Corpus Callosum Abnormalities Research Articles

Structural brain abnormalities in Pallister-Killian syndrome: a neuroimaging study of 31 children

BackgroundPallister-Killian syndrome (PKS) is a rare genetic disorder caused by mosaic tetrasomy of 12p with wide neurological involvement. Intellectual disability, developmental delay, behavioral problems, epilepsy, sleep disturbances, and brain malformations have been described in most individuals, with a broad phenotypic spectrum. This observational study, conducted through brain MRI scan analysis on a cohort of patients with genetically confirmed PKS, aims to systematically investigate the neuroradiological features of this syndrome and identify the possible existence of a typical pattern. Moreover, a literature review differentiating the different types of neuroimaging data was conducted for comparison with our population.ResultsThirty-one individuals were enrolled (17 females/14 males; age range 0.1–17.5 years old at first MRI). An experienced pediatric neuroradiologist reviewed brain MRIs, blindly to clinical data. Brain abnormalities were observed in all but one individual (compared to the 34% frequency found in the literature review). Corpus callosum abnormalities were found in 20/30 (67%) patients: 6 had callosal hypoplasia; 8 had global hypoplasia with hypoplastic splenium; 4 had only hypoplastic splenium; and 2 had a thin corpus callosum. Cerebral hypoplasia/atrophy was found in 23/31 (74%) and ventriculomegaly in 20/31 (65%). Other frequent features were the enlargement of the cisterna magna in 15/30 (50%) and polymicrogyria in 14/29 (48%). Conversely, the frequency of the latter was found to be 4% from the literature review. Notably, in our population, polymicrogyria was in the perisylvian area in all 14 cases, and it was bilateral in 10/14.ConclusionsBrain abnormalities are very common in PKS and occur much more frequently than previously reported. Bilateral perisylvian polymicrogyria was a main aspect of our population. Our findings provide an additional tool for early diagnosis.Further studies to investigate the possible correlations with both genotype and phenotype may help to define the etiopathogenesis of the neurologic phenotype of this syndrome.

Corpus Callosum Abnormalities at Term-Equivalent Age Are Associated with Language Development at 2 Years’ Corrected Age in Infants Born Very Preterm

Corpus Callosum Abnormalities at Term-Equivalent Age Are Associated with Language Development at 2 Years’ Corrected Age in Infants Born Very Preterm

Fetal MRI Analysis of Corpus Callosal Abnormalities: Classification, and Associated Anomalies.

Corpus callosal abnormalities (CCA) are midline developmental brain malformations and are usually associated with a wide spectrum of other neurological and non-neurological abnormalities. The study aims to highlight the diagnostic role of fetal MRI to characterize heterogeneous corpus callosal abnormalities using the latest classification system. It also helps to identify associated anomalies, which have prognostic implications for the postnatal outcome. In this study, retrospective data from antenatal women who underwent fetal MRI between January 2014 and July 2023 at Rush University Medical Center were evaluated for CCA and classified based on structural morphology. Patients were further assessed for associated neurological and non-neurological anomalies. The most frequent class of CCA was complete agenesis (79.1%), followed by hypoplasia (12.5%), dysplasia (4.2%), and hypoplasia with dysplasia (4.2%). Among them, 17% had isolated CCA, while the majority (83%) had complex forms of CCA associated with other CNS and non-CNS anomalies. Out of the complex CCA cases, 58% were associated with other CNS anomalies, while 8% were associated with non-CNS anomalies. 17% of cases had both. The use of fetal MRI is valuable in the classification of abnormalities of the corpus callosum after the confirmation of a suspected diagnosis on prenatal ultrasound. This technique is an invaluable method for distinguishing between isolated and complex forms of CCA, especially in cases of apparent isolated CCA. The use of diffusion-weighted imaging or diffusion tensor imaging in fetal neuroimaging is expected to provide further insights into white matter abnormalities in fetuses diagnosed with CCA in the future.

Quantitative fetal MRI with diffusion tensor imaging in cases with 'short' corpus callosum.

