Dysgenesis Of Corpus Callosum Research Articles

TRIM71 mutations cause a neurodevelopmental syndrome featuring ventriculomegaly and hydrocephalus.

Congenital hydrocephalus (CH), characterized by cerebral ventriculomegaly, is one of the most common reasons for pediatric brain surgery. Recent studies have implicated lin-41 (lineage variant 41)/TRIM71 (tripartite motif 71) as a candidate CH risk gene, however, TRIM71 variants have not been systematically examined in a large patient cohort or conclusively linked with an OMIM syndrome. Through cross-sectional analysis of the largest assembled cohort of patients with cerebral ventriculomegaly, including neurosurgically-treated CH (totaling 2,697 parent-proband trios and 8,091 total exomes), we identified 13 protein-altering de novo variants (DNVs) in TRIM71 in unrelated children exhibiting variable ventriculomegaly, CH, developmental delay, dysmorphic features, and other structural brain defects including corpus callosum dysgenesis and white matter hypoplasia. Eight unrelated patients were found to harbor arginine variants, including two recurrent missense DNVs, at homologous positions in RPXGV motifs of different NHL domains. Seven additional patients with rare, damaging, unphased or transmitted variants of uncertain significance were also identified. NHL-domain variants of TRIM71 exhibited impaired binding to the canonical TRIM71 target CDKN1A; other variants failed to direct the subcellular localization of TRIM71 to processing bodies. Single-cell transcriptomic analysis of human embryos revealed expression of TRIM71 in early first-trimester neural stem cells of the brain. These data show TRIM71 is essential for human brain morphogenesis and that TRIM71 mutations cause a novel neurodevelopmental syndrome featuring ventriculomegaly and CH.

Clinical Case of Rare Genetic Disorder (Proud Syndrome) in a Child

Background. Proud syndrome is rare inherited disease with X-linked inheritance associated with mutations in the homeobox gene ARX. Typical clinical signs of this syndrome are severe mental retardation, intractable epilepsy, agenesis (dysgenesis) of corpus callosum. Less common features are genital abnormalities, microcephaly, facial dysmorphia, and skeletal malformations. Clinical case description. The article describes the clinical findings of Proud syndrome in girl A., admitted to Children’s City Clinical Hospital No. 1 in Nizhny Novgorod. The girl was born without asphyxia at term through natural vaginal delivery after the first uneventful pregnancy. Body weight at birth was 2600 g. The genealogical history is burdened by the presence of epilepsy in girl’s father relatives. There were no deviations in psychomotor skills development before disease onset. Hemi-convulsive seizures (switching sides) have appeared at the age of 6 months. These attacks had status course and were resistant to anticonvulsant therapy. Neuroimaging has revealed agenesis of corpus callosum. Regression of psychomotor development, new behavioral disorders (stereotypes and auto-aggression), hyperexcitability, and sleep disorders were observed in dynamics. The diagnosis of Proud syndrome was confirmed by identification of probably pathogenic mutation in the ARX gene (c.1111C>T, p. Arg 371*64). The features of anticonvulsant management were demonstrated in the patient. Conclusion. This clinical case presents typical clinical picture of Proud syndrome. The disease is non-curable. Such patients should be administered with syndromic therapy: constant anticonvulsant therapy, correction of behavioral disorders (classes with specialist on mental defects), neurologist, epileptologist, psychiatrist observations. Parental examination is crucial ARX mutation search in order to determine the prognosis for further child-bearing (parents refused to perform genetic study at the time of article writing).

Interhemispheric coherence of EEG rhythms in children: Maturation and differentiation in corpus callosum dysgenesis

ObjectivesTo evaluate the evolution of interhemispheric coherences (ICo) in background and spindle frequency bands during childhood and use it to identify individuals with corpus callosum dysgenesis (CCd). MethodsA monocentric cohort of children aged from 0.25 to 15 years old, consisting of 13 children with CCd and 164 without, was analyzed. The ICo of background activity (ICOBckgrdA), sleep spindles (ICOspindles), and their sum (sICO) were calculated. The impact of age, gender, and CC status on the ICo was evaluated, and the sICO was used to discriminate children with or without CCd. ResultsICOBckgrdA, ICOspindles and sICO increased significantly with age without any effect of gender (p < 10−4), in both groups. The regression equations of the different ICo were stronger, with adjusted R2 values of 0.54, 0.35, and 0.57, respectively. The ICo was lower in children with CCd compared to those without CCd (p < 10−4 for all comparisons). The area under the precision recall curves for predicting CCd using sICO was 0.992 with 98.9 % sensitivity and 87.5 % specificity. DiscussionICo of spindles and background activity evolve in parallel to brain maturation and depends on the integrity of the corpus callosum. sICO could be an effective diagnostic biomarker for screening children with interhemispheric dysfunction.

