Corpus Callosum Malformations Research Articles

Prenatal and Postnatal Diagnosis and Genetic Background of Corpus Callosum Malformations and Neonatal Follow-Up.

The corpus callosum is one of the five main cerebral commissures. It is key to combining sensory and motor functions. Its structure can be pathological (dysgenesis) or completely absent (agenesis). The corpus callosum dys- or agenesis is a rare disease (1:4000 live births), but it can have serious mental effects. In our study, we processed the data of 64 pregnant women. They attended a prenatal diagnostic center and genetic counseling from 2005 to 2019 at the Department of Obstetrics and Gynecology at Semmelweis University. The pregnancies had the following outcomes: 52 ended in delivery, 1 in spontaneous abortion, and 11 in termination of pregnancy (TOP) cases (n = 64). The average time of detection with imaging tests was 25.24 gestational weeks. In 16 cases, prenatal magnetic resonance imaging (MRI) was performed. If the abnormality was detected before the 20th week, a genetic test was performed on an amniotic fluid sample obtained from a genetic amniocentesis. Karyotyping and cytogenetic tests were performed in 15 of the investigated cases. Karyotyping gave normal results in three cases (46,XX or XY). In one of these cases, postnatally chromosomal microarray (CMA) was later performed, which confirmed Aicardi syndrome (3q21.3-21.1 microdeletion). In one case, postnatally, the test found Wiedemann-Rautenstrauch syndrome. In other cases, it found X ring, Di George syndrome, 46,XY,del(13q)(q13q22) and 46,XX,del(5p)(p13) (Cri-du-chat syndrome). Edwards syndrome was diagnosed in six cases, and Patau syndrome in one case. We found that corpus callosum abnormalities are often linked to chromosomal problems. We recommend that a cytogenetic test be performed in all cases to rule out inherited diseases. Also, the long-term outcome does not just depend on the disease's severity and the associated other conditions, and hence proper follow-up and early development are also key. For this reason, close teamwork between neonatology, developmental neurology, and pediatric surgery is vital.

Clinical phenotype and genetic characteristics of SZT2 related diseases: A case report and literature review

PurposeSeizure threshold 2 protein homolog gene (SZT2, MIM: 615463) related diseases are extremely rare autosomal recessive disorders with a wide spectrum of clinical phenotypes ranging from mild intellectual impairment to severe developmental epileptic encephalopathy (DEE). Most SZT2 related diseases are accompanied by craniofacial malformation and corpus callosum malformation. This study attempts to analyze and summarize the clinical phenotype and genetic characteristics of SZT2 related diseases, providing a basis for early diagnosis, treatment, and prognosis. MethodWe analyzed the clinical characteristics of a Chinese child with pathogenic variants of SZT2. We also performed whole-exome sequencing (WES) on the patient. In addition, we conducted a literature review of previously reported patients with pathogenic mutations in the SZT2 gene. ResultThe proband was a boy aged 1 year and 9 months with severe global developmental delay, transient drug-controlled focal epilepsy, cluster epilepsy, autism spectrum disorder, craniofacial deformity, hypotonia, focal EEG discharge, corpus callosum malformation, and persistent cavum septum pellucidum. WES revealed that the patient carried the SZT2 gene c.7584dupA and c.6302A>C complex heterozygous variants; the former being Likely Pathogenic (LP) and the latter Uncertain Significance (VUS) according to ACMG classification guidelines. According to our literature review, 43 cases of SZT2 related diseases have been reported so far; these include 15 cases with homozygous variations and 28 cases with complex heterozygous variations. A total of 57 types of variation were found, including 47 genetic variants, 2 de novo variants, and 8 unknown genetic modes. In addition, 2 high-frequency variants were found (c.5949_5951delTGT and c.6553C>T). The main clinical manifestations of the 40 patients were global developmental delay (GDD) of varying degrees (38/40, 95.00%), seizures (36/40, 90.00%), cranial deformity (27/40, 67.50%), facial deformity (22/40, 55.00%), hypotonia (22/40, 55.00%), abnormal interseizure EEG discharge (26/40, 65.00%), slow background activity (20/40, 50.00%), corpus callosum deformity (18/40, 45.00%). There was also one case of sudden unexpected death in epilepsy (SUDEP) and 3 cases of death from infection. In addition, three fetuses with the same variant had hydrocephalus and encephalocele. ConclusionThe compound heterozygous mutation of c.7584dupA and c.6302A>C in the SZT2 gene is the genetic etiology of this patient, expanding the mutation spectrum of SZT2 related diseases. Early genetic testing is the best choice for clear diagnosis, treatment, and prognosis.

