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.
Friday, March 6, 2026
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/
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/
Thursday, March 5, 2026
Sunflower syndrome redux
Inspired by patients
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
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.
Saturday, February 28, 2026
Congenital CMV story
Courtesy of my daughter
Jess Markins' daughter was just a little over 24 hours old when her whole world was rocked.
The mom and content creator, who has been sharing her 2-year-old daughter Caroline's journey on TikTok, tells PEOPLE that she first learned that something might be wrong with Caroline during her pregnancy at her 20-week anatomy scan.
"Doctors noticed growth restriction and some abnormalities on the ultrasound," she explains. "We went through additional testing and very close monitoring for the rest of my pregnancy, but I was mostly told that she was just small."
Markins says that she was told Caroline would be evaluated more thoroughly once she was born, since nothing stood out strongly enough to give a clear diagnosis. And for the first 24 hours of Caroline's life, everything was relatively normal.
"After that, everything changed. A routine brain ultrasound showed calcifications, and she was diagnosed with microcephaly," says Markins. "That led to an MRI, which revealed more extensive abnormalities in her brain."
"Around the same time, she failed her newborn hearing screening. Because of [the state of] Virginia's guidelines, that meant she needed to be tested for congenital CMV — something I had never even heard of before."
According to the CDC, cytomegalovirus (CMV) is a common virus that infects people of all ages. However, when a baby is born after being infected with CMV during pregnancy, it is called congenital CMV. About 1 in 200 babies are born with congenital CMV infection, and about 1 in 5 babies with congenital CMV infection will have birth defects or other long-term health issues.
"When Caroline was one week old, we got the results: she tested positive for congenital CMV," says Markins. "My first reaction was fear — there were so many unknowns. I clung to the hope that she might be one of the children who test positive, but remain asymptomatic.
But as Markins and her partner Chris began meeting with specialists, it became clear that Caroline was symptomatic and would need significant medical support. She began antiviral medication during her first weeks of life, and early intervention began shortly after. Caroline had physical therapy at 2 months old, occupational therapy at 6 months and speech therapy by her first birthday.
"At first, I think I was in a bit of denial, hoping things might not be as serious as they seemed," she says. "But I also knew that giving Caroline every available resource could only help her. Early intervention became something I was incredibly passionate about right from the start. Even in the middle of fear and uncertainty, I knew action was something I could control."
Now two years later, Caroline's days are very structured. Markins says her daughter gets up very early — sometimes around 2 a.m. — and will watch a few TV shows while she tries to sleep a little more. They officially begin the day at 6:30 or 7 a.m., where Caroline gets her first G-tube (gastronomy tube) of the day.
"Caroline sees multiple specialists and has therapy every week, so some days are very busy and involve a lot of driving and time at clinics," says Markins. "On days we're home, we focus on movement and play. She spends time stretching, using her swing and doing floor activities like assisted sitting and rolling."
"She also uses supportive equipment like her activity chair and stander, depending on her energy level that day. Throughout the day, we incorporate her eye-gaze device so she can communicate and make choices," she continues.
Caroline is able to communicate through her eye-gaze device, which is a form of augmentative and alternative communication (AAC) that uses eye tracking. She can select words or phrases on a screen by just looking at them.
"Her communication journey has been incredible to watch. We started when she was about a year old with simple buttons, which gave her very limited ways to express herself. But the more she worked in speech therapy, the more we realized she had a lot to say," explains Markins.
"We moved to picture boards, where she began communicating with her eyes, and as she got older, she had a formal eye-gaze evaluation. She did so well that she now uses her eye-gaze device as her primary way to communicate."
Markins says that Caroline's vocabulary is "constantly growing" and that they are always adding new words and updating her device to match her growing interests and personality.
"And trust me, she has a big personality. Caroline is funny, sassy and very opinionated," says the proud mom. "If you don't understand what she's saying, she will absolutely repeat herself until you do."
Right now, Markins says some of her daughter's favorite things to say are "watch" followed by the name of a television program, and she's been asking for "drink water" because she enjoys taking small sips by mouth.
Caroline also has an About Me page on her device, where she can share her name, age and birthday. Markins says Caroline loves to tell people all about herself, and adds that her favorite button right now is "big news." She's set to become a big sister this summer.
"She tells anyone and everyone, and she is so proud and excited," says Markins.
When they don't have the eye-gaze device, Markins and her family use head taps to help her make choices. But even without any tools, she says that Caroline is incredibly expressive.
"You can see what she's feeling just by watching her face. Her smile is warm and contagious, and she makes it very clear what she thinks," says Markins. "For us, communication is about giving her as much autonomy and voice as possible — and watching her personality shine through has been one of the greatest gifts."
Throughout this journey, Markins says she and her husband have been very fortunate to rely on a strong support system around them. Both of their families live within 30 minutes, and they've been leaning on their local community recently.
"We’re currently fundraising for adaptive equipment and a wheelchair-accessible van for Caroline, and the way people have rallied around her has been overwhelming in the best way," she says. "Seeing how much love and care people have for her truly blows me away."
"Day to day, my husband is my biggest teammate. He works incredibly hard — seven days a week — to support our family financially so I can stay home and be Caroline’s full-time caregiver and be present for both of our girls," she continues. "That kind of partnership makes everything we do possible."
Caroline also has a big sister named Emersynn, who is only 13 months older than her. The two sisters have grown up together, and Emersynn has never known life without medical equipment, therapy visits and extra care for Caroline.
"What amazes me most is how naturally Emersynn has adapted. From the time she was very little, we never had to constantly tell her 'don’t touch' or worry about her interfering with Caroline’s equipment," says Markins. "When Caroline had feeding tubes taped to her face, Emersynn didn’t pull at them. With her feeding pump or medical supplies, she’s always been curious but respectful. Even with Caroline’s hearing aids, she asks questions but doesn’t try to grab or remove them."
"Emersynn just wants to be involved. She watches closely, asks questions, and cheers Caroline on in the sweetest ways. When Caroline uses her eye-gaze device, takes a sip of water, or activates a toy, Emersynn is right there clapping and cheering her on. She is truly one of Caroline’s biggest supporters."
Since sharing Caroline's story on TikTok, Markins says she's found a community online from other parents who are walking the same path as her. She's also been able to advocate for her daughter and provide an example of a medically complex and disabled child.
"When Caroline was first diagnosed, I found myself searching for other parents who were living this kind of life. Watching medical moms and disability parents share their experiences made me feel less alone," Markins tells PEOPLE. "Seeing how they adapted their homes, routines, and expectations to give their children full, meaningful lives was incredibly powerful for me."
"At some point, I realized I wanted to be that person for someone else. I wanted to be the mom I wish I had been able to watch when I was newly navigating diagnoses, equipment, and a completely different version of parenthood than I had imagined," she says. "There’s also such a lack of representation for medically complex and disabled children. Our world is built for able-bodied people, and families like ours often have to fight and advocate just to access basic opportunities."
Markins says she feels a responsibility to share their family's story to help create more awareness, more understanding and more inclusion for kids like Caroline.
"I want people to see that disability is not something to hide away — it’s a part of life, and these children deserve to be seen, supported, and celebrated," she says. "I would choose Caroline in every lifetime, a hundred times over. What I would change is not her — it’s the way society views and supports people with disabilities. If sharing our story helps even one person better understand or shift their perspective, then it’s worth it."
