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)

Wolf-Hirschhorn syndrome (WHS) is caused by a variably-sized deletion of chromosome 4 involving band 4p16 whose typical craniofacial features are "Greek warrior helmet appearance" of the nose, microcephaly, and prominent glabella. Almost all patients show mental retardation and pre- and post-natal growth delay. Patient was born at term, after a pregnancy characterized by intra-uterine growth retardation (IUGR). Delivery was uneventful. Developmental delay was evident since the first months of life. At 2 years, he developed generalized tonic-clonic seizures. Because of short stature, low growth velocity and delayed bone age, at 4 years he underwent growth hormone (GH) evaluation. Peak GH after two provocative tests revealed a partial GH deficiency. Clinical observation at 7 years disclosed a distinctive facial appearance, with microcephaly, prominent eyes, and beaked nose. Brain MRI showed left temporal mesial sclerosis. GTG banded karyotype was normal. Because of mental retardation, subtelomeric fluorescence in situ hybridization (FISH) analysis was performed, disclosing a relatively large deletion involving 4p16.2 --> pter (about 4.5 Mb), in the proband, not present in the parents. The smallest deletion detected in a WHS patient thus far includes two candidate genes, WHSC1 and WHSC2. Interestingly, that patient did not show shortness of stature, and that could be due to the haploinsufficiency of other genes localized in the flanking regions. Contribution of GH alterations and possible GH therapy should be further considered in WHS patients.
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PMID:Mild Wolf-Hirschhorn phenotype and partial GH deficiency in a patient with a 4p terminal deletion. 1510 11

Adenosine is an inhibitory modulator of neuronal activity and its possible involvement in seizures is of interest. We have examined changes in adenosine, its metabolites and receptors in brains of hippocampus-kindled rats, a model of partial epilepsy. Purine levels were measured by in vivo microdialysis and showed a small increase in adenosine and a dramatic increase in its metabolites after kindled seizures. Adenosine A1 receptor binding using [H]DPCPX was unaltered after seizures, whereas A1 agonist stimulated binding of GTP[gamma-S] and A1 mRNA expression increased in the CA3 and other regions. Striatal adenosine A2A mRNA and receptor binding with [H]SCH-58261 decreased. These findings indicate that kindled seizures increase adenosine release and metabolism and induces adaptive changes in adenosine receptors.
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PMID:Changes in purine levels and adenosine receptors in kindled seizures in the rat. 1523 88

Acute and chronic administration of the nucleoside guanosine have been shown to prevent quinolinic acid (QA) and alpha-dendrotoxin-induced seizures, as well as to impair memory and anxiety in rats and mice. In this study, we investigated the effect of i.c.v. administration of guanine-based purines (GTP, GDP, GMP, and guanosine) against seizures induced by the NMDA agonist and glutamate releaser quinolinic acid in mice. We also aimed to study the effects of the poorly hydrolysable analogs of GTP (GppNHp and GTPgammaS) and GDP (GDPbetaS) in this seizure model. QA produced seizures in 100% of mice, an effect partially prevented by guanine-based purines. In contrast to GTP (480 nmol), GDP (320-640 nmol), GMP (320-480 nmol) and guanosine (300-400 nmol), the poorly hydrolysable analogs of GTP and GDP did not affect QA-induced seizures. Thus, the protective effects of guanine nucleotides seem to be due to their conversion to guanosine. Altogether, these findings suggest a potential role of guanine-based purines for treating diseases involving glutamatergic excitotoxicity.
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PMID:Intracerebroventricular guanine-based purines protect against seizures induced by quinolinic acid in mice. 1575 34

Extracellular guanine-based purines, namely the nucleotides GTP, GDP, GMP and the nucleoside guanosine, exert important neuroprotective and neuromodulator roles in the central nervous system, which may be related to inhibition of the glutamatergic neurotransmission activity. In this study, we investigated GMP effects on mice inhibitory avoidance performance and the dependence on its conversion to guanosine for such effect, by using the ecto-5'-nucleotidase specific inhibitor AOPCP. We also investigated if this conversion occurs in the central nervous system or peripherally, and if guanosine and GMP affect nociception by the tail-flick test. I.p. GMP or guanosine (7.5 mg/kg) or i.c.v. GMP (480 nmol) pretraining administration was amnesic for the inhibitory avoidance task. I.c.v. AOPCP (1 nmol) administration completely reversed the amnesic effect of i.c.v. GMP, but not of i.p. GMP, indicating that peripheral conversion of GMP to guanosine is probably relevant to this effect. AOPCP alone did not interfere with the performance. Furthermore, tail-flick measurement was unaffected by i.p. GMP and guanosine, suggesting that the amnesic effect of both purines was not due to some antinociceptive effect against the footshock used in the task. All these data together, in accordance to those previously observed in studies involving glutamate uptake and seizures reinforce the idea that guanosine is the specific extracellular guanine-based purines effector and indicate that its conversion occurs not only in the central nervous system but also peripherally.
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PMID:Amnesic effect of GMP depends on its conversion to guanosine. 1632 34