It has been suggested previously that the presence of Probst bundles (PB) in cases with a short corpus callosum (SCC) on diffusion tensor imaging (DTI) may help to differentiate between corpus callosal (CC) dysplasia and a variant of normal CC development. The objectives of this study were to compare DTI parameters between cases of SCC vs normal CC and between cases of SCC with PB (SCC-PB+) vs SCC without PB (SCC-PB-). This was a retrospective study of patients referred to the Necker Hospital in Paris, France, for magnetic resonance imaging (MRI) evaluation of an apparently isolated SCC detected by sonography between November 2016 and December 2022 (IRB: 00011928). MRI was performed using a 1.5-Tesla Signa system. T2-weighted axial and sagittal sequences of the fetal brain were used to measure the length and thickness of the CC. 16-direction DTI axial brain sequences were performed to identify the presence of PB and to generate quantitative imaging parameters (fractional anisotropy (FA) and apparent diffusion coefficient (ADC)) of the entire CC, genu, body and splenium. Cases in which other associated brain abnormalities were detected on MRI were excluded. Cases were matched for fetal gender and gestational age with controls in a 1:3 ratio. Control cases were normal fetuses included in the LUMIERE on the FETUS trial (NCT04142606) that underwent the same DTI evaluation of the brain. Comparisons between SCC and normal CC cases, and between SCC-PB+ and SCC-PB- cases were performed using ANOVA and adjusted for potential confounders using ANCOVA. Twenty-two SCC cases were included and compared with 66 fetuses with a normal CC. In 10/22 (45.5%) cases of SCC, PB were identified. As expected, dimensions of the CC were significantly smaller in SCC compared with normal CC cases (all P < 0.01). In SCC-PB+ vs SCC-PB- cases, FA values were significantly lower in the entire CC (median, 0.21 (range, 0.19-0.24) vs 0.24 (range, 0.22-0.28); P < 0.01), genu (median, 0.21 (range, 0.15-0.29) vs 0.24 (range, 0.17-0.29); P = 0.04), body (median, 0.21 (range, 0.18-0.23) vs 0.23 (range, 0.21-0.27); P = 0.04) and splenium (median, 0.22 (range, 0.16-0.30) vs 0.25 (range, 0.20-0.29); P = 0.03). ADC values were significantly higher in the entire CC, genu and body in SCC-PB+ vs SCC-PB- cases (all P < 0.05). In SCC-PB+ cases, all FA values were significantly lower, and ADC values in the CC body were significantly higher compared with normal CC cases (all P < 0.05). In SCC-PB- cases, there was no significant difference in FA and ADC compared with normal CC cases (all P > 0.05). Fetal DTI evaluation of the CC showed that FA values were significantly lower and ADC values tended to be significantly higher in SCC-PB+ compared with normal CC cases. This may highlight alterations of the white matter microstructure in SCC-PB+. In contrast, isolated SCC-PB- did not demonstrate significant changes in DTI parameters, strengthening the possibility that this is a normal CC variant. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Demographic and clinical characteristics, seizure disorders, and antiepileptic drug usage in different types of corpus callosum disorders: a comparative study in children

BackgroundThis study aimed to investigate the demographic and clinical characteristics, types of seizure disorders, and antiepileptic drug usage among individuals with different types of corpus callosum disorders.MethodsA total of 73 individuals were included in the study and divided into three groups based on the type of corpus callosum abnormality: hypoplasia (H), agenesis (A), and dysgenesis (D). Demographic data, including gender and preterm birth, as well as clinical characteristics such as seizure disorders, attention deficit hyperactivity disorder (ADHD), severe developmental delay/intellectual disability, and other brain malformations, were analyzed. The types of seizure disorders and antiepileptic drugs used were also examined.ResultsThe H group had the highest number of participants (n = 47), followed by the A group (n = 11) and the D group (n = 15). The A group had the highest percentage of males and preterm births, while the D group had the highest percentage of seizure disorders, other brain malformations, and severe developmental delay/intellectual disability. The A group also had the highest percentage of ADHD. Focal seizures were observed in all three groups, with the highest proportion in the A group. Focal impaired awareness seizures (FIAS) were present in all groups, with the highest proportion in the D group. Generalized tonic-clonic seizures (GTCS) were observed in all groups, with the highest proportion in the H group. Different types of antiepileptic drugs were used among the groups, with variations in usage rates for each drug.ConclusionThis study provided insights into the demographic and clinical characteristics, seizure disorders, and antiepileptic drug usage among individuals with different types of corpus callosum disorders. Significant differences were found between the groups, indicating the need for tailored management approaches. However, the study has limitations, including a small sample size and a cross-sectional design. Further research with larger sample sizes and longitudinal designs is warranted to validate these findings and explore the relationship between corpus callosum abnormality severity and clinical outcomes.

Novel loss-of-function variants expand ABCC9-related intellectual disability and myopathy syndrome.

