Absence Of Corpus Callosum Research Articles

Septo-Optic Dysplasia: A Case Series of 33 Patients

ABSTRACT The objective of this study was to record the clinical, neuro-radiological, and systemic features of patients with septo-optic dysplasia (SOD). A retrospective review of patients was conducted to identify patients with features consistent with SOD over a 6-year period, including optic nerve hypoplasia with agenesis of midline structures, along with an absent septum pellucidum and/or agenesis of the corpus callosum. Thirty-three patients were identified. The male to female ratio was 2:1, while the median age at diagnosis was 5 years (interquartile range = 10 years, range = 0–44 years). Optic nerve hypoplasia (ONH) was bilateral in 81.81% of cases (n = 27) and unilateral in 18.18% of cases (n = 6), with three cases in each eye. Developmental delay was documented in 24.2% (n = 8). The most frequent magnetic resonance imaging features that were consistent with SOD included: isolated absent septum pellucidum reported in 51.51% (n = 17); isolated corpus callosum agenesis in 33.33% (n = 11); and both absent septum pellucidum and corpus callosum agenesis in 15.15% (n = 5). Pituitary gland abnormalities, including pituitary hypoplasia in 9% (n = 3) or hypoplasia of pituitary infundibulum in 6% (n = 2) were less common. Pituitary hormonal abnormalities were present in 50% of the 10 tested patients (n = 5). Although bilateral ONH is more frequent, hypoplasia of just one optic nerve could be a presenting feature of SOD. Therefore, additional neuro-imaging is important for a diagnosis in cases of unilateral and bilateral ONH and a multidisciplinary approach is beneficial.

Brain plasticity following corpus callosum agenesis or loss: a review of the Probst bundles.

The corpus callosum is the largest axonal tract in the human brain, connecting the left and right cortical hemipheres. This structure is affected in myriad human neurodevelopmental disorders, and can be entirely absent as a result of congenital or surgical causes. The age when callosal loss occurs, for example via surgical section in cases of refractory epilepsy, correlates with resulting brain morphology and neuropsychological outcomes, whereby an earlier loss generally produces relatively improved interhemispheric connectivity compared to a loss in adulthood (known as the "Sperry's paradox"). However, the mechanisms behind these age-dependent differences remain unclear. Perhaps the best documented and most striking of the plastic changes that occur due to developmental, but not adult, callosal loss is the formation of large, bilateral, longitudinal ectopic tracts termed Probst bundles. Despite over 100 years of research into these ectopic tracts, which are the largest and best described stereotypical ectopic brain tracts in humans, much remains unclear about them. Here, we review the anatomy of the Probst bundles, along with evidence for their faciliatory or detrimental function, the required conditions for their formation, patterns of etiology, and mechanisms of development. We provide hypotheses for many of the remaining mysteries of the Probst bundles, including their possible relationship to preserved interhemispheric communication following corpus callosum absence. Future research into naturally occurring plastic tracts such as Probst bundles will help to inform the general rules governing axon plasticity and disorders of brain miswiring.

Symposium 07: Early Development in Infants and Toddlers with Agenesis of the Corpus Callosum

