Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004352 (autism)
 32,579 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ca2+ has been proposed to regulate Na+ channels through the action of calmodulin (CaM) bound to an IQ motif or through direct binding to a paired EF hand motif in the Nav1 C terminus. Mutations within these sites cause cardiac arrhythmias or autism, but details about how Ca2+ confers sensitivity are poorly understood. Studies on the homologous Cav1.2 channel revealed non-canonical CaM interactions, providing a framework for exploring Na+ channels. In contrast to previous reports, we found that Ca2+ does not bind directly to Na+ channel C termini. Rather, Ca2+ sensitivity appears to be mediated by CaM bound to the C termini in a manner that differs significantly from CaM regulation of Cav1.2. In Nav1.2 or Nav1.5, CaM bound to a localized region containing the IQ motif and did not support the large Ca(2+)-dependent conformational change seen in the Cav1.2.CaM complex. Furthermore, CaM binding to Nav1 C termini lowered Ca2+ binding affinity and cooperativity among the CaM-binding sites compared with CaM alone. Nonetheless, we found suggestive evidence for Ca2+/CaM-dependent effects upon Nav1 channels. The R1902C autism mutation conferred a Ca(2+)-dependent conformational change in Nav1.2 C terminus.CaM complex that was absent in the wild-type complex. In Nav1.5, CaM modulates the Cterminal interaction with the III-IV linker, which has been suggested as necessary to stabilize the inactivation gate, to minimize sustained channel activity during depolarization, and to prevent cardiac arrhythmias that lead to sudden death. Together, these data offer new biochemical evidence for Ca2+/CaM modulation of Na+ channel function.
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PMID:Calmodulin mediates Ca2+ sensitivity of sodium channels. 1531 14

The teratogenicity of the widely popular antiepileptic drug (AED) and mood stabiliser sodium valproate (also known as valproate, VPA) has been evidenced by previous research; however, these findings have often been limited by a small population sample of exposed women and a retrospective study design. Many factors contribute to the teratogenicity of VPA. These include the number of drugs that are co-administered, drug dosage, differences in maternal and/or infant metabolism, the gestational age of the fetus at exposure, and hereditary susceptibility. VPA has been associated with a variety of major and minor malformations, including a 20-fold increase in neural tube defects, cleft lip and palate, cardiovascular abnormalities, genitourinary defects, developmental delay, endocrinological disorders, limb defects, and autism. It has been suggested that polytherapy treatment in epileptic pregnant women increases the risk of teratogenicity in offspring. Furthermore, there is an established relationship between VPA dose and adverse outcome. Large single doses of VPA potentially cause high peak levels in the fetal serum resulting in deleterious effects. Currently there is an increase in the number of national and international pregnancy registries being formed in an effort to better identify the teratogenic effects of AEDs. These efforts hope to enhance our understanding of AEDs and their associated risks by addressing past study limitations.
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PMID:Teratogenicity of sodium valproate. 1579 25

The aim of this study was to evaluate the clinical features and frequency of autistic disorder or Asperger syndrome (AS; according to Diagnostic and Statistical Manual of Mental Disorders, 4th edition [DSM-IV] criteria) in children exposed to anticonvulsant medication in utero. During a 20-year study period, 626 children were born in Aberdeen to mothers taking antiepileptic drugs (AEDs). The study examined long-term effects of prenatal exposure to AEDs in 260 children (122 males, 138 females). Of these, 26 (16 males) were reported by parents to have social or behavioural difficulties. Eleven children (6 males, 5 females) fulfilled the DSM-IV criteria for autistic disorder and one (female) fulfilled the DSM-IV criteria for AS. These children comprised 4.6% of the exposed children studied, and 1.9% of all exposed children born during the study period. Mean age of these children at diagnosis was 5 years 4 months (SD 2y 11mo) and 9 years 10 months (SD 3y 10mo) at the time of this study. Other children from the group of 26 had difficulties in areas of speech and language development and social communication but did not meet the criteria for an autism spectrum disorder (ASD). Sodium valproate was the drug most commonly associated with autistic disorder, five of 56 (8.9%) of the study children exposed to sodium valproate alone had either autistic disorder or AS. It was concluded that prenatal exposure to anticonvulsant medication is a risk factor for the development of an ASD. Fetal anticonvulsant syndrome associated autistic disorder is characterized by an even sex ratio, absence of regression or skill loss, and language delay in the absence of global delay.
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PMID:Characteristics of fetal anticonvulsant syndrome associated autistic disorder. 1610 56