Loss-of-function mutation of ABCC9, the gene encoding the SUR2 subunit of ATP sensitive-potassium (KATP) channels, was recently associated with autosomal recessive ABCC9-related intellectual disability and myopathy syndrome (AIMS). Here we identify nine additional subjects, from seven unrelated families, harbouring different homozygous loss-of-function variants in ABCC9 and presenting with a conserved range of clinical features. All variants are predicted to result in severe truncations or in-frame deletions within SUR2, leading to the generation of non-functional SUR2-dependent KATP channels. Affected individuals show psychomotor delay and intellectual disability of variable severity, microcephaly, corpus callosum and white matter abnormalities, seizures, spasticity, short stature, muscle fatigability and weakness. Heterozygous parents do not show any conserved clinical pathology but report multiple incidences of intra-uterine fetal death, which were also observed in an eighth family included in this study. In vivo studies of abcc9 loss-of-function in zebrafish revealed an exacerbated motor response to pentylenetetrazole, a pro-convulsive drug, consistent with impaired neurodevelopment associated with an increased seizure susceptibility. Our findings define an ABCC9 loss-of-function-related phenotype, expanding the genotypic and phenotypic spectrum of AIMS and reveal novel human pathologies arising from KATP channel dysfunction.

Evaluation of Cerebral and Spinal Abnormalities on Magnetic Resonance Imaging in Infants with Myelomeningocele: A Retrospective Observational Study

Introduction: Spinal dysraphism includes a diverse collection of congenital spinal abnormalities that occur due to flawed closure of the neural tube and can be classified as open or closed types. The most common form of open spinal dysraphism is Myelomeningocele (MMC), which is characterised by a bony spinal defect and a sac in the back region containing dysplastic neural tissue and cerebrospinal fluid. MMC is associated with various intracranial and spinal anomalies that can lead to neurological, intellectual, and cognitive impairments. Imaging is necessary for the diagnosis of these anomalies and for surgical management planning and follow-up. Aim: To evaluate the associated intracranial and spinal anomalies in infants with MMC who presented with low back swelling since birth. Materials and Methods: The retrospective observational study was conducted in the Department of Radiology at Gajara Raja Medical College, Gwalior, Madhya Pradesh, India, from January 2020 to December 2022. A total of 117 subjects under one year of age, clinically diagnosed with MMC, were included in the study. Brain Magnetic Resonance Imaging (MRI) images were available for 84 patients, and spine MRI images were available for 113 patients. The MRI images were evaluated for bony and spinal anomalies. Data analysis was performed using IBM’s Statistical Package for Social Sciences (SPSS) version 20.0. Results: The mean age of the study participants was 1.7±2.9 months, with 70 males and 47 females (M:F=1.5:1). The most common location of spina bifida was lumbosacral 36 (31.9%), followed by lumbar 31 (27.4%), dorsolumbar 30 (26.5%), and sacral 16 (14.2%). A low-level spinal defect was observed in 39 cases (34.5%), and a high-level spinal defect was observed in 74 cases (65.5%). The spinal anomalies detected on MRI included syringomyelia 80 (70.8%), low-lying cord 59 (52.2%), bony abnormalities 26 (23.01%), diastematomyelia 16 (14.2%), and fatty filum terminale 3 (2.7%). Among the intracranial anomalies, the most common was dilated lateral ventricles 62 (73.8%). The most common infratentorial anomaly was Chiari II malformation 58 (69.1%). Corpus Callosum (CC) abnormalities were found in 40 cases (47.6%), with complete agenesis seen in three cases (3.6%), cerebellar hypoplasia in 20 cases (23.8%), absent septum in 15 cases (17.9%), and colpocephaly in 10 cases (11.9%). Conclusion: Spinal dysraphism, such as MMC, and cerebral anomalies often co-exist and can have an impact on neurological, intellectual, and cognitive functions. Chiari II malformation, corpus callosal anomalies, ventriculomegaly, and syringomyelia are frequently associated with MMC. Therefore, imaging evaluation of both the spine and brain is necessary for surgical treatment planning and long-term follow-up in MMC.

Biallelic NUDT2 variants defective in mRNA decapping cause a neurodevelopmental disease.