Summary AbstractThe corpus callosum is the largest transverse white matter fiber tract connecting the two hemispheres of the brain. It plays an essential role in the interhemispheric transfer and bihemispheric coordination involved in perception and sensory-motor integration, as well as higher level cognition (e.g., memory, executive functioning). The corpus callosum forms prenatally (10-15 weeks gestation) and continues to develop through early adulthood. Damage to the corpus callosum throughout the lifespan, but especially later in life, can result in sensory and motor coordination deficits and produces disconnection syndromes.However, individuals born with a partial or fully absent corpus callosum, known as Agenesis of the Corpus Callosum (ACC), do not exhibit a full disconnection syndrome and may, in fact, demonstrate many intact skills including broadly average intellectual abilities. Agenesis of the corpus callosum (ACC) is a relatively common congenital brain malformation that occurs in 1 out of ∼4000 live births (Glass, Shaw, Ma, & Sherr, 2008; Paul et al., 2007). There is significant heterogeneity in outcomes for these individuals, often related to the presence of additional neuropathology, and the presence of co-occurring medical and genetic conditions. In adults for whom ACC is the primary neurological finding, there is a core constellation of cognitive symptoms that include reduced interhemispheric transfer, slowed processing, and difficulty with complex novel problem solving (Brown & Paul, 2019). There is also an elevated likelihood of autism spectrum disorders in this population as well (Paul et al, 2014).Modern ultrasound technology facilitates diagnosis of ACC in utero, offering a unique opportunity to study these individuals’ development from infancy. However, no studies to date have examined early development in this population using validated measures, leaving neuropsychologists, neurologists and primary care providers to make educated guesses about what families should expect and appropriate therapies/treatment.This symposium presents a series of studies examining the early development of individuals with primary ACC across domains including language, adaptive skills, autism symptomology, and temperament/anxiety. We will provide the first in-depth prospective characterization of development in ACC relative to typically developing children at 6, 12, 18 and 24 months and discuss what these findings reveal about brain development and plasticity more broadly (e.g. how does early disruption in interhemispheric connection impact cognitive development across key domains?).Finally, while ACC is defined specifically by corpus callosum anatomy, the corpus callosum has been implicated in other neurodevelopmental conditions (Paul, 2011). Utilizing extant comparison, we also assess how early development in ACC both overlaps and differs from two monogenic conditions (e.g. Fragile X and Down Syndrome) and a developmental behavioral diagnoses (e.g. autism) and discuss how early disruptions in interhemispheric transfer may contribute to shared behavioral phenotypes in these conditions.

3 Emotional Expression in Infants with Agenesis of the Corpus Callosum: The Role of Callosal Connectivity in Early Temperament

Objective:Accumulating evidence suggests that corpus callosum development is critically involved in the emergence of behavioral and cognitive skills during the first two years of life and that structural abnormalities of the corpus callosum are associated with a variety of neurodevelopmental disorders. Indeed by adulthood ∼30% of individuals with agenesis of the corpus callosum (ACC), a congenital condition resulting in a partial or fully absent corpus callosum, exhibit phenotypic features consistent with autism spectrum disorder (ASD). However, very little is known about developmental similarities and/or differences among infants with ACC and infants who develop ASD. This study describes temperament in infants with ACC during the first year of life in comparison with a neurotypical control group. Additionally, it examines the potential contribution of disrupted callosal connectivity to early expression of temperament in ASD through comparison to children with high familial likelihood of ASD.Participants and Methods:Longitudinal ratings of positive and negative emotionality were acquired at 6 and 12 months on the Infant Behavior Questionnaire-Revised across four groups of infants: isolated complete and partial ACC (n=104), high familial likelihood of ASD who do and do not have a confirmed ASD diagnosis (HL+ n=81, HL- n=282), and low-likelihood controls (LL- n=152).Results:Overall, the ACC group demonstrated blunted affect, with significantly lower positive and negative emotionality than LL controls at both timepoints. Specifically, the ACC group exhibited lower activity and approach dimensions of positive emotionality at both timepoints, with lower high-intensity pleasure at 6 months and lower vocal reactivity at 12 months. On negative emotionality subscales, the ACC group exhibited lower distress to limitations and sadness at both timepoints, as well as lower falling reactivity at 6 months. The ACC and HL groups did not differ significantly on positive emotionality at either timepoint. However, negative emotionality was lower in the ACC group than the HL- group at both timepoints and lower than the HL+ group at 12 months, with lower distress to limitations and sadness ratings than both HL groups at both timepoints.Conclusions:These findings highlight the importance of interhemispheric connections in facilitating active engagement and pursuit of pleasurable activities during the first year of life, as well as expression of sadness and distress to limitations. Notably, similarities between infants with ACC and infants at elevated familial risk of ASD suggest that disrupted callosal connectivity may specifically contribute to reductions in positive emotionality.