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.

Clinical and molecular characterization of 1q43q44 deletion and corpus callosum malformations: 2 new cases and literature review

BackgroundCorpus callosum malformations (CCM) represent one of the most common congenital cerebral malformations with a prevalence of around one for 4000 births. There have been at least 230 reports in the literature concerning 1q43q44 deletions of varying sizes discovered using chromosomal microarrays. This disorder is distinguished by global developmental delay, seizures, hypotonia, corpus callosum defects, and significant craniofacial dysmorphism. In this study, we present a molecular cytogenetic analysis of 2 Tunisian patients with corpus callosum malformations. Patient 1 was a boy of 3 years old who presented psychomotor retardation, microcephaly, behavioral problems, interventricular septal defect, moderate pulmonary stenosis, hypospadias, and total CCA associated with delayed encephalic myelination. Patient 2 was a boy of 9 months. He presented a facial dysmorphia, a psychomotor retardation, an axial hypotonia, a quadri pyramidal syndrome, a micropenis, and HCC associated with decreased volume of the periventricular white matter. Both the array comparative genomic hybridization and fluorescence in situ hybridization techniques were used.ResultsArray CGH analysis reveals that patient 1 had the greater deletion size (11,7 Mb) at 1q43. The same region harbors a 2,7 Mb deletion in patient 2. Here, we notice that the larger the deletion, the more genes are likely to be involved, and the more severe the phenotype is likely to be. In both patients, the commonly deleted region includes six genes: PLD5, AKT3, ZNF238, HNRNPU, SDCCAG8 and CEP170. Based on the role of the ZNF238 gene in neuronal proliferation, migration, and cortex development, we hypothesized that the common deletion of ZNF238 in both patients seems to be the most responsible for corpus callosum malformations. Its absence may directly cause CCM. In addition, due to their high expression in the brain, PLD5 and FMN2 could modulate in the CCM phenotype.ConclusionOur findings support and improve the complex genotype–phenotype correlations previously reported in the 1qter microdeletion syndrome and define more precisely the neurodevelopmental phenotypes associated with genetic alterations of several genes related to this pathology.

Long-term outcome of consecutive case series of congenital isolated agenesis of corpus callosum.

To describe the long-term outcome of children with prenatally diagnosed isolated complete agenesis of the corpus callosum (cACC). In this single-center case series, we reviewed retrospectively the charts of fetuses referred to our fetal therapy unit from January 2004 to July 2020 for a suspected anomaly of the corpus callosum (CC). Cases with prenatally diagnosed isolated cACC were included. Fetal karyotype and comparative genomic hybridization microarray of amniotic fluid, in addition to fetal magnetic resonance imaging, were offered to all pregnant women with a diagnosis of fetal CC malformation. The surviving children were enrolled in the neurodevelopmental follow-up program at our institution, which included postnatal magnetic resonance imaging, serial neurological examinations and neurodevelopmental evaluations with standardized tests according to age. Families living in remote areas or far from our institution were offered a structured ad-hoc phone interview. A total of 128 pregnancies with fetal CC malformation were identified (mean gestational age at diagnosis, 24.5 (range, 21-34) weeks), of which 53 cases were diagnosed prenatally with apparently isolated cACC. Of these, 12 cases underwent termination of pregnancy, one resulted in intrauterine demise at 24 weeks of gestation and 13 cases were lost to follow-up. Of the remaining 27 children, one was excluded due to an associated chromosomal anomaly (8p21.3q11.21 mosaic duplication) diagnosed after birth, which could have been detected prenatally if the parents had consented to amniocentesis. In the 26 children included in the analysis, neurodevelopmental follow-up was available for a median of 3 (range, 1-16) years. Three (11.5%) infants had severe neurodevelopmental impairment, two of which were diagnosed postnatally with a genetic syndrome (Mowat-Wilson syndrome and Vici syndrome) that would not have been diagnosed prenatally. Seven (26.9%) children had mild neurodevelopmental impairment and 16 (61.5%) had normal neurodevelopmental outcome. The Full-Scale Intelligence Quotients of the three children with severe neurodevelopmental impairment were 50, 64 and 63, respectively, while that of the remaining children was in the normal range (median, 101; range, 89-119). In 88% of the children with cACC included in this study, neurodevelopment was not severely impaired. However, long-term follow-up is recommended in all cases of congenital isolated cACC to recognize subtle neurodevelopmental disorders as early as possible. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Demographic, ocular and associated neurological findings in corpus callosum malformations

