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

KDM2B-related neurodevelopmental disorder

Inspired by a patient

Gomes A, Martín-Rodríguez Á, Del Campo M, Bird LM. KDM2B-Related Neurodevelopmental Disorder A Case-Series Supporting the CxxC Domain Phenotype With Emphasis on Ocular and Dermatologic Features. Am J Med Genet A. 2025 Dec 29. doi: 10.1002/ajmga.70036. Epub ahead of print. PMID: 41457890.

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?

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.

Upright and positional MRI for Chiari 1 detection

Inspired by a patient

Verderame J, Arslan MS, Mukhtar F, Abbas Z. Weight-bearing MRI of the cervical spine: A scoping review of clinical utility and emerging applications. Eur J Radiol Open. 2025 Oct 8;15:100694. doi: 10.1016/j.ejro.2025.100694. PMID: 41127038; PMCID: PMC12539231.

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.

In the best interest of the children

A Christian couple’s years-long fight to regain custody of their daughters from the Swedish government was dealt a major setback last week after a top European court rejected their plea for help.

The European Court of Human Rights (ECtHR) ruled the case brought by Daniel and Bianca Samson "inadmissible" on March 10, a final decision that cannot be appealed. 

According to Alliance Defending Freedom International, which supported the family’s application before the ECtHR, the children have been separated from their parents since December 2022.

ADF International said the case began after the couple’s eldest daughter, Sara, then 11, made a false abuse report at school following a fight with her parents over not being allowed to have a smartphone or wear makeup. ADF International said the girl quickly retracted the allegation and that prosecutors found no evidence of abuse, but the Swedish state refused to return the children.

According to the legal group, the state cited the family’s habit of attending church three times a week and their parenting choices as evidence of "religious extremism" and justification for keeping the children.

The girls have pleaded to be reunited with their parents and have suffered worsening mental and physical health, according to ADF International. Their parents reported that both girls attempted suicide while in state care.

The parents have completed state-mandated parenting courses and were later deemed fit to parent, according to the legal group, but they still have not been reunited with their daughters. They have also allegedly sought to move the girls into foster care in their home country of Romania, but have been denied.

The European Court of Human Rights "deemed the case inadmissible on the grounds of failure to exhaust legal remedies in Sweden," ADF International said, despite the Swedish Supreme Court refusing to hear the family's case in 2025.

"We love our children. We trusted Sweden to protect them — and when the truth emerged, we expected our daughters to come home," Daniel Samson said in a statement. "Yet they remain away from us, and their mental health continues to deteriorate."  

ADF International told Premier Christian News that social services in Hässleholm are now moving to permanently sever the family's ties and place the girls for adoption.

"We deeply regret the Court’s decision to reject this case, considering that this family has been torn apart for over three years despite a full investigation that cleared Mr. and Mrs. Samson of any abuse and the fact that the Social Services certified their capacity and fitness for parenting after they successfully completed an official training," said Guillermo A. Morales Sancho, legal counsel for ADF International. "Families should be free to live according to their convictions without fear of losing their children to the state."

Sweden's Social Services did not immediately respond to Fox News Digital's requests for comment.

The European Court of Human Rights told Fox News Digital it considers cases on a "case by case basis" and does not provide comment "on general events or matters." The court also said a single judge declared the case inadmissible, according to its guidelines.

Kristine Parks

https://www.foxnews.com/media/christian-parents-lose-final-appeal-after-swedish-state-took-daughters-following-false-abuse-claim

ADHD brains show sleep-like activity even while awake

Summary:

Researchers have identified a surprising brain pattern that may help explain why people with ADHD often struggle to stay focused. Even while awake, their brains can slip into brief episodes of “sleep-like” activity during demanding tasks. These moments are linked to more mistakes, slower reaction times, and lapses in attention.

A new study published in JNeurosci explores how brief bursts of sleep like brain activity during wakefulness affect a person's ability to stay focused. Elaine Pinggal of Monash University and her team investigated whether this type of brain activity plays a role in attention challenges, particularly in adults with ADHD.

To examine this, researchers measured sleep like brain activity in 32 adults with ADHD who had stopped taking medication and compared them with 31 neurotypical adults. All participants completed a task that required sustained attention.

The results showed that individuals with ADHD experienced more frequent episodes of sleep like brain activity. These moments were linked to more frequent lapses in attention. Further analysis suggested that this brain activity may help explain why ADHD is associated with attention difficulties, including increased errors during tasks, slower reaction times, and greater feelings of sleepiness.

Why the Brain Slips Into Sleep Like States

Pinggal explains that these brief shifts in brain activity are not unusual, especially during mentally demanding tasks.