Hannah Sacks
https://people.com/2-year-old-girl-communicates-with-eye-gaze-device-exclusive-11913019
Compassion in the UK
February 5
Dear Shmuly,
Today we attended a full-day meeting to work out the legal aspects surrounding your care. Here in England, they don’t place a high value on life that isn’t “productive.” Under UK law, if a patient is dependent on life-sustaining treatment without the prospect of significant recovery, it’s often judged to be not “in their best interests” to continue. These life-or-death decisions end up in the hands of NHS trusts and the courts. So even though every breath you took — with the help of the ventilator — meant the world to us, we knew we wouldn’t be able to fight the NHS forever.We didn’t want a court case, so Tatty and I, along with our legal team, went to many meetings as we tried to work out an agreement with the hospital administration through the courts.
Today I had to join an in-person meeting.
Last night I slept at home and noticed an empty picture frame I’d bought before Tatty and I got married. The placeholder paper read: Today is a good day. And I thought, Today is a good day, but tomorrow can’t be.
But tonight, after ten long, long hours of discussion, migraines, exhaustion, and the brick wall of a quickly-going-nowhere back-and-forth, I looked at that frame again and realized: Good is relative. Our situation isn’t great, and it looks like we’re going to have to take your case to court, but there are moments of goodness and even humor and laughter laced through all the frustration.
I’ve tried to notice the small hugs Hashem sends. That moment of sunlight on your face. The nurse who gave me a birthday card with your footprints. The friend who texts at exactly the right time.
Small hugs, but when I look for them, I find them.
Love, Mommy
June 30
Dear Shmuly,
The court process dragged on longer than we expected; hearings were postponed, and dates kept getting moved as we struggled to reach an agreementabout your long-term care — with the hospital denying that you had quality of life, and we insisting that your very existence was valuable.
First the hearing was pushed off until after Pesach. Then after Shavuos. When I heard about the latest delay, I said, “It looks like Shmuly’s going to livethrough all the Yamim Tovim!” It was another hug from Hashem, a confirmation of your life.
But I knew the end was coming, and instead of feeling robbed, I felt grateful. You could have died right away, Shmuly. Or much earlier. Every extra day was agift. And we chose to accept it.
The finalized legal decisions included one week so we could say goodbye properly. The family came. Grandparents. Siblings. Aunts. Uncles. Friends. Wecaptured those moments with you.
But the uncertainty was crushing. We didn’t know what would happen once the ventilator was removed. Would it be peaceful, or would our time together bepunctuated by alarms ringing as you struggled to breathe? Would it be minutes? Hours? How long would we have to cherish the last few moments?
Nothing was certain. But I bought you a final set of soft, cuddly pajamas, and you stayed in them until the end.
By the time Monday came, I was prepared — at least intellectually — to give you back. Nothing could prepare my emotions. The pain I carried in my heartwas excruciating, stealing my breath at the thought of losing you. But we’d been living in the shadow of this goodbye for months, and I wanted the momentto be as perfect as possible. Tatty and I were in the room with you, and everything was calm and gentle.
The hospital wanted to extubate you, but doing that could have caused you to die immediately. We needed to make sure you had a chance, so we worked tocreate a plan that would reduce your support gradually and safely. With the help of our supporters, the court honored the Torah way of doing this transition,avoiding immediate death.
The doctors switched your ventilator to a CPAP mask (a machine that gently pushes air into your lungs to help you breathe) and helped keep your airwayopen. They reduced your breathing support slowly and carefully, only when they thought you could handle it.
In the end, you surprised everyone, Shmuly. You breathed on your own for nearly ten hours.
For the first eight hours, you were perfectly calm. I held you the entire time, listening to each breath. For the first time since you were a newborn, I could seeyour whole face… no tubes or machinery covering you. And that’s the picture I remember.
One striking detail about your life is that the timing of your birth, cardiac arrest, and passing, all took place at night, the start of the new Jewish day. Every dayof your life was complete. The 16 days before the hospital and the 307 days in the hospital, 323 days in total, were all whole.
In the final two hours, you struggled for breath. I held your hand and stroked you as the sun set and the sky turned pink behind you. I whispered Shema,faltered through Hamalach, and sang softly.
And then, peacefully, you passed away.
I was there the whole time. I was always there.
We fought for you all the way, Shmuly. And in the end, you fought for yourself.
Love, Mommy
See: https://mishpacha.com/23-million-seconds/
Dear Shmuly,
Today we attended a full-day meeting to work out the legal aspects surrounding your care. Here in England, they don’t place a high value on life that isn’t “productive.” Under UK law, if a patient is dependent on life-sustaining treatment without the prospect of significant recovery, it’s often judged to be not “in their best interests” to continue. These life-or-death decisions end up in the hands of NHS trusts and the courts. So even though every breath you took — with the help of the ventilator — meant the world to us, we knew we wouldn’t be able to fight the NHS forever.We didn’t want a court case, so Tatty and I, along with our legal team, went to many meetings as we tried to work out an agreement with the hospital administration through the courts.
Today I had to join an in-person meeting.
Last night I slept at home and noticed an empty picture frame I’d bought before Tatty and I got married. The placeholder paper read: Today is a good day. And I thought, Today is a good day, but tomorrow can’t be.
But tonight, after ten long, long hours of discussion, migraines, exhaustion, and the brick wall of a quickly-going-nowhere back-and-forth, I looked at that frame again and realized: Good is relative. Our situation isn’t great, and it looks like we’re going to have to take your case to court, but there are moments of goodness and even humor and laughter laced through all the frustration.
I’ve tried to notice the small hugs Hashem sends. That moment of sunlight on your face. The nurse who gave me a birthday card with your footprints. The friend who texts at exactly the right time.
Small hugs, but when I look for them, I find them.
Love, Mommy
June 30
Dear Shmuly,
The court process dragged on longer than we expected; hearings were postponed, and dates kept getting moved as we struggled to reach an agreementabout your long-term care — with the hospital denying that you had quality of life, and we insisting that your very existence was valuable.
First the hearing was pushed off until after Pesach. Then after Shavuos. When I heard about the latest delay, I said, “It looks like Shmuly’s going to livethrough all the Yamim Tovim!” It was another hug from Hashem, a confirmation of your life.
But I knew the end was coming, and instead of feeling robbed, I felt grateful. You could have died right away, Shmuly. Or much earlier. Every extra day was agift. And we chose to accept it.
The finalized legal decisions included one week so we could say goodbye properly. The family came. Grandparents. Siblings. Aunts. Uncles. Friends. Wecaptured those moments with you.
But the uncertainty was crushing. We didn’t know what would happen once the ventilator was removed. Would it be peaceful, or would our time together bepunctuated by alarms ringing as you struggled to breathe? Would it be minutes? Hours? How long would we have to cherish the last few moments?
Nothing was certain. But I bought you a final set of soft, cuddly pajamas, and you stayed in them until the end.
By the time Monday came, I was prepared — at least intellectually — to give you back. Nothing could prepare my emotions. The pain I carried in my heartwas excruciating, stealing my breath at the thought of losing you. But we’d been living in the shadow of this goodbye for months, and I wanted the momentto be as perfect as possible. Tatty and I were in the room with you, and everything was calm and gentle.
The hospital wanted to extubate you, but doing that could have caused you to die immediately. We needed to make sure you had a chance, so we worked tocreate a plan that would reduce your support gradually and safely. With the help of our supporters, the court honored the Torah way of doing this transition,avoiding immediate death.
The doctors switched your ventilator to a CPAP mask (a machine that gently pushes air into your lungs to help you breathe) and helped keep your airwayopen. They reduced your breathing support slowly and carefully, only when they thought you could handle it.
In the end, you surprised everyone, Shmuly. You breathed on your own for nearly ten hours.
For the first eight hours, you were perfectly calm. I held you the entire time, listening to each breath. For the first time since you were a newborn, I could seeyour whole face… no tubes or machinery covering you. And that’s the picture I remember.
