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)

Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine (Phe) metabolism resulting from deficiency of phenylalanine hydroxylase (PAH). Most forms of PKU and hyperphenylalaninaemia (HPA) are caused by mutations in the PAH gene on chromosome 12q23.2. Untreated PKU is associated with an abnormal phenotype which includes growth failure, poor skin pigmentation, microcephaly, seizures, global developmental delay and severe intellectual impairment. However, since the introduction of newborn screening programs and with early dietary intervention, children born with PKU can now expect to lead relatively normal lives. A better understanding of the biochemistry, genetics and molecular basis of PKU, as well as the need for improved treatment options, has led to the development of new therapeutic strategies.
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PMID:Phenylketonuria: an inborn error of phenylalanine metabolism. 1856 68

Defects in the metabolism or regeneration of tetrahydrobiopterin (BH4) were initially discovered in patients with hyperphenylalaninaemia who had progressive neurological deterioration despite optimal metabolic control (malignant hyperphenylalaninaemia). BH4 is an essential cofactor not only for phenylalanine hydroxylase, but also for tyrosine and two tryptophan hydroxylases, three nitric oxide synthases, and glyceryl-ether monooxygenase. Defective activity of tyrosine and tryptophan hydroxylases explains the neurological deterioration in patients with BH4 deficiency with progressive mental and physical retardation, central hypotonia and peripheral spasticity, seizures and microcephaly. Five separate genetic conditions affect BH4 synthesis or regeneration: deficiency of GTP cyclohydrolase I, 6-pyruvoyl tetrahydropterin synthase, sepiapterin reductase, dihydropteridine reductase (DHPR) and pterin-4alpha-carbinolamine dehydratase. Only the latter of these conditions is relatively benign and is associated with transient hyperphenylalaninaemia. All these conditions can be identified in newborns by an elevated phenylalanine, with the exception of sepiapterin reductase and the dominant form of GTP cyclohydrolase I deficiency that results in biopterin deficiency/insufficiency only in the brain. Diagnosis relies on the measurement of pterin metabolites in urine, dihydropteridine reductase in blood spots, neurotransmitters and pterins in the CSF and on the demonstration of reduced enzyme activity (red blood cells or fibroblasts) or causative mutations in the relative genes. The outcome of BH4 deficiency is no longer malignant if therapy is promptly initiated to reduce plasma phenylalanine levels and replace missing neurotransmitters. This is accomplished by a special diet and/or BH4 supplements and administration of L-dopa, carbidopa, 5-hydroxytryptophan, and, in certain cases, a MAO-B inhibitor. Patients with DHPR deficiency also require folinic acid supplements, since DHPR may help in maintaining folate in the tetrahydro form. Several patients with BH4 deficiency treated since the newborn period have reached adult age with good outcome.
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PMID:Disorders of biopterin metabolism. 1923 59

Chemical-induced seizures up-regulated brain-derived neurotrophic factor (BDNF) mRNA expression. Intracerebroventricular (i.c.v.) administration of endogenous opioids preferentially activating mu opioid receptor (MOR) could also increase BDNF mRNA expression. The aim of this study was to determine to what extent i.c.v. administration of synthetic MOR-selective agonists in rats can modulate both seizure activity and up-regulation of BDNF mRNA expression. Effects and potencies of i.c.v. administration of morphine and [D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin (DAMGO), were directly investigated by scoring behavioral seizures and measuring BDNF mRNA expression. In addition, effects of the opioid receptor antagonist naloxone and antiepileptic drugs, diazepam, phenobarbital, and valproate, on i.c.v. MOR agonist-induced behavioral seizures and up-regulation of BDNF mRNA expression were determined. A single i.c.v. administration of morphine (10-100 microg) or DAMGO (0.15-1.5 microg) dose-dependently elicited behavioral seizures and increased BDNF mRNA expression in the widespread brain regions. However, s.c. administration of MOR agonists neither produced behavioral seizures nor increased BDNF mRNA expression. Pretreatment with naloxone 1 mg/kg significantly reduced behavioral seizure scores and the up-regulation of BDNF mRNA expression elicited by i.c.v. morphine or DAMGO. Similarly, diazepam 10 mg/kg and phenobarbital 40 mg/kg significantly blocked i.c.v. MOR agonist-induced actions. Pretreatment with valproate 300 mg/kg only attenuated behavioral seizures, but it did not affect morphine-induced increase of BDNF mRNA expression. This study provides supporting evidence that seizure activity plays an important role in the up-regulation of BDNF mRNA expression elicited by central MOR activation and that decreased inhibitory action of GABAergic system through the modulation on GABA receptor synaptic function by central MOR activation is involved in its regulation of BDNF mRNA expression.
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PMID:Seizure activity involved in the up-regulation of BDNF mRNA expression by activation of central mu opioid receptors. 1930 19