"Sleep-like brain activity is a normal phenomenon that happens during demanding tasks. Think of going for a long run and getting tired after a while, which makes you pause to take a break. Everyone experiences these brief moments of sleep-like activity. In people with ADHD, however, this activity occurs more frequently, and our research suggests this increased sleep-like activity may be a key brain mechanism that helps explain why these individuals have more difficulty maintaining consistent attention and performance during tasks."

Potential Future Treatments Target Sleep Related Brain Activity

Previous research in neurotypical individuals has shown that auditory stimulation during sleep can enhance slow wave activity. This may help reduce sleep like brain activity during the following day while a person is awake.

According to Pinggal, a possible next step is to test whether this same method could reduce daytime sleep like brain activity in people with ADHD. If effective, it could point to new ways of improving attention and task performance.

About ADHD

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental condition that affects both children and adults. It is characterized by persistent patterns of inattention, hyperactivity, and impulsivity that can interfere with daily life, including school, work, and relationships. People with ADHD may have trouble staying focused, following through on tasks, organizing activities, or controlling impulses.

The condition is linked to differences in brain function and development, particularly in areas involved in attention, self-control, and executive function. Symptoms can vary widely, with some individuals primarily experiencing inattentiveness, while others show more hyperactive or impulsive behavior, or a combination of both.

https://www.sciencedaily.com/releases/2026/03/260317015928.htm

Elaine Pinggal, James Jackson, Anikó Kusztor, David Chapman, Jennifer Windt, Sean P.A. Drummond, Tim J. Silk, Mark A. Bellgrove, Thomas Andrillon Sleep-like Slow Waves During Wakefulness Mediate Attention and Vigilance Difficulties in Adult Attention-Deficit/Hyperactivity Disorder. Journal of Neuroscience 16 March 2026, e1694252025; DOI: 10.1523/JNEUROSCI.1694-25.2025

Abstract

Attention-Deficit/Hyperactivity Disorder (ADHD) is characterised by behavioural variability and heightened inattention associated with increased mind wandering (MW) and mind blanking (MB). Individuals with ADHD frequently experience sleep disorders and excessive daytime sleepiness, suggesting interactions between attention and arousal systems. Research examining brain activity using electroencephalography (EEG) has demonstrated that sleep-like slow waves (SW) during wakefulness are linked to inattention in neurotypical individuals following sleep deprivation, yet their role in ADHD remains unclear. This study investigated whether individuals with ADHD present with altered waking SW distribution compared to neurotypical controls and whether SW explain attentional difficulties in ADHD.

Adults with (n = 32) and without ADHD (n = 31) completed a sustained attention task while EEG recorded brain activity. Mental state probes (on-task, MW, MB) were embedded within the task. Sleep-like SW reflect cortical slowing and were detected from EEG activity. Omission/commission errors, reaction time (RT), RT variability, mental state reports and subjective sleepiness were analysed. Mediation analysis examined whether SW density explained ADHD-related performance differences.

Individuals with ADHD exhibited more commission errors, MW and MB, more theta oscillations over fronto-temporal electrodes and higher SW density (SW/min) over parieto-temporal electrodes. Increased SW density correlated with higher omission errors, slower RTs, greater RT variability, and elevated sleepiness ratings. On-task reports were negatively correlated with SW density. Mediation analysis revealed that SW density significantly accounted for ADHD-related attentional difficulties.

Wake SW may explain attentional difficulties in ADHD, providing a potential mechanistic link between sleep disturbances and attentional fluctuations.

Significance Statement We investigated whether slow waves during wakefulness could explain attentional difficulties in ADHD by comparing neurotypical adults and medication-withdrawn adults with ADHD during a sustained attention task with embedded mental state probes. Using electroencephalography, we quantified slow-wave activity and examined its relationship with objective performance measures and subjective reports of mind wandering and blanking. The ADHD group exhibited significantly higher slow wave activity which correlated with increased objective and subjective attentional lapses. Importantly, mediation analysis revealed that slow wave density accounted for performance differences between groups, suggesting that wake slow waves represent a neurophysiological mechanism underlying attentional difficulties in ADHD. These findings bridge sleep and attention research in ADHD, offering new insights into ADHD’s heterogeneous nature and potential intervention targets.

Ververi-Brady syndrome (QRICH mutations)

Inspired by a patient

Föhrenbach M, Jamra RA, Borkhardt A, Brozou T, Muschke P, Popp B, Rey LK, Schaper J, Surowy H, Zenker M, Zweier C, Wieczorek D, Redler S. QRICH1 variants in Ververi-Brady syndrome-delineation of the genotypic and phenotypic spectrum. Clin Genet. 2021 Jan;99(1):199-207. doi: 10.1111/cge.13853. Epub 2020 Nov 10. PMID: 33009816.