Dysfunctional RNA processing caused by genetic defects in RNA processing enzymes has a profound impact on the nervous system, resulting in neurodevelopmental conditions. We characterized a recessive neurological disorder in 18 children and young adults from 10 independent families typified by intellectual disability, motor developmental delay and gait disturbance. In some patients peripheral neuropathy, corpus callosum abnormalities and progressive basal ganglia deposits were present. The disorder is associated with rare variants in NUDT2, a mRNA decapping and Ap4A hydrolysing enzyme, including novel missense and in-frame deletion variants. We show that these NUDT2 variants lead to a marked loss of enzymatic activity, strongly implicating loss of NUDT2 function as the cause of the disorder. NUDT2-deficient patient fibroblasts exhibit a markedly altered transcriptome, accompanied by changes in mRNA half-life and stability. Amongst the most up-regulated mRNAs in NUDT2-deficient cells, we identified host response and interferon-responsive genes. Importantly, add-back experiments using an Ap4A hydrolase defective in mRNA decapping highlighted loss of NUDT2 decapping as the activity implicated in altered mRNA homeostasis. Our results confirm that reduction or loss of NUDT2 hydrolase activity is associated with a neurological disease, highlighting the importance of a physiologically balanced mRNA processing machinery for neuronal development and homeostasis.

A novel SMARCC1 BAFopathy implicates neural progenitor epigenetic dysregulation in human hydrocephalus.

Hydrocephalus, characterized by cerebral ventriculomegaly, is the most common disorder requiring brain surgery in children. Recent studies have implicated SMARCC1, a component of the BRG1-associated factor (BAF) chromatin remodelling complex, as a candidate congenital hydrocephalus gene. However, SMARCC1 variants have not been systematically examined in a large patient cohort or conclusively linked with a human syndrome. Moreover, congenital hydrocephalus-associated SMARCC1 variants have not been functionally validated or mechanistically studied in vivo. Here, we aimed to assess the prevalence of SMARCC1 variants in an expanded patient cohort, describe associated clinical and radiographic phenotypes, and assess the impact of Smarcc1 depletion in a novel Xenopus tropicalis model of congenital hydrocephalus. To do this, we performed a genetic association study using whole-exome sequencing from a cohort consisting of 2697 total ventriculomegalic trios, including patients with neurosurgically-treated congenital hydrocephalus, that total 8091 exomes collected over 7 years (2016-23). A comparison control cohort consisted of 1798 exomes from unaffected siblings of patients with autism spectrum disorder and their unaffected parents were sourced from the Simons Simplex Collection. Enrichment and impact on protein structure were assessed in identified variants. Effects on the human fetal brain transcriptome were examined with RNA-sequencing and Smarcc1 knockdowns were generated in Xenopus and studied using optical coherence tomography imaging, in situ hybridization and immunofluorescence. SMARCC1 surpassed genome-wide significance thresholds, yielding six rare, protein-altering de novo variants localized to highly conserved residues in key functional domains. Patients exhibited hydrocephalus with aqueductal stenosis; corpus callosum abnormalities, developmental delay, and cardiac defects were also common. Xenopus knockdowns recapitulated both aqueductal stenosis and cardiac defects and were rescued by wild-type but not patient-specific variant SMARCC1. Hydrocephalic SMARCC1-variant human fetal brain and Smarcc1-variant Xenopus brain exhibited a similarly altered expression of key genes linked to midgestational neurogenesis, including the transcription factors NEUROD2 and MAB21L2. These results suggest de novo variants in SMARCC1 cause a novel human BAFopathy we term 'SMARCC1-associated developmental dysgenesis syndrome', characterized by variable presence of cerebral ventriculomegaly, aqueductal stenosis, developmental delay and a variety of structural brain or cardiac defects. These data underscore the importance of SMARCC1 and the BAF chromatin remodelling complex for human brain morphogenesis and provide evidence for a 'neural stem cell' paradigm of congenital hydrocephalus pathogenesis. These results highlight utility of trio-based whole-exome sequencing for identifying pathogenic variants in sporadic congenital structural brain disorders and suggest whole-exome sequencing may be a valuable adjunct in clinical management of congenital hydrocephalus patients.

Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders.