Development of neonatal-specific sequences for portable ultralow field magnetic resonance brain imaging: a prospective, single-centre, cohort study

Magnetic Resonance (MR) imaging is key for investigation of suspected newborn brain abnormalities. Access is limited in low-resource settings and challenging in infants needing intensive care. Portable ultralow field (ULF) MRI is showing promise in bedside adult brain imaging. Use in infants and children has been limited as brain-tissue composition differences necessitate sequence modification. The aim of this study was to develop neonatal-specific ULF structural sequences and test these across a range of gestational maturities and pathologies to inform future validation studies. Prospective cohort study within a UK neonatal specialist referral centre. Infants undergoing 3T MRI were recruited for paired ULF (64mT) portable MRI by convenience sampling from the neonatal unit and post-natal ward. Key inclusion criteria: 1) Infants with risk or suspicion of brain abnormality, or 2) preterm and term infants without suspicion of major genetic, chromosomal or neurological abnormality. Exclusions: presence of contra-indication for MR scanning. ULF sequence parameters were optimised for neonatal brain-tissues by iterative and explorative design. Neuroanatomic and pathologic features were compared by unblinded review, informing optimisation of subsequent sequence generations in a step-wise manner. Main outcome: visual identification of healthy and abnormal brain tissues/structures. ULF MR spectroscopy, diffusion, susceptibility weighted imaging, arteriography, and venography require pre-clinical technical development and have not been tested. Between September 23, 2021 and October 25, 2022, 102 paired scans were acquired in 87 infants; 1.17 paired scans per infant. Median age 9 days, median postmenstrual age 40+2 weeks (range: 31+3-53+4). Infants had a range of intensive care requirements. No adverse events observed. Optimised ULF sequences can visualise key neuroanatomy and brain abnormalities. In finalised neonatal sequences: T2w imaging distinguished grey and white matter (7/7 infants), ventricles (7/7), pituitary tissue (5/7), corpus callosum (7/7) and optic nerves (7/7). Signal congruence was seen within the posterior limb of the internal capsule in 10/11 infants on finalised T1w scans. In addition, brain abnormalities visualised on ULF optimised sequences have similar MR signal patterns to 3T imaging, including injury secondary to infarction (6/6 infants on T2w scans), hypoxia-ischaemia (abnormal signal in basal ganglia, thalami and white matter 2/2 infants on T2w scans, cortical highlighting 1/1 infant on T1w scan), and congenital malformations: polymicrogyria 3/3, absent corpus callosum 2/2, and vermian hypoplasia 3/3 infants on T2w scans. Sequences are susceptible to motion corruption, noise, and ULF artefact. Non-identified pathologies were small or subtle. On unblinded review, optimised portable MR can provide sufficient contrast, signal, and resolution for neuroanatomical identification and detection of a range of clinically important abnormalities. Blinded validation studies are now warranted. The Bill and Melinda Gates Foundation, the MRC, the Wellcome/EPSRC Centre for Medical Engineering, the MRC Centre for Neurodevelopmental Disorders, and the National Institute for Health Research (NIHR) Biomedical Research Centres based at Guy's and St Thomas' and South London & Maudsley NHS Foundation Trusts and King's College London.

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...

Clinical and molecular characteristics of a novel rare de novo variant in PPP2CA in a patient with a developmental disorder, autism, and epilepsy.

