) had IGT; 683 children [15.0%] had ASD, 2054 [45.2%] had developmental delay, and 1809 [39.8%] were controls. GDM was not associated with increased odds of ASD (aOR, 1.15 [95% CI, 0.83-1.60]) or developmental delay (aOR, 1.24 [95% CI, 0.98-1.57]) overall. In sex-stratified analyses, GDM was associated with increased odds of ASD only among females (females: aOR, 2.05 [95% CI, 1.15-3.56]; males: aOR, 0.93 [95% CI, 0.62-1.37]; P for interaction = .04). When assessed by timing, early GDM was associated with increased odds of ASD among females (aOR, 3.23 [95% CI, 1.11-8.91]) but not among males (aOR, 0.78 [95% CI, 0.38-1.56]; P for interaction = .02). There were no associations between standard or late GDM and ASD in either sex. Prenatal IGT was associated with increased odds of developmental delay among females only (females: aOR, 3.25 [95% CI, 1.34-8.68]; males: aOR, 1.07 [95% CI, 0.50-2.39]; P for interaction = .08).
Conclusions and relevance: In this case-control study, GDM was associated with NDD in a gestational timing- and sex-specific manner. IGT associations with NDD were also sex-specific, adding to a body of research demonstrating influences of prenatal IGT on child outcomes.
Upright and positional MRI for Chiari 1 detection
Inspired by a patient
Abstract
Objective: Weight-bearing magnetic resonance imaging enables assessment of the cervical spine and craniocervical junction under physiological load, potentially revealing pathology that is occult on conventional supine imaging. This scoping review synthesizes current evidence, maps clinical and emerging applications, and identifies key gaps requiring further investigation.
Methods: A structured search was conducted in PubMed, Scopus, Web of Science, Google Scholar, and Semantic Scholar (July 2025). Eligible studies were reviewed for diagnostic utility, technical considerations, clinical indications, and outcomes. Methodological quality was appraised descriptively in line with Joanna Briggs Institute guidance.
Results: Nine studies, published between 2008 and 2025, met inclusion criteria. Upright and dynamic MRI detected posture-dependent changes including spinal canal narrowing, cord compression, foraminal stenosis, ligamentous buckling, cerebellar tonsillar descent, altered sagittal alignment, and CSF flow differences. Findings were more pronounced in flexion extension and upright postures compared with supine imaging. Normative studies established reference metrics for CCJ motion and prevertebral soft tissue width. Preliminary evidence also highlights applications in connective tissue disorders, Chiari malformation, and upper cervical chiropractic practice, although most studies were feasibility reports with small sample sizes and heterogeneous protocols.
Conclusion: Emerging evidence suggests that WBMRI provides added diagnostic value in selected cervical spine and CCJ conditions by revealing dynamic or load-sensitive pathology not captured on standard supine imaging. While current evidence remains preliminary, standardized protocols, higher-field technologies, and large multicenter outcome-based studies are essential to validate diagnostic thresholds, improve reproducibility, and define the role of WBMRI in routine clinical care.
Health Quality Ontario. Positional Magnetic Resonance Imaging for People With Ehlers-Danlos Syndrome or Suspected Craniovertebral or Cervical Spine Abnormalities: An Evidence-Based Analysis. Ont Health Technol Assess Ser. 2015 Jul 1;15(13):1-24. PMID: 26366238; PMCID: PMC4561548.
Abstract
Background: Ehlers-Danlos syndrome (EDS) is an inherited disorder affecting the connective tissue. EDS can manifest with symptoms attributable to the spine or craniovertebral junction (CVJ). In addition to EDS, numerous congenital, developmental, or acquired disorders can increase ligamentous laxity in the CVJ and cervical spine. Resulting abnormalities can lead to morbidity and serious neurologic complications. Appropriate imaging and diagnosis is needed to determine patient management and need for complex surgery. Some spinal abnormalities cause symptoms or are more pronounced while patients sit, stand, or perform specific movements. Positional magnetic resonance imaging (pMRI) allows imaging of the spine or CVJ with patients in upright, weight-bearing positions and can be combined with dynamic maneuvers, such as flexion, extension, or rotation. Imaging in these positions could allow diagnosticians to better detect spinal or CVJ abnormalities than recumbent MRI or even a combination of other available imaging modalities might allow.
Objectives: To determine the diagnostic impact and clinical utility of pMRI for the assessment of (a) craniovertebral or spinal abnormalities among people with EDS and (b) major craniovertebral or cervical spine abnormalities among symptomatic people.
Data sources: A literature search was performed using Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid Embase, and EBM Reviews, for studies published from January 1, 1998, to September 28, 2014.
Review methods: Studies comparing pMRI to recumbent MRI or other available imaging modalities for diagnosis and management of spinal or CVJ abnormalities were reviewed. All studies of spinal or CVJ imaging in people with EDS were included as well as studies among people with suspected major CVJ or cervical spine abnormalities (cervical or craniovertebral spine instability, basilar invagination, cranial settling, cervical stenosis, spinal cord compression, Chiari malformation).
