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)

Glucosidase I is an important enzyme in N-linked glycoprotein processing, removing specifically distal alpha-1,2-linked glucose from the Glc3Man9GlcNAc2 precursor after its en bloc transfer from dolichyl diphosphate to a nascent polypeptide chain in the endoplasmic reticulum. We have identified a glucosidase I defect in a neonate with severe generalized hypotonia and dysmorphic features. The clinical course was progressive and was characterized by the occurrence of hepatomegaly, hypoventilation, feeding problems, seizures, and fatal outcome at age 74 d. The accumulation of the tetrasaccharide Glc(alpha1-2)Glc(alpha1-3)Glc(alpha1-3)Man in the patient's urine indicated a glycosylation disorder. Enzymological studies on liver tissue and cultured skin fibroblasts revealed a severe glucosidase I deficiency. The residual activity was <3% of that of controls. Glucosidase I activities in cultured skin fibroblasts from both parents were found to be 50% of those of controls. Tissues from the patient subjected to SDS-PAGE followed by immunoblotting revealed strongly decreased amounts of glucosidase I protein in the homogenate of the liver, and a less-severe decrease in cultured skin fibroblasts. Molecular studies showed that the patient was a compound heterozygote for two missense mutations in the glucosidase I gene: (1) one allele harbored a G-->C transition at nucleotide (nt) 1587, resulting in the substitution of Arg at position 486 by Thr (R486T), and (2) on the other allele a T-->C transition at nt 2085 resulted in the substitution of Phe at position 652 by Leu (F652L). The mother was heterozygous for the G-->C transition, whereas the father was heterozygous for the T-->C transition. These base changes were not seen in 100 control DNA samples. A causal relationship between the alpha-glucosidase I deficiency and the disease is postulated.
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PMID:A novel disorder caused by defective biosynthesis of N-linked oligosaccharides due to glucosidase I deficiency. 1078 35

Severe falciparum malaria, with its associated hyperpyrexia, distorts plasma levels of large neutral amino acids (NAA) and consequently, brain uptake of individual NAA. Since brain levels of NAA determine cerebral synthesis of monoamines (serotonin, histamine, catecholamines), we measured plasma concentrations of NAA, and also plasma histamine (Hm) in children with falciparum malaria and in uninfected controls. Malaria elicited a marked (P < 0.025) increase in plasma histidine (His) with a 5-fold significant (P < 0.001) elevation in histamine, as well as a 2.5-fold increase (P < 0.005) in plasma phenylalanine (Phe), with no changes in the other NAA. Using kinetic parameters of NAA transport at human blood-brain barrier (BBB), we showed that malaria significantly altered calculated brain uptake of His (+30%), Phe (+96%), Trp (-30%) and Ile (-27%), with no change in the other NAA, compared with controls. Our data suggested enhanced cerebral synthesis of Hm with impaired production of serotonin and the catecholamines in the patients, and therefore, the need to evaluate the encephalopathy in severe malaria within the context of abnormalities in metabolism of Hm and other monoamines resulting from imbalance in plasma levels of the large neutral amino acids. Of clinical relevance also is the impaired inactivation of increased brain Hm by antimalarials such as the widely used aminoisoquinolines leading to elevated brain levels of imidazole-4-acetic acid (IAA), a potent inducer of a sleep-like state often accompanied by seizures, analgesia, decreased blood pressure and other effects.
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PMID:Increased plasma levels of histidine and histamine in falciparum malaria: relevance to severity of infection. 1114 3

Previous data indicate that intracerebroventricular administration of agonists for mu- and delta-opioid receptors induces limbic seizures in rats, but no data are reported in rabbits. We found that the mu- and delta-opioid peptides [D-Ala(2)-N,Me-Phe(4)-Gly(5)-ol]enkephalin (DAMGO), beta-endorphin and deltorphin II, induced EEG non-convulsive hippocampal seizures, and changes in hippocampal background EEG, physical parameters and overt behaviour after central administration. Dexamethasone pre-treatment prevented DAMGO-, deltorphin II- and beta-endorphin-induced seizures as well as changes in background EEG, physical parameters and overt behaviour induced by mu-opioid agonists. Dexamethasone antagonism on opioid action was blocked by pre-treatment with a protein synthesis inhibitor, cycloheximide or by the kappa-opioid antagonist nor-binaltorphimine. Our data suggest that dexamethasone influences opioid actions at mu- and delta-receptors via a protein synthesis mechanism involving kappa-opioid receptors.
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PMID:Dexamethasone blocking effects on mu- and delta-opioid-induced seizures involves kappa-opioid activity in the rabbit. 1128 2