PP2A-related (neuro) developmental disorders are a family of genetic diseases caused by a heterozygous alteration in one of several genes encoding a subunit of type 2A protein phosphatases. Reported affected genes, so far, are PPP2R5D, encoding the PP2A regulatory B56δ subunit; PPP2R1A, encoding the scaffolding Aα subunit; and PPP2CA, encoding the catalytic Cα subunit-in that order of frequency. Patients with a pathogenic de novo mutation in one of these genes, in part, present with overlapping features, such as generalized hypotonia, intellectual and developmental delay, facial dysmorphologies, seizures, and autistic features, and, in part, with opposite features, e.g., smaller versus larger head sizes or normal versus absent corpus callosum. Molecular variant characterization has been consistent so far with loss-of-function or dominant-negative disease mechanisms for all three affected genes. Here, we present a case report of another PPP2CA-affected individual with a novel de novo missense variant, resulting in a one-amino acid substitution in the Cα subunit: p.Cys196Arg. Biochemical characterization of the variant revealed its pathogenicity, as it appeared severely catalytically impaired, showed mildly affected A subunit binding, and moderately decreased binding to B/B55, B"/PR72, and all B56 subunits, except B56γ1. Carboxy-terminal methylation appeared unaffected, as was binding to B"'/STRN3-all being consistent with a partial loss of function. Clinically, the girl presented with mild-to-moderate developmental delay, a full-scale IQ of 83, mild dysmorphic facial features, tonic-clonic seizures, and autistic behaviors. Brain MRI appeared normal. We conclude that this individual falls within the milder end of the clinical and molecular spectrum of previously reported PPP2CA cases.

133. Incidental finding of the 1st degree of parental relatedness in a newborn with JBS and homozygous UBR1 mutation

A 2-month-old newborn girl presented multiple congenital anomalies at birth, including ventriculomegaly, imperforate anus, absent nasal alae, absent corpus callosum, anemia, need for thermoregulation, feeding difficulty and failure to thrive. Clinical features are suggestive of autosomal recessive Johanson-Blizzard syndrome (JBS). Rapid interphase FISH of peripheral blood using centromere probes for X, Y and 18 was normal, and G-banding at 550 band levels showed a normal female karyotype. Whole genome microarray analysis using Affymetrix CytoScan® Dx showed no clinically significant copy number changes. However, the SNP analysis identified 30 regions of homozygosity (ROH)>5 Mb involving 17 autosomes and totaling ∼600 Mb (∼21.6% of ∼2,782 Mb total autosome length); which suggests a 1st degree of parental relatedness (ave. 25%; 95% CI: 21.3-28.7%; PMID: 22858719, 25118026). Such ROHs increase risk for imprinting and/or recessive Mendelian disorders. Noticeably, there was a 74 Mb ROH region in 15q11.2q26.2 encompassing UBR1 gene at 15q15.2, which pointed to possible homozygosity of an UBR1 mutation causing JBS. As expected, Next Generation Sequencing identified a homozygous UBR1 variant at C.1993C>T, exon 17 (UBR1, NM_174916.2), which is predicted to cause a premature protein termination p.(Arg665*). This variant is interpreted pathogenic, as it was reported in a patient with JBS (PMID:24599544) and multiple protein truncating variants were reported to be pathogenic in this gene. These findings supported a diagnosis of JBS in this proband. Our case illustrates that identification of ROHs can aid in investigation and diagnosis of autosomal diseases.

Glass-brain mapping provides an adjunct tool for structural analysis in mouse models of neurodevelopmental disease

Neurodevelopmental disorders are complex diseases with genetic and environmental factors shaping brain architecture. Here we undertook a proof of concept study to investigate brain structure using a glass-brain clearing and 3D-mapping workflow at high-resolution. Whole brain and sub-structure analysis included the genetic developmental and epileptic encephalopathy mouse model of Dravet syndrome (DS). In addition, we included the Black and Tan BRachyury (BTBR) mouse strain, which has acknowledged major and minor structural anomalies. Ex vivo P16 mouse brains were cleared using a modified solvent-based clearing method. The high-quality autofluorescence signal from light-sheet imaging provided unambiguous anatomical feature determination including the barrel-like regions of the cortex and absence of corpus callosum in BTBR mice. BTBR volume estimates were consistent with previous reports showing reduced hippocampal commissure volume. An automated image registration and statistical analysis pipeline was used to compare the control and DS model groups. Glass-brain images were registered to the scalable Allen Brain Atlas and annotations transformed into native space, with 20 μm isotropic voxels. Overall, glassbrain mapping provided a high-resolution measure of the premature mouse brain anatomy. We report novel structural changes in the DS model, which are consistent with cognitive and behavioural co-morbidities reported in this neurodevelopmental disease model.

