To explore the clinical phenotypes and genetic etiology of a child with MRXS34 syndrome due to a variant of NONO gene. A child patient who presented at Shanxi Provincial Maternity and Child Care Hospital on September 28, 2020 was selected as study subject. Clinical data of the child were retrospectively collected. Peripheral blood samples were collected from the child and his parents. Following extraction of genomic DNA, whole exome sequencing (WES) was carried out. Candidate variant was verified by Sanger sequencing of the family members. Pathogenicity of the variant was assessed based on guidelines from the American College of Medical Genetics and Genomics (ACMG). Quantitative reverse transcription polymerase chain reaction (RT-qPCR) was used to detect the effect of the NONO gene variant on messenger RNA (mRNA) expression level in the proband, and complementary DNA (cDNA) sequencing was performed to validate the splicing patterns of the NONO gene variant in the proband. Using the keywords "NONO gene" "MRXS34" "developmental delay" "intellectual disability" and "congenital heart disease", a literature search was conducted in databases including the China National Knowledge Infrastructure(CNKI), Wanfang Data and PubMed databases to identify studies on the clinical and genotypic characteristics of children with MRXS34 caused by NONO gene variants. The search period was set from the inception of the databases to April 2025, and a comprehensive analysis of the findings from the identified studies was performed. This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: IRB-KYHZ-2019-006). The proband, a 3-year-old male, exhibited global developmental delay, intellectual disability, facial dysmorphism, macrocephaly, corpus callosum dysgenesis, cavum septum pellucidum, atrial septal defect, tricuspid valve insufficiency with regurgitation, cryptorchidism, inguinal hernia, and anal cutaneous fistula. The results of WES and Sanger sequencing validation showed that the proband carried a heterozygous variant of the NONO gene c.577_581del (p.Val193fs), while both parents were wild-type, indicating that this variant was a de novo variant. According to the ACMG guidelines, this variant was classified as pathogenic (PVS1+PS2_Moderate+PM2_Supporting). RT-qPCR results showed that the relative mRNA expression level of the NONO gene in the proband was significantly lower than that in the control group of normal children, and cDNA sequencing results verified that the frameshift variant due to base deletion led to nonsense-mediated mRNA decay (NMD), causing premature termination of transcription without exon skipping at the splice site. Using the literature search strategy established in this study, a total of 15 studies on the clinical and genotypic characteristics of children with MRXS34 caused by NONO gene variants were identified, involving a total of 32 patients. Together with the proband of this study, a total of 33 patients were included in the comprehensive analysis. The results revealed a total of 23 types of variants involving the NONO gene. The main clinical manifestations of MRXS34 included developmental delay/intellectual disability (23/24, 95.8%), cardiovascular abnormalities (23/30, 76.7%), craniofacial/somatic malformations (21/24, 87.5%), and corpus callosum dysgenesis (16/21, 76.2%). The NONO gene variant probably underlay the pathogenesis of MRXS34 in this proband. The findings of this study has expanded of the variant and clinical spectra associated with the NONO gene.

