2q13 duplication

Inspired by a colleague's patient

Messina C, Zuccarello M. Parietal Lobe Epilepsy Associated With 2q13 Duplication: Expanding the Neurogenetic Spectrum. Cureus. 2025 Aug 19;17(8):e90456. doi: 10.7759/cureus.90456. PMID: 40979016; PMCID: PMC12444579.

Abstract

Copy number variations (CNVs) involving the 2q13 region have been associated with a wide range of phenotypes, including developmental delay, dysmorphic features, hypotonia, and congenital heart defects. However, parietal lobe epilepsy has not yet been reported in association with 2q13 duplication. We describe the case of a 20-year-old woman with a duplication of the 2q13 region identified during childhood, who later presented with recurrent, brief episodes of right upper limb paresthesia spreading to other limbs, followed by transient pain. Her past medical history included dyspraxia, polycystic ovary syndrome, atrial fibrillation, and intellectual disability. Electroencephalography (EEG) revealed interictal epileptiform discharges, consisting of paroxysmal sharp theta waves in the left parietal and temporal regions, spreading to adjacent and contralateral areas, particularly during hyperventilation. Based on clinical and EEG features, a diagnosis of parietal lobe epilepsy was established. Treatment with levetiracetam resulted in significant clinical improvement, characterized by complete resolution of the previously described episodes of recurrent, brief right upper limb paresthesia spreading to other limbs, followed by transient pain, as well as a reduction of epileptiform abnormalities on EEG. The duplicated region includes several genes involved in neuronal development, synaptic regulation, and myelination, such as MERTK, TMEM87B, and FBLN7. Their altered expression may contribute to cortical excitability and epileptogenesis. This case adds to the phenotypic variability reported in individuals with 2q13 duplication and underscores the importance of further studies to explore possible gene-specific contributions to neurological findings. This is the first report linking 2q13 duplication with parietal epilepsy, underlining the importance of considering CNVs in unexplained focal epilepsy presentations.

Digilio MC, Dentici ML, Loddo S, Laino L, Calcagni G, Genovese S, Capolino R, Bottillo I, Calvieri G, Dallapiccola B, Marino B, Novelli A, Versacci P. Congenital heart defects in the recurrent 2q13 deletion syndrome. Eur J Med Genet. 2022 Jan;65(1):104381. doi: 10.1016/j.ejmg.2021.104381. Epub 2021 Nov 8. PMID: 34763108.

Abstract

The recurrent 2q13 deletion syndrome is a rare genetic disorder associated with developmental delay, cardiac and urogenital malformations, and minor facial anomalies. Congenital heart defects (CHDs) are the most frequent malformations associated with del2q13. Experimental studies in zebrafish suggest that two genes mapping within the 2q13 critical region (FBLN7 and TMEM87B) could confer susceptibility to congenital heart defects in affected individuals. We reviewed the cardiac characteristics in four patients with 2q13 deletion admitted to our hospitals, and in published patients. Two of our patients had congenital heart defects, consisting in partial anomalous pulmonary venous connection, ostium secundum atrial septal defect ostium secundum, and small muscular ventricular septal defect in one of them, and aortic valve insufficiency with partial fusion of two commissures (incomplete bicuspid aortic valve) and mitral valve insufficiency due to trivial mitral valve prolapse in the other. The anatomic types of CHD in del2q13 syndrome are highly variable and distributed widely, including laterality defects, complex atrioventricular septal defect, septal anomalies, and cardiomyopathies. Cardiac evaluation should be part of the clinical workup at diagnosis of 2q13 deletion.

Riley KN, Catalano LM, Bernat JA, Adams SD, Martin DM, Lalani SR, Patel A, Burnside RD, Innis JW, Rudd MK. Recurrent deletions and duplications of chromosome 2q11.2 and 2q13 are associated with variable outcomes. Am J Med Genet A. 2015 Nov;167A(11):2664-73. doi: 10.1002/ajmg.a.37269. Epub 2015 Jul 31. PMID: 26227573.