Abstract

Ververi-Brady syndrome (VBS, # 617982) is a rare developmental disorder, and loss-of-function variants in QRICH1 were implicated in its etiology. Furthermore, a recognizable phenotype was proposed comprising delayed speech, learning difficulties and dysmorphic signs. Here, we present four unrelated individuals with one known nonsense variant (c.1954C > T; p.[Arg652*]) and three novel de novo QRICH1 variants, respectively. These included two frameshift mutations (c.832_833del; p.(Ser278Leufs*25), c.1812_1813delTG; p.(Glu605Glyfs*25)) and interestingly one missense mutation (c.2207G > A; p.[Ser736Asn]), expanding the mutational spectrum. Enlargement of the cohort by these four individuals contributes to the delineation of the VBS phenotype and suggests expressive speech delay, moderate motor delay, learning difficulties/mild ID, mild microcephaly, short stature and notable social behavior deficits as clinical hallmarks. In addition, one patient presented with nephroblastoma. The possible involvement of QRICH1 in pediatric cancer assumes careful surveillance a key priority for outcome of these patients. Further research and enlargement of cohorts are warranted to learn about the genetic architecture and the phenotypic spectrum in more detail.

Lui JC, Jee YH, Lee A, Yue S, Wagner J, Donnelly DE, Vogt KS, Baron J. QRICH1 mutations cause a chondrodysplasia with developmental delay. Clin Genet. 2019 Jan;95(1):160-164. doi: 10.1111/cge.13457. Epub 2018 Oct 26. PMID: 30281152; PMCID: PMC6353565.

Abstract

In many children with short stature, the etiology of the decreased linear growth remains unknown. We sought to identify the underlying genetic etiology in a patient with short stature, irregular growth plates of the proximal phalanges, developmental delay, and mildly dysmorphic facial features. Exome sequencing identified a de novo, heterozygous, nonsense mutation (c.1606C>T:p.R536X) in QRICH1. In vitro studies confirmed that the mutation impaired expression of the QRICH1 protein. SiRNA-mediated knockdown of Qrich1 in primary mouse epiphyseal chondrocytes caused downregulation of gene expression associated with hypertrophic differentiation. We then identified an unrelated individual with another heterozygous de novo nonsense mutation in QRICH1 who had a similar phenotype. A recently published study identified QRICH1 mutations in three patients with developmental delay, one of whom had short stature. Our findings indicate that QRICH1 mutations cause not only developmental delay but also a chondrodysplasia characterized by diminished linear growth and abnormal growth plate morphology due to impaired growth plate chondrocyte hypertrophic differentiation.

Ververi A, Splitt M, Dean JCS; DDD Study; Brady AF. Phenotypic spectrum associated with de novo mutations in QRICH1 gene. Clin Genet. 2018 Feb;93(2):286-292. doi: 10.1111/cge.13096. Epub 2017 Dec 21. PMID: 28692176.

Abstract

Rare de novo mutations represent a significant cause of idiopathic developmental delay (DD). The use of next-generation sequencing (NGS) has boosted the identification of de novo mutations in an increasing number of novel genes. Here we present 3 unrelated children with de novo loss-of-function (LoF) mutations in QRICH1, diagnosed through trio-based exome sequencing. QRICH1 encodes the glutamine-rich protein 1, which contains 1 caspase activation recruitment domain and is likely to be involved in apoptosis and inflammation. All 3 children had speech delay, learning difficulties, a prominent nose and a thin upper lip. In addition, 2 of them had mildly raised creatine kinase (CK) and 1 of them had autism. Despite their small number, the patients had a relatively consistent pattern of clinical features suggesting the presence of a QRICH1-associated phenotype. LoF mutations in QRICH1 are suggested as a novel cause of DD.

Wang D, Wu J. A novel variant in the QRICH1 gene was identified in a patient with severe developmental delay. Mol Genet Genomic Med. 2023 Aug;11(8):e2227. doi: 10.1002/mgg3.2227. Epub 2023 Jun 18. PMID: 37331002; PMCID: PMC10422060.

Abstract

Background: QRICH1 encodes the glutamine-rich protein 1, which contains one caspase activation recruitment domain and is likely to be involved in apoptosis and inflammation. However, the function of the QRICH1 gene was largely unknown. Recently, several studies have reported de novo variants in QRICH1, and the variants have been associated with Ververi-Brady syndrome characterized by developmental delay, nonspecific facial dysmorphism, and hypotonia.