To analyze the clinical phenotype and genetic etiology of patients with Dyggve-Melchior-Clausen syndrome (DMC syndrome). A child with DMC syndrome diagnosed at Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University in August 2020 was selected as study subject. A retrospective analysis was carried out to collect the proband's clinical data. Peripheral blood samples was collected from the proband and his parents. Following extraction of genomic DNA, whole exome sequencing (WES) was carried out. Candidate variants were validated within the family by Sanger sequencing. Pathogenicity of candidate variants was rated based on guidelines from the American College of Medical Genetics and Genomics (ACMG). This study was approved by the Medical Ethics Committee of the center (Ethics No.: SCMCIRB-K2023024-1). The proband, a 5-year-and-7-month-old girl, presented with short stature (height: -5.5 s) and intellectual disability. Physical examination revealed microcephaly (head circumference: -3.5 s), coarse facial features, long philtrum, pigeon chest, and brachydactyly of both hands. Laboratory findings revealed normal serum insulin-like growth factor-1 (IGF-1) levels (168 ng/mL). Imaging analysis demonstrated dysplasia of corpus callosum and spondyloepiphyseal dysplasia in the proband. WES revealed that she has harbored compound heterozygous variants of the DYM gene, namely c.312-313del (p.His104Glnfs*29) and c.1274A>T (p.Tyr425Phe). Both variants were unreported previously and inherited from her parents who were phenotypically normal. Based on guidelines from the ACMG, the DYM gene variant c.312-313del (p.His104Glnfs*29) was classified as pathogenic (PVS1+PM2_Supporting+PP3+PP4_supporting), while the c.1274A>T (p.Tyr425Phe) variant was classified as likely pathogenic (PM2_Supporting+PP3+PP1+PP4_supporting). By following the pre-set literature search strategy, a total of 20 articles were included, which involved a total of 73 cases of DYM gene variants leading to DMC syndrome. Among these, only one family case was documented in China. Together with proband from this study, a total of 74 DMC syndrome patients due DYM gene variants were included for a comprehensive analysis of clinical phenotypes and genetic characteristics. The age at the time of reporting ranged from 1 to 60 years. The main clinical manifestations included intellectual disability, short stature, and spondyloepiphyseal dysplasia, followed by microcephaly and coarse facial features. By genetic testing, c.1877delA variant was the most common mutation at the nucleotide level. The c.312-313del/c.1274A>T compound heterozygous variants of the DYM gene probably underlay the pathogenesis of DMC syndrome in this proband. Above finding has expanded the mutational and phenotypic spectra of the DMC syndrome.

Automatic detection of the fetal brain midsagittal plane on MRI using a deep learning pipeline.

Lateralization of brain functions, such as handedness, is thought to enhance cortical efficacy by reducing redundancy and speeding up decision-making. The corpus callosum (CC), one of the brain's largest myelinated tracts, is critical for interhemispheric connectivity and has been implicated in lateralization. However, it is unclear whether the myelination of transcallosal axons contributes causally to lateralized functions. Here, we assessed the impact of myelin integrity in the circuits that regulate paw laterality in mice. We hypothesized that myelin, an essential component of CC architecture and required for rapid axonal impulse conduction, is necessary for the establishment and maintenance of handedness. To test this, we behaviorally assessed paw preference by differentially controlling the degree, localization, and timing of hypomyelination in different mouse models. As expected, control mice were strongly lateralized and showed an equal distribution of paw preference directionality (right or left). In contrast, dysmyelinated (Mbpshi/shi) mice, which mastered the task without obvious impairments, exhibited reduced lateralization scores and were either ambidextrous or left-pawed. Interestingly, neither congenital myelination reduction (Mbpneo/neo) nor forebrain-specific disruption of developmental myelination had an effect on paw lateralization. Similarly, demyelination induced in adulthood had no impact on paw preference. We conclude that the presence of compact myelin during early brain development is essential for the establishment of handedness, in a manner that is likely independent of fine axonal conduction velocity control. We propose a model in which developmental myelination is timed to support the establishment of key functional aspects of brain function, such as lateralization.

Signatures of altered free-water and cognition and associations with symptom severity in psychosis spectrum disorders.

Asthma's impact on brain function: an investigation of changes in functional connectivity and network topology.

White matter microstructural abnormalities in neurological poste-acute sequelae of coronavirus disease: Imaging signatures consistent with persistent neuroinflammation.