Building bridges in the brain

Neurodevelopment Some 200 million axons connect the right hemisphere to the left through the brain's corpus callosum. A malformed or absent corpus callosum causes neurological or cognitive deficits. During development, astroglia build a substrate for axons to use in crossing the interhemispheric fissure. Signaling by Netrin 1 (NTN1) and its receptor, Deleted in Colorectal Carcinoma (DCC), guides axons to the midline. Morcom et al. show that NTN1 and DCC function even earlier to clear the path by regulating astroglial morphology and function. Without NTN1 and DCC function, astroglia that would normally build bridges across the interhemispheric fissure are unable to do so, and thus axons, no matter how well guided, struggle to build the corpus callosum. eLife 10 , e61769 (2021)

English

A 7-day-old new-born was referred to Department of Radiodiagnosis of North Bengal Medical College and Hospital to evaluate enlargement of head circumference. On clinical examination of this new-born we found macrocephaly and absent right thumb as well as deformed left thumb. No other clinical abnormalities were seen in this new-born apart from this. Facial structures, spine, upper and lower limbs, trunks were normal clinically. Transcranial ultrasound was done using LOGIQ P9 ultrasound machine which revealed an open lip schizencephaly involving right cerebral hemisphere with absence of corpus callosum. Trans abdominal sonography revealed non visualisation of left kidney in left renal fossa as well as in its usual ectopic position. Therefore, the new-born underwent magnetic resonance imaging (MRI) of brain and whole abdomen which confirmed ultrasound findings. MRI additionally revealed there was no ocular, anorectal and genito-urinary malformations. Infantogram was done to evaluate the skeleton of this new-born. Fetal echocardiography revealed no obvious cardiac anomalies.

Sonographic spectrum and postnatal outcomes of early-onset versus late-onset fetal cerebral ventriculomegaly

Objectives To review the prenatal characteristics and postnatal outcomes of Early-onset and Late-onset cerebral ventriculomegaly (VM). Methods Single-center retrospective study 2013–2017; VM cases grouped into Early-onset VM (EVM; Diagnosis at/before 24 weeks) and Late-onset VM (LVM; Beyond 24 weeks). LVM cases had normal ventricle width measurement at mid-trimester scan. Infection serology, cytogenetics, MRI, sonographic follow-up, perinatal and neurodevelopmental outcomes were analyzed. Results During the 5-year period, 64,662 women underwent an anomaly screening scan and 302 fetuses were identified with ventriculomegaly; 183 (60.6%) classified as early-onset and 119 (39.4%) LVM. The mean ventricular width was significantly higher in LVM cohort (14.1 mm vs 11.6 mm; p < .01). EVM cases were more often associated with structural anomalies (p < .05). Possible etiologies for EVM were aneuploidy and cerebral malformations like Absent Corpus Callosum, spina bifida, Dandy–Walker malformation, etc., whereas LVM followed aqueductal stenosis, hemorrhage, porencephaly, cerebral tumors, etc. Pregnancy outcomes were available for 251 cases. The pregnancy resulted in more live births in LVM group (87.4% vs 65.6%, p = < .01). Multivariate regression analysis demonstrated additional malformations (p < .0001, OR11.5 [95%CI: 4–35.2]), progression of VM (p = .004, OR 10.2 [95% CI: 2.1–52.3]) and severity of VM (OR 5.3 [95%CI: 0.8–37.7]) were significant predictors of Neurodevelopmental Impairment (NDI). Late gestation at diagnosis was more often associated with NDI (p = .063, OR2.4 [95%CI: 0.9–6.2]), although statistically insignificant. Conclusions EVM has a significantly different sonographic spectrum and outcomes compared to LVM. EVM is milder and associated with an increased risk of aneuploidy and structural malformations. LVM often occurs secondary to acquired brain lesions.