Materials and methods: Whole exome sequencing, clinical examinations, and functional experiments were performed to identify the etiology of our patient.

Results: Here, we added another patient with severe growth retardation, atrial septal defect, and slurred speech. Whole exome sequencing identified a novel truncation variant in the QRICH1 gene (MN_017730.3: c.1788dupC, p.Tyr597Leufs*9). Furthermore, the functional experiments confirmed the effect of genetic variation.

Conclusion: Our findings expand the QRICH1 variant spectrum in developmental disorders and provide evidence for the application of whole exome sequencing in Ververi-Brady syndrome.

ARHGEF9 mutations

Inspired by a patient with recurrent febrile seizures.

Yang H, Liao H, Gan S, Xiao T, Wu L. ARHGEF9 gene variant leads to developmental and epileptic encephalopathy: Genotypic phenotype analysis and treatment exploration. Mol Genet Genomic Med. 2022 Jul;10(7):e1967. doi: 10.1002/mgg3.1967. Epub 2022 May 31. PMID: 35638461; PMCID: PMC9266599.

Abstract

Background: The ARHGEF9 gene variants have phenotypic heterogeneity, the number of reported clinical cases are limited and the genotype-phenotype relationship is still unpredictable.

Methods: Clinical data of the patients and their family members were gathered in a retrospective study. The exome sequencing that was performed on peripheral blood samples was applied for genetic analysis. We used the ARHGEF9 gene as a key word to search the PubMed database for cases of ARHGEF9 gene variants that have previously been reported and summarized the reported ARHGEF9 gene variant sites, their corresponding clinical phenotypes, and effective treatment.

Results: We described five patients with developmental and epileptic encephalopathy caused by ARHGEF9 gene variants. Among them, the antiepileptic treatment of valproic acid and levetiracetam was effective in two cases individually. The exome sequencing results showed five children with point mutations in the ARHGEF9 gene: p.R365H, p.M388V, p.D213E, and p.R63H. So far, a total of 40 children with ARHGEF9 gene variants have been reported. Their main clinical phenotypes include developmental delay, epilepsy, epileptic encephalopathy, and autism spectrum disorders. The variants reported in the literature, including 22 de novo variants, nine maternal variants, and one unknown variant. There were 20 variants associated with epileptic phenotypes, of which six variants are effective for valproic acid treatment.

Conclusion: The genotypes and phenotypes of ARHGEF9 gene variants represent a wide spectrum, and the clinical phenotype of epilepsy is often refractory and the prognosis is poor. The p.R365H, p.M388V, p.D213E, and p.R63H variants have not been reported in the current literature, and our study has expanded the genotype spectrum of ARHGEF9 gene. Our findings indicate that levetiracetam and valproic acid can effectively control seizures in children with epileptic phenotype caused by ARGHEF9 gene variations. These findings will help clinicians improve the level of diagnosis and treatment of the genetic disease.

Scala M, Zonneveld-Huijssoon E, Brienza M, Mecarelli O, van der Hout AH, Zambrelli E, Turner K, Zara F, Peron A, Vignoli A, Striano P. De novo ARHGEF9 missense variants associated with neurodevelopmental disorder in females: expanding the genotypic and phenotypic spectrum of ARHGEF9 disease in females. Neurogenetics. 2021 Mar;22(1):87-94. doi: 10.1007/s10048-020-00622-5. Epub 2020 Sep 17. PMID: 32939676.

Abstract

Individuals harboring pathogenic variants in ARHGEF9, encoding an essential submembrane protein for gamma-aminobutyric acid (GABA)-ergic synapses named collybistin, show intellectual disability (ID), facial dysmorphism, behavioral disorders, and epilepsy. Only few affected females carrying large chromosomal rearrangements involving ARHGEF9 have been reported so far. Through next-generation sequencing (NGS)-based panels, we identified two single nucleotide variants (SNVs) in ARHGEF9 in two females with neurodevelopmental features. Sanger sequencing revealed that these variants were de novo. The X-inactivation pattern in peripheral blood cells was random. We report the first affected females harboring de novo SNVs in ARHGEF9, expanding the genotypic and phenotypic spectrum of ARHGEF9-related neurodevelopmental disorder in females.

Klein KM, Pendziwiat M, Eilam A, Gilad R, Blatt I, Rosenow F, Kanaan M, Helbig I, Afawi Z; Israeli-Palestinian Epilepsy Family Consortium. The phenotypic spectrum of ARHGEF9 includes intellectual disability, focal epilepsy and febrile seizures. J Neurol. 2017 Jul;264(7):1421-1425. doi: 10.1007/s00415-017-8539-3. Epub 2017 Jun 15. PMID: 28620718.