Infantile spasms are an epilepsy syndrome with distinctive features, including age onset during infancy, characteristic epileptic spasms, and specific electroencephalographic patterns (interictal hypsarrhythmia and ictal voltage suppression). Adrenocorticotropic hormone (ACTH) was first employed to treat infantile spasms in 1958, and since then it has been tried in prospective and retrospective studies for infantile spasms. Oral corticosteroids were also used in a few studies for infantile spasms. Variable success in cessation of infantile spasms and normalization of electroencephalograms was demonstrated. However, frequent significant adverse effects are associated with ACTH and oral corticosteroids. Vigabatrin has been used since the 1990s, and shown to be successful in resolution of infantile spasms, especially for infantile spasms associated with tuberous sclerosis. It is associated with visual field constriction, which is often asymptomatic and requires perimetric visual field study to identify. When ACTH, oral corticosteroids, and vigabatrin fail to induce cessation of infantile spasms, other alternative treatments include valproic acid, nitrazepam, pyridoxine, topiramate, zonisamide, lamotrigine, levetiracetam, felbamate, ganaxolone, liposteroid, thyrotropin-releasing hormone, intravenous immunoglobulin and a ketogenic diet. Rarely, infantile spasms in association with biotinidase deficiency, phenylketonuria, and pyridoxine-dependent seizures are successfully treated with biotin, a low phenylalanine diet, and pyridoxine, respectively. For medically intractable infantile spasms, some properly selected patients may have complete cessation of infantile spasms with appropriate surgical treatments.
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PMID:Current trends in the treatment of infantile spasms. 1955 23

Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine (Phe) metabolism resulting from deficiency of phenylalanine hydroxylase (PAH). Most forms of PKU are caused by mutations in the PAH gene. Untreated PKU is associated with an abnormal phenotype, which includes growth failure, seizures, global developmental delay and severe intellectual impairment. The maternal PKU (MPKU) syndrome is caused by high blood Phe concentrations during pregnancy and presents with serious foetal anomalies, especially microcephaly, congenital heart disease and mental retardation. However, since the introduction of newborn screening programs and with early dietary intervention, children born with PKU can now expect to lead relatively normal lives. We present the case of a 33-year-old woman who had been diagnosed as having PKU only after a pregnancy with MPKU embryopathy, to emphasize that undiagnosed maternal phenylketonuria still exists. On that ground, we reviewed updated literature on the pathogenesis of this syndrome, possibility of prophylaxis and treatment.
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PMID:Undiagnosed maternal phenylketonuria: own clinical experience and literature review. 1955 60

This study evaluated the newborn screening program for phenylketonuria (PKU) in Thailand from 1996 to 2006. During the study period, 5,243,841 newborns were screened, of which 16 were confirmed to have PKU. The phenylalanine levels ranged from 20.30-30.68 mg/dl (mean 25.82 mg/dl). All the patients who were diagnosed through the newborn screening program had normal growth and development after treatment except for 2 cases who were subsequently found to have a 6-pyruvoyltetrahydropterin synthase deficiency. Four additional cases of PKU diagnosed were siblings of screening detected cases who all presented with mental retardation, microcephaly, hypopigmented hair and skin and seizures in one case. Although these patients were treated with a phenylalanine restricted diet, all of them had moderate to severe psychomotor retardation. The results of this study confirm the benefit of early detection and treatment of PKU through the screening program.
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PMID:Detection of phenylketonuria by the newborn screening program in Thailand. 1984 39

