Loss of symmetric cell division of apical neural progenitors drives DENND5A-related developmental and epileptic encephalopathy.

Developmental and epileptic encephalopathies (DEEs) feature altered brain development, developmental delay and seizures, with seizures exacerbating developmental delay. Here we identify a cohort with biallelic variants in DENND5A, encoding a membrane trafficking protein, and develop animal models with phenotypes like the human syndrome. We demonstrate that DENND5A interacts with Pals1/MUPP1, components of the Crumbs apical polarity complex required for symmetrical division of neural progenitor cells. Human induced pluripotent stem cells lacking DENND5A fail to undergo symmetric cell division with an inherent propensity to differentiate into neurons. These phenotypes result from misalignment of the mitotic spindle in apical neural progenitors. Cells lacking DENND5A orient away from the proliferative apical domain surrounding the ventricles, biasing daughter cells towards a more fate-committed state, ultimately shortening the period of neurogenesis. This study provides a mechanism for DENND5A-related DEE that may be generalizable to other developmental conditions and provides variant-specific clinical information for physicians and families.

Identification of a Novel ASAH1 Gene Mutation in Spinal Muscular Atrophy with Progressive Myoclonic Epilepsy.

Spinal muscular atrophy (SMA) with progressive myoclonic epilepsy (PME) affects the nervous system. Symptoms appear in early childhood and include muscle weakness, difficulty walking, seizures, and cognitive decline. Despite introducing various therapies to restore acid ceramidase function or reduce ceramide accumulation and gene therapy to correct genetic mutations, there are still unknown underlying molecular mechanisms related to this disorder. This article reports a novel variant c.118G>C in the ASAH1 gene. The patient presented with clinical manifestations such as progressive muscle weakness and myoclonic convulsions. Clinical features and electrophysiological investigations revealed a motor neuron disease and generalized epileptic discharge. A significant temporal interval was observed between the initial diagnosis of SMA and the subsequent manifestation of myoclonic seizures. The proband was genetically assessed through whole exome sequencing (WES) followed by variant confirmation and bioinformatics analysis. According to this article's findings and previous research, further diagnostic testing and management are needed to determine the severity and progression of the patient's condition.

Expanding the Clinical Phenotype of PLECTIN-Related Plectinopathies.

Background: Plectinopathy-associated disorders are caused by mutations in the PLECTIN (PLEC) gene encoding Plectin protein. PLEC mutations cause a spectrum of diseases defined by varying degrees of signs, mostly with epidermolysis bullosa simplex with muscular dystrophy (EBS-MD) and plectinopathy-related disorder is limb-girdle muscular dystrophy type 2Q (LGMD2Q). Here we report three cases with EBS-MD and LGMD2Q disorders analyzed by exome sequencing followed by mutation confirmation. Methods: A complete clinical examination was done by expert specialists and clinical geneticists in Next Generation Genetic polyclinic, Mashhad, Iran (NGC, years 2020_2021),. Genomic DNA was extracted and evaluated through whole-exome sequencing analysis followed by Sanger sequencing for co-segregation analysis of PLEC candidate variants. Results: We found three cases with the plectinopathy-related disease, two patients with limb-girdle muscular dystrophy type 2Q (LGMD2Q), and the other affected proband suffers from epidermolysis bullosa simplex combined with muscular dystrophy (EBS-MD) with variable zygosity mutations for PLEC. Motor development disorder and muscular dystrophy symptoms have different age onset in affected individuals. Patients with EBS demonstrated symptoms such as blistering, skin scars, neonatal-onset, and nail dystrophy. Conclusion: We report plectinopathy-associated disorders to expand clinical phenotypes in different types of PLEC-related diseases. We suppose to design more well-organized research based on comprehensive knowledge about the genetic basis of plectinopathy diseases.

Loss of symmetric cell division of apical neural progenitors drives DENND5A-related developmental and epileptic encephalopathy.

Developmental and epileptic encephalopathies (DEEs) are a heterogenous group of epilepsies in which altered brain development leads to developmental delay and seizures, with the epileptic activity further negatively impacting neurodevelopment. Identifying the underlying cause of DEEs is essential for progress toward precision therapies. Here we describe a group of individuals with biallelic variants in DENND5A and determine that variant type is correlated with disease severity. We demonstrate that DENND5A interacts with MUPP1 and PALS1, components of the Crumbs apical polarity complex, which is required for both neural progenitor cell identity and the ability of these stem cells to divide symmetrically. Induced pluripotent stem cells lacking DENND5A fail to undergo symmetric cell division during neural induction and have an inherent propensity to differentiate into neurons, and transgenic DENND5A mice, with phenotypes like the human syndrome, have an increased number of neurons in the adult subventricular zone. Disruption of symmetric cell division following loss of DENND5A results from misalignment of the mitotic spindle in apical neural progenitors. A subset of DENND5A is localized to centrosomes, which define the spindle poles during mitosis. Cells lacking DENND5A orient away from the proliferative apical domain surrounding the ventricles, biasing daughter cells towards a more fate-committed state and ultimately shortening the period of neurogenesis. This study provides a mechanism behind DENND5A-related DEE that may be generalizable to other developmental conditions and provides variant-specific clinical information for physicians and families.

