Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0036572 (seizures)
80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An infant is described who had a combination of lobar holoprosencephaly and open-lip schizencephaly. Midline fusion of the basal ganglia was associated with bilateral absence of abundant parts of the brain mantle. Agenesis of the corpus callosum, hypoplasia of the optic nerves and chiasm, absence of the septum pellucidum, posterior pituitary and olfactory bulbs were further components of the malformation. Blindness, intractable seizures, spastic tetraplegia, somatomental retardation and diabetes insipidus were the main clinical features. A defect in the induction of the mediobasal part of the prosencephalon and failure of cell proliferation can be responsible for this complex malformation. Recent results of homeobox gene research relevant to the development of the prosencephalon are discussed.
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PMID:Mediobasal and mantle defect of the prosencephalon: lobar holoprosencephaly, schizencephaly and diabetes insipidus. 981 May 64

Mental retardation and epilepsy often occur together. They are both heterogeneous conditions with acquired and genetic causes. Where causes are primarily genetic, major advances have been made in unraveling their molecular basis. The human X chromosome alone is estimated to harbor more than 100 genes that, when mutated, cause mental retardation. At least eight autosomal genes involved in idiopathic epilepsy have been identified, and many more have been implicated in conditions where epilepsy is a feature. We have identified mutations in an X chromosome-linked, Aristaless-related, homeobox gene (ARX), in nine families with mental retardation (syndromic and nonspecific), various forms of epilepsy, including infantile spasms and myoclonic seizures, and dystonia. Two recurrent mutations, present in seven families, result in expansion of polyalanine tracts of the ARX protein. These probably cause protein aggregation, similar to other polyalanine and polyglutamine disorders. In addition, we have identified a missense mutation within the ARX homeodomain and a truncation mutation. Thus, it would seem that mutation of ARX is a major contributor to X-linked mental retardation and epilepsy.
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PMID:Mutations in the human ortholog of Aristaless cause X-linked mental retardation and epilepsy. 1188 67

Emx1 is a mammalian homolog of the Drosophila gap gene empty spiracles (ems). Although it has been implicated in the formation of the mouse forebrain, the neuronal functions of this homeobox gene remain unknown. The restricted expression of Emx1 to the cerebral cortex and hippocampus suggests that it might play a role in emotional and other behavioral processes. The present study examined the phenotypes of Emx1-deficient mice generated by gene targeting technology in a battery of behavioral tests with a fixed inter-trial interval of 7 days. Compared with their wild-type littermates, the Emx1 homozygous mutant mice displayed markedly lowered anxiety-like behaviors in the elevated plus maze and dark/light exploration tests. Moreover, they exhibited less depressive-like response as indicated by the reduced duration of immobility in the forced swimming paradigm. There was a trend toward reduction in prepulse inhibition of acoustic startle in the homozygotes. No significant alterations in locomotor activity and susceptibility to pentylenetetrazol-induced seizure were found. This behavioral profile indicates an involvement of Emx1 in the emotional responses of mice.
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PMID:Reduced anxiety-- and depression-like behaviors in Emx1 homozygous mutant mice. 1202 Aug 59

Clinical data from 50 mentally retarded (MR) males in nine X-linked MR families, syndromic and non-specific, with mutations (duplication, expansion, missense, and deletion mutations) in the Aristaless related homeobox gene, ARX, were analysed. Seizures were observed with all mutations and occurred in 29 patients, including one family with a novel myoclonic epilepsy syndrome associated with the missense mutation. Seventeen patients had infantile spasms. Other phenotypes included mild to moderate MR alone, or with combinations of dystonia, ataxia or autism. These data suggest that mutations in the ARX gene are important causes of MR, often associated with diverse neurological manifestations.
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PMID:Infantile spasms, dystonia, and other X-linked phenotypes caused by mutations in Aristaless related homeobox gene, ARX. 1214 61

X-linked West syndrome, also called "X-linked infantile spasms" (ISSX), is characterized by early-onset generalized seizures, hypsarrhythmia, and mental retardation. Recently, we have shown that the majority of the X-linked families with infantile spasms carry mutations in the aristaless-related homeobox gene (ARX), which maps to the Xp21.3-p22.1 interval, and that the clinical picture in these patients can vary from mild mental retardation to severe ISSX with additional neurological abnormalities. Here, we report a study of two severely affected female patients with apparently de novo balanced X;autosome translocations, both disrupting the serine-threonine kinase 9 (STK9) gene, which maps distal to ARX in the Xp22.3 region. We show that STK9 is subject to X-inactivation in normal female somatic cells and is functionally absent in the two patients, because of preferential inactivation of the normal X. Disruption of the same gene in two unrelated patients who have identical phenotypes (consisting of early-onset severe infantile spasms, profound global developmental arrest, hypsarrhythmia, and severe mental retardation) strongly suggests that lack of functional STK9 protein causes severe ISSX and that STK9 is a second X-chromosomal locus for this disorder.
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PMID:Disruption of the serine/threonine kinase 9 gene causes severe X-linked infantile spasms and mental retardation. 1273 70

