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.

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.

Knowledge, Skills, and Attitudes Towards Children with Epilepsy Among Egyptian Parents: A Comparative Cross-Sectional Study.

INTRODUCTION: Epilepsy is one of the most common neurological disorders affecting children. As a chronic disease, it affects not only the child but also the entire family. The attitudes towards the children suffering from epilepsy and the skills required to deal with acute seizures are influenced by the level of knowledge the parents have about that disease. AIM: To evaluate the knowledge, attitudes, and skills toward epilepsy among parents of children diagnosed with epilepsy in comparison to parents of children without epilepsy. METHOD: Data collected through a structured questionnaire that was designed, translated into Arabic, and analyzed statistically in a cross-sectional study for a total of 534 Egyptian parents as two groups, group I (n = 223) consist of parents with children with epilepsy and group II (n = 311) of parents with children without epilepsy. Parents with children with epilepsy were recruited from the Paediatric Neurology Outpatient Clinic of Alexandria University Children's Hospital (AUCH). Parents with children without epilepsy were recruited from other outpatient clinics or wards of AUCH. RESULTS: This study showed a poor knowledge score percentage of (89.7 %) among parents with children with epilepsy and (83.3 %) among parents with children without epilepsy. The difference between both groups was statistically significant with fewer knowledge scores among parents of children with epilepsy. Parents of both groups showed a negative attitude score percentage; (69.5 %) of group I and (62.7 %) of group II. The difference between both groups was statistically significant with a more negative attitude score percentage among parents with children without epilepsy. Parents of both groups had poor practice score percentage of (66.8 %) of group I and (74.3 %) of group II having poor practice skills needed for emergency management of acute seizures. A high level of education was significantly associated with fair knowledge score percentage and positive attitude score percentage. CONCLUSIONS: Poor knowledge, negative attitudes, and poor skills required for the management of acute seizures were found among both parents of children with epilepsy and those with children without epilepsy. Educational programs are needed to eliminate all the misconceptions and myths and to change attitudes of the Egyptian parents towards epilepsy.