Lipoma of the corpus callosum: Case report

Corpus callosum lipoma is a very rare congenital malformation, which may be associated with varying degrees of corpus callosum dysgenesis. It is often asymptomatic but may present with epilepsy, hemiplegia, dementia, or simple headache. We report the case of a 48-year-old adult, followed for psychomotor retardation since childhood, who presented with epileptic seizures and was found to have a lipoma of the corpus callosum. Symptoms and prognosis depend on the associated malformation. MRI is the imaging modality of choice for diagnosis. Treatment is symptomatic: antiepileptic drugs in the event of epileptic seizures, and surgery is rarely indicated.

CARACTERIZATION OF MANUAL PREFERENCE IN CORPUS CALLOSUM DYSGENESIS

CARACTERIZATION OF MANUAL PREFERENCE IN CORPUS CALLOSUM DYSGENESIS

A selective defect in the glial wedge as part of the neuroepithelium disruption in hydrocephalus development in the mouse hyh model is associated with complete corpus callosum dysgenesis.

Dysgenesis of the corpus callosum is present in neurodevelopmental disorders and coexists with hydrocephalus in several human congenital syndromes. The mechanisms that underlie the etiology of congenital hydrocephalus and agenesis of the corpus callosum when they coappear during neurodevelopment persist unclear. In this work, the mechanistic relationship between both disorders is investigated in the hyh mouse model for congenital hydrocephalus, which also develops agenesis of the corpus callosum. In this model, hydrocephalus is generated by a defective program in the development of neuroepithelium during its differentiation into radial glial cells. In this work, the populations implicated in the development of the corpus callosum (callosal neurons, pioneering axons, glial wedge cells, subcallosal sling and indusium griseum glial cells) were studied in wild-type and hyh mutant mice. Immunohistochemistry, mRNA in situ hybridization, axonal tracing experiments, and organotypic cultures from normal and hyh mouse embryos were used. Our results show that the defective program in the neuroepithelium/radial glial cell development in the hyh mutant mouse selectively affects the glial wedge cells. The glial wedge cells are necessary to guide the pioneering axons as they approach the corticoseptal boundary. Our results show that the pioneering callosal axons arising from neurons in the cingulate cortex can extend projections to the interhemispheric midline in normal and hyh mice. However, pioneering axons in the hyh mutant mouse, when approaching the area corresponding to the damaged glial wedge cell population, turned toward the ipsilateral lateral ventricle. This defect occurred before the appearance of ventriculomegaly. In conclusion, the abnormal development of the ventricular zone, which appears to be inherent to the etiology of several forms of congenital hydrocephalus, can explain, in some cases, the common association between hydrocephalus and corpus callosum dysgenesis. These results imply that further studies may be needed to understand the corpus callosum dysgenesis etiology when it concurs with hydrocephalus.

MRI analysis of neurodevelopmental anatomy in myelomeningocele: prenatal vs postnatal repair.

