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)

The contents of B6 vitamers were measured in the brains of mice treated with DL- and D-PeA. When a single convulsant dose of DL-PeA was injected, PLP content was decreased, being accompanied with production of PLP-thiazolidine. The effect of DL-PeA on PLP content was evident far before the occurrence of the convulsions. The administration of PN together with DL-PeA prevented the onset of seizures and lessened the effect of DL-PeA on PLP content. The same amount of D-PeA did not invoke seizures, but caused a small but significant decrease in PLP content.
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PMID:Effects of penicillamine on the contents of B6 vitamers of the mouse brain. 101 Oct 49

The intraventricular injection of pyridoxal phosphate (PLP; 1 mumole/brain) to rats causes convulsive seizures beginning 3 min after injection and lasting for about 20 min. The incorporation of [2-3H] glycerol into rat brain glycerides has been studied to ascertain whether treatment with PLP affects the incorporation of label into various lipid classes. The labeling pattern of glycerides is changed by the administration of PLP. The observed alterations begin a few min after injection, together with the convulsive seizures. 1 h after the injection the pattern of labeling of brain glycerides returns to normal. Different glycerides are differently affected by PLP. This work demonstrates that the labeling of diglyceride increases whereas that of phosphatidylethanolamine decreases following PLP administration.
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PMID:The effect of pyridoxal phosphate-induced convulsive seizures on rat brain phospholipid metabolism. 646 40

The intracerebroventricular injection of pyridoxal phosphate (PLP, 0.125-1.25 mumol/rat) causes epileptic seizures (4 min leads to 1 min) that are preventable or reversible by GABA (1 mumol/rat), by muscimol (0.025 mumol/rat), or by diazepam (1.75 mumol/rat). At the peak of PLP-induced convulsions, the activities of GAD and GABA-T in 14 regions of rat brain remained unaltered, whereas the concentrations of PLP remained elevated. The PLP-induced convulsion was blocked by DABA (10 mumol/rat) but was not altered by beta-alanine (50 mumol/rat). The previous in vitro studies have shown that PLP increases the uptake of [3H]GABA into synaptosomes and inhibits the binding of [3H]GABA to synaptic membranes. These data suggest that PLP-induced convulsion is due to reduced availability of GABA to its recognition sites, rather than to alteration in the activity of GABA metabolizing enzymes, or unavailability of PLP as a coenzyme for GAD and GABA-T. Since the duration of PLP-induced epileptic seizures is short and can be prevented by GABA agonists, PLP may be used as a tool to study the nature of GABA-mediated neuroinhibition and the properties of GABA receptor sites.
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PMID:Anticonvulsant activity of muscimol and gamma-aminobutyric acid against pyridoxal phosphate-induced epileptic seizures. 746 50

This study describes a new sex-linked myelin mutation in the mouse, jimpy 4J (Plpjp-4J), located in or very close to the proteolipid protein (Plp) gene. The Plpjp-4J/Y phenotype includes tremor, seizures, death during the 4th postnatal week, and the most severe central nervous system hypomyelination yet described in any mouse carrying a single myelin mutation. The few myelin sheaths are present in early myelinating areas where they form clusters of thin, usually loosely wrapped membranes which show several variations of morphology at their extracellular leaflets. Numbers of mature oligodendrocytes are sharply reduced; pycnotic glial nuclei and foamy cells are numerous. Astrocytosis is a prominent feature. No PLP protein is detected by immunoblotting in Plpjp-4J/Y brain but in spinal cord a faint band is present. Myelin basic protein and characteristic myelin lipids are also sharply reduced in both brain and spinal cord. Despite the qualitative similarity of the phenotypes reported in these and previous studies, DNA analysis demonstrate that Plpjp-4J is not a recurrence of the well known Plp mouse mutations jimpy (Plpjp) or myelin synthesis deficiency (Plpjp-msd).
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PMID:Jimpy 4J: a new X-linked mouse mutation producing severe CNS hypomyelination. 882 19

We previously showed that the jimpy-4J mouse mutation is located on the X chromosome, in or closely linked to the proteolipid protein (Plp) gene. The phenotype is characterized by the most severe hypomyelination of any of the naturally occurring myelin mutant mice, sharp reduction in oligodendrocyte number, and virtual absence of PLP protein. Affected animals show tremor, seizures, and die at about 24 postnatal days. We now report that sequencing of Plp genomic and cDNAs identifies a single nucleotide substitution in exon 2 that predicts an Ala38Ser substitutions in a hydrophilic region of PLP/DM20 protein close to a transmembrane domain. This mutation occurs in a very different region of the mouse Plp gene than that jimpy-msd mutations, yet all three produce qualitatively similar phenotypes.
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PMID:Jimpy-4J mouse has a missense mutation in exon 2 of the Plp gene. 921 79