Abstract

Copy number variation (CNV) in the long arm of chromosome 2 has been implicated in developmental delay (DD), intellectual disability (ID), autism spectrum disorder (ASD), congenital anomalies, and psychiatric disorders. Here we describe 14 new subjects with recurrent deletions and duplications of chromosome 2q11.2, 2q13, and 2q11.2-2q13. Though diverse phenotypes are associated with these CNVs, some common features have emerged. Subjects with 2q11.2 deletions often exhibit DD, speech delay, and attention deficit hyperactivity disorder (ADHD), whereas those with 2q11.2 duplications have DD, gastroesophageal reflux, and short stature. Congenital heart defects (CHDs), hypotonia, dysmorphic features, and abnormal head size are common in those with 2q13 deletions. In the 2q13 duplication cohort, we report dysmorphic features, DD, and abnormal head size. Two individuals with large duplications spanning 2q11.2-2q13 have dysmorphic features, hypotonia, and DD. This compilation of clinical features associated with 2q CNVs provides information that will be useful for healthcare providers and for families of affected children. However, the reduced penetrance and variable expressivity associated with these recurrent CNVs makes genetic counseling and prediction of outcomes challenging. © 2015 Wiley Periodicals, Inc.

Costain G, Lionel AC, Fu F, Stavropoulos DJ, Gazzellone MJ, Marshall CR, Scherer SW, Bassett AS. Adult neuropsychiatric expression and familial segregation of 2q13 duplications. Am J Med Genet B Neuropsychiatr Genet. 2014 Jun;165B(4):337-44. doi: 10.1002/ajmg.b.32236. Epub 2014 May 8. PMID: 24807792; PMCID: PMC4464821.

Abstract

New genomic disorders associated with large, rare, recurrent copy number variations (CNVs) are being discovered at a rapid pace. Detailed phenotyping and family studies are rare, however, as are data on adult phenotypic expression. Duplications at 2q13 were recently identified as risk factors for developmental delay/autism and reported in the prenatal setting, yet few individuals (all children) have been extensively phenotyped. During a genome-wide CNV study of schizophrenia, we identified two unrelated probands with 2q13 duplications. In this study, detailed phenotyping and genotyping using high-resolution microarrays was performed for 12 individuals across their two families. 2q13 duplications were present in six adults, and co-segregated with clinically significant later-onset neuropsychiatric disorders. Convergent lines of evidence implicated GABAminergic dysfunction. Analysis of the genic content revealed promising candidates for neuropsychiatric disease, including BCL2L11, ANAPC1, and MERTK. Intrafamilial genetic heterogeneity and "second hits" in one family may have been the consequence of assortative mating. Clinical genetic testing for the 2q13 duplication and the associated genetic counseling was well received. In summary, large rare 2q13 duplications appear to be associated with variable adult neuropsychiatric and other expression. The findings represent progress toward clinical translation of research results in schizophrenia. There are implications for other emerging genomic disorders where there is interest in lifelong expression.

Early diagnostic changes in autism spectrum disorder

Yeom JS, Kim YS, Park JS, Park ES, Seo JH, Lim JY, Woo HO. Early Diagnostic Changes in Autism Spectrum Disorder: A Retrospective Study. Ann Child Neurol. 2026;34(2):136-143.

Abstract

Purpose
Autism spectrum disorder (ASD) exhibits heterogeneous developmental trajectories; however, longitudinal studies using the Korean Childhood Autism Rating Scale (K-CARS) are scarce. This study examined diagnostic changes and related developmental characteristics through repeated K-CARS assessments.

Methods
We retrospectively reviewed the medical records of children who underwent repeated K-CARS assessments between May 2021 and December 2024 at Gyeongsang National University Hospital. Based on diagnostic status at the initial (T1) and follow-up (T2) evaluations, participants were classified as having persistent ASD (ASD at T1 and T2), emerging ASD (non-ASD at T1 but ASD at T2), or desisting ASD (ASD at T1 but non-ASD at T2). Developmental profiles were evaluated using the social quotient (SQ), visual-motor integration (VMI), and language quotients.

Results
Forty-three children (32 boys; median age, 2.9 years at T1 and 4.3 years at T2) were included. Twenty-two met ASD criteria at T1, and 15 (68%) retained the diagnosis at T2. Across the cohort, 15 (35%) had persistent ASD, 21 (49%) had emerging ASD, and seven (16%) had desisting ASD. The desisting group showed higher baseline VMI and better outcomes at follow-up. The emerging group initially had higher SQ and VMI than the persistent group, but these differences disappeared over time. Higher baseline VMI was associated with desisting status and higher baseline SQ with emerging ASD (odds ratios, 3.14 and 2.59 per standard deviation increase, respectively; P=0.06 and P=0.07).

