Corpus Callosum Abnormalities Research Articles

Development of the corpus callosum and cognition after neonatal encephalopathy.

Neonatal imaging studies report corpus callosum abnormalities after neonatal hypoxic-ischaemic encephalopathy (HIE), but corpus callosum development and relation to cognition in childhood are unknown. Using magnetic resonance imaging (MRI), we examined the relationship between corpus callosum size, microstructure and cognitive and motor outcomes at early school-age children cooled for HIE (cases) without cerebral palsy compared to healthy, matched controls. A secondary aim was to examine the impact of HIE-related neonatal brain injury on corpus callosum size, microstructure and growth. Participants aged 6-8 years underwent MRI, the Movement Assessment Battery for Children Second Edition and Wechsler Intelligence Scale for Children Fourth Edition. Cross-sectional area, volume, fractional anisotropy and radial diffusivity of the corpus callosum and five subdivisions were measured. Multivariable regression was used to assess associations between total motor score, full-scale IQ (FSIQ) and imaging metrics. Adjusting for age, sex and intracranial volume, cases (N=40) compared to controls (N=39) demonstrated reduced whole corpus callosum area (β=-26.9, 95% confidence interval [CI]=-53.17, -0.58), volume (β=-138.5, 95% CI=-267.54, -9.56), fractional anisotropy and increased radial diffusivity (P < 0.05) within segments II-V. In cases, segment V area (β=0.18, 95% CI=0.004, 0.35), volume (β=0.04, 95% CI=0.001, 0.079), whole corpus callosum fractional anisotropy (β=13.8 95% CI=0.6, 27.1) and radial diffusivity (β=-11.3, 95% CI=-22.22, -0.42) were associated with FSIQ. Growth of the corpus callosum was restricted in cases with a FSIQ ≤85, and volume was reduced in cases with mild neonatal multifocal injury compared to white matter injury alone. Following neonatal HIE, morphological and microstructural changes in the corpus callosum are associated with reduced cognitive function at early school age.

Blended Phenotype of Prader-Willi Syndrome and HSP-SPG11 Caused by Maternal Uniparental Isodisomy.

Uniparental isodisomy can lead to blended phenotypes of imprinting disorders and autosomal recessive diseases. To determine whether a presentation of Prader-Willi syndrome (PWS) and progressive neurologic symptoms was caused by uniparental isodisomy, a detailed clinical and molecular characterization was performed. A combination of clinical, molecular, and imaging data was included in this study. We present the case of a 12-year-old boy with a blended phenotype of PWS and hereditary spastic paraplegia type 11 (HSP-SPG11) caused by maternal uniparental isodisomy of chromosome 15 (UPiD(15)mat) covering a loss-of-function variant in SPG11 (NM_025137.4: c.733_734del; p.Met245ValfsTer2). Although symptoms in early childhood including hypotonia, global developmental delay, hyperphagia, obesity, and seizures were consistent with PWS, additional features of progressive spastic paraparesis, parkinsonism, and cognitive decline in later childhood were atypical. Brain MR imaging showed thinning of the corpus callosum and signal abnormalities of the forceps minor, consistent with a "ears of the lynx" sign. Exome sequencing confirmed a frameshift variant in SPG11 located in the PWS imprinting region on chromosome 15. This case highlights that atypical clinical features in patients with well-described imprinting disorders should lead to investigations for recessive conditions caused by variants in genes that localize to the region of homozygosity, including autosomal recessive forms of HSP.

A novel de novo KCNB1 variant altering channel characteristics in a patient with periventricular heterotopia, abnormal corpus callosum, and mild seizure outcome.

KCNB1 encodes the α-subunit of Kv2.1, the main contributor to neuronal delayed rectifier potassium currents. The subunit consists of six transmembrane α helices (S1-S6), comprising the voltage-sensing domain (S1-S4) and the pore domain (S5-P-S6). Heterozygous KCNB1 pathogenic variants are associated with developmental and epileptic encephalopathy. Here we report an individual who shows the milder phenotype compared to the previously reported cases, including delayed language development, mild intellectual disability, attention deficit hyperactivity disorder, late-onset epilepsy responsive to an antiepileptic drug, elevation of serum creatine kinase, and peripheral axonal neuropathy. On the other hand, his brain MRI showed characteristic findings including periventricular heterotopia, polymicrogyria, and abnormal corpus callosum. Exome sequencing identified a novel de novo KCNB1 variant c.574G>A, p.(Ala192Thr) located in the S1 segment of the voltage-sensing domain. Functional analysis using the whole-cell patch-clamp technique in Neuro2a cells showed that the Ala192Thr mutant reduces both activation and inactivation of the channel at membrane voltages in the range of -50 to -30 mV. Our case could expand the phenotypic spectrum of patients with KCNB1 variants, and suggested that variants located in the S1 segment might be associated with a milder outcome of seizures.