Abstract

Mutations or structural genomic alterations of the X-chromosomal gene ARHGEF9 have been described in male and female patients with intellectual disability. Hyperekplexia and epilepsy were observed to a variable degree, but incompletely described. Here, we expand the phenotypic spectrum of ARHGEF9 by describing a large Ethiopian-Jewish family with epilepsy and intellectual disability. The four affected male siblings, their unaffected parents and two unaffected female siblings were recruited and phenotyped. Parametric linkage analysis was performed using SNP microarrays. Variants from exome sequencing in two affected individuals were confirmed by Sanger sequencing. All affected male siblings had febrile seizures from age 2-3 years and intellectual disability. Three developed afebrile seizures between age 7-17 years. Three showed focal seizure semiology. None had hyperekplexia. A novel ARHGEF9 variant (c.967G>A, p.G323R, NM_015185.2) was hemizygous in all affected male siblings and heterozygous in the mother. This family reveals that the phenotypic spectrum of ARHGEF9 is broader than commonly assumed and includes febrile seizures and focal epilepsy with intellectual disability in the absence of hyperekplexia or other clinically distinguishing features. Our findings suggest that pathogenic variants in ARHGEF9 may be more common than previously assumed in patients with intellectual disability and mild epilepsy.

DHX37 gene variants and ribosomopathy

Menetrey A, Tarnopolsky M, Yoganathan S, Shroff M, Gorodetsky C. Child Neurology: Clinical and Imaging Findings in a Child With DHX37 Gene Variant: A Ribosomopathy Masquerading as Cerebral Palsy. Neurology. 2025 Oct 7;105(7):e214126. doi: 10.1212/WNL.0000000000214126. Epub 2025 Sep 11. PMID: 40934457.

Abstract

DEAH-Box helicase 37 (DHX37) gene, encoding an RNA-helicase, is essential for ribosome biogenesis. Pathogenic variants in the DHX37 gene result in a spectrum of ribosomopathies ranging from neurodevelopmental disorders with possible brain, vertebral, and/or cardiac anomalies (NEDBAVC syndrome, OMIM #618731) as well as disorders of sex development. Here, we describe a young boy with DHX37-related neurodevelopmental disorder with clinical and imaging findings masquerading as cerebral palsy. A 7.5-year-old boy presented with global developmental delay and generalized chorea of 6 months duration. He was born at 37 weeks gestation after an uneventful pregnancy with a birth weight of 2668 g. He had primary microcephaly and intractable epilepsy from infancy. Examination revealed microcephaly, spastic quadriparesis, generalized choreoathetosis and dystonia. MRI of the brain revealed T2-weighted hyperintensity in bilateral corticospinal tracts, posterior limb of the internal capsule (PLIC), corona radiata, external capsule, periventricular and deep white matter, as well as subcortical cysts. Diffusion-weighted images showed high signal in bilateral corticospinal tract and PLIC. As there were red flags pointing away from cerebral palsy such as primary microcephaly, refractory seizures, late-onset movement disorder, and persistent high signal on diffusion-weighted imaging, whole genome sequencing (WGS) was sent. WGS revealed a homozygous variant c.2417G>A (p.Ser806Asn) in the DHX37 gene. He was managed with antiseizure medications and clonazepam. DHX37-related neurodevelopmental disorder should be included in the differential for cerebral palsy mimic as affected children have global developmental delay, primary microcephaly, seizures, and movement disorders and thus may masquerade as sequel of hypoxic ischemic encephalopathy.

McElreavey K, Pailhoux E, Bashamboo A. DHX37 and 46,XY DSD: A New Ribosomopathy? Sex Dev. 2022;16(2-3):194-206. doi: 10.1159/000522004. Epub 2022 Jul 14. PMID: 35835064.

Abstract

Recently, a series of recurrent missense variants in the RNA-helicase DHX37 have been reported associated with either 46,XY gonadal dysgenesis, 46,XY testicular regression syndrome (TRS), or anorchia. All affected children have non-syndromic forms of disorders/differences of sex development (DSD). These variants, which involve highly conserved amino acids within known functional domains of the protein, are predicted by in silico tools to have a deleterious effect on helicase function. DHX37 is required for ribosome biogenesis in eukaryotes, and how these variants cause DSD is unclear. The relationship between DHX37 and human congenital disorders is complex as compound heterozygous as well as de novo heterozygous missense variants in DHX37 are also associated with a complex congenital developmental syndrome (NEDBAVC, neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies; OMIM 618731), consisting of microcephaly, global developmental delay, seizures, facial dysmorphia, and kidney and cardiac anomalies. Here, we will give a brief overview of ribosome biogenesis and the role of DHX37 in this process. We will discuss variants in DHX37, their contribution to human disease in the general context of human ribosomopathies, and the possible disease mechanisms that may be involved.