This study aimed to investigate the effect of fetal growth restriction (FGR) on cortical maturation and fissure development using detailed neurosonography. We compared cortical grades and fissure measurements between FGR and healthy fetuses to determine if growth restriction is linked to delayed cortical maturation in specific regions. This observational case-control study included singleton pregnancies at 31-35 weeks of gestation between January 2025 and September 2025. FGR was diagnosed according to the Delphi consensus criteria. All participants underwent obstetric ultrasonography, fetoplacental Doppler, and fetal neurosonography. The depths of the Sylvian, parieto-occipital, calcarine, and cingulate fissures, as well as the insula, were measured and normalized to biparietal diameter (BPD). Cortical maturation was assessed using the Pistorius grading system. A total of 148 fetuses were analyzed (74 FGR, 74 controls). The FGR group showed higher uterine artery pulsatility index (PI) (P = .015) and lower middle cerebral artery (MCA) PI (P < .001). Neurosonography revealed significantly shallower parieto-occipital (P < .001), calcarine (P < .001), and cingulate (P < .001) fissures in the FGR group, while Sylvian fissure depth showed a nonsignificant trend (P = .057). After normalization to BPD, parieto-occipital/BPD and calcarine/BPD ratios remained significantly lower. In addition to quantitative fissure measurements, cortical maturation was evaluated. Only the Sylvian fissure showed a significantly lower maturation grade (P = .003). Cerebellar, vermian, and corpus callosum measurements were comparable. FGR is associated with region-specific cortical developmental delay, predominantly involving the parieto-occipital, calcarine, and cingulate fissures, while infratentorial and commissural structures remain preserved. Neurosonography provides a practical, accessible, and reliable tool for detecting these subtle cortical alterations in high-risk pregnancies.

Copy number variations (CNVs) at the proximal 16p11.2 BP4-BP5 locus are among the most well-characterized genomic regions associated with neurodevelopmental disorders. We aimed to define the clinical and molecular spectrum of these CNVs in a pediatric cohort. A total of 19 patients with pathogenic or likely pathogenic 16p11.2 BP4-BP5 CNVs were identified among 2200 individuals referred for chromosomal microarray analysis (prevalence: 1/116, 0.86%). Deletions were detected in 16/19 (84.2%) patients and duplications in 3/19 (15.8%). Developmental delay/intellectual disability was observed in 12/16 (75%) deletion carriers and 3/3 (100%) duplication carriers. Speech delay was present in 12/16 (75%) and 3/3 (100%), and motor delay in 6/16 (37.5%) and 2/3 (66.6%), respectively. Seizures were identified in 11/16 (68.7%) deletion carriers and 1/3 (33.3%) duplication carriers. Behavioral abnormalities were observed in 6/16 (37.5%) and 2/3 (66.6%), respectively. Neuroimaging data were available in 7/19 patients, with abnormalities detected in 5/7 (71.4%), all of whom had a history of seizures. Structural findings were heterogeneous and included ventricular asymmetry, corpus callosum thinning, and prominence of cerebrospinal fluid spaces. Additional systemic findings included endocrine abnormalities (6/19, 31.6%), skeletal anomalies (4/19, 21.1%), and ophthalmologic findings (3/19, 15.8%). These findings expand the phenotypic spectrum of proximal 16p11.2 BP4-BP5 CNVs and support their early consideration in patients with neurodevelopmental and neurological features, highlighting the need for multidisciplinary evaluation.

Association between spatial neglect and lateralized asymmetry of structural brain connectivity in chronic moderate-to-severe traumatic brain injury: An exploratory pilot study.

Investigate white matter alterations in chronic insomnia (CI) using Automated Fiber Quantification (AFQ). Diffusion tensor imaging data from 49 CI patients and 27 healthy controls were profiled for fractional anisotropy (FA), axial/mean/radial diffusivity (AD/MD/RD) across 100 nodes of 18 tracts. CI showed increased AD in bilateral anterior thalamic radiations, right inferior longitudinal fasciculus, right arcuate fasciculus; increased MD in bilateral anterior thalamic radiations, right corticospinal tract, forceps minor of the corpus callosum, and right inferior longitudinal fasciculus. Changes in specific segments correlated significantly with clinical scores. AFQ reveals fiber-specific abnormalities linked to clinical scores in CI.

Two patterns of abnormal FA with different radial features and their relation to polygenic risks in first-episode schizophrenia and unaffected siblings.