Loss-of-function variants in MYCBP2 cause neurobehavioural phenotypes and corpus callosum defects.

The corpus callosum is a bundle of axon fibres that connects the two hemispheres of the brain. Neurodevelopmental disorders that feature dysgenesis of the corpus callosum as a core phenotype offer a valuable window into pathology derived from abnormal axon development. Here, we describe a cohort of eight patients with a neurodevelopmental disorder characterized by a range of deficits including corpus callosum abnormalities, developmental delay, intellectual disability, epilepsy and autistic features. Each patient harboured a distinct de novo variant in MYCBP2, a gene encoding an atypical really interesting new gene (RING) ubiquitin ligase and signalling hub with evolutionarily conserved functions in axon development. We used CRISPR/Cas9 gene editing to introduce disease-associated variants into conserved residues in the Caenorhabditis elegans MYCBP2 orthologue, RPM-1, and evaluated functional outcomes in vivo. Consistent with variable phenotypes in patients with MYCBP2 variants, C. elegans carrying the corresponding human mutations in rpm-1 displayed axonal and behavioural abnormalities including altered habituation. Furthermore, abnormal axonal accumulation of the autophagy marker LGG-1/LC3 occurred in variants that affect RPM-1 ubiquitin ligase activity. Functional genetic outcomes from anatomical, cell biological and behavioural readouts indicate that MYCBP2 variants are likely to result in loss of function. Collectively, our results from multiple human patients and CRISPR gene editing with an in vivo animal model support a direct link between MYCBP2 and a human neurodevelopmental spectrum disorder that we term, MYCBP2-related developmental delay with corpus callosum defects (MDCD).

Prenatal genetic diagnosis of the fetuses with isolated corpus callosum abnormality

Objective: To explore the application value of chromosome karyotype analysis, chromosomal microarray analysis (CMA) and whole exome sequencing (WES) in prenatal diagnosis of isolated corpus callosum abnormality (CCA) fetus. Methods: Fetuses diagnosed with isolated CCA by ultrasound and MRI and receiving invasive prenatal diagnosis in Guangzhou Women and Children's Medical Center and Qingyuan People's Hospital from January 2010 to April 2021 were selected. Karyotype analysis and/or CMA [or copy number variation sequencing (CNV-seq)] were performed on all fetal samples, and WES was performed on fetal samples and their parents whose karyotype analysis and/or CMA (or CNV-seq) results were not abnormal. Results: Among 65 fetuses with isolated CCA, 38 cases underwent karyotype analysis, and 3 cases were detected with abnormal karyotypes, with a detection rate of 8% (3/38). A total of 49 fetuses with isolated CCA underwent CMA (or CNV-seq) detection, and 6 cases of pathogenic CNV were detected, the detection rate was 12% (6/49). Among them, the karyotype analysis results were abnormal, and the detection rate of further CMA detection was 1/1. The karyotype results were normal, and the detection rate of further CMA (or CNV-seq) detection was 14% (3/21). The detection rate of CMA as the first-line detection technique was 7% (2/27). A total of 25 fetuses with isolated CCA with negative results of karyotyping and/or CMA were tested by WES, and 9 cases (36%, 9/25) were detected with pathogenic genes. The gradient genetic diagnosis of chromosomal karyotyping, CMA and WES resulted in a definite genetic diagnosis of 26% (17/65) of isolated CCA fetuses. Conclusions: Prenatal genetic diagnosis of isolated CCA fetuses is of great clinical significance. The detection rate of CMA is higher than that of traditional karyotyping. CMA detection could be used as a first-line detection technique for fetuses with isolated CCA. WES could increase the pathogenicity detection rate of fetuses with isolated CCA when karyotype analysis and/or CMA test results are negative.