The acyl-CoA-binding domain-containing protein 6 (ACBD6) is ubiquitously expressed, plays a role in the acylation of lipids and proteins and regulates the N-myristoylation of proteins via N-myristoyltransferase enzymes (NMTs). However, its precise function in cells is still unclear, as is the consequence of ACBD6 defects on human pathophysiology. Using exome sequencing and extensive international data sharing efforts, we identified 45 affected individuals from 28 unrelated families (consanguinity 93%) with bi-allelic pathogenic, predominantly loss-of-function (18/20) variants in ACBD6. We generated zebrafish and Xenopus tropicalis acbd6 knockouts by CRISPR/Cas9 and characterized the role of ACBD6 on protein N-myristoylation with myristic acid alkyne (YnMyr) chemical proteomics in the model organisms and human cells, with the latter also being subjected further to ACBD6 peroxisomal localization studies. The affected individuals (23 males and 22 females), aged 1-50 years, typically present with a complex and progressive disease involving moderate-to-severe global developmental delay/intellectual disability (100%) with significant expressive language impairment (98%), movement disorders (97%), facial dysmorphism (95%) and mild cerebellar ataxia (85%) associated with gait impairment (94%), limb spasticity/hypertonia (76%), oculomotor (71%) and behavioural abnormalities (65%), overweight (59%), microcephaly (39%) and epilepsy (33%). The most conspicuous and common movement disorder was dystonia (94%), frequently leading to early-onset progressive postural deformities (97%), limb dystonia (55%) and cervical dystonia (31%). A jerky tremor in the upper limbs (63%), a mild head tremor (59%), parkinsonism/hypokinesia developing with advancing age (32%) and simple motor and vocal tics were among other frequent movement disorders. Midline brain malformations including corpus callosum abnormalities (70%), hypoplasia/agenesis of the anterior commissure (66%), short midbrain and small inferior cerebellar vermis (38% each) as well as hypertrophy of the clava (24%) were common neuroimaging findings. Acbd6-deficient zebrafish and Xenopus models effectively recapitulated many clinical phenotypes reported in patients including movement disorders, progressive neuromotor impairment, seizures, microcephaly, craniofacial dysmorphism and midbrain defects accompanied by developmental delay with increased mortality over time. Unlike ACBD5, ACBD6 did not show a peroxisomal localization and ACBD6-deficiency was not associated with altered peroxisomal parameters in patient fibroblasts. Significant differences in YnMyr-labelling were observed for 68 co- and 18 post-translationally N-myristoylated proteins in patient-derived fibroblasts. N-myristoylation was similarly affected in acbd6-deficient zebrafish and X. tropicalis models, including Fus, Marcks and Chchd-related proteins implicated in neurological diseases. The present study provides evidence that bi-allelic pathogenic variants in ACBD6 lead to a distinct neurodevelopmental syndrome accompanied by complex and progressive cognitive and movement disorders.

Magnetic Resonance Imaging Findings and Genetic Testing Results in Children With Congenital Corneal Opacities

This study investigates brain and globe abnormalities identified on magnetic resonance imaging (MRI) in children with congenital corneal opacities (CCO). Retrospective cohort study. Clinical notes, radiology records, and genetic testing results were reviewed for patients diagnosed with corneal opacification within the first 6 months of life at a tertiary referral academic center between August 2008 and January 2018. Ocular findings, systemic anomalies, neuroimaging, and genetic testing results were summarized. A total of 135 patients presenting at age 1 day to 12 years (mean age, 1 year) were identified. Children with bilateral CCO were more likely to have systemic disease (P=0.018). Of the entire cohort, 43 (31.8%) patients received MRI, of whom 27 (62.8%) had abnormal brain findings and 30 (69.7%) had abnormal orbital findings. The most common abnormal brain findings were ventriculomegaly (n=16, 59.2%) and corpus callosum abnormalities (n=10, 37.0%) followed by brainstem/pons anomalies (n=5, 18.5%), and cerebellar anomalies (n=2, 7.4%). Abnormal brain MRI findings were associated with the presence of neurologic (P=.003) and craniofacial (P=.034) disease. A total of 44 (32.1%) patients underwent genetic testing, of whom 29 (65.9%) had pathogenic results. More than 60% of the children with CCO who underwent MRI had abnormal brain and orbit findings that were correlated with significant neurologic disease. Furthermore, almost two-thirds of patients with CCO who underwent genetic testing had pathogenic results. These data demonstrate the value of systemic workup in children with CCO, and highlight the role of ophthalmologists in facilitating the diagnosis of systemic comorbidities associated with CCO.