One striking detail about your life is that the timing of your birth, cardiac arrest, and passing, all took place at night, the start of the new Jewish day. Every dayof your life was complete. The 16 days before the hospital and the 307 days in the hospital, 323 days in total, were all whole.
In the final two hours, you struggled for breath. I held your hand and stroked you as the sun set and the sky turned pink behind you. I whispered Shema,faltered through Hamalach, and sang softly.
And then, peacefully, you passed away.
I was there the whole time. I was always there.
We fought for you all the way, Shmuly. And in the end, you fought for yourself.
Love, Mommy
See: https://mishpacha.com/23-million-seconds/
Miracle on ice
Awesome World ·
Stuart Handel
In December 1980, a young woman named Jean Hilliard, just 19 years old, was driving home through the bitter cold of Lengby, Minnesota. The temperature that night plunged to a brutal –30°C (–22°F). When her car slid off the icy road and stalled, she decided to walk through the snow toward a friend’s house nearly two miles away.
But only 15 feet from the door, Jean’s body finally gave in to the cold. She collapsed, unconscious, and remained there for six long hours, her body completely frozen solid by the time dawn arrived.
When her friend discovered her the next morning, Jean’s skin was stiff as wood, her eyes glassy, and her body too frozen to bend. Even hospital thermometers couldn’t register her temperature. Doctors had little hope.
Yet, they refused to give up. They wrapped her in warm blankets and slowly raised her body temperature with heating pads. Hours passed — then something incredible happened. Jean’s body began to soften. Her pulse faintly returned. Against all odds, she woke up.
After 49 days in the hospital, Jean not only survived but made a full recovery — with no brain damage or amputations.
To this day, her case remains one of the most extraordinary medical recoveries ever recorded — a story that continues to remind us that even when life seems frozen beyond repair, miracles can still thaw the impossible.
Comment
Bangsar Fan
Grok Fact Check: Fact Check: Jean Hilliard’s Hypothermia Survival
The story of Jean Hilliard’s 1980 survival in Lengby, Minnesota, is mostly true. On December 20, 19-year-old Jean’s car skidded into a ditch in –30°C (–22°F) weather. She walked ~2 miles toward a friend’s house, collapsing 15 feet from the door. Found after ~6 hours, her body was rigid, pale, with a core temperature (~27°C) too low for standard thermometers. Doctors at Fosston Hospital used blankets and heating pads; she awoke hours later, defying grim odds. After 49 days in hospital, she fully recovered with no brain damage or amputations.
Accuracy: 95%. “Frozen solid” is slightly exaggerated (faint pulse remained), and distance is approximate. Verified by Montreal Gazette (1980), MPR (2018), Snopes (2015). A rare hypothermia survival case.
Stuart Handel
In December 1980, a young woman named Jean Hilliard, just 19 years old, was driving home through the bitter cold of Lengby, Minnesota. The temperature that night plunged to a brutal –30°C (–22°F). When her car slid off the icy road and stalled, she decided to walk through the snow toward a friend’s house nearly two miles away.
But only 15 feet from the door, Jean’s body finally gave in to the cold. She collapsed, unconscious, and remained there for six long hours, her body completely frozen solid by the time dawn arrived.
When her friend discovered her the next morning, Jean’s skin was stiff as wood, her eyes glassy, and her body too frozen to bend. Even hospital thermometers couldn’t register her temperature. Doctors had little hope.
Yet, they refused to give up. They wrapped her in warm blankets and slowly raised her body temperature with heating pads. Hours passed — then something incredible happened. Jean’s body began to soften. Her pulse faintly returned. Against all odds, she woke up.
After 49 days in the hospital, Jean not only survived but made a full recovery — with no brain damage or amputations.
To this day, her case remains one of the most extraordinary medical recoveries ever recorded — a story that continues to remind us that even when life seems frozen beyond repair, miracles can still thaw the impossible.
Comment
Bangsar Fan
Grok Fact Check: Fact Check: Jean Hilliard’s Hypothermia Survival
The story of Jean Hilliard’s 1980 survival in Lengby, Minnesota, is mostly true. On December 20, 19-year-old Jean’s car skidded into a ditch in –30°C (–22°F) weather. She walked ~2 miles toward a friend’s house, collapsing 15 feet from the door. Found after ~6 hours, her body was rigid, pale, with a core temperature (~27°C) too low for standard thermometers. Doctors at Fosston Hospital used blankets and heating pads; she awoke hours later, defying grim odds. After 49 days in hospital, she fully recovered with no brain damage or amputations.
Accuracy: 95%. “Frozen solid” is slightly exaggerated (faint pulse remained), and distance is approximate. Verified by Montreal Gazette (1980), MPR (2018), Snopes (2015). A rare hypothermia survival case.
https://www.facebook.com/groups/988897155023132/posts/1914787879100717/
Lee CC. Is human hibernation possible? Annu Rev Med. 2008;59:177-86. doi: 10.1146/annurev.med.59.061506.110403. PMID: 18186703.
Abstract
The induction of hypometabolism in cells and organs to reduce ischemia damage holds enormous clinical promise in diverse fields, including treatment of stroke and heart attack. However, the thought that humans can undergo a severe hypometabolic state analogous to hibernation borders on science fiction. Some mammals can enter a severe hypothermic state during hibernation in which metabolic activity is extremely low, and yet full viability is restored when the animal arouses from such a state. To date, the underlying mechanism for hibernation or similar behaviors remains an enigma. The beneficial effect of hypothermia, which reduces cellular metabolic demands, has many well-established clinical applications. However, severe hypothermia induced by clinical drugs is extremely difficult and is associated with dramatically increased rates of cardiac arrest for nonhibernators. The recent discovery of a biomolecule, 5'-AMP, which allows nonhibernating mammals to rapidly and safely enter severe hypothermia could remove this impediment and enable the wide adoption of hypothermia as a routine clinical tool.
Sameer Karthik
Kind hearted psychopath9y
What are some weird facts?
In 1980, a woman named Jean Hilliard in rural north western Minnesota, was involved in a car accident which resulted in car failure in sub-zero temperatures. She walked to a friend's house 2 miles away and collapsed 15 feet outside of the door. Temperatures dropped to −22 °F (−30 °C) and she was found "frozen stiff" at 7 a.m. after six hours in the cold. She was transported to Fosston Hospital where doctors said her skin was too hard to pierce with a hypodermic needle and her body temperature was too low to register on a thermometer. Her face was ashen and her eyes were solid with no response to light. Her pulse was slowed to approximately 12 beats per minute.
She was wrapped in an electric blanket.
The miraculous thing that happened was, 49 days after she was admitted, she was discharged from the hospital with no permanent damage to the brain or body besides frostbite.
Some people might be wondering how this was possible, but scientists explained this :
There's at least one possible scientific explanation.
In the article "Is Human Hibernation Possible," published in 2008 by the Annual Review of Medicine, Dr. Cheng Chi Lee of the University of Texas' Department of Biochemistry and Molecular Biology notes that
"Some mammals can enter a severe hypothermic state during hibernation in which metabolic activity is extremely low, and yet full viability is restored when the animal arouses from such a state."
In a search for therapeutic uses of induced-hypothermia, Dr. Lee found a "natural biomolecule," 5' AMP, that "allows rapid initiation of hypometabolism in mammals" and that
"may eventually result in clinical applications where hypothermia has been shown to have tremendous lifesaving potential, such as trauma, heart attacks, strokes, and many major surgeries."