“ROLE OF FETAL MRI IN EVALUATION OF CONGENITAL ANOMALIES”

When US evaluation of the second and third-trimester foetus is limited, MR imaging might be used as a supplemental test. Due to a lack of an acceptable acoustic window, US is often limited in cases of oligohydramnios or breech presentation. In both cases, however, MR imaging can clearly show the foetal anatomy in detail. Ossification of the calvaria[1], which inhibits view of the posterior fossa at US, can also impede third trimester foetal assessment. US frequently suggests intracranial pathologic abnormalities such as posterior fossa anomalies (Chiari II syndrome, cerebellar aplasia or hypoplasia). MR imaging can corroborate the US findings, and it can also provide a diagnosis in some circumstances, such as neuronal migrational anomalies. MR imaging certainly has the advantage of being able to analyse the foetus in many planes within a greater field of view. T1-weighted MR imaging can show acute and chronic germinal matrix bleeding, as well as ischemia alterations. Although ultrasound is helpful in detecting corpus callosum abnormalities, it can miss many of the central nervous system problems associated with corpus callosum agenesis. Because the prognosis of agenesis of the corpus callosum is so unpredictable, detecting concomitant central system defects on MR imaging can help with prenatal and postnatal medical care. Although the majority of prenatal MR imaging applications are related to the cranial nervous system, new developments in foetal surgical intervention have expanded the utility of foetal MR imaging in thoracoabdominal illness detection. Fetal MR imaging can help diagnose abnormalities such congenital cystic adenomatoid malformation, congenital diaphragmatic hernia, cystic hygroma, and bronchopulmonary sequestration. Accurate assessment of foetal lung and liver sizes is critical in foetal surgical planning and postnatal prognosis in the case of congenital diaphragmatic hernia. Some high-risk pregnancies may also benefit from obstetric MR imaging, according to preliminary research. With a combination of foetal weight estimates and liver volume measurements, birth weight may be correctly predicted and the diagnosis of intrauterine growth retardation or macrosomia can be made with confidence.

MED13 mutation: A novel cause of developmental and epileptic encephalopathy with infantile spasms

PurposeMutations in the MED13 gene are reported in the literature in association with clinically variable, neurodevelopmental disorders, which are characterized by mild-to-severe intellectual disability, autism spectrum disorder, attention deficit/hyperactivity disorder, epilepsy, ocular or skeletal abnormalities, congenital cardiac defects, and facial dysmorphisms. Here, we report a patient with an epileptic phenotype carrying a novel missense mutation characterized by developmental and epileptic encephalopathy with infantile spasms. MethodsThrough trio-based WES, we identified a novel de novo heterozygous missense variant c.2501A>G in the MED13 gene. We reviewed all medical charts of the present patient and reviewed all previously reported cases with pathogenic variants of MED13. ResultsThis study involves a 24-month-old boy with epilepsy onset at the age of 3 months with drug-resistant focal seizures followed by infantile spasms at the age of 10 months. He had a severe, developmental delay along with microcephaly and dysmorphic features. From a literature review, it emerged that epilepsy is described in only one out of nineteen of previously reported patients with a phenotype of generalized, drug-resistant epilepsy with myoclonic-atonic seizures. Microcephaly, developmental delay, hypotonia, corpus callosum abnormalities, deafness, and retinal atrophy were common features in the previously described cases. ConclusionThis case expands the genetic landscape of infantile spasms as well as the phenotype of MED13-related disorders adding the electroclinical features of early-onset developmental and epileptic encephalopathy with infantile spasms to the previously described, generalized epilepsy with myoclonic-atonic seizures.

Obsessive compulsive symptom dimensions are linked to altered white-matter microstructure in a community sample of youth