Prenatal myelomeningocele (MMC) repair offers improved motor function and decreased rates of cerebrospinal fluid (CSF) diversion compared to than postnatal repair. However, comparative analysis of other associated neuroanatomical findings is lacking. The purpose of this study is to use magnetic resonance imaging (MRI) imaging to compare characteristic Chiari II malformation stigmata in patients who underwent fetal MMC repair vs. postnatal repair. A retrospective review was performed of neonates who underwent prenatal or postnatal MMC repair at our institution and had postnatal MRIs. We analyzed anatomical findings characteristically seen with Chiari II malformation on brain MRI in patients who underwent prenatal MMC repair vs. postnatal repair. CSF diversion was required in 24% of prenatal cohort vs. 67% of postnatal cohort (p=0.002), and syrinx was present in 12% of prenatal cohort compared to 42% in postnatal cohort (p=0.03). Corpus callosum (CC) morphology was abnormal in 52% of prenatal cohort vs. 53% of postnatal cohort (p=0.92), while falx morphology was normal in 92% of the prenatal cohort vs. 34% of the postnatal cohort (p = <0.001). Prenatal cohort patients had shorter tentorium to foramen magnum distance than postnatal cohort patients (18.4mm vs. 22.4mm, p=0.01), overall larger foramen magnum diameter (22.9mm vs. 18.9mm, p < 0.001), and a smaller mean degree of hindbrain herniation (1.5mm vs. 8.7mm, p < 0.001). Finally, the cerebral aqueduct was patent in 79% of prenatal cohort vs. 100% of postnatal cohort (p=0.007). There was no significant difference in presence of gray matter heterotopia, presence of septum pellucidum, or size of massa intermedia between the two cohorts. We report baseline variations in developmental neuroanatomy in patients with MMC including rates of CC dysgenesis, gray matter heterotopia and additional cranial and spinal MRI findings. We found that prenatal surgery results in changes to infratentorial anatomy, with minimal effect on supratentorial brain development. This information will be useful in myelomeningocele counseling and in understanding how prenatal repair of myelomeningocele affects brain development. This article is protected by copyright. All rights reserved.

Prevalence of corpus callosum pathology in an unselected population. Should assessment of the corpus callosum be included in the routine 20weeks scan?

To determine the prevalence of abnormalities of the corpus callosum (AbnCC) in a non-selected population, to propose a systematic screening protocol for AbnCC in all populations through direct assessment, and to describe the follow-up and prognosis of all AbnCC cases diagnosed in our clinical setting. This was a retrospective review of the prevalence of AbnCC over 11years. We included a sagittal assessment of the corpus callosum (CC) in the second-trimester scan. AbnCC was classified into complete agenesis of CC (ACC) and dysgenesis of CC (DCC; including small, partial agenesis, thick and with lipoma). Of the 38,586 second-trimester scans performed during our screening, 43 cases of AbnCC were detected (prevalence of 0.8/1000). Of the AbnCC cases, 10 cases were identified as ACC (29.40%) and 24 as DCC (70.59%). Follow-up investigations showed that in the 43 cases with AbnCC, 76.5% had other associated ultrasound abnormalities, 26.5% had genetic abnormalities, 11.8% had other MRI abnormalities, and 25% of the children had neurodevelopmental delays (8.8% of the total), which were severe in only one case. AbnCC is found in approximately 0.8/1000 of cases in an unselected population. The findings suggest that systematic and direct assessment of the CC as part of screening ultrasound in the second trimester of gestation should be recommended as a routine practice.

Surgical treatment of interhemispheric arachnoid cysts.

In children, interhemispheric arachnoid cysts (IHACs) are rare lesions often associated with corpus callosum dysgenesis. It is still controversial about surgical treatments for IHACs. We aim to report our experience with pediatric IHAC patients and evaluate surgical courses and neurological developments. Pediatric IHACs treated between 2001 and 2021 were reviewed retrospectively. IHAC was observed until they represented rapid cyst enlargement or neurological symptoms. Cyst fenestration was done by microscope or endoscope, depending on the IHAC's location. Cyst size and corpus callosum dysgenesis were evaluated with neuroimaging. Neurological development was assessed from medical records at the last follow-up. Fifteen children received cyst fenestration surgery (mean age 11.4months). Eleven patients (73.3%) under observation showed rapid cyst enlargement in a short period (median 5months). Cysto-ventriculostomy (CVS) and cysto-cisternostomy (CCS) regressed the cyst size significantly (p = 0.003). The median follow-up duration was 51months (range 14-178months). Corpus callosum dysgenesis was observed in eleven patients (73.3%, complete = 5, partial = 6). Among eight patients (53.3%) having developmental delay, five patients (33.3%) showed speech delay, including one patient with intractable seizures. Pediatric IHACs frequently present within 1year after birth, with rapid cyst enlargement. CVS and CCS were effective in regressing the cyst size. Corpus callosum dysgenesis accompanied by IHAC might have a risk of language achievement; however, development delay could rely on multifactorial features, such as epilepsy or other brain anomalies.