Congenital Anomaly of Central Nervous System Associated with Antenatal Coinfection with Cytomegalovirus and Toxoplasma: Clinical Case

Background . The development of central nervous system (CNS) malformations may occur due to antenatal infection. Specific pathomorphological changes in CNS structures require further study. Clinical Case Description . The autopsy morphological study of the brain of a child who had antenatal toxoplasma and cytomegalovirus infections and who died at the age of 2 years was performed. Thickening of the pia mater with cloudy surface due to edema and focal sclerosis, generalized thrombosis of superior sagittal sinus, sinus rectus and sinus transverses, absence of corpus callosum, major commissural fibers, opened third ventricle and vermis of cerebellum agenesia, as well as mixed forms of obstructive hydrocephalus were revealed. Diffuse gliosis with glial cysts in the periventricular zones were revealed at histological examination of the alba. Pseudocysts filled with toxoplasms were identified in the cysts’ wall. Signs of productive vasculitis were noted. Comparison of pathomorphological changes in the brain and internal organs with anamnestic data of the patient (toxoplasma and cytomegalovirus infection during recent pregnancy, brain abnormality of the fetus on the second ultrasound screening at 21–22 weeks of gestation) and the results of histological examination of placenta was carried out to prove the correlation of antenatal infection with the development of brain anomalies. Pathognomonic signs of cytomegalovirus infection and toxoplasmosis were revealed in the placenta: cytomegalic cells, vascular thrombosis, white infarcts, fibrinoid necrosis of basal lamina, placental hypoplasia. Toxoplasmic cysts were detected in chorionic villae stroma, parietal thophoblast, amnion, decidual tissue. Conclusion . Antenatal viral-parasitic infection may be the cause of brain anomalies of the fetus. However, the child had no specific signs of cytomegalovirus infection (such as cytomegalic cells — owl eye cells), even when the placenta had pathomorphological changes typical for this infection. It can be assumed that the development of brain anomaly in this child could be associated with toxoplasma infection.

Brain imaging in classic nonketotic hyperglycinemia: Quantitative analysis and relation to phenotype.

Patients with severe nonketotic hyperglycinemia (NKH) have absent psychomotor development and intractable epilepsy, whereas attenuated patients have variable psychomotor development and absent or treatable epilepsy; differences in brain magnetic resonance imaging (MRI) between phenotypes have not been reported. In a retrospective cross-sectional study, we reviewed 38 MRI studies from 24 molecularly proven NKH patients, and 2 transient NKH patients. Quantitative analyses included corpus callosum size, apparent diffusion coefficient, automated brain volumetric analysis, and glycine/creatine ratio by spectroscopy. All patients age <3 months had restricted diffusion in the posterior limb of the internal capsule, anterior brainstem, posterior tegmental tracts, and cerebellum, not present in transient NKH. In older infants, the pattern evolved and included generalized diffusion restriction in the supratentorial white matter, which quantitatively peaked between 3 and 12 months. No patient had absent corpus callosum or gyral malformation. The corpus callosum was relatively short in severe compared to attenuated phenotypes, and thin in severe cases only. The corpus callosum growth rate differed by severity; age-matched Z-scores of thickness worsened in severe cases only. Cerebral volume was decreased in the hippocampus, globus pallidus, cerebral cortex, thalamus, and cerebellum. Severe patients had greatest glycine/creatine ratios. In this study, no brain malformations were identified. The growth failure of the corpus callosum is worse in severe NKH, whereas the diffusion restriction pattern, reflecting microspongiosis, does not discriminate by phenotypic severity. NKH is therefore a disorder of brain growth best recognized in the corpus callosum, whereas spongiosis is not prognostic.