Obsessive-compulsive symptoms (OCS) are common in school-aged children and predict the development of obsessive compulsive disorder (OCD). White-matter abnormalities have been described in OCD, but the white matter correlates of OCS in the developing brain are unclear. Some correlates of OCS (or a diagnosis of OCD) may reflect correlates of a transdiagnostic or even general psychopathology factor. We examined these questions in a large sample of typically developing youth (N = 1208), using a hierarchical analysis of fixel-based white matter measures in relation to OCS and general psychopathology. General psychopathology was associated with abnormalities in the posterior corpus callosum and forceps major in an age-dependent manner, suggesting altered maturation (specifically, hypermaturation in younger subjects). A unidimensional measure of OCS did not associate with any white-matter abnormalities, but analysis of separate OCS dimensions (derived from factor analysis within this sample) revealed the ‘Bad Thoughts’ dimension to associate with white-matter abnormalities in dorsal parietal white-matter and descending corticospinal tracts, and the ‘Symmetry’ dimension to associate with abnormalities in the anterior corpus callosum. Repetition/checking and Symmetry OCS were additionally associated with posterior abnormalities overlapping with the correlates of general psychopathology. Contamination symptoms had no white-matter correlates. Secondary analysis of fractional anisotropy (FA) revealed distinct white-matter abnormalities, suggesting that fixel-based and FA analyses identify distinct features of white matter relevant to psychopathology. These findings suggest that OCS dimensions correlate with dissociable abnormalities in white matter, implicating separable networks. Future studies should examine these white-matter signatures in a longitudinal framework.

Incidence, follow-up, and postnatal clinical progress of children with central nervous system anomalies on fetal MRI.

MRI is increasingly employed to assess intrauterine fetal anomalies. Central nervous system (CNS) anomalies are common structural conditions that warrant evaluation with fetal MRI and subsequent prenatal consultation with a pediatric neurosurgeon. As the use of fetal MRI increases, there is greater impetus to understand the most common CNS structural anomalies diagnosed in utero, as well as their natural histories. The authors performed a single-center retrospective review of fetal MRI evaluations performed between January 2012 and December 2020. Children who underwent both prenatal and postnatal neurosurgical evaluations of CNS anomalies were included. Specific CNS anomalies on fetal MRI, associated extra-CNS findings, and suspicion for genetic abnormality or syndromes were noted. Postnatal clinical status and interventions were assessed. Between January 2012 and December 2020, a total of 469 fetal MRI evaluations were performed; of these, 114 maternal-fetal pairs had CNS anomalies that warranted prenatal consultation and postnatal pediatric neurosurgical follow-up. This cohort included 67 male infants (59%), with a mean ± SD follow-up of 29.8 ± 25.0 months after birth. Fetal MRI was performed at 27.3 ± 5.8 weeks of gestational age. The most frequently reported CNS abnormalities were ventriculomegaly (57%), agenesis or thinning of the corpus callosum (33%), Dandy-Walker complex (DWC) (21%), neuronal migration disorders (18%), and abnormalities of the septum pellucidum (17%). Twenty-one children (18%) required neurosurgical intervention at a mean age of 2.4 ± 3.7 months. The most common surgical conditions included myelomeningocele, moderate to severe ventriculomegaly, encephalocele, and arachnoid cyst. Corpus callosum agenesis or thinning was associated with developmental delay (p = 0.02) and systemic anomalies (p = 0.05). The majority of prenatal patients referred for DWC had Dandy-Walker variants that did not require surgical intervention. The most common conditions for prenatal neurosurgical assessment were ventriculomegaly, corpus callosum anomaly, and DWC, whereas the most common surgical conditions were myelomeningocele, hydrocephalus, and arachnoid cyst. Only 18% of prenatal neurosurgical consultations resulted in surgical intervention during infancy. The majority of referrals for prenatal mild ventriculomegaly and DWC were not associated with developmental or surgical sequelae. Patients with corpus callosum abnormalities should be concurrently referred to a neurologist for developmental assessments.

Ca2+ homeostasis maintained by TMCO1 underlies corpus callosum development via ERK signaling

Transmembrane of coiled-coil domains 1 (TMCO1) plays an important role in maintaining homeostasis of calcium (Ca2+) stores in the endoplasmic reticulum (ER). TMCO1-defect syndrome shares multiple features with human cerebro-facio-thoracic (CFT) dysplasia, including abnormal corpus callosum (CC). Here, we report that TMCO1 is required for the normal development of CC through sustaining Ca2+ homeostasis. Tmco1−/− mice exhibit severe agenesis of CC with stalled white matter fiber bundles failing to pass across the midline. Mechanistically, the excessive Ca2+ signals caused by TMCO1 deficiency result in upregulation of FGFs and over-activation of ERK, leading to an excess of glial cell migration and overpopulated midline glia cells in the indusium griseum which secretes Slit2 to repulse extension of the neural fiber bundles before crossing the midline. Supportingly, using the clinical MEK inhibitors to attenuate the over-activated FGF/ERK signaling can significantly improve the CC formation in Tmco1−/− brains. Our findings not only unravel the underlying mechanism of abnormal CC in TMCO1 defect syndrome, but also offer an attractive prevention strategy to relieve the related agenesis of CC in patients.