Absence of Neutropenia in Patient with an Exon 2 Nonsense Mutation in ELANE: Clinical Evidence to Support Gene Therapy Efforts for Severe Congenital Neutropenia

Introduction Severe congenital neutropenia (SCN) is an inherited bone marrow failure condition most often caused by heterozygous mutations in the ELANE gene. While granulocyte colony stimulating factor (G-CSF) is effective in increasing neutrophil counts in the majority of patients, approximately 15% of patients do not respond, necessitating the creation of alternative treatment strategies. Due to its association with significant, life-threatening infections and heightened risk of progression to myelodysplastic syndrome and/or acute myeloid leukemia, SCN has been the focus of recent gene therapy efforts by multiple groups (Nasri et al., 2020; Rao et al., 2021). Pathogenic variants in ELANE most often cause missense mutations or in-frame indels which lead to the production and expression of mutant neutrophil elastase (NE) proteins. Frameshift mutations resulting in out-of-frame stop codons or nonsense mutations are also seen in the third through fifth (final) exons of ELANE due to their ability to circumvent nonsense-mediated decay (NMD) and generate mutant NE. In contrast, frameshift and nonsense mutations in the first and second exons have not been shown to cause neutropenia, most likely because NMD prevents the translation of mutant NE (Rao et al., 2021; Horwitz, 2021). Collectively, these observations suggest that the pathogenicity of ELANE mutations may rely on gain-of-function alterations in mutant NE rather than loss-of-function alterations in normal NE. Because the absence of one copy of ELANE does not appear to be deleterious, one theory posits that therapeutic inactivation of mutant copies of ELANE may have corrective potential (Horwitz et al., 2019; Nasri et al., 2020; Rao et al., 2021). Thus, the focus of several gene editing efforts has been CRISPR/Cas9-mediated knockout in early exons of ELANE in hematopoietic stem and progenitor cells (HSPCs) of patients with ELANE-mutated SCN for allogeneic stem cell transplant (Nasri et al., 2020; Rao et al., 2021). With this study, we sought to understand whether an inherited ELANE mutation analogous to those utilized in gene therapy would cause neutropenia. Case Presentation Here, we present a six-month-old Caucasian male with an ELANE mutation whose clinical findings support this model. The patient was born at full term to a 35-year-old G6P2 mother. The patient's constellation of complex symptoms, including polymicrogyria, corpus callosum dysgenesis, hypotonia, seizures, and feeding difficulties prompted clinical trio whole genome sequencing (WGS) at approximately two months of age. The patient was incidentally found to have a de novo nonsense variant in exon 2 of the ELANE gene (NM_001972.2:c.151G&amp;gt;T, p.[G51*]), predicted to result in protein truncation or NMD. WGS also identified variants of uncertain significance in CHRNB2 and HFE. Importantly, although the ELANE variant was classified as likely pathogenic in the clinical genetics report, the patient has not had clinically significant neutropenia. Absolute neutrophil counts have ranged from 1.27 - 10.95 K cells/μL, with mean and median values of 4.09 and 2.95 K cells/μL, respectively (n=10). The patient has not had a significant infectious history, nor has he required any treatment for hematologic concerns. Discussion The absence of a neutropenia pathology in this patient, at least in his first six months of life, provides evidence in support of gene therapy efforts which seek to ameliorate pathogenic ELANE mutations with gene editing to produce frameshifts in early exons. Most likely, in this patient, NMD of mutant ELANE mRNA prevented its translation, thus allowing for ample production and maturation of neutrophils. A similar pattern was observed in another report which examined patients with whole gene deletions of ELANE (Horwitz et al., 2019), but this is the first report of a nonsense variant analogous to those proposed to be introduced by gene or base editing for gene therapy of SCN. Thus, the present case adds to a growing body of evidence which suggests that ELANE knockout may have therapeutic potential for SCN.

Heterotopic connectivity of callosal dysgenesis in mice and humans.