Mutations of the proteolipid protein (Plp) gene cause a generalized central nervous system (CNS) myelin deficit in Pelizaeus-Merzbacher disease of man and various tremor syndromes in animal models. X-linked spastic paraplegia is also due to Plp gene mutations but has a different clinical profile and more restricted pathology involving specific tracts and regions. We have shown previously that PLP overexpression in mice homozygous for a Plp transgene results in premature arrest of CNS myelination and premature death. Here, we demonstrate that a low-level increase in Plp gene expression in transgenic mice causes significant axonal degeneration and demyelination with predilection for specific tracts. Following normal motor development, aged mice develop progressive myelin loss, axonal swellings with resultant Wallerian degeneration, and marked vacuolation of the neuropil associated with ataxia, tremor, and seizures. The age of onset and severity of the phenotype is a function of Plp gene dosage. The corticospinal tracts, optic nerve, fasciculus gracilis cerebellum, and brainstem are particularly involved. Although oligodendrocyte cell bodies show little abnormality, their inner adaxonal tongue is often abnormal, suggesting a perturbation of the axon/glial interface that may underlie the axonal changes. We conclude that abnormal expression of an oligodendrocyte-specific gene can cause axonal damage, a finding that is relevant to the pathogenesis of PLP-associated disorders and probably to other myelin-related diseases.
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PMID:Late-onset neurodegeneration in mice with increased dosage of the proteolipid protein gene. 959 May 58

To identify the roles of pyridoxal kinase (PLK) in epileptogenesis and the recovery mechanisms in spontaneous seizure, a chronological and comparative analysis of PLK expression in the gerbil hippocampus was conducted. PLK immunoreactivity in a pre-seizure group of seizure sensitive (SS) gerbils was more strongly detected than that in a seizure resistant (SR) group. The density of PLK immunoreactivity in a 30-min postictal group was significantly lower than that of a pre-seizure group. In a 12 h postictal group, PLK immunodensity recovered to pre-seizure level. The over-expression of PLK in the hippocampus of pre-seizure SS gerbils suggests that PLP play an important role in the modulation of GAD activity and GABA reuptake as mediated by membrane transporter via neurons.
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PMID:Changes in pyridoxal kinase immunoreactivity in the gerbil hippocampus following spontaneous seizure. 1244 66

We describe the electroencephalographic and clinical seizure manifestations of pyridoxal 5'-phosphate-dependent epilepsy (PLP-DE) in two patients [diagnosis confirmed by low cerebrospinal fluid (CSF) PLP, complete resolution of previously intractable seizures with PLP supplementation, negative pyridoxine-dependent epilepsy CSF biomarkers, and/or positive disease causing pyridox(am)ine 5'-phosphate oxidase gene mutation] along with a comprehensive review of the literature. One patient presented with neonatal tonic status epilepticus with subsequent generalized tonic-clonic seizures, and the second, with refractory complex partial seizures starting at 2 years of age. The pretreatment EEG revealed, interictally, burst suppression, multifocal independent sharp waves, and electrical status epilepticus in sleep. Ictally and interictally, it revealed runs of unilateral spike/slow waves. Previously reported features include burst suppression, myoclonus, tonic seizures, clonic seizures, and spasms. In the appropriate clinical scenario, the aforementioned features should raise the possibility of PLP-DE and appropriate treatment should be initiated. The first late-onset case (at 2 years) of PLP-DE is reported.
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PMID:Electroencephalographic and seizure manifestations of pyridoxal 5'-phosphate-dependent epilepsy. 2129 58

To date we know of four inborn errors of autosomal recessive inheritance that lead to vitamin B6-dependent seizures. Among these, pyridoxine-dependent seizures due to antiquitin deficiency is by far the most common, although exact incidence data are lacking. In PNPO deficiency, samples have to be collected prior to treatment, while PDE, hyperprolinemia type II and congenital HPP can be diagnosed while on vitamin B6 supplementation. A vitamin B6 withdrawal for diagnostic purposes is nowadays only indicated in patients with a clear vitamin B6 response but normal biochemical work-up. In the presence of therapy-resistant neonatal seizures, early consideration of a vitamin B6 trial over 3 consecutive days is crucial in order to prevent irreversible brain damage. While PLP would be effective in all four disorders, pyridoxine fails to treat seizures in PNPO deficiency. As PLP is unlicensed within Europe and North America, pyridoxine is widely used as the first line drug, but if it is ineffective it should be followed by a trial with PLP, especially in neonates. As severe apnea has been described in responders, resuscitation equipment should be at hand during a first pyridoxine/PLP administration. Patients and parents have to be informed about the lifelong dependency and recurrence risks in forthcoming pregnancies.
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PMID:Pyridoxine and pyridoxalphosphate-dependent epilepsies. 2362 3

Pyridoxine-dependent epilepsy (PDE) is a rare genetic condition characterized by intractable and recurrent neonatal seizures that are uniquely alleviated by high doses of pyridoxine (vitamin B6). This recessive disease is caused by mutations in ALDH7A1, a gene encoding Antiquitin, an enzyme central to lysine degradation. This results in the pathogenic accumulation of the lysine intermediates Aminoadipate Semialdehyde (AASA) and its cyclic equilibrium form Piperideine-6-carboxylate (P6C) in body fluids; P6C reacts with pyridoxal-5'-phosphate (PLP, the active form of vitamin B6) causing its inactivation and leading to pyridoxine-dependent seizures. While PDE is responsive to pharmacological dosages of pyridoxine, despite lifelong supplementation, neurodevelopment delays are observed in >75% of PDE cases. Thus, adjunct treatment strategies are emerging to both improve seizure control and moderate the delays in cognition. These adjunctive therapies, lysine restriction and arginine supplementation, separately or in combination (with pyridoxine thus termed 'triple therapy'), have shown promising results and are recommended in all PDE patients. Other new therapeutic strategies currently in preclinical phase of study include antisense therapy and substrate reduction therapy. We present here a comprehensive review of current treatment options as well as PDE phenotype, differential diagnosis, current management and views upon the future of PDE research.
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PMID:Current knowledge for pyridoxine-dependent epilepsy: a 2016 update. 3005 81


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