Jiang W, Yu J, Mao Y, Tang Y, Cao L, Du Q, Li J, Yang J. Identification and functional analysis of a rare variant of gene DHX37 in a patient with 46,XY disorders of sex development. Mol Genet Genomic Med. 2024 May;12(5):e2453. doi: 10.1002/mgg3.2453. PMID: 38769888; PMCID: PMC11106588.

Abstract

Background: 46,XY sex reversal 11 (SRXY11) [OMIM#273250] is characterized by genital ambiguity that may range from mild male genital defects to gonadal sex reversal in severe cases. DHX37 is an RNA helicase that has recently been reported as a cause of SRXY11. So far, a total of 21 variants in DHX37 have been reported in 58 cases with 46,XY disorders of sex development (DSD).

Methods: Whole exome sequencing (WES) was conducted to screen for variations in patients with 46,XY DSD. The subcellular localization of mutant DHX37 proteins was detected by immunofluorescence. And the levels of mutant DHX37 proteins were detected via Western blotting.

Results: A novel pathogenic variant of DHX37 was identified in a patient with 46,XY DSD c.2012G > C (p.Arg671Thr). Bioinformatics analysis showed that the protein function of the variant was impaired. Compared with the structure of the wild-type DHX37 protein, the number of hydrogen bonds and interacting amino acids of the variant protein were changed to varying degrees. In vitro assays revealed that the variant had no significant effect on the intracellular localization of the protein but significantly reduced the expression level of the protein.

Conclusions: Our finding further expands the spectrum of the DHX37 variant and could assist in the molecular diagnosis of 46,XY DSD patients.

Medicine only goes so far

As her husband, Rabbi Meshulom Weiss, shared with JEM’s My Encounter:

When we went to see the Rebbe for a blessing a few days before our wedding, she started to cry and asked that I leave the room so she could speak to the Rebbe alone. Puzzled, I complied.

After twenty minutes, she came out no longer crying, and she said nothing to me about it until after we were married. Then she confessed, “I hope that you won’t be upset about what I told the Rebbe. I had wanted to call the wedding off because I am very impatient and have a bad temper; I feared that my temperament made me unsuitable to be a wife and mother. I told the Rebbe that I would rather not get married than to get married only to get divorced. But the Rebbe just smiled at me and said, ‘G-d will bless you with many children, and these children will teach you patience. Meanwhile, do volunteer work – preferably in a hospital with children – and you will find your patience growing. But don’t call off the wedding.”

Having the Rebbe’s promise of many children, we looked forward to starting our family, but months came and went, and my wife – who was eighteen at the time we got married – did not get pregnant. When we sought the advice of a gynecologist, she was informed that she had an undeveloped womb – what is called an “infantile uterus” – which meant she could not bear children. My wife was absolutely devastated to hear this, so we went to get a second opinion and a third opinion, both of which only confirmed the first.

Then we called New York and reported this news to the Rebbe. His response was to reiterate the promise of many children and to give us a blessing. A month later my wife became pregnant with our first child, a boy whom we named Mordechai. And as it turned out, he was the first of fifteen!

After our sixth or seventh child was born, the doctor called me in and said, “Listen, your wife is having a child every year. This is not good for her body. You must give her a rest.” He scared the daylights out of me. I came home and reported this to my wife, who said, “Let’s consult a rabbi. We need to know what the opinion of Jewish law in a case such as ours.”

The rabbi we consulted ruled that, if the doctor said my wife’s life was in danger, we had to listen to him and take a break from having children. Maybe have no more kids at all.

We accepted that decision, but shortly thereafter, we had an opportunity to be in New York, and my wife decided to pose this question to the Rebbe. She told him about the doctor’s opinion and the rabbi’s opinion. She also said, “Despite these opinions, I don’t want to stop having children. But my husband has been scared by the doctor and he fears something might happen to me.”

Hearing that, the Rebbe called me in and said, “Meshulom, don’t mix in G-d’s business. If your wife is not supposed to have any more children, she won’t. And if she is, she will. It’s not up to you.”

Even though the Rebbe usually referred people to a rabbinic authority in such situations, he made an exception in our case. With that we continued and had a total of fifteen beautiful children, thank G-d, each of whom is a tremendous blessing.