The corpus callosum is a primary commissural part of the brain which connects the two hemispheres. Processing sensory, motor, visuo-motor and cognitive functions are related to a healthy connection. In this study, we aimed to evaluate the ocular, neurologic and other systemic findings of corpus callosum malformations and to focus on the association between the ocular and neurological findings and the type of callosal malformation according to cranial magnetic resonance imaging (MRI). A retrospective chart review of 57 patients with corpus callosum malformation was performed. Demographic features, neurologic, ocular and other systemic findings were noted. Patients were divided into 3 groups according to the severity of corpus callosum malformation on MRI (total agenesis, partial agenesis and hypoplasia) and also evaluated as a part of a genetic disorder/syndrome or not. The differences between demographic features, ocular and neurological findings between these 3 groups and also between syndromic and non-syndromic groups were evaluated statistically. Only 35.1% of patients had fixation and following pattern of visual acuity. Anterior segment pathologies were observed in 6.9% of patients. However, 57.9% of patients had posterior segment malformations. Only 19.3% of patients had a normal ocular alignment. There was no statistically significant difference of demographic features, ocular and neurologic findings between the 3 groups or between the syndromic/non-syndromic groups. Ocular findings can be reliable depending on the severity of the corpus callosum malformations. However, delay in fixation reflex development or loss of fixation should remind us of central nervous system pathologies especially corpus callosum malformations.

Variants in ADD1 Cause Intellectual Disability, Corpus Callosum Dysgenesis, and Ventriculomegaly in Humans

Purpose: Adducins interconnect spectrin and actin filaments to form polygonal scaffolds beneath the cell membranes and ring-like structures in neuronal axons. Adducins regulate mouse neural development, but their essential function in human brain development is unknown. Methods: We used exome sequencing to uncover ADD1 variants in individuals affected by intellectual disability (ID) and structural brain malformations. We analyzed ADD1 splice isoforms in neocortex development with RNA-Seq, super resolution imaging and immunoblotting. We modeled ADD1 variants by CRISPR/Cas9 editing, introducing variant proteins into human cells, and investigating neural development in Add1 knockout mice. Results: We uncovered loss-of-function (LoF) ADD1 variants in four affected individuals affected by ID and structural brain defects. De novo copy number variations covering the ADD1 locus were identified in three other affected individuals. ADD1 splice isoforms are highly and differentially expressed between neural progenitors and postmitotic neurons in the developing human and mouse neocortex. Human variants impair ADD1 protein level and/or dimerization with ADD2. Add1 knockout mice recapitulate the corpus callosum dysgenesis and ventriculomegaly found in humans with ADD1 LoF variants. Conclusion: Our human and mouse genetics results indicate that ADD1 loss-of-function is associated with corpus callosum malformation, ventriculomegaly, and intellectual disability.

Basal Ganglia Dysmorphism in Patients With Aicardi Syndrome.

Aiming to detect associations between neuroradiologic and EEG evaluations and long-term clinical outcome in order to detect possible prognostic factors, a detailed clinical and neuroimaging characterization of 67 cases of Aicardi syndrome (AIC), collected through a multicenter collaboration, was performed. Only patients who satisfied Sutton diagnostic criteria were included. Clinical outcome was assessed using gross motor function, manual ability, and eating and drinking ability classification systems. Brain imaging studies and statistical analysis were reviewed. Patients presented early-onset epilepsy, which evolved into drug-resistant seizures. AIC has a variable clinical course, leading to permanent disability in most cases; nevertheless, some cases presented residual motor abilities. Chorioretinal lacunae were present in 86.56% of our patients. Statistical analysis revealed correlations between MRI, EEG at onset, and clinical outcome. On brain imaging, 100% of the patients displayed corpus callosum malformations, 98% cortical dysplasia and nodular heterotopias, and 96.36% intracranial cysts (with similar rates of 2b and 2d). As well as demonstrating that posterior fossa abnormalities (found in 63.63% of cases) should also be considered a common feature in AIC, our study highlighted the presence (in 76.36%) of basal ganglia dysmorphisms (never previously reported). The AIC neuroradiologic phenotype consists of a complex brain malformation whose presence should be considered central to the diagnosis. Basal ganglia dysmorphisms are frequently associated. Our work underlines the importance of MRI and EEG, both for correct diagnosis and as a factor for predicting long-term outcome. This study provides Class II evidence that for patients with AIC, specific MRI abnormalities and EEG at onset are associated with clinical outcomes.

