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.
Wednesday, March 18, 2026
Upright and positional MRI for Chiari 1 detection
Inspired by a patient
Abstract
Objective: Weight-bearing magnetic resonance imaging enables assessment of the cervical spine and craniocervical junction under physiological load, potentially revealing pathology that is occult on conventional supine imaging. This scoping review synthesizes current evidence, maps clinical and emerging applications, and identifies key gaps requiring further investigation.
Methods: A structured search was conducted in PubMed, Scopus, Web of Science, Google Scholar, and Semantic Scholar (July 2025). Eligible studies were reviewed for diagnostic utility, technical considerations, clinical indications, and outcomes. Methodological quality was appraised descriptively in line with Joanna Briggs Institute guidance.
Results: Nine studies, published between 2008 and 2025, met inclusion criteria. Upright and dynamic MRI detected posture-dependent changes including spinal canal narrowing, cord compression, foraminal stenosis, ligamentous buckling, cerebellar tonsillar descent, altered sagittal alignment, and CSF flow differences. Findings were more pronounced in flexion extension and upright postures compared with supine imaging. Normative studies established reference metrics for CCJ motion and prevertebral soft tissue width. Preliminary evidence also highlights applications in connective tissue disorders, Chiari malformation, and upper cervical chiropractic practice, although most studies were feasibility reports with small sample sizes and heterogeneous protocols.
Conclusion: Emerging evidence suggests that WBMRI provides added diagnostic value in selected cervical spine and CCJ conditions by revealing dynamic or load-sensitive pathology not captured on standard supine imaging. While current evidence remains preliminary, standardized protocols, higher-field technologies, and large multicenter outcome-based studies are essential to validate diagnostic thresholds, improve reproducibility, and define the role of WBMRI in routine clinical care.
Health Quality Ontario. Positional Magnetic Resonance Imaging for People With Ehlers-Danlos Syndrome or Suspected Craniovertebral or Cervical Spine Abnormalities: An Evidence-Based Analysis. Ont Health Technol Assess Ser. 2015 Jul 1;15(13):1-24. PMID: 26366238; PMCID: PMC4561548.
Abstract
Background: Ehlers-Danlos syndrome (EDS) is an inherited disorder affecting the connective tissue. EDS can manifest with symptoms attributable to the spine or craniovertebral junction (CVJ). In addition to EDS, numerous congenital, developmental, or acquired disorders can increase ligamentous laxity in the CVJ and cervical spine. Resulting abnormalities can lead to morbidity and serious neurologic complications. Appropriate imaging and diagnosis is needed to determine patient management and need for complex surgery. Some spinal abnormalities cause symptoms or are more pronounced while patients sit, stand, or perform specific movements. Positional magnetic resonance imaging (pMRI) allows imaging of the spine or CVJ with patients in upright, weight-bearing positions and can be combined with dynamic maneuvers, such as flexion, extension, or rotation. Imaging in these positions could allow diagnosticians to better detect spinal or CVJ abnormalities than recumbent MRI or even a combination of other available imaging modalities might allow.
Objectives: To determine the diagnostic impact and clinical utility of pMRI for the assessment of (a) craniovertebral or spinal abnormalities among people with EDS and (b) major craniovertebral or cervical spine abnormalities among symptomatic people.
Data sources: A literature search was performed using Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid Embase, and EBM Reviews, for studies published from January 1, 1998, to September 28, 2014.
Review methods: Studies comparing pMRI to recumbent MRI or other available imaging modalities for diagnosis and management of spinal or CVJ abnormalities were reviewed. All studies of spinal or CVJ imaging in people with EDS were included as well as studies among people with suspected major CVJ or cervical spine abnormalities (cervical or craniovertebral spine instability, basilar invagination, cranial settling, cervical stenosis, spinal cord compression, Chiari malformation).
Results: No studies were identified that met the inclusion criteria.
Conclusions: We did not identify any evidence that assessed the diagnostic impact or clinical utility of pMRI for (a) craniovertebral or spinal abnormalities among people with EDS or (b) major craniovertebral or cervical spine abnormalities among symptomatic people relative to currently available diagnostic modalities.
Tubbs RS, Kirkpatrick CM, Rizk E, Chern JJ, Oskouian RJ, Oakes WJ. Do the cerebellar tonsils move during flexion and extension of the neck in patients with Chiari I malformation? A radiological study with clinical implications. Childs Nerv Syst. 2016 Mar;32(3):527-30. doi: 10.1007/s00381-016-3014-5. Epub 2016 Jan 12. PMID: 26758883.