But there is postscript to the story.

Years later, when my wife was older, she went to see a gynecologist again. He examined her and said, “You must be very disappointed – as a religious woman, you undoubtedly wanted many children, but with your infantile uterus you obviously never could have any.”

My wife said nothing, but she went out the door laughing. When she came home and told me about it, we had a good laugh together. And I said to her, “All those doctors could not have been wrong. But something amazing happened. The Rebbe promised you that you would have many children and gave you a blessing. Without the Rebbe’s blessing, without his advice and foresight, none of our children would be here!”

https://anash.org/mrs-eileen-weiss-86-ah/

Sunflower syndrome redux

Inspired by patients

Capobianco F 3rd, Beal R, Vemuri P, Bhatia S. A Girl Who Seeks the Light: Diagnosis of Sunflower Syndrome and Review of Management Options. Neurol India. 2025 Mar 1;73(2):346-348. doi: 10.4103/neurol-india.Neurol-India-D-23-00564. Epub 2025 Apr 3. PMID: 40176229.

Abstract

Sunflower syndrome (SS) is a rare self-induced, reflexive epilepsy with photic triggers having highly unique and specific clinical features as patients will characteristically flap their fingers in front of their eyes upon exposure to bright light. Many clinicians are perhaps unaware of this entity, making SS prone to infrequent consideration and misdiagnosis. The purpose of this case is to increase awareness of this diagnosis. We present an adolescent girl in whom this diagnosis was missed/delayed and discuss workup/management in hopes of minimizing holdup in care for individuals affected by this syndrome.

Baumer FM, Julich K, Friedman J, Nespeca M, Thiele EA, Bhatia S, Joshi C. Sunflower Syndrome: A Survey of Provider Awareness and Management Preferences. Pediatr Neurol. 2024 Mar;152:177-183. doi: 10.1016/j.pediatrneurol.2023.11.013. Epub 2023 Nov 30. PMID: 38295719; PMCID: PMC10936539.

Abstract

Background: Sunflower syndrome is a rare photosensitive pediatric epilepsy characterized by stereotyped hand-waving in response to bright lights. These stereotyped movements with maintained awareness can be mistaken for a movement disorder. This study assessed neurology providers' diagnostic reasoning, evaluation, and treatment of Sunflower syndrome.

Methods: A 32-question anonymized electronic survey, including a clinical vignette and video of hand-waving in sunlight, was distributed to child neurology providers to assess (1) initial diagnosis and evaluation based on clinical information, (2) updated diagnosis and management after electroencephalography (EEG), and (3) prior experience with Sunflower syndrome.

Results: Among 277 viewed surveys, 211 respondents provided information about initial diagnosis and evaluation, 200 about updated diagnosis, 191 about management, and 189 about prior clinical experience. Most providers (135, 64%) suspected seizure, whereas fewer suspected movement disorders (29, 14%) or were unsure of the diagnosis (37, 22%). EEG was recommended by 180 (85%). After EEG, 189 (95%) diagnosed epilepsy, 111 of whom specifically diagnosed Sunflower syndrome. The majority (149, 78%) recommended antiseizure medications (ASMs) and sun avoidance (181, 95%). Only 103 (55%) had managed Sunflower syndrome. Epileptologists and those with prior clinical experience were more likely to suspect a seizure, order an EEG, and offer ASMs than those without prior experience.

Conclusions: Although many providers had not managed Sunflower syndrome, the majority recognized this presentation as concerning for epilepsy. Epilepsy training and prior clinical experience are associated with improved recognition and appropriate treatment. Educational initiatives that increase awareness of Sunflower syndrome may improve patient care.

Sourbron J, Proost R, Vandenneucker J, Ticcinelli V, Roelens F, Schoonjans AS, Sercu E, Verhelst H, Jansen K, Lagae L. Seizure quantification in sunflower syndrome by a wrist-worn device. Epileptic Disord. 2025 Apr;27(2):219-227. doi: 10.1002/epd2.20318. Epub 2024 Dec 5. PMID: 39636535.

Abstract

Objective: Sunflower syndrome is a rare photosensitive childhood-onset epilepsy, featuring repetitive handwaving events (HWE) triggered by light. Objective documentation of these HWE can be difficult due to the numerous events occurring daily and/or caregivers who document the seizures but are not always present. Hence, seizure diaries can be underreporting.