Autism is a neurodevelopmental disorder characterized by impairment in three core symptom domains: socialization, communication, and repetitive/stereotyped behaviours. Other associated symptom domains are also affected including impulsivity/aggression, self-injury, anxiety, and mood lability. Divalproex has been shown to have efficacy in treating epilepsy, bipolar disorder, mood lability, and impulsive aggression. The present study evaluated the use of divalproex in the treatment of repetitive, compulsive-like symptoms of autism spectrum disorder (ASD). Thirteen individuals with ASD participated in an 8-wk, double-blind, placebo-controlled trial of divalproex sodium vs. placebo. There was a significant group difference on improvement in repetitive behaviours as measured by the Children's Yale-Brown Obsessive Compulsive Scale (C-YBOCS) (p=0.037) and a large effect size (d=1.616). This study provides preliminary support for the use of divalproex in treating repetitive behaviours in ASD. Further research is needed to evaluate the specificity and mechanism of action of these findings.
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PMID:Divalproex sodium vs. placebo in the treatment of repetitive behaviours in autism spectrum disorder. 1631 86

Autism symptoms, including impairments in language development, social interactions, and motor skills, have been difficult to model in rodents. Since children exposed in utero to sodium valproate (VPA) demonstrate behavioral and neuroanatomical abnormalities similar to those seen in autism, the neurodevelopmental effects of this antiepileptic agent were examined in mice following its pre- or postnatal administration. Exposed pups were evaluated in a battery of neurodevelopmental procedures designed to assess VPA-induced retardation (wherein a behavior fails to mature on schedule), regression (wherein a behavior does mature on time but then deteriorates), or intrusions (wherein normal behaviors are overshadowed by stereotypic or self-injurious behaviors). The resulting observations were interpreted in the context of this new strategy to model autism.
J Autism Dev Disord 2006 Aug
PMID:A new neurobehavioral model of autism in mice: pre- and postnatal exposure to sodium valproate. 1660 25

Serotonin transporter (5-HTT) is a transmembrane protein belonging to Na+/Cl- dependent membrane transporter family and transports 5-HT across the membranes of presynaptic neurons. 5-HTT-linked polymorphic region (5-HTTLPR) gained much interest because of the differential regulation of expression and activity of 5-HTT by its various genotypes. A population-based study has been conducted on 5-HTTLPR with 358 individuals, which included 79 autistic probands, 136 parents, and 143 controls from two subpopulations of east and northeast regions of India. The genotypic frequencies of all the groups conform to Hardy-Weinberg equilibrium. With the finding of efficacy of serotonin reuptake inhibitors in ameliorating ritualistic behavior in autistic disorder, 5-HTT emerged as a putative candidate gene for autism and association studies have been carried out in different ethnic populations. But these studies were inconclusive due to conflicting results on association. Because such a study has never been performed in the Indian population, we have tested the possible involvement of 5-HTTLPR polymorphism with autism. The present study failed to establish any association or linkage of 5-HTTLPR with autism in the Indian population by case-control studies (chi2 = 1.314, P = 0.63) and family-based approaches (TDT chi2 = 0.22, P = 0.64 and HHRR-chi2 = 0.25, P = 0.61). However, when a meta-analysis of all the available TDT data, inclusive of the present study is carried out, we observed a significant preferential transmission of S-allele from parents to the affected offspring (chi2 = 7.51, P = 0.006) indicating an association of 5-HTTLPR with autism.
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PMID:Serotonin transporter promoter variants: Analysis in Indian autistic and control population. 1667 32

Perturbation of sodium channel inactivation, a finely tuned process that critically regulates the flow of sodium ions into excitable cells, is a common functional consequence of inherited mutations associated with epilepsy, skeletal muscle disease, autism, and cardiac arrhythmias. Understanding the structural basis of inactivation is key to understanding these disorders. Here we identify a novel role for a structural motif in the COOH terminus of the heart NaV1.5 sodium channel in determining channel inactivation. Structural modeling predicts an interhelical hydrophobic interface between paired EF hands in the proximal region of the NaV1.5 COOH terminus. The predicted interface is conserved among almost all EF hand-containing proteins and is the locus of a number of disease-associated mutations. Using the structural model as a guide, we provide biochemical and biophysical evidence that the structural integrity of this interface is necessary for proper Na+ channel inactivation gating. We thus demonstrate a novel role of the sodium channel COOH terminus structure in the control of channel inactivation and in pathologies caused by inherited mutations that disrupt it.
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PMID:A carboxyl-terminal hydrophobic interface is critical to sodium channel function. Relevance to inherited disorders. 1679 29