Neurometabolic disorders and congenital malformations of the central nervous system.

Both malformations of the central nervous system and neurometabolic disorders are common, mainly in highly consanguineous populations. Both metabolic pathways and developmental pathways are closely related and interact with each other. Neurometabolic disorders can lead to disturbances in brain development through multiple mechanisms that include deficits in energy metabolism, critical nutrient deficiency, accumulation of neurotoxic substrates, abnormality in cell membrane constituents, and interference in cell-to-cell signaling pathways. The anomalies observed include absent or hypoplastic corpus callosum, midline brain defects, and malformations of the cortex, the cerebellum and the brain stem. Early diagnosis of an underlying inherited neurometabolic disorders is critical for the institution of treatment, which may positively influence prognosis, and allow for proper genetic counseling. In this review, we discuss those disorders in which the structural brain malformation is a dominant feature, and propose a practical approach that will permit a physician to investigate, and treat these disorders.

Clinical and genetic spectrum of AMPD2-related pontocerebellar hypoplasia type 9.

Pontocerebellar hypoplasia (PCH) represents a group of autosomal-recessive progressive neurodegenerative disorders of prenatal onset. Eleven PCH subtypes are classified according to clinical, neuroimaging and genetic findings. Individuals with PCH type 9 (PCH9) have a unique combination of postnatal microcephaly, hypoplastic cerebellum and pons, and hypoplastic or absent corpus callosum. PCH9 is caused by biallelic variants in AMPD2 encoding adenosine monophosphate deaminase 2; however, a homozygous AMPD2 frameshift variant has recently been reported in two family members with spastic paraplegia type 63 (SPG63). We identified homozygous or compound heterozygous AMPD2 variants in eight PCH-affected individuals from six families. The eight variants likely affect function and comprise one frameshift, one nonsense and six missense variants; seven of which were novel. The main clinical manifestations in the eight new patients and 17 previously reported individuals with biallelic AMPD2 variants were postnatal microcephaly, severe global developmental delay, spasticity, and central visual impairment. Brain imaging data identified hypomyelination, hypoplasia of the cerebellum and pons, atrophy of the cerebral cortex, complete or partial agenesis of the corpus callosum and the "figure 8" shape of the hypoplastic midbrain as consistent features. We broaden the AMPD2-related clinical spectrum by describing one individual without microcephaly and absence of the characteristic "figure 8" shape of the midbrain. The existence of various AMPD2 isoforms with different functions possibly explains the variability in phenotypes associated with AMPD2 variants: variants leaving some of the isoforms intact may cause SPG63, while those affecting all isoforms may result in the severe and early-onset PCH9.

Clues for Polygenic Inheritance of Pituitary Stalk Interruption Syndrome From Exome Sequencing in 20 Patients.

Pituitary stalk interruption syndrome (PSIS) consists of a small/absent anterior pituitary lobe, an interrupted/absent pituitary stalk, and an ectopic posterior pituitary lobe. Mendelian forms of PSIS are detected infrequently (<5%), and a polygenic etiology has been suggested. GLI2 variants have been reported at a relatively high frequency in PSIS. To provide further evidence for a non-Mendelian, polygenic etiology of PSIS. Exome sequencing (trio approach) in 20 patients with isolated PSIS. In addition to searching for (potentially) pathogenic de novo and biallelic variants, a targeted search was performed in a panel of genes associated with midline brain development (223 genes). For GLI2 variants, both (potentially) pathogenic and relatively rare variants (<5% in the general population) were studied. The frequency of GLI2 variants was compared with that of a reference population. We found four additional candidate genes for isolated PSIS (DCHS1, ROBO2, CCDC88C, and KIF14) and one for syndromic PSIS (KAT6A). Eleven GLI2 variants were present in six patients. A higher frequency of a combination of two GLI2 variants (M1352V + D1520N) was found in the study group compared with a reference population (10% vs 0.68%). (Potentially) pathogenic variants were identified in genes associated with midline brain anomalies, including holoprosencephaly, hypogonadotropic hypogonadism, and absent corpus callosum and in genes involved in ciliopathies. Combinations of variants in genes associated with midline brain anomalies are frequently present in PSIS and sustain the hypothesis of a polygenic cause of PSIS.

