Autism gene drug

Numerous studies reported an association between GABA A R subunit genes and epilepsy, eating disorders, autism spectrum disorders, neurodevelopmental disorders, and bipolar disorders. This study was aimed to find some potential positive allosteric modulators and was performed by combining the in silico approach with further in vitro evaluation of its real activity. We started from the GABA A R-diazepam complexes and assembled a lipid embedded protein ensemble to refine it via molecular dynamics (MD) simulation...

OBJECTIVE: Variants in several potassium channel genes, including KCNA1 and KCNA2, cause Developmental and Epileptic Encephalopathies (DEEs). We investigated whether variants in KCNA3, another mammalian homologue of the Drosophila shaker family and encoding for Kv1.3 subunits, can cause DEE. METHODS: Genetic analysis of study individuals was performed by routine exome or genome sequencing, usually of parent-offspring trios. Phenotyping was performed via a standard clinical questionnaire...

BACKGROUND: Tuberous sclerosis complex (TSC) is a rare multisystem disorder caused by mutations in the TSC1 or TSC2 gene. More than 90% of patients with TSC develop neurological and/or neuropsychiatric manifestations. The aim of the present study was to determine the developmental and cognitive long-term outcomes of pediatric TSC patients. METHODS: This cross-sectional, monocenter study included pediatric TSC patients who received multidisciplinary long-term care with a last visit between 2005 and 2019...

Valproic acid (VPA) is an effective drug, which is preferred for the treatments of epilepsy and various kinds of seizures. Nonetheless, VPA has many side effects associated with autism spectrum disorder (ASD). Therefore, we conducted molecular and behavior tests in adult proactive zebrafish after VPA exposure to investigate gene transcription changes, social behavior, aggression, anxiety and locomotion. Our findings revealed that VPA exposure generates ASD-like phenotypes and behaviors: genes associated with autism, such as adsl, mbd5 and shank3a altered; social interaction deficit...

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Genetic mutations are increasingly recognized as etiologic factors for epilepsy and neurodevelopmental disorders. Loss of function mutations in STXBP1, one of such genes, has, in recent years, been demonstrated to cause a broad spectrum of epilepsy syndromes and chronic neurodisabilities. Syntaxin-binding protein 1 (STXBP1) is a well-recognized membrane trafficking protein responsible for synaptic transmission and is expressed ubiquitously across the brain. Our case series presents the neurodevelopmental phenotype of children with STXBP1 mutations and is the first to be reported in an Emirati patient cohort...

INTRODUCTION: Up to 73% of individuals with autism spectrum disorder (ASD) and intellectual disability (ID) currently have prescriptions for psychotropic drugs. This is explained by a higher prevalence of medical and psychiatric chronic comorbidities, which favors polypharmacy, increasing the probability of the appearance of adverse events (AEs). These could be a preventable cause of harm to patients with ASD and an unnecessary waste of healthcare resources. OBJECTIVE: To study the impact of pharmacogenetic markers on the prevention of AE appearance in a population with ASD and ID...

The Aristaless-related homeobox ( ARX ) gene is located on the X chromosome and encodes a transcription factor that is essential for brain development. While the clinical spectrum of ARX -related disorders is well described in males, from X linked lissencephaly with abnormal genitalia syndrome to syndromic and non-syndromic intellectual disability (ID), its phenotypic delineation in females is incomplete. Carrier females in ARX families are usually asymptomatic, but ID has been reported in some of them, as well as in others with de novo variants...

Dysregulated cholesterol metabolism represents an increasingly recognized feature of Autism spectrum disorder (ASD). Children with fetal valproate syndrome caused by prenatal exposure to valproic acid (VPA), an anti-epileptic and mood-stabilizing drug, have a higher incidence of developing ASD. However, the role of VPA in cholesterol homeostasis in neurons and microglial cells remains unclear. Therefore, we examined the effect of VPA exposure on regulation of cholesterol homeostasis in the human microglial clone 3 (HMC3) cell line and the human neuroblastoma cell line SH-SY5Y...

In situ physiological signals of in vitro neural disease models are essential for studying pathogenesis and drug screening. Currently, an increasing number of in vitro neural disease models are established using human-induced pluripotent stem cell (hiPSC) derived neurons (hiPSC-DNs) to overcome interspecific gene expression differences. Microelectrode arrays (MEAs) can be readily interfaced with two-dimensional (2D), and more recently, three-dimensional (3D) neural stem cell-derived in vitro models of the human brain to monitor their physiological activity in real time...

Despite intensive studies in modeling neuropsychiatric disorders especially autism spectrum disorder (ASD) in animals, many challenges remain. Genetic mutant mice have contributed substantially to the current understanding of the molecular and neural circuit mechanisms underlying ASD. However, the translational value of ASD mouse models in preclinical studies is limited to certain aspects of the disease due to the apparent differences in brain and behavior between rodents and humans. Non-human primates have been used to model ASD in recent years...