The Effect of Melatonin on Sleep Disorders in Children with Cerebral Palsy A Randomized Clinical Trial.

Objectives: Cerebral palsy (CP) is one of the most common causes of serious physical disability in childhood and is a persistent movement disorder before the age of three. This disorder can negatively affect both the child and their family. In recent years, the use of melatonin as a safe, effective, and cheap drug has been expanding in improving the sleep disorders of these children. Therefore, this study aimed to investigate melatonin's effect on sleep disorders in children with CP. Materials & Methods: This double-blind clinical trial was conducted on children aged 2 to 12 years with CP who were referred to the pediatric neurology clinic for sleep problems. The participants were included in the study by convenience sampling. After obtaining informed consent from parents, patients were divided randomly into two intervention (melatonin) and control (placebo) groups. In the intervention group, patients received oral melatonin tablets, and in the control group, patients received a placebo (3 mg oral lactose) 30 minutes before going to sleep. Results: The results of this study showed no significant relationship between age and gender with sleep disorders in children with CP (P>0.05). A significant effect of melatonin on sleep disorders was found in children with CP. The greatest effect of melatonin is the time required to start falling asleep. Melatonin was associated with decreased time needed to fall asleep and increased sleep duration. Conclusion: The results of the study demonstrated that sleep disorders are prevalent among children with CP. Therefore, proper and timely treatment of these children is crucial. According to the present study's findings, melatonin effectively improves the time of falling asleep and these children's sleep duration.

Biomedical applications of cerium vanadate nanoparticles: a review.

Cerium vanadate nanoparticles (CeVO4 NPs), which are members of the rare earth orthovanadate nanomaterial family, have generated considerable interest due to their diverse properties and prospective biomedical applications. The current study, which provides a comprehensive overview of the synthesis and characterization techniques for CeVO4 NPs, emphasizes the sonochemical method as an efficient and straightforward technique for producing CeVO4 NPs with tunable size and shape. This paper investigates the toxicity and biocompatibility of CeVO4 NPs, as well as their antioxidant and catalytic properties, which allow them to modify the redox state of biological systems and degrade organic pollutants. In addition, the most recent developments in the medicinal applications of CeVO4 NPs, such as cancer treatment, antibacterial activity, biosensing, and drug or gene delivery, are emphasized. In addition, the disadvantages of CeVO4 NPs, such as stability, aggregation, biodistribution, and biodegradation, are outlined, and several potential solutions are suggested. The research concludes with data and recommendations for developing and enhancing CeVO4 NPs in the biomedical industry.

Bi-allelic genetic variants in the translational GTPases GTPBP1 and GTPBP2 cause a distinct identical neurodevelopmental syndrome.

The homologous genes GTPBP1 and GTPBP2 encode GTP-binding proteins 1 and 2, which are involved in ribosomal homeostasis. Pathogenic variants in GTPBP2 were recently shown to be an ultra-rare cause of neurodegenerative or neurodevelopmental disorders (NDDs). Until now, no human phenotype has been linked to GTPBP1. Here, we describe individuals carrying bi-allelic GTPBP1 variants that display an identical phenotype with GTPBP2 and characterize the overall spectrum of GTP-binding protein (1/2)-related disorders. In this study, 20 individuals from 16 families with distinct NDDs and syndromic facial features were investigated by whole-exome (WES) or whole-genome (WGS) sequencing. To assess the functional impact of the identified genetic variants, semi-quantitative PCR, western blot, and ribosome profiling assays were performed in fibroblasts from affected individuals. We also investigated the effect of reducing expression of CG2017, an ortholog of human GTPBP1/2, in the fruit fly Drosophila melanogaster. Individuals with bi-allelic GTPBP1 or GTPBP2 variants presented with microcephaly, profound neurodevelopmental impairment, pathognomonic craniofacial features, and ectodermal defects. Abnormal vision and/or hearing, progressive spasticity, choreoathetoid movements, refractory epilepsy, and brain atrophy were part of the core phenotype of this syndrome. Cell line studies identified a loss-of-function (LoF) impact of the disease-associated variants but no significant abnormalities on ribosome profiling. Reduced expression of CG2017 isoforms was associated with locomotor impairment in Drosophila. In conclusion, bi-allelic GTPBP1 and GTPBP2 LoF variants cause an identical, distinct neurodevelopmental syndrome. Mutant CG2017 knockout flies display motor impairment, highlighting the conserved role for GTP-binding proteins in CNS development across species.