Compound Heterozygous ROBO3 Mutation in Two Siblings Presenting with Horizontal Gaze Palsy without Scoliosis: Case-Based Review

Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare, autosomal recessively inherited disorder characterized by a congenital absence of conjugated horizontal eye movements with progressive scoliosis developing in childhood and adolescence. HGPPS is caused by mutations of the ROBO3 gene that disrupts the midline crossing of the descending corticospinal and ascending lemniscal sensory tracts in the medulla. We present two siblings, 5-year-old and 2-year-old boys with HGPPS, from non-consanguineous parents. The older brother was brought for the evaluation of moderate psychomotor retardation. He had bilateral horizontal gaze palsy with preserved vertical gaze and convergence. Scoliosis was absent. Cranial MRI showed brainstem abnormalities, and diffusion tensor imaging showed absent decussation of cortico-spinal tracts in the medulla. Clinical diagnosis of HGPPS was confirmed by sequencing of ROBO3 gene, IVS4–1G > A (c.767–1G > A) and c.328_329delinsCCC (p.Asp110Profs*57) compound heterozygous variations were found, and segregated in parents. The younger boy was first reported at 16 months of age and had the same clinical and neuroradiological findings, unlike mild psychomotor retardation. ROBO3 gene analysis showed the same variants in his brother. Our cases show the importance of evaluating eye movements in children with neurodevelopmental abnormalities and looking for brainstem abnormalities in children with bilateral horizontal gaze palsy.

A human iPSC-astroglia neurodevelopmental model reveals divergent transcriptomic patterns in schizophrenia

While neurodevelopmental abnormalities have been associated with schizophrenia (SCZ), the role of astroglia in disease pathophysiology remains poorly understood. In the present study, we used a human induced pluripotent stem cell (iPSC)-derived astrocyte model to investigate the temporal patterns of astroglia differentiation during developmental stages critical for SCZ using RNA sequencing. The model generated astrocyte-specific gene expression patterns during differentiation that corresponded well to astroglia-specific expression signatures of in vivo cortical fetal development. Using this model we identified SCZ-specific expression dynamics, and found that SCZ-associated differentially expressed genes were significantly enriched in the medial prefrontal cortex, striatum, and temporal lobe, targeting VWA5A and ADAMTS19. In addition, SCZ astrocytes displayed alterations in calcium signaling, and significantly decreased glutamate uptake and metalloproteinase activity relative to controls. These results implicate novel transcriptional dynamics in astrocyte differentiation in SCZ together with functional changes that are potentially important biological components of SCZ pathology.

Developmental exposure to non-dioxin-like polychlorinated biphenyls promotes sensory deficits and disrupts dopaminergic and GABAergic signaling in zebrafish

The most abundant polychlorinated biphenyl (PCB) congeners found in the environment and in humans are neurotoxic. This is of particular concern for early life stages because the exposure of the more vulnerable developing nervous system to neurotoxic chemicals can result in neurobehavioral disorders. In this study, we uncover currently unknown links between PCB target mechanisms and neurobehavioral deficits using zebrafish as a vertebrate model. We investigated the effects of the abundant non-dioxin-like (NDL) congener PCB153 on neuronal morphology and synaptic transmission linked to the proper execution of a sensorimotor response. Zebrafish that were exposed during development to concentrations similar to those found in human cord blood and PCB contaminated sites showed a delay in startle response. Morphological and biochemical data demonstrate that even though PCB153-induced swelling of afferent sensory neurons, the disruption of dopaminergic and GABAergic signaling appears to contribute to PCB-induced motor deficits. A similar delay was observed for other NDL congeners but not for the potent dioxin-like congener PCB126. The effects on important and broadly conserved signaling mechanisms in vertebrates suggest that NDL PCBs may contribute to neurodevelopmental abnormalities in humans and increased selection pressures in vertebrate wildlife.

3q27.1 Microdeletion Causes a Clinically Recognizable Syndrome Characterized by Severe Prenatal and Postnatal Growth Restriction and Neurodevelopmental Abnormalities

BackgroundConstitutional deletions/rearrangements involving chromosome 3q are uncommon and overlapping microdeletions of chromosome 3q26-3q28 have only been reported in eight individuals. The common phenotype observed in these individuals include severe intrauterine growth restriction and postnatal growth impairment, feeding difficulties, characteristic facial features, feet abnormalities and developmental delay. The most striking clinical features shared among all reported cases is severe prenatal and postnatal growth restriction and neurodevelopmental abnormalities. Case presentationWe identified two additional individuals with overlapping deletions and shared clinical features by high-resolution SNP oligonucleotide microarray, and refined the smallest region of overlap (SRO) to a 1.2 Mb genomic location in chromosome 3q27.1 by reviewing and comparing all published cases. We evaluated the SRO using ACMG/ClinGen current recommendations for classifying copy number variants (CNVs), and discussed the contribution of the genes deleted in the SRO to the abnormal phenotype observed in these individuals. ConclusionsThis study provides further evidence supporting the existence of a novel 3q26q28 microdeletion syndrome and suggests that haploinsufficiency of potential candidate genes, DVL3, AP2M1, and PARL in the SRO in 3q27.1 is responsible for the phenotype. It also demonstrates the clinical utility of the newly released ACMG/Clingen standards for CNV interpretation.