Conclusion
Early ASD diagnoses were generally stable yet variable, supporting repeated assessment. Baseline VMI and SQ may relate to later diagnostic changes.

KIF1A associated neurological disorder (KAND)

Father shares daughter’s rare neurological disorder, partnership with Murdoch research center

KIF1A.org founder Luke Rosen discusses his daughter’s battle with a rare neurological disorder and the Murdoch Children’s Research Institute’s work to advance potential treatments on ‘Fox & Friends.’

KIF1A Associated Neurological Disorder (KAND) is a rare, progressive neurodegenerative disorder often described as a form of childhood dementia that currently has no cure, but researchers at the Murdoch Children’s Research Institute (MCRI) in Australia are working to change that.

"[Their research] is helping all of the kids, which is really incredible," said Luke Rosen, founder of KIF1A.org, whose daughter Susannah was diagnosed with the disorder at age 2.

"And the folks at Murdoch, I say they're extended family to us, and they really are."

KAND is a severe and progressive condition. Children can experience seizures and, over time, lose cognitive function, motor skills and vision. The disorder affects each patient differently, often making it difficult to diagnose.

Rosen said what sets MCRI apart is its personal approach — with researchers taking the time to truly know the families they’re trying to help.

"The first thing [a researcher] said to me is, 'How's Susannah? How's she doing?' And he really got to know our family, and he travels and so does their whole team... to our yearly Scientific and Family Conference, so they really get to meet all the families."

A new Fox Nation special spotlights MCRI’s work, as well as families like the Rosens who are working with researchers to treat the debilitating disorder.

Rosen has since dedicated his life to advancing research and finding treatment options. He works closely with MCRI in an effort that is already showing promise.

Susannah was among the first patients to receive antisense oligonucleotide (ASO) therapy, and her family says they’ve seen meaningful improvements in her condition.

While the treatment is not yet approved in Australia, Rosen continues working with doctors to expand access with the hope that, eventually, families won’t have to travel for care.

"Their research is really translational research that helps everybody," Rosen said.

"While we don't have a therapeutic yet from Australia, they're really working hard to develop it, and they're accelerating that entire process. What's special about Murdoch is they work in multimodalities, so there's gene therapy and then traditional drug development, and then they work non-sequentially, and they are just trying to throw as many shots on goal as we can for the kids."

"Hope Starts Here," hosted by Fox News' Benjamin Hall, is available now on Fox Nation.

Taylor Penley

https://www.foxnews.com/media/researchers-race-treat-rare-childhood-dementia-cure-giving-families-new-hope

Lin Q, Verden D, Christodoulou J, Gold WA, Kaur S. KIF1A-associated neurological disorders: therapeutic opportunities and challenges. Eur J Hum Genet. 2025 Nov 27. doi: 10.1038/s41431-025-01978-8. Epub ahead of print. PMID: 41310149.

Abstract

KIF1A-Associated Neurological Disorder (KAND) is a rare, progressive neurodegenerative condition caused by variants in the KIF1A gene, which encodes a kinesin-3 motor protein essential for anterograde axonal transport of synaptic vesicles, dense core vesicles, and organelles in neurons. KAND comprises a broad spectrum of overlapping neurological phenotypes, including hereditary spastic paraplegia, intellectual disability, peripheral neuropathy, optic nerve atrophy, epilepsy, and progressive motor decline. Pathogenic variants in KIF1A disrupt the balance of intracellular transport and neuronal signalling through diverse mechanisms, manifesting with highly variable disease onset, severity, and clinical progression. Although advances in genomic testing have improved diagnosis, reported KAND cases remain concentrated in developed countries, highlighting ongoing global inequities in access to diagnosis and care. At present, no cure exists for KAND; treatment is limited to symptom management. A deeper understanding of KIF1A function, supported by the development of robust cellular and animal models, is critical for therapeutic development. This review summarises the clinical and molecular features of KAND and highlights current and emerging strategies aimed at slowing disease progression or correcting its underlying causes. We emphasise the urgent need for targeted treatment strategies addressing the heterogeneity of KAND.

Chen Z, Chai Y, Guo Z, Fu X, Li W, Zhang J, Ou G, Wang H. Allele-specific conformational rescue of KIF1A T99M by genetic suppressors in a C. elegans model of KIF1A-associated neurological disorder. J Cell Sci. 2025 Oct 1;138(19):jcs264216. doi: 10.1242/jcs.264216. Epub 2025 Oct 14. PMID: 40964787.