X-linked lissencephaly with abnormal genitalia is the first human disorder in which deficient tangential migration in the brain has been demonstrated. Male patients with X-linked lissencephaly with abnormal genitalia show intractable seizures, especially clonic convulsions or myoclonus from the first day of life, but neither infantile spasms nor hypsarrhythmia on electroencephalograms so far. Brain magnetic resonance imaging shows anterior pachygyria and posterior agyria with a mildly thick cortex, agenesis of the corpus callosum, and dysplastic basal ganglia. ARX, a paired-class homeobox gene with four polyalanine sequences, is a responsible gene for X-linked lissencephaly with abnormal genitalia. The brain of Arx knockout mice shows aberrant tangential migration and differentiation of gamma-aminobutyric acid (GABA)ergic interneurons. In human X-linked lissencephaly with abnormal genitalia, a neuropathologic study has suggested a loss of interneurons. Meanwhile, polyalanine expansion of ARX causes symptomatic or nonsymptomatic West's syndrome and nonsyndromic mental retardation. The striking epileptogenicity of X-linked lissencephaly with abnormal genitalia and West's syndrome associated with ARX mutations i s considered to be caused by a disorder of interneurons involving a tangentialmigration disorder. We propose "interneuronopathy" as a term for this.
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PMID:X-linked lissencephaly with abnormal genitalia as a tangential migration disorder causing intractable epilepsy: proposal for a new term, "interneuronopathy". 1592 Dec 44

Mutations in the X-linked aristaless-related homeobox gene (ARX) have been linked to structural brain anomalies as well as multiple neurocognitive deficits. The generation of Arx-deficient mice revealed several morphological anomalies, resembling those observed in patients and an interneuron migration defect but perinatal lethality precluded analyses of later phenotypes. Interestingly, many of the neurological phenotypes observed in patients with various ARX mutations can be attributed, in part, to interneuron dysfunction. To directly test this possibility, mice carrying a floxed Arx allele were generated and crossed to Dlx5/6(CRE-IRES-GFP)(Dlx5/6(CIG)) mice, conditionally deleting Arx from ganglionic eminence derived neurons including cortical interneurons. We now report that Arx(-/y);Dlx5/6(CIG) (male) mice exhibit a variety of seizure types beginning in early-life, including seizures that behaviourally and electroencephalographically resembles infantile spasms, and show evolution through development. Thus, this represents a new genetic model of a malignant form of paediatric epilepsy, with some characteristics resembling infantile spasms, caused by mutations in a known infantile spasms gene. Unexpectedly, approximately half of the female mice carrying a single mutant Arx allele (Arx(-/+);Dlx5/6(CIG)) also developed seizures. We also found that a subset of human female carriers have seizures and neurocognitive deficits. In summary, we have identified a previously unrecognized patient population with neurological deficits attributed to ARX mutations that are recapitulated in our mouse model. Furthermore, we show that perturbation of interneuron subpopulations is an important mechanism underling the pathogenesis of developmental epilepsy in both hemizygous males and carrier females. Given the frequency of ARX mutations in patients with infantile spasms and related disorders, our data unveil a new model for further understanding the pathogenesis of these disorders.
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PMID:Targeted loss of Arx results in a developmental epilepsy mouse model and recapitulates the human phenotype in heterozygous females. 2012 36