Clinical and genetic analysis of three children with 22q13 deletion syndrome

To explore the clinical and genetic characteristics of three children with 22q13 deletion syndrome. Clinical data were collected and copy number variations in the patients and their parents were detected by using array-based comparative genomic hybridization (aCGH) and copy number variation sequencing (CNV-seq). The DECIPHER, ClinGen, OMIM, PubMed and Gene Review databases were retrieved for pathogenicity analysis. The common phenotypes of the three children have included variable global developmental delay, among which speech delay was the most obvious. Patient 1 had abnormalities of corpus callosum shown by magnetic resonance imaging. Patient 2 had dental crowding, pale skin, thick palms, hypotonia, and other facial features. Patient 3 had the mildest symptoms including language dysfunction, which has caught up with the development and improved significantly. All of the three children had harbored de novo deletions of 22q13.33q13.33 region, which spanned 0.84 Mb, 8.70 Mb and 0.90 Mb and involved 37, 126, and 34 genes, respectively. Above finding has enriched the clinical and genetic characteristics of 22q13 deletion syndrome and laid a foundation for genetic counseling and prenatal diagnosis.

Corpus Callosum Volume in Patients with First-Episode Psychosis

Objective In first-episode psychosis, a relationship may exist between disruption communication between two brain hemispheres and psychosis symptomatology. We aimed to investigate the relationship between corpus callosum (CC) volume and psychosis symptomatology in patients with first-episode psychosis. Methods This is a retrospective case-control study wherein first-episode psychosis cases and healthy controls were included from inpatient unit archives of the Department of Psychiatry and Department of Radiology, Dokuz Eylül University School of Medicine. Psychosis symptoms were assessed using the positive and negative syndrome scale (PANSS). The CC, the chief connection between two brain hemispheres, was examined using magnetic resonance imaging (MRI); 27 patients with first-episode psychosis and 29 healthy volunteers were evaluated via 1.5-T MR. MRI findings of CC volumes of the two groups were compared. Correlations between PANSS scores and CC volume were also evaluated. Results The CC volume was lower in patients with first-episode psychosis than in healthy controls. Moreover, we observed a significant negative correlation between the CC volume and emotional withdrawal scores, and a significant positive correlation between the CC volume and hallucinations. Conclusions The CC is a vital structure that connects two frontal lobes of the brain. There may be CC abnormalities in first-episode psychosis. Emotional withdrawal is associated with decreased CC volume, whereas hallucinations are associated with increased CC volume. The development of these symptoms may be associated with changes in CC connections.

The effect of corpus callosum abnormalities on myelin development in the fetal brain using the fast macromolecular proton fraction mapping

INTRODUCTION: There is evidence, indicate early compensatory axonal remodeling connections in the prenatal period, providing a favorable neurological outcome in isolated anomalies of the corpus callosum (CC). Mapping of the macromolecular proton fraction (MPF) is proven method of quantitative determination of myelin, which has been adapted for prenatal studies.OBJECTIVE: To investigate the relationship between CC anomalies and prenatal myelination of the brain using the fast macromolecular proton fraction (MPF) mapping.MATERIALS AND METHODS: Fetal MR imaging were performed on a 1.5 scanner (Achieva, Philips) using a 16-channel body coil. Of 66 fetal brains MRI, 12 studies were selected with MT abnormalities (22.8±2.8, 19–28.5 WG) and 21 without brain pathology (23.1±2.3, 20–29.5 WG). The images were analyzed according to structural MRI data (T2-Ssh and T1-GE, EPI, DWI, MYUR, T2-BFE-DYN) by two experienced radiologists. Fast-3D-MPF scan protocol with the MPF maps reconstruction was carried out according to a specialized protocol (open-source software: https://www.macroatomicmri.org /). Quantitative data were obtained by choosing the region of interest (ROI) in numerous brain structures bilateral (bridge, medulla oblongata, thalamus, cerebellum, and cerebral hemispheres). Statistics: distinctions between the groups and structures were assessed using repeated-measures analysis of covariance (ANCOVA), Pearson correlation analysis.RESULTS: MPF was significantly increased in the CC anomalies group as compared to controls in the medulla (3.26±0.63% vs. 2.75±0.59%, р=0.001) and cerebellum (2.02±0.55% vs. 1.76±0.34%, р=0.006). In hemispheres significant correlation with GA was observed in CC anomalies group (r=0.81, р=0.002), but was absent in controls (r=0.32, р=0.16).CONCLUSION: Primary observed MPF increase in the medulla and cerebellum as well as the dependence of the large hemispheres myelination on gestational age indicates that fetal cerebral matter undergoes early compensatory axonal remodeling in the cases of the interhemispheric connections’ reduction.