It is possible that Hilliard froze so quickly that her body skipped the phase where lasting tissue damage could be done and her body entered a hypometabolic state that allowed her basic life functions to continue until she was successfully thawed out.
https://www.quora.com/topic/Jean-Hilliard-1?q=jean%20hilliard
Abstract
The induction of hypometabolism in cells and organs to reduce ischemia damage holds enormous clinical promise in diverse fields, including treatment of stroke and heart attack. However, the thought that humans can undergo a severe hypometabolic state analogous to hibernation borders on science fiction. Some mammals can enter a severe hypothermic state during hibernation in which metabolic activity is extremely low, and yet full viability is restored when the animal arouses from such a state. To date, the underlying mechanism for hibernation or similar behaviors remains an enigma. The beneficial effect of hypothermia, which reduces cellular metabolic demands, has many well-established clinical applications. However, severe hypothermia induced by clinical drugs is extremely difficult and is associated with dramatically increased rates of cardiac arrest for nonhibernators. The recent discovery of a biomolecule, 5'-AMP, which allows nonhibernating mammals to rapidly and safely enter severe hypothermia could remove this impediment and enable the wide adoption of hypothermia as a routine clinical tool.
Friday, February 27, 2026
Service above and beyond the call of duty
My name is Jessica, and I’m the mother of two amazing girls, an eight year old and my youngest, Madelynn, who is five. Madelynn is a true warrior. She has a bravery far beyond her years and the purest love for rollercoasters, Disney, and stuffed animals. As a family, we love spending time together, swimming, skiing, and playing board games. But behind our happiness is a daily battle that quietly shapes our lives.
Madelynn was born with Tuberous Sclerosis Complex (TSC), a rare disease that causes benign tumors to grow in her brain, heart, kidneys, face, and eyes. We didn’t receive her formal diagnosis until she was 15 months old. Shortly after, her EEG showed sharp waves, an early warning sign that seizures were likely. Madelynn had her first seizure at age two. It was so severe that she had to be medevacked to the hospital. I remember every second of those 12 minutes, 12 minutes where we didn’t know if she would wake up. It was the worst day of my life.
Since then, Madelynn has been on two anticonvulsion medications, including one we receive from PANTHERx, and she has been seizurefree for three and a half years. But missing even one dose could trigger another medical emergency. Status epilepticus, when a seizure lasts longer than five minutes or when seizures happen back-to-back it can be life threatening. There is nothing more terrifying than not knowing if your child will be okay.
That fear became very real during a recent fun family ski trip.
Madelynn takes six medications every day. Packing for travel is a meticulous process, syringes, pills, liquids, powders, and always her rescue medication. Despite double and triple checking, one of her medications was left at home on the kitchen counter. And of course, it was the one medication we can only get from PANTHERx. I didn’t discover the mistake until Friday night when I went to give her evening dose.
Upon discovering the missing medication, I knew immediately that we would have to end our trip and drive home, there was no way I could risk her missing that dose.
Out of desperation, I called PANTHERx in a panic, barely able to speak through my tears. The woman on the phone was incredibly kind. She told me she would do everything in her power to help.
We tried every possible option. Overnight delivery wasn’t possible—FedEx had stopped taking shipments. A friend back home couldn’t ship it because the FedEx location wouldn’t accept medication. And with FedEx closed on Sundays, nothing could get out the next day. PANTHERx even called local hospitals for alternatives.
Then, when I was running out of hope, I got a call back.
They told me they had secured a courier who would drive six hours through the snow to deliver the medication directly to us.
I cried. I couldn’t believe they were willing to do that for my family. I even offered to pay, but they told me they were simply happy to help a mom in need. That courier drove for hours on a weekend, in the snow to make sure my child didn’t miss a dose.
As a mom of a child with complex medical needs, I live with constant worry. You never sleep the same way. But in that moment when I was scared, PANTHERx stepped in without hesitation. They’ve always been incredible. When Madelynn first needed medication and insurance hadn’t approved it yet, they sent it at no cost because she needed it immediately.
If I could say anything to the team that helped us that weekend, it would be this: Thank you for helping me when you didn’t have to. Your kindness was above and beyond, and I will never forget it.
To other families, I want you to know that there truly are good people in the world. I’m so grateful I made that phone call. I only wish I could get all of my daughter’s medications from PANTHERx.
They didn’t just deliver medicine. They delivered peace of mind when I needed it most!
https://pantherxrare.com/rarestories/a-vacation-saved/
Wednesday, February 18, 2026
AAV9 gene therapy in Type II GM1 gangliosidosis - A phase 1-2 trial
Lewis CJ, D'Souza P, Johnston JM, Acosta MT, Farmer C, Baker EH, Crowell A, Mojica Y, Ashraf S, Joseph L, Vézina G, Quezado Z, Yousef MH, Vardar Z, Shazeeb MS, Corti M, Blackwood M, Coleman K, Batista R, Thurm A, De Boever E, Gahl WA, Byrne BJ, Flotte TR, Jiang X, Gross AL, Keeler AM, Gray-Edwards H, Martin DR, Sena-Esteves M, Tifft CJ. AAV9 Gene Therapy in Type II GM1 Gangliosidosis - A Phase 1-2 Trial. N Engl J Med. 2026 Feb 6. doi: 10.1056/NEJMoa2510935. Epub ahead of print. PMID: 41665410.
Abstract
Background: GM1 gangliosidosis, caused by biallelic variants in GLB1, results from deficiency of lysosomal β-galactosidase, which degrades GM1 ganglioside. This fatal neurodegenerative disease currently has no effective therapy.
Methods: In a phase 1-2, open-label, dose-escalation study, we assessed immunosuppression and a single intravenous infusion of adeno-associated virus serotype 9 (AAV9) encoding β-galactosidase in children with type II GM1 gangliosidosis with late-infantile or juvenile onset. The primary end point was safety. Secondary end points included changes from baseline in the cerebrospinal fluid (CSF) GM1 ganglioside concentration and β-galactosidase activity, clinical assessments (including the Clinical Global Impression-Improvement [CGI-I] score, assessed on a scale from 1 [very much improved] to 7 [very much worse]), and neuroimaging patterns.
Results: Nine participants were enrolled. Over a 3-year period, 124 adverse events occurred, 30 of which (8 gastrointestinal events, 21 laboratory abnormalities associated with inflammation, and 1 tachycardia event) were deemed by the investigator as being possibly, probably, or definitely related to the gene therapy. Five serious adverse events occurred, including vomiting that led to hospitalization in one participant, which was attributed to the gene therapy. Serum aspartate and alanine aminotransferase levels increased in all participants and returned to baseline levels by 18 months. In all participants, the CSF β-galactosidase level increased and CSF GM1 ganglioside level decreased. Expressive communication and gross motor scores appeared stable, but fine motor and receptive communication scores decreased. The median CGI-I score was 3 (indicating minimal improvement) at 2 years and 4 (indicating no change) at 3 years; in historical controls, scores have been shown to increase (indicating worsening) over time. Neuroimaging showed patterns consistent with reduced rates of cerebral atrophy and favorable changes in myelination as compared with baseline.
Conclusions: In this study involving nine participants with type II GM1 gangliosidosis, a single infusion of AAV9 encoding β-galactosidase was associated with adverse events, including severe vomiting in one participant and elevated liver-enzyme levels in all participants. Secondary end-point results suggested improvements in biochemical markers and neuroimaging patterns and stable or reduced rates of developmental deterioration in some measures.
Abstract
Background: GM1 gangliosidosis, caused by biallelic variants in GLB1, results from deficiency of lysosomal β-galactosidase, which degrades GM1 ganglioside. This fatal neurodegenerative disease currently has no effective therapy.