ARX (the aristaless-related homeobox gene) is a transcription factor that participates in the development of GABAergic and cholinergic neurons in the forebrain. Many ARX mutations have been identified in X-linked lissencephaly and mental retardation with epilepsy, and thus ARX is considered to be a causal gene for the two syndromes although the neurobiological functions of each mutation remain unclear. We attempted to elucidate the causal relationships between individual ARX mutations and disease phenotypes by generating a series of mutant mice. We generated three types of mice with knocked-in ARX mutations associated with X-linked lissencephaly (P353R) and mental retardation [P353L and 333ins(GCG)7]. Mice with the P355R mutation (equivalent to the human 353 position) that died after birth were significantly different in Arx transcript/protein amounts, GABAergic and cholinergic neuronal development, brain morphology and lifespan from mice with P355L and 330ins(GCG)7 but considerably similar to Arx-deficient mice with truncated ARX mutation in lissencephaly. Mice with the 330ins(GCG)7 mutation showed severe seizures and impaired learning performance, whereas mice with the P355L mutation exhibited mild seizures and only slightly impaired learning performance. Both types of mutant mice exhibited the mutation-specific lesser presence of GABAergic and cholinergic neurons in the striatum, medial septum and ventral forebrain nuclei when compared with wild-type mice. Present findings that reveal a causal relationship between ARX mutations and the pleiotropic phenotype in mice, suggest that the ARX-related syndrome, including lissencephaly or mental retardation, is caused by only the concerned ARX mutations without the involvement of other genetic factors.
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PMID:Three human ARX mutations cause the lissencephaly-like and mental retardation with epilepsy-like pleiotropic phenotypes in mice. 1960 12

Ohtahara syndrome or Early Infantile Epileptic Encephalopathy (EIEE) with Suppression-Burst, is the most severe and the earliest developing age-related epileptic encephalopathy. Clinically, the syndrome is characterized by early onset tonic spasms associated with a severe and continuous pattern of burst activity. It is a debilitating and early progressive neurological disorder, resulting in intractable seizures and severe mental retardation. Specific mutations in at least four genes (whose protein products are essential in lower brain's neuronal and interneuronal functions, including mitochondrial respiratory chains have been identified in unrelated individuals with EIEE and include: (a) the ARX (aristaless-related) homeobox gene at Xp22.13 (EIEE-1 variant); (b) the CDKL5 (SYK9) gene at Xp22 (EIEE-2 variant); (c) the SLC25A22 (GC1) gene at 11p15.5 (EIEE-3 variant); and (d) the Stxbp1 (MUNC18-1) gene at 9q34-1 (EIEE-4 variant). A yet unresolved issue involves the relationship between early myoclonic encephalopathy (EME-ErbB4 mutations) versus the EIEE spectrum of disorders.
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PMID:Ohtahara syndrome with emphasis on recent genetic discovery. 2196 65

GABA is the key inhibitory neurotransmitter in the cortex but regulation of its synthesis during forebrain development is poorly understood. In the telencephalon, members of the distal-less (Dlx) homeobox gene family are expressed in, and regulate the development of, the basal ganglia primodia from which many GABAergic neurons originate and migrate to other forebrain regions. The Dlx1/Dlx2 double knock-out mice die at birth with abnormal cortical development, including loss of tangential migration of GABAergic inhibitory interneurons to the neocortex (Anderson et al., 1997a). We have discovered that specific promoter regulatory elements of glutamic acid decarboxylase isoforms (Gad1 and Gad2), which regulate GABA synthesis from the excitatory neurotransmitter glutamate, are direct transcriptional targets of both DLX1 and DLX2 homeoproteins in vivo Further gain- and loss-of-function studies in vitro and in vivo demonstrated that both DLX1 and DLX2 are necessary and sufficient for Gad gene expression. DLX1 and/or DLX2 activated the transcription of both Gad genes, and defects in Dlx function disrupted the differentiation of GABAergic interneurons with global reduction in GABA levels in the forebrains of the Dlx1/Dlx2 double knock-out mouse in vivo Identification of Gad genes as direct Dlx transcriptional targets is significant; it extends our understanding of Dlx gene function in the developing forebrain beyond the regulation of tangential interneuron migration to the differentiation of GABAergic interneurons arising from the basal telencephalon, and may help to unravel the pathogenesis of several developmental brain disorders.SIGNIFICANCE STATEMENT GABA is the major inhibitory neurotransmitter in the brain. We show that Dlx1/Dlx2 homeobox genes regulate GABA synthesis during forebrain development through direct activation of glutamic acid decarboxylase enzyme isoforms that convert glutamate to GABA. This discovery helps explain how Dlx mutations result in abnormal forebrain development, due to defective differentiation, in addition to the loss of tangential migration of GABAergic inhibitory interneurons to the neocortex. Reduced numbers or function of cortical GABAergic neurons may lead to hyperactivity states such as seizures (Cobos et al., 2005) or contribute to the pathogenesis of some autism spectrum disorders. GABAergic dysfunction in the basal ganglia could disrupt the learning and development of complex motor and cognitive behaviors (Rubenstein and Merzenich, 2003).
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PMID:GABAergic Interneuron Differentiation in the Basal Forebrain Is Mediated through Direct Regulation of Glutamic Acid Decarboxylase Isoforms by Dlx Homeobox Transcription Factors. 2882 66


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