Methods: We performed a feasibility study in three Belgian Sunflower syndrome individuals to assess the possibility to quantify the HWE by a wrist-worn wearable device (Axivity AX6). We conducted a structured exercise aiming to capture patterns of possible confounders in a controlled environment. Subsequently, patients wore the device for three to six consecutive days and nights at home. Spectral power analyses were performed to characterize the frequency signature of the different movements.

Results: The HWE of patient A and B showed homogeneity and narrow-band frequencies. Patient C did not experience any HWE at the start of the study due to proper seizure control. Regarding HWE, there was a higher spectral power for Gyroscope Z (Gz) compared to Gy. The inter-subject variability for HWE frequency peaks was in the 3-6 Hz range. Computer analysis by visual annotation, without checking the seizure diary, detected 71% of the HWE if the HWE lasted for longer than 5 s (sensitivity 64%). For shorter HWE duration, the detection rate was 50% but seemed to be higher if there was a concordant change of eye movement (63%) (sensitivity 36%). The most obvious confounder was toothbrushing (TB). However, TB showed a different pattern: that is, higher or comparable spectral power for Gy compared to Gz. There was also a higher or comparable spectral power for Gy compared to Gz for "waving hello".

Significance: We show that the wearable movement sensor Axivity AX6 can detect HWE in Sunflower syndrome individuals and distinguish them from confounders in a real-world setting.

Sunflower syndrome: ocular treatment

Inspired by patients

Geenen KR, Yap SV, Tsega L, Cantrell S, Bruno PL, Thiele EA. Efficacy and tolerability of blue-tinted contact lenses in the treatment of Sunflower syndrome: A questionnaire-based study. Epilepsy Behav. 2026 Mar;176:110921. doi: 10.1016/j.yebeh.2026.110921. Epub 2026 Jan 31. PMID: 41621154.

Abstract

Aim: The goal of this study was to assess the efficacy and tolerability of the Cantrell Notch Filtering soft contact lens as a treatment for patients with Sunflower syndrome.

Methods: A questionnaire was distributed to patients with Sunflower syndrome that were being treated with the Cantrell Notch Filtering contact lenses. The survey was hosted on REDCap, and covered topics pertaining to the respondent's history of Sunflower syndrome, including frequency of seizures, tolerability of the lenses, and the perceived benefit of the lenses with regard to reduction of handwaving episodes.

Results: Nineteen people participated in this study. Sixteen of the 19 respondents provided numerical data regarding the frequency of handwaving episodes with and without contact lenses. At the time of survey completion, the average length of time that patients reported wearing the contact lenses was 11.5 months (range: 1 week-2 years 6 months). There was an average 72.9% reduction in handwaving episodes with the use of the contact lenses. Many respondents were able to reduce the use of other non-pharmacological interventions, such as hats and sunglasses, while wearing the contact lenses. However, 10 respondents (52.6%) reported difficulty with tolerability of the contact lenses, including stinging, burning, and color distortion. Of note, these contact lenses filter light between 250 and 650 nm, compared to a Zeiss Z1 lens which filters light between 550 and 700 nm.

Conclusion: The Cantrell Notch Filtering contact lens for Sunflower syndrome may be a beneficial non-pharmacological treatment option for some patients with Sunflower syndrome, although many patients have difficulty with tolerability.

Geenen KR, Yap SV, Tsega L, Dowless D, Bruno PL, Thiele EA. Eye patches and seizure frequency in young people with Sunflower syndrome. Dev Med Child Neurol. 2026 Jan 10. doi: 10.1111/dmcn.70140. Epub ahead of print. PMID: 41518217.

Abstract

The goal of this study was to assess the impact of wearing an eye patch on seizure frequency in patients with Sunflower syndrome, a reflex photosensitive epilepsy. Caregivers were instructed to record the number of handwaving episodes (HWEs) that occurred per hour under each of the following conditions: (1) no eye patch, (2) wearing an eye patch on the eye ipsilateral to the hand involved in handwaving, and (3) wearing an eye patch on the eye contralateral to the hand involved in handwaving. Patients performed each trial three times, for a total of nine 1-hour trials. Seven patients (five females, two males; age range 8 years 10 months-21 years 5 months, median age = 11 years 2 months) participated in this study. All patients experienced a decrease in HWEs while wearing an eye patch on either eye. Across all patients, the median frequency of HWEs with no eye patch (baseline) was 136 HWEs/hour. When patching the contralateral eye, the median frequency was 26 HWEs/hour. When patching the ipsilateral eye, the median frequency was 23 HWEs/hour. The findings in this study suggest that blocking sensory input to one eye may significantly reduce seizure frequency in patients with Sunflower syndrome. This may inform theories around the pathophysiology of Sunflower syndrome and provide insight into more effective treatment options.