Clinical Outcome of Children With Corpus Callosum Agenesis

BackgroundAgenesis of the corpus callosum is a rare congenital brain malformation that can be associated with other cerebral malformations and/or underlying genetic causes. Prenatal counseling is hampered due to the lack of reliable long-term data on neurodevelopmental outcome. MethodsSince 2010, a total of 23 children with agenesis of the corpus callosum (mean age 3.8 years, range 0.7 to 9.7 years) were registered in our ACC outpatient clinic and diagnosed in a standardized manner; the data were analyzed retrospectively. Prenatal and postnatal imaging, associated malformations, genetic and clinical findings, and psychological testing (Bayley Scales, Kaufman Assessment Battery for Children II, Snijders-Oomen Non-verbal Test, Wechsler Preschool and Primary Scale I-III) were included. The clinical outcome was classified as “normal” (intelligence quotient 85 to 115, unremarkable motor skills), “moderate developmental delay” (intelligence quotient 70 to 85, mild motor abnormalities), and “severe developmental delay” (intelligence quotient less than 70, severe movement disorder). ResultsIsolated corpus callosum malformation was diagnosed in 15 of 23 (65%), associated cerebral malformations in four of 23 (17%), and associated cerebral malformations plus intracranial cyst in four of 23 (17%) children. Prenatal diagnosis changed in nine of 23 (39%) cases. Overall, a normal outcome or moderate or severe developmental delay was present in 15 of 23 (65%) or five of 23 (22%) or three of 23 (13%) children, respectively. Also six of eight children with associated cerebral malformations showed normal outcome. ConclusionOur findings support the notion that developmental outcome is favorable in about two-thirds of children with prenatally diagnosed agenesis of corpus callosum. However, the individual outcome in children with agenesis of corpus callosum is difficult to predict. Even children with correctly characterized phenotypes show a variety of outcomes, making prenatal counseling challenging.

Utilization of neurosonography for evaluation of the corpus callosum malformations in the era of fetal magnetic resonance imaging.

We evaluated the ability of fetal neurosonography and magnetic resonance imaging (MRI) to asses callosal anomalies (CA) and associated cranial malformations. We also aimed to determine the long-term prognosis of the cases. Thirty-six cases of CA diagnosed combined with neurosonography and MRI between January 2012 and October 2017 were retrospectively reviewed. Seventeen of 36 fetuses were diagnosed complete agenesis of corpus callosum (CACC) (47.2%), 9 had partial agenesis of corpus callosum (PACC) (25%) and 10 was dysgenesis of the corpus callosum (DCC) (27.2%) at ultrasonography (US) examination. Fetal MRI reported 16 of cases as CACC (44.4%), 11 PACC (30.5%) and nine (25%) DCC. The overall consistency between neurosonography and MRI in the definition of CA were 91% of cases. Sulcation anomalies were present in 9 cases in the US (25%) and 11 cases in MRI (30.4%). Seven of cases showed posterior fossa abnormalities in the US (19.4%) and eight cases in MRI (22.1%). Neonatal MRI added new findings to fetal MRI and neurosonography including grade-1 intraventricular hemorrhage and periventricular leukomalacia in two cases (12.5%). Eighteen cases were terminated (50%), 17 cases were followed up and mean follow up interval was 39 ± 5.1 months. The neurologic outcome was abnormal in seven (41.7%) patients. Presence of associated brain anomalies worsened the prognosis. Fetal neurosonography has a comparable performance with MRI in the diagnosis of CA and associated anomalies. It should be used in collaboration with MRI to achieve accurate diagnosis which is crucial for counseling.