The corpus callosum (CC), the largest brain commissure and the primary white matter pathway for interhemispheric cortical connectivity, was traditionally viewed as a predominantly homotopic structure, connecting mirror areas of the cortex. However, new studies verified that most callosal commissural fibers are heterotopic. Recently, we reported that ~75% of the callosal connections in the brains of mice, marmosets, and humans are heterotopic, having an essential role in determining the global properties of brain networks. In the present study, we leveraged high-resolution diffusion-weighted imaging and graph network modeling to investigate the relationship between heterotopic and homotopic callosal fibers in human subjects and in a spontaneous mouse model of Corpus Callosum Dysgenesis (CCD), a congenital developmental CC malformation that leads to widespread whole-brain reorganization. Our results show that the CCD brain is more heterotopic than the normotypical brain, with both mouse and human CCD subjects displaying highly variable heterotopicity maps. CCD mice have a clear heterotopicity cluster in the anterior CC, while hypoplasic humans have strongly variable patterns. Graph network-based connectivity profile showed a direct impact of heterotopic connections on CCD brains altering several network-based statistics. Our collective results show that CCD directly alters heterotopic connections and brain connectivity.

A chromosomal deletion leading to BACH2 haploinsufficiency, hypogammaglobulinemia and recurrent infections without intestinal inflammation or autoimmunity

Afzali et al. described 3 patients with heterozygous point mutations in the transcription factor BACH2, characterized by lymphocyte maturation defects, immunoglobulin deficiency and intestinal inflammation secondary to BACH2-related immunodeficiency and autoimmunity (BRIDA). Molecular testing suggested these mutations lead to disruption of protein stability. Mice with heterozygous Bach2 deficiency display similar lymphocyte defects, supporting that the disease-mechanism was BACH2 haploinsufficiency. We present a patient with recurrent infections and hypogammaglobulinemia with heterozygous chromosome 6 deletion encompassing the BACH2 gene, in absence of gastrointestinal or rheumatologic manifestations.A 3-year old boy with developmental delay, corpus callosum dysgenesis, dextrocardia, renal pyelectasis, abnormal ear canal shape and congenital hypotonia presented to immunology clinic for evaluation of recurrent infections. In his first 18 months he was isolated, but subsequently developed notable respiratory infections in daycare. Genetic testing identified a chromosome 6 deletion of 8.18Mb (6q14.3-q16); chr6:85227585-93409505, likely de novo, given no affected family members and mother’s chromosomal analysis revealed no translocation. Research WES showed no other variants of interest. 7 known disease genes lie within this region (Figure 1). MAP3K7 and TBX18 deletion were thought to explain the developmental and cardiac phenotypes.Table 1. (abstract: 96)Selected laboratory test results. Values below or above reference are indicated with blue and red respectively. Not shown: IL-2, IL-4, IL-5, IL-8, IL-12, IL-13, IL-17 were normal. Fecal blood testing at baseline was negative. T cell memory population percentages were normal. T cell proliferation studies were normal. Pre-SCIG = pre-subcutaneous IgG (SCIG) treatment. Post SCIG = post-SCIG treatment sample obtained after ~ 4 months of SCIG. n/a = sample not available.ParameterValue pre-SCIGValue post-SCIG UnitWBC19.6810.15 K cells/ulHgb12.211.9 K cells/ulPlatelet274279 K cells/ulANC13.114.05 K cells/ulALC4.724.98 K cells/ulIgG459871 mg/dLIgA4946 mg/dLIgM4039 mg/dLIgE7866 unit/mLC3n/a116 mg/dLC4n/a18 mg/dLC-reactive protein (CRP)0.4<0.06 mg/dLErythrocyte Secimentation Rate (ESR)101 mm/hrsIL2R27411154.1 pg/mLIFN-gamma<4.2<4.2 pg/mLIL-1020.13.6 pg/mLIL-68.4<2.0 pg/mLIL-1beta<6.5<6.5 pg/mLTNF-alpha2.3<1.7 pg/mLTotal T cells (CD3+)29543566 cells/ulCD4+ T cells (CD3+CD4+)19302229 cells/ulCD8+ T Cells (CD3+CD8+)9081167 cells/ulB cells (CD19+)10681051 cells/ulNK cells (CD3-/CD16+ or CD56+)751188 cells/ulNaïve CD4+ (CD45RA+CCR7+)83.774.1 %Naïve CD8+ (CD45RA+CCR7+)77.376 %Treg (CD4+ CD25hiCD127lo)5.68.8 %Naïve B cells (IgD+CD27-)88.4n/a %Unswitchedmem B cells (IgD+CD27+)4n/a %Switched mem B cells (IgD-CD27+)4.2n/a %Transitional B cells (CD24hiCD38hi)31.527.2 %Marginal Zone-like B cells (CD24hiCD38lo)614.5 %CD 19+CD21loCD38lo B cells2.81.6 %Plasmablasts (CD24loCD38hi)0.90.6 %Fecal calprotectin30n/a mcg/gFecal lactoferrinnegn/a mcg/mL [Display omitted] We assessed the impact of heterozygous BACH2 deletion on his immunophenotype. Detailed in Table 1, laboratory findings partially consistent with published BACH2 patients were hypogammaglobulinemia, decreased “Treg”% (CD25hiCD127lo, Foxp3 expression pending) and elevated transitional B cells. Contrary to patients previously described, he had no decreased memory B cells and had normal T cell proliferation. Prior patients had intestinal inflammation and one was ANCA+. Our patient’s cytokine panel showed mild elevations in sIL2R, IL-10 and IL-6, which resolved after SCIG initiation. Stool inflammatory markers were normal and evaluation by gastroenterology and rheumatology was reassuring. Of note, our patient is significantly younger than published patients, thus autoimmunity could develop with time. The frequency of patient’s infections improved since initiation of SCIG.In summary, we describe the first patient with immunodeficiency and clear BACH2 haploinsufficiency due to a chromosomal deletion, with recurrent infections and hypogammaglobulinemia in absence of intestinal inflammation or autoimmunity to date. He exhibits partially overlapping immunophenotype compared to described patients with BACH2 point mutations.