Investigating the use of plasma pTau181 in retired contact sports athletes.

Considering the wide range of outcomes following sport-related concussions, biomarkers are needed to detect underlying pathological changes. The objective was to analyze the use of plasma phosphorylated tau 181 (pTau181) as a non-invasive measure of underlying brain changes in a cohort of retired contact sports athletes at risk of neurodegeneration. Fifty-four retired contact sport athletes and 27 healthy controls whose blood plasma was analyzed for pTau181 were included. A portion (N = 21) of retired athletes had a 2-years follow-up visit. All participants had completed a neuropsychological battery and MRI imaging. Plasma pTau181 was significantly higher in retired athletes compared to healthy controls (8.94 ± 5.08pg/mL vs. 6.00 ± 2.53pg/mL, respectively; 95% BCa CI 1.38-4.62; p = 0.02); and was significantly associated with fornix fractional anisotropy values only in the athletes group (β = - 0.002; 95% BCa CI - 0.003 to - 0.001; p = 0.002). When the retired athletes cohort was divided into high vs. normal pTau181 groups, the corpus callosum (CC) volume and white-matter integrity was significantly lower in high pTau181 compared to older healthy controls (CC volume: 1.57 ± 0.19 vs. 2.02 ± 0.32, p = 0.002; CC medial diffusivity: 0.96 ± 0.04 × 10-3 mm2/s vs. 0.90 ± 0.03 × 10-3 mm2/s, p = 0.003; CC axial diffusivity: 1.49 ± 0.04 × 10-3 mm2/s vs. 1.41 ± 0.02 × 10-3 mm2/s, p < 0.001, respectively). Although high plasma pTau181 levels were associated with abnormalities in CC and fornix, baseline pTau181 did not predict longitudinal changes in regional brain volumes or white-matter integrity in the athletes. pTau181 may be useful for identifying those with brain abnormalities related to repeated concussion but not for predicting progression.

MTORC1 functional assay reveals SZT2 loss-of-function variants and a founder in-frame deletion.

Biallelic pathogenic variants in SZT2 result in a neurodevelopmental disorder with shared features, including early-onset epilepsy, developmental delay, macrocephaly, and corpus callosum abnormalities. SZT2 is as a critical scaffolding protein in the amino acid sensing arm of the mTORC1 signalling pathway. Due to its large size (3432 amino acids), lack of crystal structure, and absence of functional domains, it is difficult to determine the pathogenicity of SZT2 missense and in-frame deletions, but these variants are increasingly detected and reported by clinical genetic testing in individuals with epilepsy. To exemplify this latter point, here we describe a cohort of 12 individuals with biallelic SZT2 variants and phenotypic overlap with SZT2-related neurodevelopmental disorders. However, the majority of individuals carried one or more SZT2 variants of uncertain significance (VUS), highlighting the need for functional characterization to determine, which, if any, of these VUS were pathogenic. Thus, we developed a novel individualized platform to identify SZT2 loss-of-function variants in the context of mTORC1 signalling and reclassify VUS. Using this platform, we identified a recurrent in-frame deletion (SZT2 p.Val1984del) which was determined to be a loss-of-function variant and therefore likely pathogenic. Haplotype analysis revealed that this single in-frame deletion is a founder variant in those of Ashkenazi Jewish ancestry. Moreover, this approach allowed us to tentatively reclassify all of the VUS in our cohort of 12 individuals, identifying five individuals with biallelic pathogenic or likely pathogenic variants. Clinical features of these five individuals consisted of early-onset seizures (median 24 months), focal seizures, developmental delay and macrocephaly similar to previous reports. However, we also show a widening of the phenotypic spectrum, as none of the five individuals had corpus callosum abnormalities, in contrast to previous reports. Overall, we present a rapid assay to resolve VUS in SZT2, identify a founder variant in individuals of Ashkenazi Jewish ancestry, and demonstrate that corpus callosum abnormalities is not a hallmark feature of this condition. Our approach is widely applicable to other mTORopathies including the most common causes of the focal genetic epilepsies, DEPDC5, TSC1/2, MTOR and NPRL2/3.