Results: No studies were identified that met the inclusion criteria.
Conclusions: We did not identify any evidence that assessed the diagnostic impact or clinical utility of pMRI for (a) craniovertebral or spinal abnormalities among people with EDS or (b) major craniovertebral or cervical spine abnormalities among symptomatic people relative to currently available diagnostic modalities.
Tubbs RS, Kirkpatrick CM, Rizk E, Chern JJ, Oskouian RJ, Oakes WJ. Do the cerebellar tonsils move during flexion and extension of the neck in patients with Chiari I malformation? A radiological study with clinical implications. Childs Nerv Syst. 2016 Mar;32(3):527-30. doi: 10.1007/s00381-016-3014-5. Epub 2016 Jan 12. PMID: 26758883.
Abstract
Background: In the past, diagnosis of the Chiari I malformation has primarily been made on midsagittal MRI. We hypothesized that based on the frequent presentation of opisthotonos in patients with hindbrain hernia (primarily Chiari II malformation but sometimes Chiari I malformation) that the hyperextension might be a compensatory technique used by such patients to bring the cerebellar tonsils up out of the cervical spine.
Patients and methods: This prospective study reviewed imaging of patients with Chiari I malformation who underwent flexion/extension MRI for evaluation of their hindbrain herniation. Age-matched controls were used for comparison.
Results: In general, there was elevation of the cerebellar tonsils with extension and increased descent with flexion of the cervical spine. In 72 % of patients, flexion of the neck resulted in descent of the cerebellar tonsils. In 64 % of patients, extension of the neck resulted in ascent of the cerebellar tonsils. In the 14 patients with an associated syrinx, 71 % were found to have caudal movement of the cerebellar tonsils with neck flexion, and only 43 % were observed to have any movement of the cerebellar tonsils in neck extension compared to patients without a syrinx where ascent of the tonsils was seen in only nine during neck extension. Two patients were observed to have the reverse finding of ascent of the cerebellar tonsils with neck flexion and descent of the cerebellar tonsils with neck extension. Five patients had no movement of the cerebellar tonsils in either flexion or extension of the neck, and one of these had a small syrinx.
Conclusions: Although minimal and not in all patients, we observed elevation of the herniated cerebellar tonsils with extension of the cervical spine in patients with Chiari I malformation. This finding provides evidence as to why some patients with hindbrain herniation present with opisthotonos and supports earlier findings that CSF flow is reduced at the craniocervical junction in flexion in patients with Chiari I malformation.
Tam SKP, Chia J, Brodbelt A, Foroughi M. Assessment of patients with a Chiari malformation type I. Brain Spine. 2021 Dec 3;2:100850. doi: 10.1016/j.bas.2021.100850. PMID: 36248113; PMCID: PMC9560699.
Abstract
Introduction
The prevalence of Chiari malformation type I (CM-I) has been estimated as up to 1% of the general population. The majority of patients are asymptomatic and usually do not need treatment. Symptomatic patients, and some asymptomatic patients with associated conditions, may benefit from further assessment and treatment.
Research question
The aim of this review was to describe the clinical and radiological assessment of patients presenting with a CM-I.
Material and methods
A literature search was performed using the PubMed and Embase databases focused on clinical assessment and imaging techniques used to diagnose CM-I.
Results
Following a complete clinical evaluation in patients with symptomatic CM-I and/or radiologically significant CM-I (tonsillar impaction, resulting tonsillar asymmetry and loss of CSF spaces), MRI of the brain and whole spine enables an assessment of the CM-I and potential associated or causative conditions. These include hydrocephalus, syringomyelia, spinal dysraphism, and tethered cord. Flow and Cine MRI can provide information on CSF dynamics at the craniocervical junction, and help in surgical decision-making. Hypermobility or instability at the upper cervical and craniocervical junction is less common and can be measured with CT imaging and flexion/extension or upright MRI.
Discussion and conclusion
The majority of CM-I detected are incidental findings on MRI imaging of brain or spine, and do not require intervention. Once a radiological diagnosis and concern has been raised, clinical assessment by an appropriate specialist is required. A MRI brain and cervical spine is indicated in all radiologically labelled CM-I. In symptomatic patients or cases of radiologically significant CM-I, MRI of the brain and entire spine is indicated. Further investigations should be tailored to individuals’ needs.
David Chu, Michael Boitano, Dan Culver, Raymond Damadian, Mary Gianni, Rob Viel, Jan Votruba, Robert Wolf. First Upright Study of CSF Flow in Chiari I Malformation with Cine Phase-Contrast MRI. https://archive.ismrm.org/2009/0940.html
Cerebrospinal fluid (CSF) flow abnormalities are generally known to correlate better with symptomatology than the degree of tonsillar herniation in Chiari I malformation (CMI) patients. However, all MRI studies of CSF flow in CMI patients have been restricted to the recumbent position. We present the first study of CSF flow and spinal cord pulsation in the upright posture in a CMI patient. Upright imaging revealed major CSF flow abnormalities that were absent in the supine posture.
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