Mirror movements and callosal dysgenesis in a family with a DCC mutation: Neuropsychological and neuroimaging outcomes.

Corpus callosum dysgenesis is a congenital abnormality whereby the corpus callosum fails to develop normally, and has been associated with a range of neuropsychological outcomes. One specific finding in some individuals with corpus callosum dysgenesis is "congenital mirror movement disorder", which is the presence of involuntary movements on one side of the body that mimic voluntary movements of the other side. Mirror movements have also been associated with mutations in the deleted in colorectal carcinoma (DCC) gene. The current study aims to comprehensively document the neuropsychological outcomes and neuroanatomical mapping of a family (a mother, daughter and son) with known DCC mutations. All three family members experience mirror movements, and the son additionally has partial agenesis of the corpus callosum (pACC). All family members underwent extensive neuropsychological testing, spanning general intellectual functioning, memory, language, literacy, numeracy, psychomotor speed, visuospatial perception, praxis and motor functioning, executive functioning, attention, verbal/nonverbal fluency, and social cognition. The mother and daughter had impaired memory for faces, and reduced spontaneous speech, and the daughter demonstrated scattered impairments in attention and executive functioning, but their neuropsychological abilities were largely within normal limits. By contrast, the son showed areas of significant impairment across multiple domains including reduced psychomotor speed, fine motor dexterity and general intellectual functioning, and he was profoundly impaired across areas of executive functioning and attention. Reductions in his verbal/non-verbal fluency, with relatively intact core language, resembled dynamic frontal aphasia. His relative strengths included aspects of memory and he demonstrated largely sound theory of mind. Neuroimaging revealed an asymmetric sigmoid bundle in the son, connecting, via the callosal remnant, the left frontal cortex with contralateral parieto-occipital cortex. Overall, this study documents a range of neuropsychological and neuroanatomical outcomes within one family with DCC mutations and mirror movements, including one with more severe consequences and pACC.