Corpus callosum in children with neurodevelopmental delay: MRI standard qualitative assessment versus automatic quantitative analysis

BackgroundThe corpus callosum (CC) is a key brain structure. In children with neurodevelopmental delay, we compared standard qualitative radiological assessments with an automatic quantitative tool.MethodsWe prospectively enrolled 73 children (46 males, 63.0%) with neurodevelopmental delay at single university hospital between September 2020 and September 2022. All of them underwent 1.5-T brain magnetic resonance imaging (MRI) including a magnetization-prepared 2 rapid acquisition gradient echoes − MP2RAGE sequence. Two radiologists blindly reviewed the images to classify qualitatively the CC into normal, hypoplasic, hyperplasic, and/or dysgenetic classes. An automatic tool (QuantiFIRE) was used to provide brain volumetry and T1 relaxometry automatically as well as deviations of those parameters compared with a healthy age-matched cohort. The MRI reference standard for CC volumetry was based on the Garel et al. study. Cohen κ statistics was used for interrater agreement. The radiologists and QuantiFIRE’s diagnostic accuracy were compared with the reference standard using the Delong test.ResultsThe CC was normal in 42 cases (57.5%), hypoplastic in 20 cases (27.4%), and hypertrophic in 11 cases (15.1%). T1 relaxometry values were abnormal in 26 children (35.6%); either abnormally high (18 cases, 24.6%) or low (8 cases, 11.0%). The interrater Cohen κ coefficient was 0.91. The diagnostic accuracy of the QuantiFIRE prototype was higher than that of the radiologists for hypoplastic and normal CC (p = 0.003 for both subgroups, Delong test).ConclusionsAn automated volumetric and relaxometric assessment can assist the evaluation of brain structure such as the CC, particularly in the case of subtle abnormalities.Relevance statementAutomated brain MRI segmentation combined with statistical comparison to normal volume and T1 relaxometry values can be a useful diagnostic support tool for radiologists.Key points• Corpus callosum abnormality detection is challenging but clinically relevant.• Automated quantitative volumetric analysis had a higher diagnostic accuracy than that of visual appreciation of radiologists.• Quantitative T1 relaxometric analysis might help characterizing corpus callosum better.Graphical

Prenatal diagnosis of lanosterol synthase deficiency: Fetal ultrasound findings as a window on family genetics

Cholesterol is essential in the brain from the earliest stages of embryonic development. Disruption of cholesterol synthesis pathways that leads to cholesterol deficiency underlies a few syndromes, including desmosterolosis and Smith–Lemli–Opitz syndrome. In both syndromes, brain anomalies can occur. The LSS gene encodes lanosterol synthase (LSS), an important enzyme in the cholesterol biosynthesis pathway. Biallelic pathogenic variants in this gene cause alopecia–intellectual disability type 4 syndrome (APMR4, MIM 618840), a rare autosomal recessive disorder. Here, we describe two new LSS variants (c.1016C > T; p. Ser339Leu and c.1522G > C; p. Gly508Arg) found in a compound heterozygous fetus diagnosed prenatally with brain abnormalities by ultrasound scanning. Two of his siblings from the same parents also harbored these variants. Both siblings had alopecia, mild intellectual disability, autism spectrum disorder, and cataracts. To the best of our knowledge, this case represents the first prenatal diagnosis of APMR4 first suspected by ultrasound. In addition, the phenotypic features of the siblings are extensive compared with those described in previous reports and include abnormal corpus callosum, cataracts, alopecia, and developmental delay.

Midline suprapineal pseudocyst in brain of fetuses with open spina bifida.

Recently, it was noted that fetuses with open spina bifida (OSB) may have a midline cystic structure evident on ultrasound. Our aims were to determine the prevalence of this cystic structure, shed light on its pathophysiology and investigate the association between its presence and other characteristic brain findings in fetuses with OSB. This was a single-center retrospective study of all fetuses with OSB and available cineloop images in the axial plane referred to the Ontario Fetal Centre, Toronto, Canada, between June 2017 and May 2022. Ultrasound and magnetic resonance imaging (MRI) data obtained between 18 + 0 and 25 + 6 weeks were reviewed in search of a midline cystic structure. Pregnancy and lesion characteristics were collected. Transcerebellar diameter (TCD), clivus-supraocciput angle (CSA) and additional brain abnormalities (abnormal cavum septi pellucidi (CSP), abnormal corpus callosum (CC) and periventricular nodular heterotopia (PNH)) were assessed. In cases of in-utero repair, imaging findings were reviewed postoperatively. In cases of termination, neuropathological findings were reviewed, if available. Of 76 fetuses with OSB, 56 (73.7%) had a suprapineal cystic structure on ultrasound. The percentage of agreement between ultrasound and MRI detection was 91.5% (Cohen's kappa coefficient, 0.78 (95% CI, 0.57-0.98)). Brain autopsy in terminated cases revealed a dilatation of the posterior third ventricle, with redundant tela choroidea and arachnoid forming the membranous roof of the third ventricle, anterior and superior to the pineal gland. A cyst wall could not be identified, indicating that the structure was a pseudocyst. The presence of the pseudocyst was associated with a smaller CSA (pseudocyst absent, 62.11 ± 9.60° vs pseudocyst present, 52.71 ± 8.22°; P = 0.04). When the pseudocyst was present, its area was correlated inversely with TCD (r, -0.28 (95% CI, -0.51 to -0.02); P = 0.04). Fetal surgery did not have any impact on the growth rate of the pseudocyst (fetal surgery, 5.07 ± 3.29 mm2 /week vs expectant management, 4.35 ± 3.17 mm2 /week; P = 0.58). The presence of the pseudocyst was not associated with abnormal CSP, CC or presence of PNH. None of the cases with available postnatal follow-up required surgical procedure related to the pseudocyst. Approximately 75% of all OSB cases have a suprapineal pseudocyst. Its presence is associated with the degree of hindbrain herniation but not with abnormalities of the CSP and CC or presence of PNH. Thus, it should not be regarded as additional brain pathology and should not preclude fetuses from undergoing fetal surgery for OSB. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Further delineation of the rare GDACCF (global developmental delay, absent or hypoplastic corpus callosum, dysmorphic facies syndrome): genotype and phenotype of 22 patients with ZNF148 mutations