Postictal movement dysfunction is a common symptom in patients with epilepsy. We investigated the involvement of opioid receptors in the nucleus accumbens (NAC) in amygdaloid kindling-induced postictal decrease in locomotion (PDL) in rats. Seizures were induced by daily electrical stimulation of the basolateral amygdala until four consecutive stage 5 seizures were elicited. Locomotion was quantified before and after infusion of an opioid receptor antagonist or saline into the NAC. Whereas PDL was induced after a stage 5 seizure in saline-infused rats, pre-infusion of the mu opioid receptor antagonist H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP, 5 microg/1 microL/side) into the NAC prevented PDL. Pre-infusion of delta (naltrindole, 30 microg/1 microL/side), kappa (nor-binaltorphimine, 1.8 microg/1 microL/side), or nonselective (naloxone, 10 microg/1 microL/side) opioid receptor antagonists did not block PDL, but late postictal hyperactivity was blocked by naltrindole. None of the antagonists affected amygdaloid evoked afterdischarge duration. It is suggested that mu opioid receptors in the NAC participate in amygdaloid seizure-induced PDL without affecting seizure duration.
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PMID:Nucleus accumbens mu opioid receptors mediate immediate postictal decrease in locomotion after an amygdaloid kindled seizure in rats. 2011 38

Phenylketonuria (PKU) is one of the most common inherited metabolic disorders, which is characterized by excessive accumulation of phenylalanine (Phe) in tissues. Generalized seizures occur in 25% of the patients. Little is known about seizures and their treatment in adult PKU patients, and information with newer antiepileptic drugs is lacking. Here we report an adult patient who developed generalized seizures later in life, despite strict dietary control, and whose seizures were aggravated by levetiracetam (LEV). Convulsions ceased after discontinuation of LEV and the patient has been seizure free on topiramate 125 mg/day.
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PMID:Generalized seizures aggravated by levetiracetam in an adult patient with phenylketonuria. 2042 3

We have examined the correlation between the presence of epilepsy in humans, and plasma amino acid levels. Subjects were divided into those having pure generalized tonic-clonic seizures (grand mal group), those having generalized tonic-clonic seizures plus other types of epilepsy (mixed group), and those suffering from epilepsies other than grand mal (no grand mal group). Compared to non-epileptic controls, the grand mal group had significantly higher fasting plasma levels of aspartate (100% increase) and glutamate (380% increase) but significant decreases were seen with phenylalanine (?23%), lysine (?27%), and tryptophan (?30%). The no grand mal group showed similar changes except for lysine. The mixed group showed elevations in glutamate, but decreases only in cysteine and methionine. In response to a high protein meal, plasma levels of alanine, cysteine and methionine rose significantly less for the no grand mal group compared to the control group. Increases in aspartate and glutamate concentrations strongly correlated with the prescription of phenytoin. However, the concentrations of these amino acids were not significantly correlated with the actual plasma levels of phenytoin.
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PMID:Epilepsy and the concentrations of plasma amino acids in humans. 2048 33

Axial myopathy is a rare neuromuscular disease that is characterized by paraspinal muscle atrophy and abnormal posture, most notably camptocormia (also known as bent spine). The genetic cause of familial axial myopathy is unknown. Described here are the clinical features and cause of late-onset predominant axial myopathy and encephalopathy. A 73-year-old woman presented with a 10-year history of severe paraspinal muscle atrophy and cerebellar ataxia. Her 84-year-old sister also developed late-onset paraspinal muscle atrophy and generalized seizures with encephalopathy. Computed tomography showed severe atrophy and fatty degeneration of their paraspinal muscles. Their mother and maternal aunt also developed bent spines. The existence of many ragged-red fibers and cytochrome c oxidase-negative fibers in the biceps brachii muscle of the proband indicated a mitochondrial abnormality. No significant abnormalities were observed in the respiratory chain enzyme activities; however, the activities of complexes I and IV were relatively low compared with the activities of other complexes. Sequence analysis of the mitochondrial DNA from the muscle revealed a novel heteroplasmic mutation (m.602C>T) in the mitochondrial tRNA(Phe) gene. This familial case of late-onset predominant axial myopathy and encephalopathy may represent a new clinical phenotype of a mitochondrial disease.
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PMID:A new phenotype of mitochondrial disease characterized by familial late-onset predominant axial myopathy and encephalopathy. 2142 49


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