WD40-repeat 47, a microtubule-associated protein, is essential for brain development and autophagy

The family of WD40-repeat (WDR) proteins is one of the largest in eukaryotes, but little is known about their function in brain development. Among 26 WDR genes assessed, we found 7 displaying a major impact in neuronal morphology when inactivated in mice. Remarkably, all seven genes showed corpus callosum defects, including thicker (Atg16l1, Coro1c, Dmxl2, and Herc1), thinner (Kif21b and Wdr89), or absent corpus callosum (Wdr47), revealing a common role for WDR genes in brain connectivity. We focused on the poorly studied WDR47 protein sharing structural homology with LIS1, which causes lissencephaly. In a dosage-dependent manner, mice lacking Wdr47 showed lethality, extensive fiber defects, microcephaly, thinner cortices, and sensory motor gating abnormalities. We showed that WDR47 shares functional characteristics with LIS1 and participates in key microtubule-mediated processes, including neural stem cell proliferation, radial migration, and growth cone dynamics. In absence of WDR47, the exhaustion of late cortical progenitors and the consequent decrease of neurogenesis together with the impaired survival of late-born neurons are likely yielding to the worsening of the microcephaly phenotype postnatally. Interestingly, the WDR47-specific C-terminal to LisH (CTLH) domain was associated with functions in autophagy described in mammals. Silencing WDR47 in hypothalamic GT1-7 neuronal cells and yeast models independently recapitulated these findings, showing conserved mechanisms. Finally, our data identified superior cervical ganglion-10 (SCG10) as an interacting partner of WDR47. Taken together, these results provide a starting point for studying the implications of WDR proteins in neuronal regulation of microtubules and autophagy.

X-Linked Lissencephaly With Absent Corpus Callosum and Abnormal Genitalia: An Evolving Multisystem Syndrome With Severe Congenital Intestinal Diarrhea Disease.

X-linked lissencephaly with abnormal genitalia is a rare and devastating syndrome. The authors present an infant with a multisystem phenotype where the intestinal manifestations were as life limiting as the central nervous system features. Severe chronic diarrhea resulted in failure to thrive, dehydration, electrolyte derangements, long-term hospitalization, and prompted transition to palliative care. Other multisystem manifestations included megacolon, colitis, pancreatic insufficiency hypothalamic dysfunction, hypothyroidism, and hypophosphatasia. A novel aristaless-related homeobox gene mutation, c.1136G>T/p.R379L, was identified. This case contributes to the clinical, histological, and molecular understanding of the multisystem nature of this disorder, especially the role of ARX in the development of the enteroendocrine system.

Ambiguous genitalia associated with an extremely rare syndrome: a case report of xlag syndrome and review of the literature

X-linked lissencephaly, absent corpus callosum, and epilepsy of neonatal onset with ambiguous genitalia comprises the XLAG syndrome and only 15 cases have been reported in literature. Due to its rarity, the exact clinical course and outcome are not known. Exact associations of this disease are also elusive. Hereby we are reporting this extremely rare entity and we searched the English literature extensively to get consolidated knowledge regarding this entity that would help the readers. Pre-natal radiological work-up can detect these malformations, which should be followed by medical termination, counseling and karyotyping. Till date the longest survival noted was 4 years only.