The use of diffusion tractography to characterize a corpus callosum malformation in a dog.

IntroductionThe pathogenesis of corpus callosum malformations (CCM) is not well defined in the dog because of inherent limitations of structural magnetic resonance imaging (MRI) to evaluate the white matter. We used the advanced neuroimaging technique of tractography to virtually dissect the white matter projections in a dog with a CCM and in a normal control dog.MethodsA 9‐month‐old male Coonhound that had a previous structural MRI diagnosis of CCM and a normal control dog underwent anesthesia and 3‐Tesla MRI. Diffusion‐tensor imaging and 3D T1‐weighted and 2D T2‐weighted sequences were acquired. Diffusion data were processed before tensor reconstruction and fiber tracking. Virtual dissections were performed to dissect out the major white matter projections in each dog.ResultsIn the dog with CCM, the corpus callosum exhibited interhemispheric crossing fibers at the level of the splenium and formed longitudinal callosal fasciculi (Probst bundles). In addition, the fornix was small and the cingula enlarged and exhibited increased dorsal connectivity relative to the normal control.Conclusions and Clinical ImportanceWe used tractography to describe a white matter malformation in a dog. The results suggest that, embryologically, formed axons fail to cross midline and instead create Probst bundles.

Mutations in MAST1 Cause Mega-Corpus-Callosum Syndrome with Cerebellar Hypoplasia and Cortical Malformations

Corpus callosum malformations are associated with a broad range of neurodevelopmental diseases. We report that de novo mutations in MAST1 cause mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations (MCC-CH-CM) in the absence of megalencephaly. We show that MAST1 is a microtubule-associated protein that is predominantly expressed in post-mitotic neurons and is present in both dendritic and axonal compartments. We further show that Mast1 null animals are phenotypically normal, whereas the deletion of a single amino acid (L278del) recapitulates the distinct neurological phenotype observed in patients. In animals harboring Mast1 microdeletions, we find that the PI3K/AKT3/mTOR pathway is unperturbed, whereas Mast2 and Mast3 levels are diminished, indicative of a dominant-negative mode of action. Finally, we report that de novo MAST1 substitutions are present in patients with autism and microcephaly, raising the prospect that mutations in this gene give rise to a spectrum of neurodevelopmental diseases.

Magnetic resonance imaging of the fetal brain at 3 Tesla: Preliminary experience from a single series.

To report our preliminary experience with cerebral fetal magnetic resonance imaging (MRI) with a 3 Tesla (3T) scanner. We assessed feasibility, time of acquisition, and possibility to establish a diagnosis.Fifty-nine pregnant women had fetal MRI performed during the third trimester of pregnancy due to clinical or sonography concern of a central nervous system anomaly. No fetal or maternal sedation was used. The MRI protocol consisted of T2 turbo-spin-echo images in 3 planes of space. No T1-weighted images were performed. All images were analyzed by 2 pediatric neuroradiologists, who evaluated spatial resolution, artifacts, time of acquisition, and possibility to establish a diagnosis suspected by sonography.Examinations were performed safely for all patients. The images required longer time of acquisition (approximately 75 seconds for each plane in the space). The specific absorption rate was not exceeded in any fetus. Cerebral fetal MRI was normal in 22 cases. The spectrum of diagnostics included isolated ventriculomegaly, posterior fossa malformation, corpus callosum malformation, gyration anomalies, craniosynostosis, tuberous sclerosis, microcephaly, external hydrocephaly, midline arachnoid cyst, cerebral lesions, and persistent hyperplastic primitive vitreous.In our series, 3 T MRI of fetal brain was feasible and able to establish a diagnosis but required longer time of acquisition.

Plasticity of Interhemispheric Temporal Lobe White Matter Pathways Due to Early Disruption of Corpus Callosum Development in Spina Bifida.