Abstract

KIF1A-associated neurological disorder (KAND) arises from mutations in the microtubule motor KIF1A, disrupting synaptic vesicle transport. Here, we investigate the pathogenic T99M substitution in the P-loop of KIF1A, which induces steric hindrance, impairing ATP/ADP coordination and motor activity. Using CRISPR-engineered Caenorhabditis elegans expressing the homologous UNC-104(T95M) mutation, we conducted forward genetic screens and identified recurrent intragenic suppressors (T95V and T95I; T95V/I) that restored animal motility and synaptic vesicle distribution. Molecular dynamics simulations revealed that replacing the methionine residue with valine or isoleucine residues alleviated steric clashes in the nucleotide-binding pocket and stabilized Mg2+-ATP coordination. Biochemical assays showed that T95V/I partially recovered microtubule gliding velocity and processivity, demonstrating that even modest motor reactivation mitigates neuronal dysfunction. Inspired by prior success showing that treatment with the plant flavonol fisetin rescues the effects of the KIF1A R11Q variant, we propose allele-specific conformational stabilization as a therapeutic strategy for KAND. Our findings highlight the structural plasticity of motor domains and provide a framework for precision therapies targeting pathogenic variants through genetic suppressors.

See: https://childnervoussystem.blogspot.com/2020/01/kif1a-mutations.html

Adjunctive cannabidiol in intractable pediatric epilepsy

Shim Y, Yang DH, Byeon JH, Eun BL. Adjunctive cannabidiol in intractable pediatric epilepsy: A retrospective study on tolerability, efficacy, and safety across genetic and nongenetic etiologies. Medicine (Baltimore). 2026 Jan 30;105(5):e47425. doi: 10.1097/MD.0000000000047425. PMID: 41630268; PMCID: PMC12863898.

Abstract

This retrospective cohort study evaluated the tolerability, efficacy, and safety of adjunctive cannabidiol (CBD) therapy in pediatric-onset intractable epilepsy across diverse genetic and nongenetic etiologies. Twenty-nine patients aged 6 to 24 years, treated at Korea University Hospitals between April 2019 and May 2024, were included. The median follow-up duration was 14.3 months. Confirmed genetic etiologies included SCN1A-related epilepsy (6.9%); GABRB3-, SCN2A-, KCNT1-, KIF1A-, and COL4A1-related epilepsies (3.4% each); Angelman syndrome and Down syndrome (3.4% each). Presumed genetic etiologies included hemimegalencephaly (3.4%) and cortical dysplasia (6.9%). Acquired causes included hypoxic brain injury (6.9%) and CNS infection (10.3%). In 41.4% of cases, the etiology was unidentified; among them, 58.3% had a history of infantile spasms. At CBD initiation, patients were receiving a median of 5 antiseizure medications, most commonly valproic acid (93.1%), clobazam (82.8%), and levetiracetam (75.9%). The median maintenance dose of CBD was 14.2 mg/kg/d. The retention rate was above 86% at both 12 and 24 months. At 12 months, 79.3% achieved a ≥50% reduction in seizure frequency, and 34.5% achieved a ≥75% reduction without generalized motor seizures. One patient with a GABRB3 variant achieved seizure freedom. Adverse events occurred in 37.9%, most commonly somnolence and lethargy. These were mild and resolved with antiseizure medication adjustments. CBD was discontinued in 3 patients due to pneumonia, lethargy, or seizure aggravation. CBD therapy demonstrated favorable retention, efficacy, and safety profiles in pediatric-onset intractable epilepsy across a spectrum of etiologies.

González-Alguacil E, García Peñas JJ, Lamagrande Casanova N, Santana Cabrera EM, Duat Rodríguez A, Soto Insuga V. Cannabidiol as Adjunctive Treatment in Drug-Resistant Epilepsy With Epileptic Spasms Beyond Two Years of Age. Pediatr Neurol. 2026 Jan;174:81-85. doi: 10.1016/j.pediatrneurol.2025.10.013. Epub 2025 Oct 24. PMID: 41197417.

Abstract

Background: To assess the efficacy and safety of adjunctive cannabidiol (CBD) in children with drug-resistant epileptic spasms (ES) beyond age 2 years.