Demyelinating diseases are characterized by the progressive loss of myelin in the central nervous system (CNS). Myelin protection can be achieved by fostering the differentiation of oligodendrocyte progenitor cells to mature oligodendrocytes, the only myelinating cells in the brain. Oligodendrocytes maturation is sustained, among others, by the neuromodulator adenosine through the activation of its specific receptors: A1, A2A, A2B, A3, all expressed in the brain on neurons and glial cells. The role of A2B receptors (A2BRs) in a cuprizone-induced demyelination model in male C57BL/6 mice was investigated by administering the selective A2BR agonist BAY60-6583 or antagonist PSB 603 during the last 2 weeks of a 5-week cuprizone-based diet. We performed body weight evaluation, behavioural tests and immunofluorescence analysis. Cuprizone-fed mice showed a significant decrease in body weight gain, a motor impairment and a reduced spontaneous mobility. These effects were associated with a decrease in myelin levels, a reactive astrogliosis and microgliosis in corpus callosum medialis, striatum and motor cortex. PSB 603, was able to prevent cuprizone effects on glia, whereas both compounds promoted a significant recovery in motor deficits. The antagonism of A2BRs might represent an attractive strategy to alleviate myelin damage and glial activation in the CNS under conditions of demyelination.

Systematic analysis of copy number variants (CNVs) in large datasets is challenging, and there are limited studies of homozygous copy number losses in rare disease exomes. Here, we leveraged the genomic uniqueness and relative under-representation of the Indian population in the current public genomic databases and identified 42,386 possible homozygous losses (median 20 per individual) in a heterogeneous cohort of 2021 individuals with suspected Mendelian disorders, who had undergone exome sequencing using 12 different capture kits in a resource-limited setting. Employing a genomic position loss-count-based approach, we filtered 1224 rare homozygous loss calls in 718 individuals (median 1 per individual) for further analysis, thus significantly reducing the analysis burden. Clinical correlation and validation of these rare calls enabled 10 new diagnoses in 240 unsolved individuals. This led to a two-fold increase in diagnosis owing to homozygous deletions. Further analysis of the data and identification of additional affected individuals through collaboration led to identification of biallelic FILIP1 and FAM177A1 variants as causes of a syndromic arthrogryposis and a neuromuscular disorder respectively. Both conditions were recently reported as ultra-rare recessive disorders, thus validating our approach. We also show that biallelic loss-of-function TFCP2L1 variants cause chronic kidney disease and VPS36 variants cause a severe recessive neurodevelopmental disorder characterised by microcephaly, motor delay, agenesis of the corpus callosum, cerebellar atrophy, seizures, hypotonia, spasticity and early death. Overall, these results demonstrate a scalable approach to screen homozygous losses for improving diagnostic yield and discovering disease-genes in large exome cohorts.

Adaptations of the limbic system and corpus callosum white matter in early-stage PD with RBD.

Callosal projections connect both cortical hemispheres via the corpus callosum, allowing bilateral integration of sensory information. Callosal axons originate mainly from layer (L)2/3 pyramidal neurons in primary sensory areas and project to homotopic contralateral regions. The projections display a stereotyped layer-specific pattern, targeting distinct dendritic domains of contralateral L2/3 neurons. In mouse somatosensory cortex, such precise innervation emerges in an activity-dependent manner during the second and third postnatal weeks but the molecular determinants are largely unknown. Using in utero electroporation of fluorescent reporters to label axonal and dendritic arbors of L2/3 neurons through postnatal development, we show that loss-of-function of Grin3a (gene encoding the nonconventional NMDA receptor GluN3A subunit) disrupts region- and layer-specific contralateral targeting by callosal axons without affecting early axonal navigation or midline crossing. Rather than concentrating at the border between primary/secondary somatosensory cortex (S1/S2), callosal axons in male and female GluN3A knockout mice form a second column laterally in S2. Within the S1/S2 border, axonal arbors fail to innervate their normal destinations in L1 and outer L2/3 and shift toward inner L2/3 regions. Analysis of dendritic architecture revealed that GluN3A deletion drives proximal bifurcation and premature branching of apical dendrites of L2/3 neurons, with inward expansion of recipient dendritic trees matching callosal axon profiles in Grin3a knockouts. Together with conditional loss of function experiments, our results suggest that the dendritic patterning of postsynaptic L2/3 neurons directs the position of callosal axons within their target fields and implicate GluN3A in the postnatal timing and specificity of this process.