Spina bifida myelomeningocele (SBM) is commonly associated with anomalous development of the corpus callosum (CC) because of congenital partial hypogenesis and hydrocephalus-related hypoplasia. It represents a model disorder to examine the effects of early disruption of CC neurodevelopment and the plasticity of interhemispheric white matter connections. Diffusion tensor imaging was acquired on 76 individuals with SBM and 27 typically developing individuals, aged 8-36 years. Probabilistic tractography was used to isolate the interhemispheric connections between the posterior superior temporal lobes, which typically traverse the posterior third of the CC. Early disruption of CC development resulted in restructuring of interhemispheric connections through alternate commissures, particularly the anterior commissure (AC). These rerouted fibers were present in people with SBM and both CC hypoplasia and hypogenesis. In addition, microstructural integrity was reduced in the interhemispheric temporal tract in people with SBM, indexed by lower fractional anisotropy, axial diffusivity, and higher radial diffusivity. Interhemispheric temporal tract volume was positively correlated with total volume of the CC, such that more severe underdevelopment of the CC was associated with fewer connections between the posterior temporal lobes. Therefore, both the macrostructure and microstructure of this interhemispheric tract were reduced, presumably as a result of more extensive CC malformation. The current findings suggest that early disruption in CC development reroutes interhemispheric temporal fibers through both the AC and more anterior sections of the CC in support of persistent hypotheses that the AC may serve a compensatory function in atypical CC development.

Clinical, genetic and neuropathological findings in a series of 138 fetuses with a corpus callosum malformation.

Corpus callosum malformation (CCM) is the most frequent brain malformation observed at birth. Because CCM is a highly heterogeneous condition, the prognosis of fetuses diagnosed prenatally remains uncertain, making prenatal counseling difficult. We evaluated retrospectively a total of 138 fetuses, 117 with CCM observed on prenatal imaging examination, and 21 after postmortem autopsy. On ultrasound and/or magnetic resonance imaging, CCM was either isolated (N = 40) or associated with other neurological (N = 57) or extra cerebral findings (N = 21/20, respectively). Most fetuses (N = 132) remained without a diagnosis at the time of pregnancy termination. This emphasizes the need to establish a neuropathological classification and to perform a genomic screening using comparative genomic hybridization. A neuropathological examination performed on 138 cases revealed a spectrum of CCMs, classified as follows: agenesis of corpus callosum (55), CC hypoplasia (30), CC dysmorphism (24), and CCM associated with a malformation of cortical development (29). Of interest, after fetopathological examination, only 16/40 malformations were classified as isolated, highlighting the importance of the autopsy following termination of pregnancy. Among the 138 cases, the underlying etiology was found in 46 cases: diabetes (one case), cytomegalovirus infection (one case), 23 chromosome abnormalities, and 21 mendelian conditions. In our series of 138 cases of CCM, prenatal and postmortem examinations identified a variety of genetic causes. However, no diagnosis could be established in 67% of cases. The classification based on the underlying neurodevelopmental defects paves the way for further genetic studies and genotype-phenotype correlations.

Detection of corpus callosum malformations in pediatric population using the discriminative direction in multiple kernel learning.

In this paper we propose a Multiple Kernel Learning (MKL) classifier to detect malformations of the Corpus Callosum (CC) and apply it in a pediatric population. Furthermore, we extend the concept of discriminative direction to the linear MKL methods, implementing it in a single subject analysis framework. The CC is characterized using different measures derived from Magnetic Resonance Imaging (MRI) data and the MKL approach is used to efficiently combine them. The discriminative direction analysis highlights those features that lead the classification for each given subject. In the case of a CC with malformation this means highlighting the abnormal characteristics of the CC that guide the diagnosis. Experiments show that the method correctly identifies the malformative aspects of the CC. Moreover, it is able to identify dishomogeneus, localized or widespread abnormalities among the different features. The proposed method is therefore suitable for supporting neuroradiologists in the decision-making process, providing them not only with a suggested diagnosis, but also with a description of the pathology.

Could a mutation in the TGIF-1 gene result in phenotypical expressions like pachygyria, intracerebral calcification, and neonatal epilepsy?

Mutations of the TGIF-1 gene in humans may be seen in connection with various complex malformation syndromes. Phenotypical expression may include microcephaly, hypotelorism, a single large incisor, clefts of lip and palate, and structural abnormalities of the brain (holoprosencephaly, corpus callosum malformation). Carriers of the mutation without physical signs have been described.