Methods: We conducted a retrospective longitudinal study of patients with childhood epileptic spasms (CESs) treated with purified CBD (Epidyolex) at Niño Jesus Hospital in Madrid, Spain, from 2020 to 2024. All patients were older than 2 years and had drug-resistant epilepsy and ES as the primary seizure type. Efficacy was assessed by comparing ES frequency before and after CBD treatment, with a good response defined as a ≥50% reduction in ES. Adverse effects (AEs) were recorded to assess safety and tolerability.

Results: Of the 53 patients included, 58.5% achieved a ≥50% reduction in ES frequency, 15% of whom attained complete freedom from ES. Patients with malformations of cortical development and Down syndrome showed the highest response rates. Clobazam was the most frequently associated medication (77.3%), indicating a potential synergistic effect. AEs were reported in 62.2% of patients, with drowsiness, hyperammonemia, and behavioral disturbances being the most common. CBD was discontinued in 17% due to lack of efficacy and in 11.3% due to AEs.

Conclusions: CBD appears to be an effective and well-tolerated adjunctive treatment for drug-resistant ES in children older than 2 years. Significant response rates were found, particularly in patients with Down syndrome and malformations of cortical development. Future studies with larger cohorts and longer follow-up are needed to validate these findings and explore the potential for earlier use of CBD in treatment-resistant epilepsy.

Herlopian A, Hess EJ, Barnett J, Geffrey AL, Pollack SF, Skirvin L, Bruno P, Sourbron J, Thiele EA. Cannabidiol in treatment of refractory epileptic spasms: An open-label study. Epilepsy Behav. 2020 May;106:106988. doi: 10.1016/j.yebeh.2020.106988. Epub 2020 Mar 10. PMID: 32169600.

Abstract

Objective: This study aimed to evaluate clinical efficacy and safety of purified pharmaceutical cannabidiol (CBD) as an adjunctive therapy in refractory childhood-onset epileptic spasms (ES).

Methods: Nine patients with ES were enrolled in an Institutional Review Board (IRB)- and Food and Drug Administration (FDA)-approved expanded access investigational new drug trial. Patients received plant-derived highly purified CBD in oral solution in addition to their baseline medications at an initial dosage of 5 mg/kg/day, which was increased by 5 mg/kg/day every week to an initial target dosage of 25 mg/kg/day. Seizure frequency, adverse event, and parents' subjective reports of cognitive and behavioral changes were recorded after 2 weeks and 1, 2, 3, 6, 9, and 12 months of CBD treatment. Responder rates (percent of patients with >50% reduction in ES frequency from baseline) were calculated. Electrographic changes were studied in relation to CBD initiation and clinical response.

Results: Overall, the responder rates in 9 patients were 67%, 78%, 67%, 56%, 78%, 78%, and 78% after 2 weeks and 1, 2, 3, 6, 9, and 12 months of CBD treatment, respectively. Three out of nine patients (33%) were ES free after two months of treatment. Parents reported subjective improvements in cognitive and behavioral domains. Side effects, primarily drowsiness, were seen in 89% of patients (n = 8). Eight of the nine (89%) patients had electroencephalographic (EEG) studies prior to and after initiation of CBD. Three out of five patients (60%) had resolution in their hypsarrhythmia pattern.

Significance: Purified pharmaceutical CBD may be an effective and safe adjunctive therapy in refractory ES and may also be associated with improvements in electrographic findings.

Disease-modifying therapies for Rett syndrome

Samanta D. Disease-modifying therapies for Rett syndrome: a review for neurologists. Front Neurol. 2026 Jan 20;17:1766679. doi: 10.3389/fneur.2026.1766679. PMID: 41641323; PMCID: PMC12864443.