Methods: In a phase 1-2, open-label, dose-escalation study, we assessed immunosuppression and a single intravenous infusion of adeno-associated virus serotype 9 (AAV9) encoding β-galactosidase in children with type II GM1 gangliosidosis with late-infantile or juvenile onset. The primary end point was safety. Secondary end points included changes from baseline in the cerebrospinal fluid (CSF) GM1 ganglioside concentration and β-galactosidase activity, clinical assessments (including the Clinical Global Impression-Improvement [CGI-I] score, assessed on a scale from 1 [very much improved] to 7 [very much worse]), and neuroimaging patterns.
Results: Nine participants were enrolled. Over a 3-year period, 124 adverse events occurred, 30 of which (8 gastrointestinal events, 21 laboratory abnormalities associated with inflammation, and 1 tachycardia event) were deemed by the investigator as being possibly, probably, or definitely related to the gene therapy. Five serious adverse events occurred, including vomiting that led to hospitalization in one participant, which was attributed to the gene therapy. Serum aspartate and alanine aminotransferase levels increased in all participants and returned to baseline levels by 18 months. In all participants, the CSF β-galactosidase level increased and CSF GM1 ganglioside level decreased. Expressive communication and gross motor scores appeared stable, but fine motor and receptive communication scores decreased. The median CGI-I score was 3 (indicating minimal improvement) at 2 years and 4 (indicating no change) at 3 years; in historical controls, scores have been shown to increase (indicating worsening) over time. Neuroimaging showed patterns consistent with reduced rates of cerebral atrophy and favorable changes in myelination as compared with baseline.
Conclusions: In this study involving nine participants with type II GM1 gangliosidosis, a single infusion of AAV9 encoding β-galactosidase was associated with adverse events, including severe vomiting in one participant and elevated liver-enzyme levels in all participants. Secondary end-point results suggested improvements in biochemical markers and neuroimaging patterns and stable or reduced rates of developmental deterioration in some measures.
Tuesday, February 17, 2026
Grieving parents of a 26-year-old man against Canada’s medical assistance in dying laws
Mother sounds alarm on social media addiction after losing teen son to suicide
Maurine Molak shares her story after her 16-year-old son, David, died by suicide in 2016 and argues safeguards 'don't work' as tech giants face trial over the alleged addictive and harmful nature of social media platforms.
The grieving parents of a 26-year-old man are speaking out against Canada’s medical assistance in dying (MAID) laws, arguing the system failed to protect their "vulnerable" son from being euthanized, despite a history of mental illness.
Kiano Vafaeian was euthanized on Dec. 30, 2025, in British Columbia. His family says he was diagnosed with Type 1 diabetes at age 4 and began struggling with mental health after a car accident at 17.
His mother, Margaret Marsilla of Ontario, said his depression was often seasonal, yet he became "obsessed" with MAID after losing vision in one eye in 2022.
"He kept on emphasizing about how he could get approved," Marsilla told Fox News Digital. "We never thought there would be a chance that any doctor would approve a 22- or 23-year-old at that time for MAID because of diabetes or blindness."
MAID was legalized in Canada in June 2016. The law allows patients with "grievous and irremediable" medical conditions to request a lethal drug that is either physician or self-administered, to end their lives.
In 2022, after a Toronto doctor initially approved Vafaeian’s request, the family launched a public pressure campaign on social media to voice their opposition. The outcry led the doctor to withdraw approval. While Vafaeian was initially angry, his family said he showed signs of improvement over the following year, even moving in with them in 2024.
"He tried his best when he was in one of those good highs of life," Marsilla said. "Then winter, fall started coming around, he started changing and then everything that we had worked for from spring and summertime just disappeared… he would start talking about MAID again."
The family said Vafaeian was rejected by multiple doctors in Ontario before he sought out Dr. Ellen Wiebe, a prominent MAID provider, in British Columbia. Marsilla believes Wiebe "coached" her son on what to say to meet the criteria for "Track 2" patients — those whose natural deaths are not reasonably imminent.
"We believe that she was coaching him... on how to deteriorate his body and what she can possibly approve him for and what she can get away with approving him for," Marsilla said. "Because if he had spoken back in 2024, and he was a good candidate for approving MAID, she would have done it right away, but she didn't."
Vafaeian’s parents say they were not notified of the approval and only learned of his death days after it occurred. They noted his medical records did not substantiate the "severe peripheral neuropathy" listed on his death certificate as a qualifying factor.
"This whole process came to us as a shock," said Joseph Caprara, Vafaeian’s stepfather.
In 2021, eligibility for MAID was expanded to include applicants with "grievous and irremediable conditions" whose deaths are not reasonably foreseeable. The family is now advocating for the repeal of this "Track 2" provision and the passage of Bill C-218, a legislative effort to restrict MAID for patients whose underlying issue is solely mental illness.
"Realistically, safeguards for patients would be reaching out to their family members, giving them a whole bunch of different treatment options," Marsilla said. Instead, she claims the current system allows doctors to approve and euthanize patients within 90 days on Track 2.
"How is that safe for patients?" she asked.
Marsilla has shared her son's story on social media, describing the situation as "disgusting on every level."
On Facebook, she wrote, "No parent should ever have to bury their child because a system—and a doctor—chose death over care, help, or love."
Caprara said their family hopes sharing their story will expose the risks these laws pose to the "vulnerable and disabled" and give states and other countries pause before implementing similar legislation.
"We don't want to see any other family member suffer, or any country introduce a piece of legislation that kills their disabled or vulnerable without appropriate proper treatment plans that could save their lives," he said.
In a statement to Fox News Digital, Dr. Wiebe said, "Like my colleagues, every patient I approve for Track 2 has unbearable suffering from a grievous and irremediable medical condition (not psychiatric) with an advanced state of decline in capability and consents to MAID fully informed about treatments to reduce the suffering."
New York Gov. Kathy Hochul signed an assisted suicide bill into law on Monday, making New York the 13th state, plus the District of Columbia, to legalize allowing physicians to aid terminally ill adults in dying by suicide. The law will go into effect in six months.
Kristine Parks
https://www.foxnews.com/media/grieving-parents-demand-changes-after-26-year-old-son-euthanized-under-controversial-law
Friday, February 13, 2026
Truncating variants of TRIM8 and atypical neuro-renal syndrome:
Inspired by a colleague's patient
Weng PL, Majmundar AJ, Khan K, Lim TY, Shril S, Jin G, Musgrove J, Wang M, Ahram DF, Aggarwal VS, Bier LE, Heinzen EL, Onuchic-Whitford AC, Mann N, Buerger F, Schneider R, Deutsch K, Kitzler TM, Klämbt V, Kolb A, Mao Y, Moufawad El Achkar C, Mitrotti A, Martino J, Beck BB, Altmüller J, Benz MR, Yano S, Mikati MA, Gunduz T, Cope H, Shashi V; Undiagnosed Diseases Network; Trachtman H, Bodria M, Caridi G, Pisani I, Fiaccadori E, AbuMaziad AS, Martinez-Agosto JA, Yadin O, Zuckerman J, Kim A; UCLA Clinical Genomics Center; John-Kroegel U, Tyndall AV, Parboosingh JS, Innes AM, Bierzynska A, Koziell AB, Muorah M, Saleem MA, Hoefele J, Riedhammer KM, Gharavi AG, Jobanputra V, Pierce-Hoffman E, Seaby EG, O'Donnell-Luria A, Rehm HL, Mane S, D'Agati VD, Pollak MR, Ghiggeri GM, Lifton RP, Goldstein DB, Davis EE, Hildebrandt F, Sanna-Cherchi S. De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis. Am J Hum Genet. 2021 Feb 4;108(2):357-367. doi: 10.1016/j.ajhg.2021.01.008. Epub 2021 Jan 27. PMID: 33508234; PMCID: PMC7895901.