BackgroundPathogenic variants in the zinc finger protein coding genes are rare causes of intellectual disability and congenital malformations. Mutations in the ZNF148 gene causing GDACCF syndrome (global developmental delay, absent...

Neuroimaging features in children with optic nerve hypoplasia and septo-optic-pituitary dysplasia.

Optic nerve hypoplasia (ONH) and septo-optic-pituitary dysplasia (SOD) are common causes of congenital visual impairment. Our primary aim was to investigate the prevalence of abnormal neuroimaging features in patients with these disorders in Manitoba, Canada, and compare them with published reports. A retrospective neuroimaging review was performed in patients resident in Manitoba with ONH/SOD. There were 128 patients (M = 70) with ONH/SOD who had neuroimaging. Their mean age (SD) at the end of the study was 13.2 (7.5) years. Males were significantly more likely to have bilateral ONH and a small optic chiasm size, while females were more likely to have a left ONH and a small left optic chiasm size on neuroimaging (p = 0.049). ONH and small optic chiasm size were seen in most patients on neuroimaging. Absent septum pellucidum was noted in 40%, small pituitary gland size in 28%, neuronal migration disorders (NMD) in 20% (>1 type and bilateral in 13 cases), corpus callosum abnormalities were present in 9%, while olfactory bulbs-tracts and olfactory sulci were absent in 8.6% of cases. Unilateral ONH was not significantly associated with other structural brain abnormalities, while NMD were significantly associated with other midline brain abnormalities including a symmetrically small optic chiasm size. The prevalence of structural neuroimaging abnormalities in our cohort with ONH/SOD was generally in the same range reported in other studies with corpus callosum abnormalities being relatively less common in our study. Bilateral NMD were relatively common among patients with NMD. The association between sex and ONH laterality requires further study.

Corpus Callosum Agenesis in a Child with Attention Deficit Hyperactivity Disorder with Prenatal Exposure to Sodium Valproate: A Case Report

Neuropsychiatric manifestations are common in children with congenital abnormality in corpus callosum. Both macrostructural as well as microstructural anomalies of the corpus callosum can be seen in those with Attention deficit hyperactivity disorder (ADHD). We herein have described one case of a 7 year old boy with ADHD and dull average intelligence with complete agenesis of the trunk and splenium of corpus callosum. To the best of our knowledge, this is one of the rare case being reported from India on the morphological abnormalities of the corpus callosum in a patient suffering from ADHD. Keywords: Attention deficit hyperactivity disorder, corpus callosum

SLC4A10 mutation causes a neurological disorder associated with impaired GABAergic transmission.