The combinatorial guidance activities of draxin and Tsukushi are essential for forebrain commissure formation

We have shown that draxin is a repulsive axon guidance molecule for a variety of neuron classes and that genetic deletion of draxin in mice results in the absence of all forebrain commissures. Moreover, we also identified a secreted molecule, Tsukushi (TSK), that belongs to the small leucine-rich proteoglycan family (SLRP) and inhibits signaling molecules, such as BMP and Wnt. TSK knockout mice show malformation of the corpus callosum (CC) and agenesis of the anterior commissure (AC), suggesting the importance of TSK function in forebrain commissure formation. There is a possibility that the combined function of these two proteins is essential for the formation of these commissures. In this study, we investigate this possibility by generating draxin/TSK doubly heterozygous mice and comparing their forebrain commissure phenotypes with those of singly heterozygous mice. We found that, although draxin and TSK did not interact directly, their genetic interaction was evident from the significantly higher prevalence of CC malformation and agenesis of the AC in the draxin/TSK doubly heterozygous mice. Importantly, in this study, we demonstrated a new function of TSK in guiding anterior olfactory neuronal (AON) and cortical axons. TSK bound to and provided growth inhibitory signals dose-dependently to AON and cortical axons in outgrowth assay. TSK also induced growth cone collapse when applied acutely to these cultured neurons. Furthermore, TSK and draxin had additive effects in inhibiting cortical and AON neurite outgrowth. Thus, based on a combination of genetic analyses and in vitro experiments, we propose that the combined guidance activities of draxin and TSK regulate forebrain commissure formation.

The ciliogenic transcription factor RFX3 regulates early midline distribution of guidepost neurons required for corpus callosum development.

The corpus callosum (CC) is the major commissure that bridges the cerebral hemispheres. Agenesis of the CC is associated with human ciliopathies, but the origin of this default is unclear. Regulatory Factor X3 (RFX3) is a transcription factor involved in the control of ciliogenesis, and Rfx3–deficient mice show several hallmarks of ciliopathies including left–right asymmetry defects and hydrocephalus. Here we show that Rfx3–deficient mice suffer from CC agenesis associated with a marked disorganisation of guidepost neurons required for axon pathfinding across the midline. Using transplantation assays, we demonstrate that abnormalities of the mutant midline region are primarily responsible for the CC malformation. Conditional genetic inactivation shows that RFX3 is not required in guidepost cells for proper CC formation, but is required before E12.5 for proper patterning of the cortical septal boundary and hence accurate distribution of guidepost neurons at later stages. We observe focused but consistent ectopic expression of Fibroblast growth factor 8 (Fgf8) at the rostro commissural plate associated with a reduced ratio of GLIoma-associated oncogene family zinc finger 3 (GLI3) repressor to activator forms. We demonstrate on brain explant cultures that ectopic FGF8 reproduces the guidepost neuronal defects observed in Rfx3 mutants. This study unravels a crucial role of RFX3 during early brain development by indirectly regulating GLI3 activity, which leads to FGF8 upregulation and ultimately to disturbed distribution of guidepost neurons required for CC morphogenesis. Hence, the RFX3 mutant mouse model brings novel understandings of the mechanisms that underlie CC agenesis in ciliopathies.

Processing Speed Delays Contribute to Executive Function Deficits in Individuals with Agenesis of the Corpus Callosum

Corpus callosum malformation and dysfunction are increasingly recognized causes of cognitive and behavioral disability. Individuals with agenesis of the corpus callosum (AgCC) offer unique insights regarding the cognitive skills that depend specifically upon callosal connectivity. We examined the impact of AgCC on cognitive inhibition, flexibility, and processing speed using the Color-Word Interference Test (CWIT) and Trail Making Test (TMT) from the Delis-Kaplan Executive Function System. We compared 36 individuals with AgCC and IQs within the normal range to 56 matched controls. The AgCC cohort was impaired on timed measures of inhibition and flexibility; however, group differences on CWIT Inhibition, CWIT Inhibition/Switching and TMT Number-Letter Switching appear to be largely explained by slow performance in basic operations such as color naming and letter sequencing. On CWIT Inhibition/Switching, the AgCC group was found to commit significantly more errors which suggests that slow performance is not secondary to a cautious strategy. Therefore, while individuals with agenesis of the corpus callosum show real deficits on tasks of executive function, this impairment appears to be primarily a consequence of slow cognitive processing. Additional studies are needed to investigate the impact of AgCC on other aspects of higher order cortical function.