Clinical features of epilepsy in 5 children with Mowat-Wilson syndrome

Objective: To summarize and investigate the clinical characters of epilepsy in children with Mowat-Wilson syndrome (MWS), thus to improve the understanding of this disease. Methods: Clinical characters of epilepsy episodes in 5 children with MWS admitted to Department of Pediatrics, Peking University First Hospital from June to December 2020 were retrospectively reviewed. Clinical data including onset age of seizures, clinical features, characters of electroencephalogram (EEG), magnetic resonance imaging (MRI) findings, results of ZEB2 gene testing and responses to the anti-seizure medications (ASM) were summarized. Results: The onset age of seizures in the 5 patients (3 males and 2 females) ranged from 6 months to 4 years. Four patients showed focal motor seizures with diverse expressions, while the other 1 patient had epileptic spasms. All the 5 patients showed distinctive face, different degrees of intellectual disability, development delay and other congenital malformations. EEG of 4 patients presented the slowing of background rhythm and epileptiform discharges mainly occurred in the posterior region of the brain. The other 1 patient showed hypsarrhythmia at the beginning of the disease, changing into multifocal discharges mainly occurred in posterior region later. Corpus callosum abnormality and white matter disability were found from investigations of MRI in 2 patients, respectively. All the 5 patients carried a de novo heterozygous variation in the ZEB2 gene, 4 were nonsense variants and 1 was frame-shift variant. Within the follow-up of 14 months to 20 months, 3 patients achieved seizure-free more than 1 year, 2 patients achieved seizure-free more than 6 months. Two patients used valproate only and 2 patients received valproate combined with other ASM. Conclusions: Epileptic seizures are common clinical phenotype of MWS. Focal motor seizure may be the most common seizure type and epileptic spasms exist. The manifestations of EEG can be age-related. The most common type of variation of the ZEB2 gene is de novo nonsense variation. Valproate might be the first-line ASM for patients with MWS.

Prevalence of supratentorial anomalies assessed by magnetic resonance imaging in fetuses with open spina bifida.

To determine the prevalence of brain anomalies at the time of preoperative magnetic resonance imaging (MRI) assessment in fetuses eligible for prenatal open spina bifida (OSB) repair, and to explore the relationship between brain abnormalities and features of the spinal defect. This was a retrospective cross-sectional study, conducted in three fetal medicine centers, of fetuses eligible for OSB fetal surgery repair between January 2009 and December 2019. MRI images obtained as part of the presurgical assessment were re-evaluated by two independent observers, blinded to perinatal results, to assess: (1) the type and area of the defect and its anatomical level; (2) the presence of any structural central nervous system (CNS) anomaly and abnormal ventricular wall; and (3) fetal head and brain biometry. Binary regression analyses were performed and data were adjusted for type of defect, upper level of the lesion (ULL), gestational age (GA) at MRI and fetal medicine center. Multiple logistic regression analysis was performed in order to identify lesion characteristics and brain anomalies associated with a higher risk of presence of abnormal corpus callosum (CC) and/or heterotopia. Of 115 fetuses included, 91 had myelomeningocele and 24 had myeloschisis. Anatomical level of the lesion was thoracic in seven fetuses, L1-L2 in 13, L3-L5 in 68 and sacral in 27. Median GA at MRI was 24.7 (interquartile range, 23.0-25.7) weeks. Overall, 52.7% of cases had at least one additional brain anomaly. Specifically, abnormal CC was observed in 50.4% of cases and abnormality of the ventricular wall in 19.1%, of which 4.3% had nodular heterotopia. Factors associated independently with higher risk of abnormal CC and/or heterotopia were non-sacral ULL (odds ratio (OR), 0.51 (95% CI, 0.26-0.97); P = 0.043), larger ventricular width (per mm) (OR, 1.23 (95% CI, 1.07-1.43); P = 0.005) and presence of abnormal cavum septi pellucidi (OR, 3.76 (95% CI, 1.13-12.48); P = 0.031). Half of the fetuses assessed for OSB repair had an abnormal CC and/or an abnormal ventricular wall prior to prenatal repair. The likelihood of brain abnormalities was increased in cases with a non-sacral lesion and wider lateral ventricles. These findings highlight the importance of a detailed preoperative CNS evaluation of fetuses with OSB. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Fetal corpus callosum abnormalities: Ultrasound and magnetic resonance imaging role.