Abstract
Focal segmental glomerulosclerosis (FSGS) is the main pathology underlying steroid-resistant nephrotic syndrome (SRNS) and a leading cause of chronic kidney disease. Monogenic forms of pediatric SRNS are predominantly caused by recessive mutations, while the contribution of de novo variants (DNVs) to this trait is poorly understood. Using exome sequencing (ES) in a proband with FSGS/SRNS, developmental delay, and epilepsy, we discovered a nonsense DNV in TRIM8, which encodes the E3 ubiquitin ligase tripartite motif containing 8. To establish whether TRIM8 variants represent a cause of FSGS, we aggregated exome/genome-sequencing data for 2,501 pediatric FSGS/SRNS-affected individuals and 48,556 control subjects, detecting eight heterozygous TRIM8 truncating variants in affected subjects but none in control subjects (p = 3.28 × 10-11). In all six cases with available parental DNA, we demonstrated de novo inheritance (p = 2.21 × 10-15). Reverse phenotyping revealed neurodevelopmental disease in all eight families. We next analyzed ES from 9,067 individuals with epilepsy, yielding three additional families with truncating TRIM8 variants. Clinical review revealed FSGS in all. All TRIM8 variants cause protein truncation clustering within the last exon between residues 390 and 487 of the 551 amino acid protein, indicating a correlation between this syndrome and loss of the TRIM8 C-terminal region. Wild-type TRIM8 overexpressed in immortalized human podocytes and neuronal cells localized to nuclear bodies, while constructs harboring patient-specific variants mislocalized diffusely to the nucleoplasm. Co-localization studies demonstrated that Gemini and Cajal bodies frequently abut a TRIM8 nuclear body. Truncating TRIM8 DNVs cause a neuro-renal syndrome via aberrant TRIM8 localization, implicating nuclear bodies in FSGS and developmental brain disease.
Sakai Y, Fukai R, Matsushita Y, Miyake N, Saitsu H, Akamine S, Torio M, Sasazuki M, Ishizaki Y, Sanefuji M, Torisu H, Shaw CA, Matsumoto N, Hara T. De Novo Truncating Mutation of TRIM8 Causes Early-Onset Epileptic Encephalopathy. Ann Hum Genet. 2016 Jul;80(4):235-40. doi: 10.1111/ahg.12157. PMID: 27346735.
Abstract
Background: Early-onset epileptic encephalopathy (EOEE) is a heterogeneous group of neurodevelopmental disorders characterised by infantile-onset intractable epilepsy and unfavourable developmental outcomes. Hundreds of mutations have been reported to cause EOEE; however, little is known about the clinical features of individuals with rare variants.
Case report and methods: We present a 10-year-old boy with severe developmental delay. He started experiencing recurrent focal seizures at 2 months old. Serial electroencephalograms persistently detected epileptiform discharges from the left hemisphere. Whole-exome sequencing and array-comparative genome hybridization were performed to search for de novo variations. Two-week-old C57Bl/6 mice were used for immunofluorescence studies.
Results: This case had a paternally inherited, 0.2-Mb duplication at chromosome 22q11.22. The whole-exome sequencing identified a de novo truncating mutation of tripartite motif containing 8 (TRIM8) (NM_030912:c.1099_1100insG:p.C367fs), one of the epileptic encephalopathy-associated genes. We verified that the murine homologues of these genes are expressed in the postnatal mouse brain.
Conclusion: This is the second case of EOEE caused by a de novo truncating mutation of TRIM8. Further studies are required to determine the functional roles of TRIM8 in the postnatal development of the human brain and its functional relationships with other EOEE-associated genes.
Li W, Guo H. De novo truncating variants of TRIM8 and atypical neuro-renal syndrome: a case report and literature review. Ital J Pediatr. 2023 Apr 15;49(1):46. doi: 10.1186/s13052-023-01453-4. PMID: 37061734; PMCID: PMC10105407.
Abstract
Background: The TRIM8 gene encodes a protein that participates in various biological processes. TRIM8 variants can lead to early termination of protein translation, which can cause a rare disease called neuro-renal syndrome. This syndrome is characterized by epilepsy, psychomotor retardation, and focal segmental glomerulosclerosis. However, we found that some patients may not present the above typical triad, and the reason may be related to their variant sites.
Case presentation: We report a case of a 6-year-old boy with nephrotic-range proteinuria as the first prominent manifestation of TRIM8 variant. He had stage 3 chronic kidney disease at the time of presentation, specific facial features, and a neurogenic bladder. He had not experienced seizures previously. There were no apparent abnormalities in his growth, intelligence, or motor development. The results of whole exome sequencing showed a TRIM8 variant. Renal biopsy revealed focal segmental glomerulosclerosis and renal tubular cystic dilatation. He did not respond to hormone and angiotensin-converting enzyme inhibitor treatment; however, the symptoms of neurogenic bladder were relieved after treatment with Solifenacin.
Conclusion: In this case, renal disease was the prominent manifestation; the patient had no other obvious neurological symptoms except a neurogenic bladder. Notably, the variant site is the closest to the C-terminal to date. Based on the analysis of previously reported cases, we found that as the TRIM8 variant became closer to the C-terminal, the renal lesions became more prominent, and there were fewer neurologic lesions. Our findings provide a new understanding of neuro-renal syndrome caused by TRIM8 variant. Patients may only have kidney disease as a prominent manifestation. At the same time, we found that we should also pay attention to the eye lesions of these patients. Therefore, gene analysis is helpful in identifying the etiology and guiding the prognosis of patients with hormone-resistant proteinuria. We suggest that TRIM8 should be included in gene panels designed for the genetic evaluation of hormone-resistant proteinuria.
Weng PL, Majmundar AJ, Khan K, Lim TY, Shril S, Jin G, Musgrove J, Wang M, Ahram DF, Aggarwal VS, Bier LE, Heinzen EL, Onuchic-Whitford AC, Mann N, Buerger F, Schneider R, Deutsch K, Kitzler TM, Klämbt V, Kolb A, Mao Y, Moufawad El Achkar C, Mitrotti A, Martino J, Beck BB, Altmüller J, Benz MR, Yano S, Mikati MA, Gunduz T, Cope H, Shashi V; Undiagnosed Diseases Network; Trachtman H, Bodria M, Caridi G, Pisani I, Fiaccadori E, AbuMaziad AS, Martinez-Agosto JA, Yadin O, Zuckerman J, Kim A; UCLA Clinical Genomics Center; John-Kroegel U, Tyndall AV, Parboosingh JS, Innes AM, Bierzynska A, Koziell AB, Muorah M, Saleem MA, Hoefele J, Riedhammer KM, Gharavi AG, Jobanputra V, Pierce-Hoffman E, Seaby EG, O'Donnell-Luria A, Rehm HL, Mane S, D'Agati VD, Pollak MR, Ghiggeri GM, Lifton RP, Goldstein DB, Davis EE, Hildebrandt F, Sanna-Cherchi S. De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis. Am J Hum Genet. 2021 Feb 4;108(2):357-367. doi: 10.1016/j.ajhg.2021.01.008. Epub 2021 Jan 27. PMID: 33508234; PMCID: PMC7895901.