BACKGROUND:  Kleefstra syndrome (KS) or 9q34.3 microdeletion syndrome (OMIM #610253) is a rare genetic condition featuring intellectual disability, hypotonia, and dysmorphic facial features. Autism spectrum disorder, severe language impairment, and sleep disorders have also been described. The syndrome can be either caused by a microdeletion in 9q34.3 or by pathogenic variants in the euchromatin histone methyltransferase 1 gene ( EHMT1 , *607001). Although epilepsy has been reported in 20 to 30% of subjects, a detailed description of epileptic features and underlying etiology is still lacking...

Thousands of voltage-gated sodium (Nav) channel variants contribute to a variety of disorders, including epilepsy, autism, cardiac arrhythmia, and pain disorders. Yet variant effects of more mutations remain unclear. The conventional gain-of-function (GoF) or loss-of-function (LoF) classifications is frequently employed to interpret of variant effects on function and guide precision therapy for sodium channelopathies. Our study challenges this binary classification by analyzing 525 mutations associated with 34 diseases across 366 electrophysiology studies, revealing that diseases with similar phenotypic effects can stem from unique molecular mechanisms...

Guillain-Barré syndrome (GBS) is one of the most prominent and acute immune-mediated peripheral neuropathy, while autism spectrum disorders (ASD) are a group of heterogeneous neurodevelopmental disorders. The complete mechanism regarding the neuropathophysiology of these disorders is still ambiguous. Even after recent breakthroughs in molecular biology, the link between GBS and ASD remains a mystery. Therefore, we have implemented well-established bioinformatic techniques to identify potential biomarkers and drug candidates for GBS and ASD...

Hypoxia-inducible factor 1 has been identified as an important therapeutic target in psychiatric illnesses. Hypoxia is a condition in which tissues do not receive enough oxygen, resulting in less oxidative energy production. HIF-1, the master regulator of molecular response to hypoxia, is destabilized when oxygen levels fall. HIF-1, when activated, increases the gene transcription factors that promote adaptive response and longevity in hypoxia. HIF-regulated genes encode proteins involved in cell survival, energy metabolism, angiogenesis, erythropoiesis, and vasomotor control...

BACKGROUND: Phelan-McDermid syndrome (PMS) is a rare multisystem disease with global developmental delay and autistic features. Genetically, the disease is based on a heterozygous deletion of chromosome 22q13.3 with involvement of at least part of the SHANK3 gene or heterozygous pathogenic variants in SHANK3. Pathophysiologically, this syndrome has been regarded as a synaptopathy, but current data suggest an additional concept, since axonal functions of neurons are also impaired, thus, the specific pathophysiological processes in this disease are not yet fully understood...

N-methyl-D-aspartate receptors (NMDAR), ionotropic glutamate receptors, mediate a slow component of excitatory synaptic transmission in the central nervous system and play a key role in normal brain function and development. Genetic variations in GRIN genes encoding NMDAR subunits that alter the receptor's functional characteristics are associated with a wide range of neurological and neuropsychiatric conditions. Pathological GRIN variants located in the M2 re-entrant loop lining the channel pore cause significant functional changes, the most consequential alteration being a reduction in voltage-dependent Mg2+ inhibition...

Prenatal exposure to valproic acid (VPA), a drug widely used to treat epilepsy and bipolar disorder, is an environmental risk factor for autism spectrum disorder (ASD). VPA has been used to reproduce the core symptoms of ASD in animal model organisms, including zebrafish. Visual system functioning is essential in the interpretation of social conditions and plays an important role of several behavioral responses. We hypothesized that behavioral deficits displayed by ASD patients may involve impaired visual processing...

Autism spectrum disorders (ASD) are diagnosed in 1/100 children worldwide, based on two core symptoms, deficits in social interaction and communication and stereotyped behaviours. G protein-coupled receptors (GPCRs) are the largest family of cell-surface receptors that transduce extracellular signals to convergent intracellular signalling and downstream cellular responses that are commonly dysregulated in ASD. Despite hundreds of GPCRs being expressed in the brain, only 23 are genetically associated with ASD according to the Simons Foundation Autism Research Initiative (SFARI) gene database: oxytocin OTR, vasopressin V1A , V1B , metabotropic glutamate mGlu5 , mGlu7 , GABAB2 , dopamine D1 , D2 , D3 , serotoninergic 5-HT1B , β2 -adrenoceptor, cholinergic M3 , adenosine A2A , A3 , angiotensin AT2 , cannabinoid CB1 , chemokine CX3 CR1, orphan GPR37, GPR85 and olfactory OR1C1, OR2M4, OR2T10, OR52M1...

Autism spectrum disorder (ASD) is a neurodevelopmental disorder associated with impaired social behavior and communication, repetitive behaviors, and restricted interests. In addition to genetic factors, environmental factors such as prenatal drug exposure contribute to the development of ASD. However, how those prenatal factors induce behavioral deficits in the adult stage is not clear. To elucidate ASD pathogenesis at the molecular level, we performed a high-resolution mass spectrometry-based quantitative proteomic analysis on the prefrontal cortex (PFC) of mice exposed to valproic acid (VPA) in utero, a widely used animal model of ASD...