YWHAE loss of function causes a rare neurodevelopmental disease with brain abnormalities in human and mouse

PurposeMiller-Dieker syndrome is caused by a multiple gene deletion, including PAFAH1B1 and YWHAE. Although deletion of PAFAH1B1 causes lissencephaly unambiguously, deletion of YWHAE alone has not clearly been linked to a human disorder. MethodsCases with YWHAE variants were collected through international data sharing networks. To address the specific impact of YWHAE loss of function, we phenotyped a mouse knockout of Ywhae. ResultsWe report a series of 10 individuals with heterozygous loss-of-function YWHAE variants (3 single-nucleotide variants and 7 deletions <1 Mb encompassing YWHAE but not PAFAH1B1), including 8 new cases and 2 follow-ups, added with 5 cases (copy number variants) from literature review. Although, until now, only 1 intragenic deletion has been described in YWHAE, we report 4 new variants specifically in YWHAE (3 splice variants and 1 intragenic deletion). The most frequent manifestations are developmental delay, delayed speech, seizures, and brain malformations, including corpus callosum hypoplasia, delayed myelination, and ventricular dilatation. Individuals with variants affecting YWHAE alone have milder features than those with larger deletions. Neuroanatomical studies in Ywhae−/− mice revealed brain structural defects, including thin cerebral cortex, corpus callosum dysgenesis, and hydrocephalus paralleling those seen in humans. ConclusionThis study further demonstrates that YWHAE loss-of-function variants cause a neurodevelopmental disease with brain abnormalities.

TDCS as an adjunct tool for enchance cognitive, language and motor skills of a child with corpus callosum dysgenesis - case report

tDCS as an adjunct tool for enchance cognitive, language and motor skills of a child with corpus callosum dysgenesis - case report

CLEC16A interacts with retromer and TRIM27, and its loss impairs endosomal trafficking and neurodevelopment

CLEC16A is a membrane-associated C-type lectin protein that functions as a E3-ubiquitin ligase. CLEC16A regulates autophagy and mitophagy, and reportedly localizes to late endosomes. GWAS studies have associated CLEC16A SNPs to various auto-immune and neurological disorders, including multiple sclerosis and Parkinson disease. Studies in mouse models imply a role for CLEC16A in neurodegeneration. We identified bi-allelic CLEC16A truncating variants in siblings from unrelated families presenting with a severe neurodevelopmental disorder including microcephaly, brain atrophy, corpus callosum dysgenesis, and growth retardation. To understand the function of CLEC16A in neurodevelopment we used in vitro models and zebrafish embryos. We observed CLEC16A localization to early endosomes in HEK293T cells. Mass spectrometry of human CLEC16A showed interaction with endosomal retromer complex subunits and the endosomal ubiquitin ligase TRIM27. Expression of the human variant leading to C-terminal truncated CLEC16A, abolishes both its endosomal localization and interaction with TRIM27, suggesting a loss-of-function effect. CLEC16A knockdown increased TRIM27 adhesion to early endosomes and abnormal accumulation of endosomal F-actin, a sign of disrupted vesicle sorting. Mutagenesis of clec16a by CRISPR–Cas9 in zebrafish embryos resulted in accumulated acidic/phagolysosome compartments, in neurons and microglia, and dysregulated mitophagy. The autophagocytic phenotype was rescued by wild-type human CLEC16A but not the C-terminal truncated CLEC16A. Our results demonstrate that CLEC16A closely interacts with retromer components and regulates endosomal fate by fine-tuning levels of TRIM27 and polymerized F-actin on the endosome surface. Dysregulation of CLEC16A-mediated endosomal sorting is associated with neurodegeneration, but it also causes accumulation of autophagosomes and unhealthy mitochondria during brain development.

Placental chorioangioma with Dysgenesis of corpus callosum: A case report

Placental chorioangioma with Dysgenesis of corpus callosum: A case report

The relevance of heterotopic callosal fibers to interhemispheric connectivity of the mammalian brain.

