Elucidating the clinical and genetic spectrum of inositol polyphosphate phosphatase INPP4A-related neurodevelopmental disorder.

Purpose: Biallelic INPP4A variants have recently been associated with severe neurodevelopmental disease in single case reports. Here, we expand and elucidate the clinical-genetic spectrum and provide a pathomechanistic explanation for genotype-phenotype correlations.

Methods: Clinical and genomic investigations of 30 individuals were undertaken alongside molecular and in silico modelling and translation reinitiation studies.

High Diagnostic Yield and Clinical Utility of Next-Generation Sequencing in Children with Epilepsy and Neurodevelopmental Delays: A Retrospective Study.

Advances in genetics led to the identification of hundreds of epilepsy-related genes, some of which are treatable with etiology-specific interventions. However, the diagnostic yield of next-generation sequencing (NGS) in unexplained epilepsy is highly variable (10-50%). We sought to determine the diagnostic yield and clinical utility of NGS in children with unexplained epilepsy that is accompanied by neurodevelopmental delays and/or is medically intractable.

A novel autism-associated UBLCP1 mutation impacts proteasome regulation/activity.

The landscape of autism spectrum disorder (ASD) in Lebanon is unique because of high rates of consanguinity, shared ancestry, and increased remote consanguinity. ASD prevalence in Lebanon is 1 in 68 with a male-to-female ratio of 2:1. This study aims to investigate the impact of an inherited deletion in UBLCP1 (Ubiquitin-Like Domain-Containing CTD Phosphatase 1) on the ubiquitin-proteasome system (UPS) and proteolysis.

Noncoding variants alter GATA2 expression in rhombomere 4 motor neurons and cause dominant hereditary congenital facial paresis.

Hereditary congenital facial paresis type 1 (HCFP1) is an autosomal dominant disorder of absent or limited facial movement that maps to chromosome 3q21-q22 and is hypothesized to result from facial branchial motor neuron (FBMN) maldevelopment. In the present study, we report that HCFP1 results from heterozygous duplications within a neuron-specific GATA2 regulatory region that includes two enhancers and one silencer, and from noncoding single-nucleotide variants (SNVs) within the silencer. Some SNVs impair binding of NR2F1 to the silencer in vitro and in vivo and attenuate in vivo enhancer reporter expression in FBMNs.

Whole-exome screening for primary congenital glaucoma in Lebanon.

Purpose: Mutations were previously identified in the CYP1B1 gene in six out of 18 Lebanese families (33%) with primary congenital glaucoma (PCG). The purpose of this study is to determine the frequency and type of pathogenic mutations in other genes and compare to other populations using whole-exome sequencing and perform genotype-phenotype correlations.

Methods: Twelve PCG patients previously negative for CYP1B1/MYOC mutations were subjected to whole-exome sequencing.

Amblyopia risk factors among pediatric patients in a hospital-based setting using photoscreening.

Purpose: The aim of our study was to determine the prevalence of amblyopia risk factors in children visiting the American University of Beirut Medical Center (AUBMC) using automated vision screening.

Methods: This was a hospital-based screening of 1102 children aged between 2 and 6 years. Vision screening was performed using PlusoptiX S12 over 2 years (2018-2020).

A Signature of Four Circulating microRNAs as Potential Biomarkers for Diagnosing Early-Stage Breast Cancer.

Breast cancer (BC) is the most predominant type of cancer among women. The aim of this study is to find new biomarkers that can help in early detection of BC, especially for those who are too young to be screened using mammography as per guidelines. Using microRNA microarray, we previously showed dysregulation of 74 microRNAs in tumors from early BC patients as compared with normal adjacent tissues, which we were interested in studying in blood circulation.

LINE-1 methylation mediates the inverse association between body mass index and breast cancer risk: A pilot study in the Lebanese population.

Introduction: Lebanon is among the top countries worldwide in combined incidence and mortality of breast cancer, which raises concern about risk factors peculiar to this country. The underlying molecular mechanisms of breast cancer require elucidation, particularly epigenetics, which is recognized as a molecular sensor to environmental exposures.