Focal demyelination refers to localized loss of myelin sheath that surrounds the nerve fibers. It impairs the efficient transmission of nerve impulses results in neurological symptoms. Here, our goal is to investigate the differential and combined effects of lysolecithin (LPC) and lipopolysaccharides (LPS) on brain and spinal cord demyelinating process. To confirm the pattern of demyelination, behavioural analysis was performed. Further, brain and spinal cord samples were collected at Day-post injection-1, 3, 7, and 28. The loss of axonal structures and neuronal bodies were assessed using Luxol fast blue and Nissl staining respectively. Immunofluorescence studies were done to examine demyelination and its impact on endothelial activation, astrogliosis, and activated microglia. Our data revealed that the combination group exhibited remarkable demyelination compared to the LPC and LPS groups alone. Additionally, endothelial activation, astrogliosis, and activated microglia were more pronounced in the combination group. Moreover, we found much of these effects were most pronounced in the spinal cord compared to corpus callosum, suggesting the presence of compensatory mechanisms and a unique brain microenvironment. This study is the first to demonstrate the synergistic effects of LPC and LPS toxins compared to their individual effects in both the brain and spinal cord.

A lethal form of ASCC3 disease: severe global developmental delay, axial hypotonia, hypoplasia of corpus callosum, hypothyroidism and micropenis.

Numerous mood and behavior disorders have developmental origins resulting from genetic and environmental interactions. Maternal tryptophan hydroxylase 1 (TPH-1)-dependent serotonin (5-HT) depletion alters embryonic brain development, but its long-term impact on adult progeny has never been investigated. Here we demonstrate that adult WT male offspring born to hyposerotonergic Tph1+/- dams ( ~ 60% deficit) display hyperlocomotion, impaired self-care and an increased anxiety relative to those from WT dams. Concomitantly, norepinephrine (NE) levels and dopamine (DA) turnover are significantly reduced in the mesencephalon and brainstem, whereas monoaminergic cell density is not affected. In the frontal cortex of the offspring, maternal hyposerotonergic status results in significant reduction in DA, NE and 5-HT levels, accompanied by transcriptomic changes, notably in monoaminergic system signaling, synaptic function and plasticity, methylation processes and myelination. Myelination is also impaired as revealed by a reduced thickness of the corpus callosum. Maternal hyposerotonemia thus appears sufficient to affect the phenotype of the adult WT progeny. TPH-1-dependent 5-HT deficit during pregnancy could be considered as a risk factor for neurodevelopmental disorders in the offspring.

Hypersarcosinemia, resulting from sarcosine dehydrogenase (SARDH) gene mutation, is a rare autosomal recessive disorder with variable, often nonspecific clinical presentations, leading to diagnostic difficulty and low clinical awareness. A 6-year-old boy presented with clinical features suggestive of viral encephalitis, including headache, vomiting, intermittent fever, and lethargy. Initial MRI revealed cytotoxic edema in the subcortical white matter and splenium of the corpus callosum. Although symptoms improved transiently with steroid therapy, persistent imaging abnormalities prompted metabolic and genetic evaluations. Metabolic and genetic investigations confirmed a diagnosis of hypersarcosinemia, with markedly elevating sarcosine levels and compounding heterozygous SARDH mutations. Genetic testing identified compound heterozygous mutations in the SARDH gene (c.293G > C and c.679C > T), confirming hypersarcosinemia. Following initiation of folic acid and mecobalamin, partial radiological improvement was observed, although a causal relationship could not be established. This case highlights the diagnostic challenge of hypersarcosinemia and its potential mimicry of acquired encephalitis. To our knowledge, this is the first report describing an acute encephalitis-like presentation accompanied by persistent cytotoxic edema on MRI, thereby suggesting a possible expansion of the known clinical and neuroimaging spectrum of this disorder, although this observation requires confirmation in additional cases. However, given the rarity of hypersarcosinemia and the possibility of underreporting, the absence of prior similar reports should be interpreted with caution. In this case, genetic testing was essential for establishing the diagnosis, although the necessity of genetic testing in all cases of unexplained white matter changes cannot be determined from a single report. The temporal association of partial radiological improvement with folic acid and mecobalamin supplementation is hypothesis-generating only and requires further investigation ; no causal or therapeutic conclusion can be drawn from this single case.