The corpus callosum (CC) is the largest white matter structure and the primary pathway for interhemispheric brain communication. Investigating callosal connectivity is crucial to unraveling the brain's anatomical and functional organization in health and disease. Classical anatomical studies have characterized the bulk of callosal axonal fibers as connecting primarily homotopic cortical areas. Whenever detected, heterotopic callosal fibers were ascribed to altered sprouting and pruning mechanisms in neurodevelopmental diseases such as CC dysgenesis (CCD). We hypothesized that these heterotopic connections had been grossly underestimated due to their complex nature and methodological limitations. We used the Allen Mouse Brain Connectivity Atlas and high-resolution diffusion-weighted imaging to identify and quantify homotopic and heterotopic callosal connections in mice, marmosets, and humans. In all 3 species, we show that ~75% of interhemispheric callosal connections are heterotopic and comprise the central core of the CC, whereas the homotopic fibers lay along its periphery. We also demonstrate that heterotopic connections have an essential role in determining the global properties of brain networks. These findings reshape our view of the corpus callosum's role as the primary hub for interhemispheric brain communication, directly impacting multiple neuroscience fields investigating cortical connectivity, neurodevelopment, and neurodevelopmental disorders.

Increased persuadability and credulity in people with corpus callosum dysgenesis

Corpus callosum dysgenesis is one of the most common congenital neurological malformations. Despite being a clear and identifiable structural alteration of the brain's white matter connectivity, the impact of corpus callosum dysgenesis on cognition and behaviour has remained unclear. Here we build upon past clinical observations in the literature to define the clinical phenotype of corpus callosum dysgenesis better using unadjusted and adjusted group differences compared with a neurotypical sample on a range of social and cognitive measures that have been previously reported to be impacted by a corpus callosum dysgenesis diagnosis. Those with a diagnosis of corpus callosum dysgenesis (n = 22) demonstrated significantly higher persuadability, credulity, and insensitivity to social trickery than neurotypical (n = 86) participants, after controlling for age, sex, education, autistic-like traits, social intelligence, and general cognition. To explore this further, we examined the covariance structure of our psychometric variables using a machine learning algorithm trained on a neurotypical dataset. The algorithm was then used to test whether these dimensions possessed the capability to discriminate between a test-set of neurotypical and corpus callosum dysgenesis participants. After controlling for age and sex, and with Leave-One-Out-Cross-Validation across 250 training-set bootstrapped iterations, we found that participants with a diagnosis of corpus callosum dysgenesis were best classed within dimension space along the same axis as persuadability, credulity, and insensitivity to social trickery, with a mean accuracy of 71.7%. These results have implications for a) the characterisation of corpus callosum dysgenesis, and b) the role of the corpus callosum in social inference.

Hydrocephalus in encephalocele.

Encephalocele is a rare congenital neural tube defect (NTD) characterized by herniation of intracranial contents through a defect in the skull. In our study, encephalocele was diagnosed in our clinic and its association with hydrocephalus was evaluated. The effect of this association on the prognosis was discussed. Patients who underwent surgery and follow-up with the diagnosis of encephalocele in the neurosurgery clinic of our hospital in an 8-year period from 2013 to 2021 were retrospectively examined. Patient records were obtained from the case notes of patients who underwent excision and repair for encephalocele. Of the 78 patients included in the study, 88.4% underwent surgery in the neonatal period. Moreover, 47% of the patients are male, and 31% are female. Encephalocele was present in 62.8% of patients and meningocele in 37.2%. Furthermore, 82.1% of encephalocele sacs were located in the occipital region. Chiari type 3 malformation was present in 57.6% of patients. Hydrocephalus developed in 56.4% of patients. There was an additional syndrome in 10.3% of the cases. The most common additional syndromes were corpus callosum dysgenesis with 39.7% and colpocephaly with 29.5%. The additional disease was present in 43.6% of patients. Preoperative and postoperative examination findings of more than half of patients were normal, but 33.3% were apathetic. Furthermore, 67.9% of patients, who underwent complete repair, survived, and 32.1% died. Hydrocephalus was present in 73.5% of patients with encephalocele (p<0.05). Hydrocephalus developed in 77.8% of patients with Chiari type 3 malformation (p<0.05). Hydrocephalus was found in 88.0% of patients with Ex (p<0.05). Encephalocele, which is a subgroup of NTD, differs clinically by its location and accompanying additional anomalies. In encephaloceles, the risk of morbidity and mortality can only be reduced with the multidisciplinary approach. Hydrocephalus and Chiari type 3 malformation are common in patients with encephalocele. These associations adversely affect the prognosis of the disease. Further research should be conducted on the evaluation of risk factors of NTD and methods of prevention from NTD. In this regard, we recommend that the training be repeated at certain intervals and that people's awareness should be raised.