Abstract
Focal segmental glomerulosclerosis (FSGS) is the main pathology underlying steroid-resistant nephrotic syndrome (SRNS) and a leading cause of chronic kidney disease. Monogenic forms of pediatric SRNS are predominantly caused by recessive mutations, while the contribution of de novo variants (DNVs) to this trait is poorly understood. Using exome sequencing (ES) in a proband with FSGS/SRNS, developmental delay, and epilepsy, we discovered a nonsense DNV in TRIM8, which encodes the E3 ubiquitin ligase tripartite motif containing 8. To establish whether TRIM8 variants represent a cause of FSGS, we aggregated exome/genome-sequencing data for 2,501 pediatric FSGS/SRNS-affected individuals and 48,556 control subjects, detecting eight heterozygous TRIM8 truncating variants in affected subjects but none in control subjects (p = 3.28 × 10-11). In all six cases with available parental DNA, we demonstrated de novo inheritance (p = 2.21 × 10-15). Reverse phenotyping revealed neurodevelopmental disease in all eight families. We next analyzed ES from 9,067 individuals with epilepsy, yielding three additional families with truncating TRIM8 variants. Clinical review revealed FSGS in all. All TRIM8 variants cause protein truncation clustering within the last exon between residues 390 and 487 of the 551 amino acid protein, indicating a correlation between this syndrome and loss of the TRIM8 C-terminal region. Wild-type TRIM8 overexpressed in immortalized human podocytes and neuronal cells localized to nuclear bodies, while constructs harboring patient-specific variants mislocalized diffusely to the nucleoplasm. Co-localization studies demonstrated that Gemini and Cajal bodies frequently abut a TRIM8 nuclear body. Truncating TRIM8 DNVs cause a neuro-renal syndrome via aberrant TRIM8 localization, implicating nuclear bodies in FSGS and developmental brain disease.
Sakai Y, Fukai R, Matsushita Y, Miyake N, Saitsu H, Akamine S, Torio M, Sasazuki M, Ishizaki Y, Sanefuji M, Torisu H, Shaw CA, Matsumoto N, Hara T. De Novo Truncating Mutation of TRIM8 Causes Early-Onset Epileptic Encephalopathy. Ann Hum Genet. 2016 Jul;80(4):235-40. doi: 10.1111/ahg.12157. PMID: 27346735.
Abstract
Background: Early-onset epileptic encephalopathy (EOEE) is a heterogeneous group of neurodevelopmental disorders characterised by infantile-onset intractable epilepsy and unfavourable developmental outcomes. Hundreds of mutations have been reported to cause EOEE; however, little is known about the clinical features of individuals with rare variants.
Case report and methods: We present a 10-year-old boy with severe developmental delay. He started experiencing recurrent focal seizures at 2 months old. Serial electroencephalograms persistently detected epileptiform discharges from the left hemisphere. Whole-exome sequencing and array-comparative genome hybridization were performed to search for de novo variations. Two-week-old C57Bl/6 mice were used for immunofluorescence studies.
Results: This case had a paternally inherited, 0.2-Mb duplication at chromosome 22q11.22. The whole-exome sequencing identified a de novo truncating mutation of tripartite motif containing 8 (TRIM8) (NM_030912:c.1099_1100insG:p.C367fs), one of the epileptic encephalopathy-associated genes. We verified that the murine homologues of these genes are expressed in the postnatal mouse brain.
Conclusion: This is the second case of EOEE caused by a de novo truncating mutation of TRIM8. Further studies are required to determine the functional roles of TRIM8 in the postnatal development of the human brain and its functional relationships with other EOEE-associated genes.
Li W, Guo H. De novo truncating variants of TRIM8 and atypical neuro-renal syndrome: a case report and literature review. Ital J Pediatr. 2023 Apr 15;49(1):46. doi: 10.1186/s13052-023-01453-4. PMID: 37061734; PMCID: PMC10105407.
Abstract
Background: The TRIM8 gene encodes a protein that participates in various biological processes. TRIM8 variants can lead to early termination of protein translation, which can cause a rare disease called neuro-renal syndrome. This syndrome is characterized by epilepsy, psychomotor retardation, and focal segmental glomerulosclerosis. However, we found that some patients may not present the above typical triad, and the reason may be related to their variant sites.
Case presentation: We report a case of a 6-year-old boy with nephrotic-range proteinuria as the first prominent manifestation of TRIM8 variant. He had stage 3 chronic kidney disease at the time of presentation, specific facial features, and a neurogenic bladder. He had not experienced seizures previously. There were no apparent abnormalities in his growth, intelligence, or motor development. The results of whole exome sequencing showed a TRIM8 variant. Renal biopsy revealed focal segmental glomerulosclerosis and renal tubular cystic dilatation. He did not respond to hormone and angiotensin-converting enzyme inhibitor treatment; however, the symptoms of neurogenic bladder were relieved after treatment with Solifenacin.
Conclusion: In this case, renal disease was the prominent manifestation; the patient had no other obvious neurological symptoms except a neurogenic bladder. Notably, the variant site is the closest to the C-terminal to date. Based on the analysis of previously reported cases, we found that as the TRIM8 variant became closer to the C-terminal, the renal lesions became more prominent, and there were fewer neurologic lesions. Our findings provide a new understanding of neuro-renal syndrome caused by TRIM8 variant. Patients may only have kidney disease as a prominent manifestation. At the same time, we found that we should also pay attention to the eye lesions of these patients. Therefore, gene analysis is helpful in identifying the etiology and guiding the prognosis of patients with hormone-resistant proteinuria. We suggest that TRIM8 should be included in gene panels designed for the genetic evaluation of hormone-resistant proteinuria.
Monday, February 9, 2026
15q11.2 microdeletions
Inspired by a patient
Abstract
15q11.2 BP1-BP2 copy number variants involving NIPA1, NIPA2, CYFIP1, and TUBGCP5 genes may not warrant a clinical outcome because of the phenotypic variability and low penetrance. The study aims to provide a greater understanding of the phenotypic diversity associated with these copy number variants. We conducted a retrospective analysis of 37 pediatric patients with deletions or duplications in 15q11.2 BP1-BP2 region, and compared the results systemically with the previous literature. Of the 37 patients, 67.6% had microduplications and 32.4% had microdeletions. The mean copy number variant size was 482 ± 157 kb. Patients had a variety of phenotypes including neurodevelopmental delay, hypotonia, speech impairment, intellectual and learning disability, behavioral and psychiatric symptoms, epilepsy and seizures, neuroimaging abnormalities, and dysmorphism. These findings, in combination with previous reports, confirm that copy number variants in this region are linked to phenotypes ranging from normal to severe neurodevelopmental and neuropsychiatric features. Our data also confirm that microcephaly is a particularly prevalent phenotype in patients with microdeletions, rather than in those with microduplications.
Vanlerberghe C, Petit F, Malan V, Vincent-Delorme C, Bouquillon S, Boute O, Holder-Espinasse M, Delobel B, Duban B, Vallee L, Cuisset JM, Lemaitre MP, Vantyghem MC, Pigeyre M, Lanco-Dosen S, Plessis G, Gerard M, Decamp M, Mathieu M, Morin G, Jedraszak G, Bilan F, Gilbert-Dussardier B, Fauvert D, Roume J, Cormier-Daire V, Caumes R, Puechberty J, Genevieve D, Sarda P, Pinson L, Blanchet P, Lemeur N, Sheth F, Manouvrier-Hanu S, Andrieux J. 15q11.2 microdeletion (BP1-BP2) and developmental delay, behaviour issues, epilepsy and congenital heart disease: a series of 52 patients. Eur J Med Genet. 2015 Mar;58(3):140-7. doi: 10.1016/j.ejmg.2015.01.002. Epub 2015 Jan 14. PMID: 25596525.