Purpose: We aim to explore whether DNA methylation levels of AHRR (marker of cigarette smoking), SLC1A5 and TXLNA (markers of alcohol consumption), and LINE-1 (a genome-wide repetitive retrotransposon) can act as molecular mediators underlying putative associations between breast cancer risk and pertinent extrinsic (tobacco smoking and alcohol consumption) and intrinsic factors [age and body mass index (BMI)].

KIF21A pathogenic variants cause congenital fibrosis of extraocular muscles type 3.

Congenital fibrosis of the extraocular muscles (CFEOM) is characterized by ptosis and non-progressive restrictive ophthalmoplegia. CFEOM1 is a stereotypical phenotype with isolated bilateral ptosis, bilateral ophthalmoplegia, absent upgaze, and globe infraduction. CFEOM3 is a more variable phenotype that can include unilateral disease, absent ptosis, residual upgaze, and/or orthotropia.

Sex differences in gene expression with galactosylceramide treatment in Cln3Δex7/8 mice.

Background: CLN3 disease is caused by mutations in the CLN3 gene. The purpose of this study is to discern global expression patterns reflecting therapeutic targets in CLN3 disease.

Methods: Differential gene expression in vehicle-exposed mouse brain was determined after intraperitoneal vehicle/Galactosylceramide (GalCer) injections for 40 weeks with GeneChip Mouse Genome 430 2.

Exogenous Flupirtine as Potential Treatment for CLN3 Disease.

CLN3 disease is a fatal neurodegenerative disorder affecting children. Hallmarks include brain atrophy, accelerated neuronal apoptosis, and ceramide elevation. Treatment regimens are supportive, highlighting the importance of novel, disease-modifying drugs.

Eye Tracking Abnormalities in School-Aged Children With Strabismus and With and Without Amblyopia.

Purpose: To detect eye tracking abnormalities in children with strabismus in the absence or presence of amblyopia.

Methods: A total of 100 patients aged 7 to 17 years were enrolled prospectively for 2 years from the pediatric ophthalmology clinic of the American University of Beirut Medical Center: 50 children with strabismus (including 24 with amblyopia) and 50 age- and gender-matched controls. Eye tracking with different paradigms was performed.

Pre- and Post-therapy Assessment of Clinical Outcomes and White Matter Integrity in Autism Spectrum Disorder: Pilot Study.

This pilot study aims to identify white matter (WM) tract abnormalities in Autism Spectrum Disorders (ASD) toddlers and pre-schoolers by Diffusion Tensor Imaging (DTI), and to correlate imaging findings with clinical improvement after early interventional and Applied Behavior Analysis (ABA) therapies by Verbal Behavior Milestones Assessment and Placement Program (VB-MAPP). DTI scans were performed on 17 ASD toddlers/pre-schoolers and seven age-matched controls. Nine ASD patients had follow-up MRI 12 months following early intervention and ABA therapy.

Exogenous Galactosylceramide as Potential Treatment for CLN3 Disease.

Objective: CLN3 disease is the commonest of the neuronal ceroid lipofuscinoses, a group of pediatric neurodegenerative disorders. Functions of the CLN3 protein include antiapoptotic properties and facilitating anterograde transport of galactosylceramide from Golgi to lipid rafts. This study confirms the beneficial effects of long-term exogenous galactosylceramide supplementation on longevity, neurobehavioral parameters, neuronal cell counts, astrogliosis, and diminution in brain and serum ceramide levels in Cln3 knock-in mice.

Outcome of Nonketotic Hyperglycinemia in Lebanon: 14-Year Retrospective Review.

Nonketotic hyperglycinemia is a rare inborn error of glycine metabolism characterized by a severe metabolic encephalopathy with drug-resistant seizures. Here, we report the outcome of nonketotic hyperglycinemia in a cohort of patients diagnosed and followed-up at a tertiary care reference center in Lebanon, between 2000 and 2014.Eight out of 12 patients with nonketotic hyperglycinemia were retrospectively reviewed.

Developmental Comparison of Ceramide in Wild-Type and Mouse Brains and Sera.