Abstract

Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder affecting approximately 1 in 10,000-15,000 females, most often caused by loss-of-function mutations in MECP2. Until the recent approval of trofinetide, management relied exclusively on symptomatic treatment and multidisciplinary supportive care. The therapeutic landscape is now undergoing a rapid shift, driven by multiple gene therapy approaches designed to restore functional MeCP2 expression and achieve true disease modification. As these therapies progress toward potential regulatory approval, neurologists will play central roles in identifying eligible patients, counseling families, supporting clinical trial enrollment, delivering treatments, monitoring long-term outcomes, and advocating for equitable access. This review provides neurologists with the essential framework needed to understand and navigate this evolving field. We examine in detail the two most advanced gene replacement therapies currently in clinical trials. TSHA-102 uses an intrathecally delivered miniMECP2 transgene regulated by a microRNA-based autoregulatory system, whereas NGN-401 delivers full-length MECP2 via intracerebroventricular administration using a synthetic expression-feedback circuit. Both approaches have shown encouraging early efficacy, with treated children achieving developmental gains that exceed natural history expectations. However, they differ substantially in molecular design, regulatory control, delivery method, and safety considerations. We also highlight challenges unique to RTT gene therapy, including the narrow therapeutic window between insufficient expression and MeCP2 overexpression toxicity, the impact of X-chromosome inactivation mosaicism, and lessons learned from a fatal hyperinflammatory adverse event. Beyond AAV-mediated gene replacement, we review next-generation strategies in preclinical development-CRISPR-Cas9 genome editing for permanent mutation correction, ADAR-based RNA editing, translation readthrough for nonsense variants, and X-chromosome reactivation to restore endogenous MECP2 expression. Finally, we address key translational considerations such as optimal timing of intervention, dosing constraints, outcome measurement in severely impaired populations, long-term safety surveillance, and barriers to broad and equitable access. The RTT gene therapy experience serves as a model for precision medicine in other monogenic neurodevelopmental disorders, illustrating both the transformative promise and the substantial complexities of translating genetic science into meaningful clinical benefit.

Percy AK, Ananth A, Neul JL. Rett Syndrome: The Emerging Landscape of Treatment Strategies. CNS Drugs. 2024 Nov;38(11):851-867. doi: 10.1007/s40263-024-01106-y. Epub 2024 Sep 9. PMID: 39251501; PMCID: PMC11486803.

Abstract

Rett syndrome (RTT) has enjoyed remarkable progress in achieving specific therapies. RTT, a unique neurodevelopmental disorder first described in 1966, progressed slowly until the landmark paper of Hagberg and colleagues in 1983. Thereafter, rapid advances were achieved including the development of specific diagnostic criteria and the active search for a genetic etiology, resulting 16 years later in identification of variants in the methyl-CpG-binding protein (MECP2) gene located at Xq28. Shortly thereafter, the NIH Office of Rare Diseases funded the RTT Natural History Study (NHS) in 2003, initiating the acquisition of natural history data on clinical features from a large population of individuals with RTT. This information was essential for advancement of clinical trials to provide specific therapies for this disorder. In the process, the International Rett Syndrome Association (IRSA) was formed (now the International Rett Syndrome Foundation-IRSF), which participated directly in encouraging and expanding enrollment in the NHS and, subsequently, in developing the SCOUT program to facilitate testing of potential therapeutic agents in a mouse model of RTT. The overall objective was to review clinical characteristics developed from the NHS and to discuss the status of specific therapies for this progressive neurodevelopmental disorder. The NHS study provided critical information on RTT: growth, anthropometrics, longevity, key comorbidities including epilepsy, breath abnormalities, gastroesophageal dysfunction, scoliosis and other orthopedic issues, puberty, behavior and anxiety, and progressive motor deterioration including the appearance of parkinsonian features. Phenotype-genotype correlations were noted including the role of X chromosome inactivation. Development of clinical severity and quality of life measures also proved critical for subsequent clinical trials. Further, development of biochemical and neurophysiologic biomarkers offered further endpoints for clinical trials. Initial clinical trials prior to the NHS were ineffective, but advances resulting from the NHS and other studies worldwide promoted significant interest from pharmaceutical firms resulting in several clinical trials. While some of these have been unrewarding such as sarizotan, others have been quite promising including the approval of trofinetide by the FDA in 2023 as the first agent available for specific treatment of RTT. Blarcamesine has been trialed in phase 3 trials, 14 agents have been studied in phase 2 trials, and 7 agents are being evaluated in preclinical/translational studies. A landmark study in 2007 by Guy et al. demonstrated that activation of a normal MECP2 gene in a null mouse model resulted in significant improvement. Gene replacement therapy has advanced through translational studies to two current phase 1/2 clinical trials (Taysha102 and Neurogene-401). Additional genetic therapies are also under study including gene editing, RNA editing, and X-chromosome reactivation. Taken together, progress in understanding and treating RTT over the past 40 years has been remarkable. This suggests that further advances can be expected.

Testing the brain death testers

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.

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.