The corpus callosum (CC) is the major interhemispheric commissure and its abnormalities include agenesis, hypoplasia, and hyperplasia. The CC anomalies are typically related to other central nervous system (CNS) or extra-CNS malformations. The antenatal diagnosis of complete CC agenesis is easy after mid-trimester by ultrasound (US) even in the axial plane. The non-visualization of cavum septum pellucidum and colpocephaly are critical signs in the axial view. More subtle findings (i.e., hypoplasia and partial agenesis) might also be recognized antenatally. In this review, the focus was given on the prenatal diagnosis of CC abnormalities in US and magnetic resonance imaging.

Expansion of Clinical and Genetic Spectrum of DDX3X Neurodevelopmental Disorder in 23 Chinese Patients.

AimDe novo DDX3X variants account for 1–3% of unexplained intellectual disability cases in females and very rarely in males. Yet, the clinical and genetic features of DDX3X neurodevelopmental disorder in the Chinese cohort have not been characterized.MethodA total of 23 Chinese patients (i.e., 22 female and 1 male) with 22 de novo DDX3X deleterious variants were detected among 2,317 probands with unexplained intellectual disability (ID) undertaking whole exome sequencing (WES). The age, sex, genetic data, feeding situation, growth, developmental conditions, and auxiliary examinations of the cohort were collected. The Chinese version of the Gesell Development Diagnosis Scale (GDDS-C) was used to evaluate neurodevelopment of DDX3X patients. The Social Communication Questionnaire (SCQ)-Lifetime version was applied as a primary screener to assess risk for autism spectrum disorder (ASD).ResultA total of 17 DDX3X variants were novel and 22 were de novo. Missense variants overall were only slightly more common than loss-of-function variants and were mainly located in two functional subdomains. The average age of this cohort was 2.67 (±1.42) years old. The overlapping phenotypic spectrum between this cohort and previously described reports includes intellectual disability (23/23, 100%) with varying degrees of severity, muscle tone abnormalities (17/23, 73.9%), feeding difficulties (13/23, 56.5%), ophthalmologic problems (11/23, 47.8%), and seizures (6/23, 26.1%). A total of 15 individuals had notable brain anatomical disruption (15/23, 65.2%), including lateral ventricle enlargement, corpus callosum abnormalities, and delayed myelination. Furthermore, 9 patients showed abnormal electroencephalogram results (9/23, 39.1%). Hypothyroidism was first noted as a novel clinical feature (6/23, 26.1%). The five primary neurodevelopmental domains of GDDS-C in 21 patients were impaired severely, and 13 individuals were above the “at-risk” threshold for ASD.InterpretationAlthough a certain degree of phenotypic overlap with previously reported cohorts, our study described the phenotypic and variation spectrum of 23 additional individuals carrying DDX3X variants in the Chinese population, adding hypothyroidism as a novel finding. We confirmed the importance of DDX3X as a pathogenic gene in unexplained intellectual disability, supporting the necessity of the application of WES in patients with unexplained intellectual disability.

Corpus callosum abnormality in a puppy with hypernatraemia

AbstractA 3‐month‐old, female, entire, mixed breed dog presented for a 1‐day history of ataxia and a 7‐day history of gastrointestinal upset. Neurologic examination revealed dull mentation, head pressing and bruxism. The dog had generalised coarse tremors during ambulation and cervical ventroflexion. Cranial nerve examination, postural reactions and myotatic reflexes were normal. The dog was markedly hypernatraemic at 202 mmol/L (139–151 mmol/L) and was assessed to be non‐hypervolaemic. The dog received custom fluids, and once stabilised, underwent magnetic resonance imaging. Magnetic resonance imaging revealed agenesis of the rostral portion and hypoplasia of the caudal portion of the corpus callosum. Absence of the septum pellucidum and a cortical development abnormality were noted with fusion of the ventral portion of the frontal lobes and malformation of the cingulate gyrus. Cerebrospinal fluid revealed an elevated total protein with a mild lymphocytic and macrophagic pleocytosis. The dog responded well to increased dietary moisture.