Abstract
Proximal region of chromosome 15 long arm is rich in duplicons that, define five breakpoints (BP) for 15q rearrangements. 15q11.2 microdeletion between BP1 and BP2 has been previously associated with developmental delay and atypical psychological patterns. This region contains four highly-conserved and non-imprinted genes: NIPA1, NIPA2, CYFIP1, TUBGCP5. Our goal was to investigate the phenotypes associated with this microdeletion in a cohort of 52 patients. This copy number variation (CNV) was prevalent in 0.8% patients presenting with developmental delay, psychological pattern issues and/or multiple congenital malformations. This was studied by array-CGH at six different French Genetic laboratories. We collected data from 52 unrelated patients (including 3 foetuses) after excluding patients with an associated genetic alteration (known CNV, aneuploidy or known monogenic disease). Out of 52 patients, mild or moderate developmental delay was observed in 68.3%, 85.4% had speech impairment and 63.4% had psychological issues such as Attention Deficit and Hyperactivity Disorder, Autistic Spectrum Disorder or Obsessive-Compulsive Disorder. Seizures were noted in 18.7% patients and associated congenital heart disease in 17.3%. Parents were analysed for abnormalities in the region in 65.4% families. Amongst these families, 'de novo' microdeletions were observed in 18.8% and 81.2% were inherited from one of the parents. Incomplete penetrance and variable expressivity were observed amongst the patients. Our results support the hypothesis that 15q11.2 (BP1-BP2) microdeletion is associated with developmental delay, abnormal behaviour, generalized epilepsy and congenital heart disease. The later feature has been rarely described. Incomplete penetrance and variability of expression demands further assessment and studies.
Picinelli C, Lintas C, Piras IS, Gabriele S, Sacco R, Brogna C, Persico AM. Recurrent 15q11.2 BP1-BP2 microdeletions and microduplications in the etiology of neurodevelopmental disorders. Am J Med Genet B Neuropsychiatr Genet. 2016 Dec;171(8):1088-1098. doi: 10.1002/ajmg.b.32480. Epub 2016 Aug 26. PMID: 27566550.
Abstract
Rare and common CNVs can contribute to the etiology of neurodevelopmental disorders. One of the recurrent genomic aberrations associated with these phenotypes and proposed as a susceptibility locus is the 15q11.2 BP1-BP2 CNV encompassing TUBGCP5, CYFIP1, NIPA2, and NIPA1. Characterizing by array-CGH a cohort of 243 families with various neurodevelopmental disorders, we identified five patients carrying the 15q11.2 duplication and one carrying the deletion. All CNVs were confirmed by qPCR and were inherited, except for one duplication where parents were not available. The phenotypic spectrum of CNV carriers was broad but mainly neurodevelopmental, in line with all four genes being implicated in axonal growth and neural connectivity. Phenotypically normal and mildly affected carriers complicate the interpretation of this aberration. This variability may be due to reduced penetrance or altered gene dosage on a particular genetic background. We evaluated the expression levels of the four genes in peripheral blood RNA and found the expected reduction in the deleted case, while duplicated carriers displayed high interindividual variability. These data suggest that differential expression of these genes could partially account for differences in clinical phenotypes, especially among duplication carriers. Furthermore, urinary Mg2+ levels appear negatively correlated with NIPA2 gene copy number, suggesting they could potentially represent a useful biomarker, whose reliability will need replication in larger samples.
Baldwin I, Shafer RL, Hossain WA, Gunewardena S, Veatch OJ, Mosconi MW, Butler MG. Genomic, Clinical, and Behavioral Characterization of 15q11.2 BP1-BP2 Deletion (Burnside-Butler) Syndrome in Five Families. Int J Mol Sci. 2021 Feb 7;22(4):1660. doi: 10.3390/ijms22041660. PMID: 33562221; PMCID: PMC7914695.
Rare and common CNVs can contribute to the etiology of neurodevelopmental disorders. One of the recurrent genomic aberrations associated with these phenotypes and proposed as a susceptibility locus is the 15q11.2 BP1-BP2 CNV encompassing TUBGCP5, CYFIP1, NIPA2, and NIPA1. Characterizing by array-CGH a cohort of 243 families with various neurodevelopmental disorders, we identified five patients carrying the 15q11.2 duplication and one carrying the deletion. All CNVs were confirmed by qPCR and were inherited, except for one duplication where parents were not available. The phenotypic spectrum of CNV carriers was broad but mainly neurodevelopmental, in line with all four genes being implicated in axonal growth and neural connectivity. Phenotypically normal and mildly affected carriers complicate the interpretation of this aberration. This variability may be due to reduced penetrance or altered gene dosage on a particular genetic background. We evaluated the expression levels of the four genes in peripheral blood RNA and found the expected reduction in the deleted case, while duplicated carriers displayed high interindividual variability. These data suggest that differential expression of these genes could partially account for differences in clinical phenotypes, especially among duplication carriers. Furthermore, urinary Mg2+ levels appear negatively correlated with NIPA2 gene copy number, suggesting they could potentially represent a useful biomarker, whose reliability will need replication in larger samples.
Baldwin I, Shafer RL, Hossain WA, Gunewardena S, Veatch OJ, Mosconi MW, Butler MG. Genomic, Clinical, and Behavioral Characterization of 15q11.2 BP1-BP2 Deletion (Burnside-Butler) Syndrome in Five Families. Int J Mol Sci. 2021 Feb 7;22(4):1660. doi: 10.3390/ijms22041660. PMID: 33562221; PMCID: PMC7914695.
Abstract
The 15q11.2 BP1-BP2 deletion (Burnside-Butler) syndrome is emerging as the most common cytogenetic finding in patients with neurodevelopmental or autism spectrum disorders (ASD) presenting for microarray genetic testing. Clinical findings in Burnside-Butler syndrome include developmental and motor delays, congenital abnormalities, learning and behavioral problems, and abnormal brain findings. To better define symptom presentation, we performed comprehensive cognitive and behavioral testing, collected medical and family histories, and conducted clinical genetic evaluations. The 15q11.2 BP1-BP2 region includes the TUBGCP5, CYFIP1, NIPA1, and NIPA2 genes. To determine if additional genomic variation outside of the 15q11.2 region influences expression of symptoms in Burnside-Butler syndrome, whole-exome sequencing was performed on the parents and affected children for the first time in five families with at least one parent and child with the 15q1l.2 BP1-BP2 deletion. In total, there were 453 genes with possibly damaging variants identified across all of the affected children. Of these, 99 genes had exclusively de novo variants and 107 had variants inherited exclusively from the parent without the deletion. There were three genes (APBB1, GOLGA2, and MEOX1) with de novo variants that encode proteins evidenced to interact with CYFIP1. In addition, one other gene of interest (FAT3) had variants inherited from the parent without the deletion and encoded a protein interacting with CYFIP1. The affected individuals commonly displayed a neurodevelopmental phenotype including ASD, speech delay, abnormal reflexes, and coordination issues along with craniofacial findings and orthopedic-related connective tissue problems. Of the 453 genes with variants, 35 were associated with ASD. On average, each affected child had variants in 6 distinct ASD-associated genes (x¯ = 6.33, sd = 3.01). In addition, 32 genes with variants were included on clinical testing panels from Clinical Laboratory Improvement Amendments (CLIA) approved and accredited commercial laboratories reflecting other observed phenotypes. Notably, the dataset analyzed in this study was small and reported results will require validation in larger samples as well as functional follow-up. Regardless, we anticipate that results from our study will inform future research into the genetic factors influencing diverse symptoms in patients with Burnside-Butler syndrome, an emerging disorder with a neurodevelopmental behavioral phenotype.
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