CLN3 disease is a neurodevelopmental disease leading to early visual failure, motor decline, and death. CLN3 pathogenesis has been linked to dysregulation of ceramide, a key intracellular messenger impacting various biological functions. Ceramide is upregulated in brains of CLN3 patients and activates apoptosis.

MAB21L1 loss of function causes a syndromic neurodevelopmental disorder with distinctive erebellar, cular, cranioacial and enital features (COFG syndrome).

Background: Putative nucleotidyltransferase MAB21L1 is a member of an evolutionarily well-conserved family of the male abnormal 21 (MAB21)-like proteins. Little is known about the biochemical function of the protein; however, prior studies have shown essential roles for several aspects of embryonic development including the eye, midbrain, neural tube and reproductive organs.

Objective: A homozygous truncating variant in has recently been described in a male affected by intellectual disability, scrotal agenesis, ophthalmological anomalies, cerebellar hypoplasia and facial dysmorphism.

Flupirtine derivatives as potential treatment for the neuronal ceroid lipofuscinoses.

Objective: Neuronal Ceroid Lipofuscinoses (NCL) are fatal inherited neurodegenerative diseases with established neuronal cell death and increased ceramide levels in brain, hence, a need for disease-modifying drug candidates, with potential to enhance growth, reduce apoptosis and lower ceramide in neuronal precursor PC12 cells and human NCL cell lines using enhanced flupirtine aromatic carbamate derivatives in vitro.

Methods: Aromatic carbamate derivatives were tested by establishing growth curves under pro-apoptotic conditions and activity evaluated by trypan blue and JC-1 staining, as well as a drop in pro-apoptotic ceramide in neuronal precursor PC12 cells following siRNA knockdown of the gene, and CLN1-/CLN2-/CLN3-/CLN6-/CLN8 patient-derived lymphoblasts. Ceramide levels were determined in CLN1-/CLN2-/CLN3-/CLN6-/CLN8 patient-derived lymphoblasts before and after treatment.

Correction to: Association of Autism with Maternal Infections, Perinatal and Other Risk Factors: A Case-Control Study.

The original version of this article unfortunately contained a mistake. The family name of Hadi Abou El Hassan was incorrect. The correct name is Hadi Abou-El-Hassan.

Association of Autism with Maternal Infections, Perinatal and Other Risk Factors: A Case-Control Study.

This case-control study explores the association between pregnancy/birth complications and other factors with Autism Spectrum Disorder (ASD) in Lebanese subjects aged 2-18 years. Researchers interviewed 136 ASD cases from the American University of Beirut Medical Center Special Kids Clinic, and 178 controls selected by systematic digit dialing in the Greater-Beirut area. Male gender (Adjusted Odds Ratio [95% CI]: 3.

microRNA Expression in Ethnic Specific Early Stage Breast Cancer: an Integration and Comparative Analysis.

Breast cancer (BC) has a higher incidence in young Lebanese woman as compared to the West. We assessed the microRNA (miRNA) microarray profile of tissues derived from Lebanese patients with early BC and performed mRNA-miRNA integration analysis. 173 miRNAs were significantly dysregulated in 45 BC versus 17 normal adjacent breast tissues, including 74 with a fold change more than two of which 17 were never reported before in cancer.

Docosahexaenoic acid (DHA) enhances the therapeutic potential of neonatal neural stem cell transplantation post-Traumatic brain injury.

Traumatic Brain Injury (TBI) is a major cause of death and disability worldwide with 1.5 million people inflicted yearly. Several neurotherapeutic interventions have been proposed including drug administration as well as cellular therapy involving neural stem cells (NSCs).

Discovery of Aromatic Carbamates that Confer Neuroprotective Activity by Enhancing Autophagy and Inducing the Anti-Apoptotic Protein B-Cell Lymphoma 2 (Bcl-2).

Neurodegenerative diseases share certain pathophysiological hallmarks that represent common targets for drug discovery. In particular, dysfunction of proteostasis and the resultant apoptotic death of neurons represent common pathways for pharmacological intervention. A library of aromatic carbamate derivatives based on the clinically available drug flupirtine was synthesized to determine a structure-activity relationship for neuroprotective activity.