Abstract
Background: In the past, diagnosis of the Chiari I malformation has primarily been made on midsagittal MRI. We hypothesized that based on the frequent presentation of opisthotonos in patients with hindbrain hernia (primarily Chiari II malformation but sometimes Chiari I malformation) that the hyperextension might be a compensatory technique used by such patients to bring the cerebellar tonsils up out of the cervical spine.
Patients and methods: This prospective study reviewed imaging of patients with Chiari I malformation who underwent flexion/extension MRI for evaluation of their hindbrain herniation. Age-matched controls were used for comparison.
Results: In general, there was elevation of the cerebellar tonsils with extension and increased descent with flexion of the cervical spine. In 72 % of patients, flexion of the neck resulted in descent of the cerebellar tonsils. In 64 % of patients, extension of the neck resulted in ascent of the cerebellar tonsils. In the 14 patients with an associated syrinx, 71 % were found to have caudal movement of the cerebellar tonsils with neck flexion, and only 43 % were observed to have any movement of the cerebellar tonsils in neck extension compared to patients without a syrinx where ascent of the tonsils was seen in only nine during neck extension. Two patients were observed to have the reverse finding of ascent of the cerebellar tonsils with neck flexion and descent of the cerebellar tonsils with neck extension. Five patients had no movement of the cerebellar tonsils in either flexion or extension of the neck, and one of these had a small syrinx.
Conclusions: Although minimal and not in all patients, we observed elevation of the herniated cerebellar tonsils with extension of the cervical spine in patients with Chiari I malformation. This finding provides evidence as to why some patients with hindbrain herniation present with opisthotonos and supports earlier findings that CSF flow is reduced at the craniocervical junction in flexion in patients with Chiari I malformation.
Tam SKP, Chia J, Brodbelt A, Foroughi M. Assessment of patients with a Chiari malformation type I. Brain Spine. 2021 Dec 3;2:100850. doi: 10.1016/j.bas.2021.100850. PMID: 36248113; PMCID: PMC9560699.
Abstract
Introduction
The prevalence of Chiari malformation type I (CM-I) has been estimated as up to 1% of the general population. The majority of patients are asymptomatic and usually do not need treatment. Symptomatic patients, and some asymptomatic patients with associated conditions, may benefit from further assessment and treatment.
Research question
The aim of this review was to describe the clinical and radiological assessment of patients presenting with a CM-I.
Material and methods
A literature search was performed using the PubMed and Embase databases focused on clinical assessment and imaging techniques used to diagnose CM-I.
Results
Following a complete clinical evaluation in patients with symptomatic CM-I and/or radiologically significant CM-I (tonsillar impaction, resulting tonsillar asymmetry and loss of CSF spaces), MRI of the brain and whole spine enables an assessment of the CM-I and potential associated or causative conditions. These include hydrocephalus, syringomyelia, spinal dysraphism, and tethered cord. Flow and Cine MRI can provide information on CSF dynamics at the craniocervical junction, and help in surgical decision-making. Hypermobility or instability at the upper cervical and craniocervical junction is less common and can be measured with CT imaging and flexion/extension or upright MRI.
Discussion and conclusion
The majority of CM-I detected are incidental findings on MRI imaging of brain or spine, and do not require intervention. Once a radiological diagnosis and concern has been raised, clinical assessment by an appropriate specialist is required. A MRI brain and cervical spine is indicated in all radiologically labelled CM-I. In symptomatic patients or cases of radiologically significant CM-I, MRI of the brain and entire spine is indicated. Further investigations should be tailored to individuals’ needs.
David Chu, Michael Boitano, Dan Culver, Raymond Damadian, Mary Gianni, Rob Viel, Jan Votruba, Robert Wolf. First Upright Study of CSF Flow in Chiari I Malformation with Cine Phase-Contrast MRI. https://archive.ismrm.org/2009/0940.html
Cerebrospinal fluid (CSF) flow abnormalities are generally known to correlate better with symptomatology than the degree of tonsillar herniation in Chiari I malformation (CMI) patients. However, all MRI studies of CSF flow in CMI patients have been restricted to the recumbent position. We present the first study of CSF flow and spinal cord pulsation in the upright posture in a CMI patient. Upright imaging revealed major CSF flow abnormalities that were absent in the supine posture.
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
Tuesday, March 17, 2026
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.
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.
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.
Saturday, March 14, 2026
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.
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.
Thursday, March 12, 2026
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.
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.
Subscribe to:
Comments (Atom)