Traumatic brain injury (TBI) is characterized by a progressive cell loss and a lack of axonal regeneration. In the central nervous system (CNS), the Rho signaling pathway regulates the neuronal response to growth inhibitory proteins and regeneration of damaged axons, and Rho activation is also correlated with an increased susceptibility to apoptosis. To evaluate whether traumatic brain injury (TBI) results in changes in Rho activation in vulnerable regions of the brain, GTP-RhoA pull down assays were performed on rat cortical and hippocampal tissue homogenates obtained from 24 h to 3 days following lateral fluid percussion brain injury (FPI). Following FPI, a significantly increased RhoA activation was observed from 24 h to 3 days post-injury in the cortex and by 3 days in the hippocampus ipsilateral to the injury. We also detected activated RhoA in the cortex and hippocampus contralateral to the injury, without concomitant changes in total RhoA levels. To determine if immediate post-traumatic events such as seizures may activate Rho, we examined RhoA activation in the brains of rats with kainic acid-induced seizures. Severe seizures resulted in bilateral RhoA activation in the cortex and hippocampus. Together, these results indicate that RhoA is activated in vulnerable brain regions following traumatic and epileptic insults to the CNS.
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PMID:Activation of Rho after traumatic brain injury and seizure in rats. 1644 51

Tissue transglutaminase (tTG) post-translationally modifies proteins in a calcium-dependent manner by incorporation of polyamines, deamination or crosslinking. Moreover, tTG can also bind and hydrolyze GTP. tTG is the major transglutaminase in the mammalian nervous system, localizing predominantly in neurons. Although tTG has been clearly demonstrated to be elevated in neurodegenerative diseases and in response to acute CNS injury, its role in these pathogenic processes remains unclear. Transgenic mice that overexpress human tTG (htTG) primarily in CNS neurons were generated to explore the role of tTG in the nervous system and its contribution to neuropathological processes. tTG transgenic mice were phenotypically normal and were born with the expected Mendelian frequency. However, when challenged systemically with kainic acid, tTG transgenic mice, in comparison to wild-type (WT) mice, developed more extensive hippocampal neuronal damage. This was evidenced by a decreased number of healthy neurons, and increased terminal deoxynucleotidyl dUTP nick end labeling (TUNEL) labeling as an indicator of neuronal cell death in the kainic acid-treated transgenic mice. Moreover, the duration and severity of seizures developed by htTG transgenics in response to kainic acid administration were significantly more pronounced than those observed in WT mice. These data indicate for the first time that tTG may play an active role in excitatory amino acid-induced neuronal cell death, which has been postulated to be an important component of acute CNS injury and chronic CNS neurodegenerative conditions.
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PMID:Tissue transglutaminase overexpression in the brain potentiates calcium-induced hippocampal damage. 1653 54

Pentylenetetrazol (PTZ) is commonly used as a convulsant drug. The enhanced seizure susceptibility induced by kindling is probably attributable to plastic changes in the synaptic efficacy. Adenosine and guanosine act both as important neuromodulators and neuroprotectors with mostly inhibitory effects on neuronal activity. Adenosine and guanosine can be released per se or generated from released nucleotides (ATP, ADP, AMP, GTP, GDP, and GMP) that are metabolized and rapidly converted to adenosine and guanosine. The aim of this study was to evaluate nucleotide hydrolysis by ecto- and soluble nucleotidases (hippocampal slices and CSF, respectively) after PTZ-kindling (stages 3, 4, or 5 seizures) or saline treatment in rats. Additionally, the levels of purines in rat cerebrospinal fluid (CSF), as well as ecto-NTPDases (1, 2, 3, 5, 6 and 8) and ecto- 5'-nucleotidase expression were determined. Ecto-enzyme assays demonstrated that ATP, AMP, GDP, and GMP hydrolysis enhanced when compared with controls. In addition, there was an increase of ADP, GDP, and GMP hydrolysis by soluble nucleotidases in PTZ-kindling rats compared to control group. The HPLC analysis showed a marked increase in PTZ-kindled CSF concentrations of GTP, ADP, and uric acid, but GDP, AMP, and hypoxanthine concentrations were decreased. Such alterations indicate that the modulatory role of purines in CNS could be affected by PTZ-kindling. However, the physiological significance of these findings remains to be elucidated.
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PMID:Pentylenetetrazol kindling alters adenine and guanine nucleotide catabolism in rat hippocampal slices and cerebrospinal fluid. 1754 58