SLC4A10 is a plasma-membrane bound transporter that utilizes the Na+ gradient to drive cellular HCO3- uptake, thus mediating acid extrusion. In the mammalian brain, SLC4A10 is expressed in principal neurons and interneurons, as well as in epithelial cells of the choroid plexus, the organ regulating the production of CSF. Using next generation sequencing on samples from five unrelated families encompassing nine affected individuals, we show that biallelic SLC4A10 loss-of-function variants cause a clinically recognizable neurodevelopmental disorder in humans. The cardinal clinical features of the condition include hypotonia in infancy, delayed psychomotor development across all domains and intellectual impairment. Affected individuals commonly display traits associated with autistic spectrum disorder including anxiety, hyperactivity and stereotyped movements. In two cases isolated episodes of seizures were reported in the first few years of life, and a further affected child displayed bitemporal epileptogenic discharges on EEG without overt clinical seizures. While occipitofrontal circumference was reported to be normal at birth, progressive postnatal microcephaly evolved in 7 out of 10 affected individuals. Neuroradiological features included a relative preservation of brain volume compared to occipitofrontal circumference, characteristic narrow sometimes 'slit-like' lateral ventricles and corpus callosum abnormalities. Slc4a10 -/- mice, deficient for SLC4A10, also display small lateral brain ventricles and mild behavioural abnormalities including delayed habituation and alterations in the two-object novel object recognition task. Collapsed brain ventricles in both Slc4a10-/- mice and affected individuals suggest an important role of SLC4A10 in the production of the CSF. However, it is notable that despite diverse roles of the CSF in the developing and adult brain, the cortex of Slc4a10-/- mice appears grossly intact. Co-staining with synaptic markers revealed that in neurons, SLC4A10 localizes to inhibitory, but not excitatory, presynapses. These findings are supported by our functional studies, which show the release of the inhibitory neurotransmitter GABA is compromised in Slc4a10-/- mice, while the release of the excitatory neurotransmitter glutamate is preserved. Manipulation of intracellular pH partially rescues GABA release. Together our studies define a novel neurodevelopmental disorder associated with biallelic pathogenic variants in SLC4A10 and highlight the importance of further analyses of the consequences of SLC4A10 loss-of-function for brain development, synaptic transmission and network properties.

Long-Term Imaging Follow-up from the Management of Myelomeningocele Study.

Short-term results demonstrate that prenatal repair of a myelomeningocele is associated with a reduction in hydrocephalus and an increased likelihood of the reversal of Chiari II malformations compared with postnatal repair. The purpose of this study was to identify the long-term imaging findings at school age among subjects who underwent pre- versus postnatal repair of a myelomeningocele. A subset of subjects enrolled in the Management of Myelomeningocele Study who underwent either prenatal (n = 66) or postnatal (n = 63) repair of a lumbosacral myelomeningocele and had follow-up brain MR imaging at school age were included. The prevalence of posterior fossa features of Chiari II malformation and supratentorial abnormalities and the change in these findings from fetal to school-age MR imaging were compared between the 2 groups. Prenatal repair of a myelomeningocele was associated with higher rates of normal location of fourth ventricle and lower rates of hindbrain herniation, cerebellar herniation, tectal beaking, brainstem distortion, and kinking at school age compared with postnatal repair (all P < .01). Supratentorial abnormalities, including corpus callosal abnormalities, gyral abnormalities, heterotopia, and hemorrhage, were not significantly different between the 2 groups (all P > .05). The rates of resolution of brainstem kinking, tectal beaking, cerebellar and hindbrain herniation, and normalization of fourth ventricle size from fetal to school age MR imaging were higher among the prenatal compared with postnatal surgery group (all, P < .02). Prenatal repair of a myelomeningocele is associated with persistent improvement in posterior fossa imaging findings of Chiari II malformation at school age compared with postnatal repair.

Prenatal detection of chromosomal abnormalities and copy number variants in fetuses with corpus callosum agenesis.

The corpus callosum is the main pathway that connects interhemispheric communication. Agenesis of corpus callosum (ACC) have not consistently detected replicate genetic risk factors, potentially due to Etiological heterogeneity of this trait. This study aimed to retrospectively analyze the molecular basis for the ACC and the potential genotyping-phenotyping association and provide the basis for genetic counselling. Karyotyping and chromosomal microarray analysis were performed for copy number variants. Three cases had 1p36 deletions, two cases had 2q31.2 and 2p16.3 microdeletions, one case had microdeletion of Xq26.3q27.1, five cases involved derived chromosomes due to unbalanced translocations. These cases had variable deletions and duplications with partial overlapping. Phenotypically, besides agenesis of corpus callosum and other brain morphological abnormalities as well as heart abnormalities. ACC may occur alone or be related to other abnormal clinical phenotypes, and its genetic mechanism is very complicated. These results revealed ACC is associated with a variety of chromosomal abnormalities. The findings of the present study expand the genotypes associated with ACC, and further delineation of the genotype-phenotype correlations for ACC. With current applications of chromosome microarray analysis, congenital submicroscopic copy-number variations in fetuses can be detected more effectively.