Sodium-coupled transporters are ubiquitous pumps that harness pre-existing sodium gradients to catalyse the thermodynamically unfavourable uptake of essential nutrients, neurotransmitters and inorganic ions across the lipid bilayer. Dysfunction of these integral membrane proteins has been implicated in glucose/galactose malabsorption, congenital hypothyroidism, Bartter's syndrome, epilepsy, depression, autism and obsessive-compulsive disorder. Sodium-coupled transporters are blocked by a number of therapeutically important compounds, including diuretics, anticonvulsants and antidepressants, many of which have also become indispensable tools in biochemical experiments designed to probe antagonist binding sites and to elucidate transport mechanisms. Steady-state kinetic data have revealed that both competitive and noncompetitive modes of inhibition exist. Antagonist dissociation experiments on the serotonin transporter (SERT) have also unveiled the existence of a low-affinity allosteric site that slows the dissociation of inhibitors from a separate high-affinity site. Despite these strides, atomic-level insights into inhibitor action have remained elusive. Here we screen a panel of molecules for their ability to inhibit LeuT, a prokaryotic homologue of mammalian neurotransmitter sodium symporters, and show that the tricyclic antidepressant (TCA) clomipramine noncompetitively inhibits substrate uptake. Cocrystal structures show that clomipramine, along with two other TCAs, binds in an extracellular-facing vestibule about 11 A above the substrate and two sodium ions, apparently stabilizing the extracellular gate in a closed conformation. Off-rate assays establish that clomipramine reduces the rate at which leucine dissociates from LeuT and reinforce our contention that this TCA inhibits LeuT by slowing substrate release. Our results represent a molecular view into noncompetitive inhibition of a sodium-coupled transporter and define principles for the rational design of new inhibitors.
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PMID:Antidepressant binding site in a bacterial homologue of neurotransmitter transporters. 1768 33

The cyclic adenosine monophosphate-specific phosphodiesterase-4 (PDE4) gene family is the target of several potential therapeutic inhibitors and the PDE4B gene has been associated with schizophrenia and depression. Little, however, is known of any connection between this gene family and autism, with limited effective treatment being available for autism. We measured the expression of PDE4A and PDE4B by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blotting in Brodmann's area 40 (BA40, parietal cortex), BA9 (superior frontal cortex), and cerebellum from subjects with autism and matched controls. We observed a lower expression of PDE4A5, PDE4B1, PDE4B3, PDE4B4, and PDE4B2 in the cerebella of subjects with autism when compared with matched controls. In BA9, we observed the opposite: a higher expression of PDE4AX, PDE4A1, and PDE4B2 in subjects with autism. No changes were observed in BA40. Our results demonstrate altered expressions of the PDE4A and PDE4B proteins in the brains of subjects with autism and might provide new therapeutic avenues for the treatment of this debilitating disorder.
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PMID:Expression of phosphodiesterase 4 is altered in the brains of subjects with autism. 1809 Mar 23

Environmental, dietary, and gastrointestinal factors may contribute to autism spectrum disorders (ASD). Propionic acid (PPA) is a short chain fatty acid, a metabolic end-product of enteric bacteria in the gut, and a common food preservative. Recent evidence indicates that PPA can cause behavioral abnormalities and a neuroinflammatory response in rats. Social behavior was examined in similarly-treated pairs of adult male Long-Evans rats placed in an open field following intracerebroventricular (ICV) injection of PPA (4 microl of 0.26 M solution) or control compounds. Behavior was analyzed using both the EthoVision behavior tracking system and by blind scoring of videotapes of social behaviors. Compared to controls, rats treated with PPA displayed social behavior impairments as indicated by significantly greater mean distance apart, reduced time spent in close proximity, reduced playful interaction, and altered responses to playful initiations. Treatment with another short chain fatty acid, sodium acetate, produced similar impairments, but treatment with the alcohol analog of PPA, 1-propanol, did not produce impairments. Immunohistochemical analysis of brain tissue taken from rats treated with PPA revealed reactive astrogliosis, indicating a neuroinflammatory response. These findings suggest that PPA can change both brain and behavior in the laboratory rat in a manner that is consistent with symptoms of human ASD.
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PMID:Intracerebroventricular injection of propionic acid, an enteric bacterial metabolic end-product, impairs social behavior in the rat: implications for an animal model of autism. 1839 59


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