We present clinical and developmental data on a patient with a de novo recombinant pseudodicentric bisatellited chromosome 22 associated with a partial trisomy 22pter-22q12.1. The patient was evaluated at birth and followed-up until 21 years of age. Clinical findings include facial and digital dysmorphism, hydrocephalus and postnatal-onset growth deficiency. The patient showed bilateral microphthalmia with severe palpebral ptosis and coloboma of the iris and left optic nerve. She also has skeletal and neurological abnormalities, cholesteatoma and seizures. She had absence of speech, poor mobility, poor vision and required help with all daily living skills. Conventional chromosome GTG banded analysis showed that the proband had an abnormal karyotype:46,XX,add(22)(q13). Fluorescence in situ hybridization (FISH) analyses and microsatellite markers for DNA polymorphism study ascertained the karyotype as 46,XX,add(22)(q13.3).ish psu dic(22;22)(q13.3;q12.1)(D14Z1/D22Z1++, N25++, ARSA+, PCP22q+). The recombinant chromosome was stable and present in all cells examined. The paternal origin of the psu dic(22;22) chromosome was determined by using five highly polymorphic microsatellite markers located to the region of chromosome 22q11.2-22q13.33. A 22q13.3 monosomy was ruled out with 22q13.3 cosmid probes covering the terminal 22q-140Kb. The proband carried a recombinant pseudodicentric bisatellited chromosome psu dic(22;22)(q13.3;q12.1). To our knowledge, this is the first report of such rearrangement resulting in partial trisomy 22pter-22q12.1.
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PMID:A 21 years follow-up of a girl patient with a pseudodicentric bisatellited chromosome 22 associated with partial trisomy 22pter-->22q12.1: clinical, cytogenetic and molecular observations. 1831 57

Subtelomeric imbalances are a significant cause of congenital disorders. Screening for these abnormalities has traditionally utilized GTG-banding analysis, fluorescence in situ hybridization (FISH) assays, and multiplex ligation-dependent probe amplification. Microarray-based comparative genomic hybridization (array-CGH) is a relatively new technology that can identify microscopic and submicroscopic chromosomal imbalances. It has been proposed that an array with extended coverage at subtelomeric regions could characterize subtelomeric aberrations more efficiently in a single experiment. The targeted arrays for chromosome microarray analysis (CMA), developed by Baylor College of Medicine, have on average 12 BAC/PAC clones covering 10 Mb of each of the 41 subtelomeric regions. We screened 5,380 consecutive clinical patients using CMA. The most common reasons for referral included developmental delay (DD), and/or mental retardation (MR), dysmorphic features (DF), multiple congenital anomalies (MCA), seizure disorders (SD), and autistic, or other behavioral abnormalities. We found pathogenic rearrangements at subtelomeric regions in 236 patients (4.4%). Among these patients, 103 had a deletion, 58 had a duplication, 44 had an unbalanced translocation, and 31 had a complex rearrangement. The detection rates varied among patients with a normal karyotype analysis (2.98%), with an abnormal karyotype analysis (43.4%), and with an unavailable or no karyotype analysis (3.16%). Six patients out of 278 with a prior normal subtelomere-FISH analysis showed an abnormality including an interstitial deletion, two terminal deletions, two interstitial duplications, and a terminal duplication. In conclusion, genomic imbalances at subtelomeric regions contribute significantly to congenital disorders. Targeted array-CGH with extended coverage (up to 10 Mb) of subtelomeric regions will enhance the detection of subtelomeric imbalances, especially for submicroscopic imbalances.
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PMID:Identification of chromosome abnormalities in subtelomeric regions by microarray analysis: a study of 5,380 cases. 1866 43

We report on a 4-year-old girl who presented with microcephaly, multiple minor anomalies of face and limbs, congenital heart defect, hypotonia, neuropsychomotor delay, deafness and seizures. A GTG-banded karyotype identified an additional fragment of unknown origin on the terminal region of 4p. Parental karyotypes were normal. FISH analysis using a whole chromosome paint probe for chromosome 4 and subtelomere probes showed a signal on the entire add (4) chromosome and loss of the 4p subtelomere region, respectively. Additional analysis using microsatellite markers for chromosome 4 and whole-genome array comparative genomic hybridization (array-CGH) identified a duplication of the region 4p13 --> 4p16.3. Her karyotype was thus interpreted as an inverted duplication with terminal deletion of 4p: 46,XX,der(4)(:p13 --> p16.3::p16.3 --> qter). The clinical features of our patient differed from those typically observed in Wolf-Hirschhorn syndrome and were more compatible with duplication 4(p14 --> p16.3), with preservation of the WHS critical region.
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PMID:Inv dup del(4)(:p13-->p16.3::p16.3-->qter) in a girl without typical manifestations of Wolf-Hirschhorn syndrome. 1944 29


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