Association between the rs8028440 polymorphism of CYFIP 1 gene in autism patients

Demonstrated no association between ASD and rs8028440 polymorphism of the CYFIP1 gene, which needs further studies in a larger population of ASD subjects to find the contribution of rs8028440 polymorphism in CYFIP1 gene with ASD in Iranian patients. Introduction: Given the importance of the Cytoplasmic FMR1 Interacting Protein 1 (CYFIP1 gene) in relation to neurodevelopmental abnormalities such as autism spectrum disorder (ASD), recognizing the interaction between single nucleotide polymorphisms (SNPs) of this gene in autism cases is important. In this study, we evaluated the probable association of rs8028440 polymorphism of the CYFIP1 gene with ASD disorder in Iranian subjects. Methods and patients: The CYFIP1 gene were amplified with specific primers and the PCR products were digested with RsaI restriction enzyme to obtain the rs8028440 polymorphism in 100 ASD patients and 100 healthy control cases. Finally, the samples were genotyped using direct sequencing to identify CC, CT, and TT genotypes. Results: The Hardy-Weinberg equilibrium showed no significant deviation in the subjected population. According to our results, the frequency of the C allele was higher in ASD groups than in the control group. The full length of PCR was 662 bp and through RFLP‐PCR, normal genotype (C/C), heterozygote genotype (T/C), and homozygous genotype (T/T) was detected. Ten PCR products were sequenced and the corresponded alleles A/T and Y (C or T) were determined. It was revealed no significant difference was found between ASD subjects and controls with respect to the frequency of the rs8028440 gene allele

Reducing Toxic Phthalate Exposures in Premature Infants

Phthalates are a ubiquitous group of industrial compounds used as industrial solvents and as additives to plastics to make products softer avnd more flexible. Phthalates are found in a variety of products including medical devices, personal care products, flooring, and food packaging. Infants in the neonatal intensive care unit are exposed to phthalates both in the building materials, but more importantly in the medical supplies and devices. Toxicity from phthalates has been of concern to researchers for many decades. Toxicity concerns to neonates includes male reproductive toxicity, hepatotoxicity, cardiotoxicity (including hypertension), neurotoxicity, and neurodevelopmental abnormalities. Limited recommendations have been given for reducing phthalate exposures to premature infants. These include avoiding infusing lipids or blood products through intravenous tubing containing phthalates. Storage of blood in containers made with phthalates has been a strong recommendation and has largely been accomplished. A comprehensive plan for phthalate reduction has heretofore been missing. This chapter has the goal of identifying the problem of phthalate exposure in premature infants, with some practical solutions that can be done today, as well as suggestions for manufacturers to complete the work.

Disorders Related to PI3Kδ Hyperactivation: Characterizing the Clinical and Immunological Features of Activated PI3-Kinase Delta Syndromes

Phosphoinositide-3-kinase δ (PI3Kδ) is found in immune cells and is part of the PI3K/AKT/mTOR/S6K signalling pathway essential to cell survival, growth and differentiation. Hyperactivation of PI3Kδ enzyme results in Activated PI3-kinase delta syndrome (APDS). This childhood onset, autosomal dominant, combined immunodeficiency, is caused by heterozygous gain of function (GOF) mutations in PIK3CD (encodes PI3Kδ catalytic subunit p110δ), mutations in PIK3R1 (encodes PI3Kδ regulatory subunit p85α) or LOF mutations in PTEN (terminates PI3Kδ signalling) leading to APDS1, APDS2 and APDS-Like (APDS-L), respectively. APDS was initially described in 2013 and over 285 cases have now been reported. Prompt diagnosis of APDS is beneficial as targeted pharmacological therapies such as sirolimus and potentially PI3Kδ inhibitors can be administered. In this review, we provide an update on the clinical and laboratory features of this primary immunodeficiency. We discuss the common manifestations such as sinopulmonary infections, bronchiectasis, lymphoproliferation, susceptibility to herpesvirus, malignancy, as well as more rare non-immune features such as short stature and neurodevelopmental abnormalities. Laboratory characteristics, such as antibody deficiency and B cell and T cell, phenotypes are also summarised.

DNA Methylome perturbations: An epigenetic basis for the Emergingly heritable neurodevelopmental abnormalities associated with maternal smoking and maternal nicotine exposure

Maternal smoking during pregnancy is associated with an ensemble of neurodevelopmental consequences in children and therefore constitutes a pressing public health concern. Adding to this burden, contemporary epidemiological and especially animal model research suggests that grandmaternal smoking is similarly associated with neurodevelopmental abnormalities in grandchildren, indicative of intergenerational transmission of the neurodevelopmental impacts of maternal smoking. Probing the mechanistic bases of neurodevelopmental anomalies in the children of maternal smokers and the intergenerational transmission thereof, emerging research intimates that epigenetic changes, namely DNA methylome perturbations, are key factors. Altogether, these findings warrant future research to fully elucidate the etiology of neurodevelopmental impairments in the children and grandchildren of maternal smokers and underscore the clear potential thereof to benefit public health by informing the development and implementation of preventative measures, prophylactics, and treatments. To this end, the present review aims to encapsulate the burgeoning evidence linking maternal smoking to intergenerational epigenetic inheritance of neurodevelopmental abnormalities, to identify the strengths and weaknesses thereof, and to highlight areas of emphasis for future human and animal model research therein.