The opiate-like peptide nociceptin/orphanin FQ (Noc) and its receptor [opiate receptor-like receptor (ORL-1)] are highly expressed in the hippocampus. Noc has inhibitory postsynaptic actions in CA1, CA3, and the dentate and seems to lack the disinhibitory, excitatory actions demonstrated for some opiate peptides in the hippocampus. The CA3 hippocampal region is important in the generation of hippocampal seizures. Therefore, we tested the action of Noc on spontaneous epileptiform activity recorded extracellularly or intracellularly in CA3 and generated by removal of Mg(2+) from the bathing solution or by raising extracellular K(+) from 3.5 to 7.5 mm. Superfusion of Noc robustly depressed spontaneous bursting without desensitization. The ORL-1 antagonist [Phe(1)Psi(CH(2)-NH)Gly(2)]NC(1-13)NH(2) (1-2 microm) greatly attenuated the reduction of spontaneous bursting by Noc. To characterize the cellular mechanism of action of Noc, we recorded intracellularly from CA3 pyramidal neurons. Noc reduced EPSCs evoked by stimulating either mossy or associational/commissural fibers. Analysis of miniature EPSCs using whole-cell voltage-clamp recording suggests that Noc acts presynaptically to inhibit glutamate release. This is the first demonstration of a presynaptic effect for Noc in the hippocampus. Noc also increased K(+) currents in CA3 pyramidal neurons, including the voltage-sensitive M-current. Blocking the M-current with linopirdine increased the duration of individual CA3 bursts but did not attenuate Noc-mediated inhibition of bursting. Thus, Noc acts via multiple mechanisms to reduce excitation in CA3. However, Noc inhibition of epileptiform events is not dependent on augmentation of the M-current.
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PMID:Nociceptin reduces epileptiform events in CA3 hippocampus via presynaptic and postsynaptic mechanisms. 1151 81

Molybdenum cofactor deficiency is a rare inborn error of metabolism with generally severe symptoms, most often including neonatal seizures and severe developmental delay. We describe a patient with an unusually mild form of the disease. Two mutations in MOCS2A (molybdenum cofactor synthesis enzyme 2A) were identified: a single base change, 16C > T, that predicts a Q6X substitution on one allele and a 19G > T transversion that predicts a valine to phenylalanine substitution, V7F, on the second. It is postulated that the milder clinical symptoms result from a low level of residual molybdopterin synthase activity derived from the 19G > T allele.
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PMID:Molybdopterin synthase mutations in a mild case of molybdenum cofactor deficiency. 1174 50

Ten cases of tetrahydrobiopterin (BH4) deficiency were identified in 1,337,490 newborns screened in a Chinese population in Taiwan. The high incidence of BH4 deficiency in the Taiwanese population may be explained by a founder effect, since all of the patients revealed 6-pyruvoyltetrahydropterin synthase gene mutations, and grouping N52S and P87S mutations together constituted 88.9% of the disease alleles. BH4 supplementation with restriction of high-protein foods gave control of plasma phenylalanine within normal range, and levodopa itself prevented seizure. However, the average intelligence quotient (IQ) score of these patients was only 76 +/- 14 (56-98). Statistically, the age of starting medication, including 5-hydroxytryptophan (5-HTP), was inversely correlated to IQ scores of these patients. We suggest the combination of BH4, levodopa and 5-HTP as the standard protocol to commence the treatment of BH4 deficiency as early as possible, although prenatal brain damage could have existed.
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PMID:Treatment and outcome of Taiwanese patients with 6-pyruvoyltetrahydropterin synthase gene mutations. 1191 14

To date about 20 activating mutations in the calcium-sensing receptor (CaR) gene have been identified to cause autosomal dominant hypocalcemia (ADH) or sporadic hypoparathyroidism. We report a novel activating mutation in the CaR gene in a Japanese family with ADH. The proband, a 15-yr-old boy, and 5 other patients in 3 generations were asymptomatic, except for the proband's grandmother who had a history of seizures. They showed mild hypocalcemia (1.68-1.98 mmol/liter) with normal urinary calcium excretion and low normal serum PTH levels. Their serum magnesium concentrations were below normal in 3 adults and within the normal range in 3 teenagers. There was a significant positive correlation (r = 0.90; P < 0.05) between the serum calcium and magnesium concentrations of 6 affected members. Nucleotide sequencing revealed that the proband had a known polymorphism (Gly(990)Arg) and a novel heterozygous mutation substituting phenylalanine for serine at codon 820 (Ser(820)Phe) in the sixth transmembrane helix of the CaR. In other family members, the Ser(820)Phe mutation cosegregated with hypocalcemia. The mutation was not detected in 50 control subjects. The Gly(990)Arg polymorphism was observed in 8 of 9 family members with or without hypocalcemia and in 36 of 50 controls. The sensitivity of the Ser(820)Phe mutant CaR to calcium was assessed using transiently transfected HEK293 cells and measuring the increases in intracellular Ca(2+) concentrations in response to the changes in extracellular Ca(2+). The concentration-response curve of the mutant receptor was left-shifted, and its EC(50) (2.5 mM) was significantly (P < 0.05) lower than that of the wild-type CaR (3.3 mM). We conclude that the Ser(820)Phe mutation in the CaR caused ADH in this family. The positive correlation between serum calcium and magnesium levels observed in this family may support the concept that renal CaR acts as a magnesium sensor as well as a calcium sensor.
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PMID:A family of autosomal dominant hypocalcemia with a positive correlation between serum calcium and magnesium: identification of a novel gain of function mutation (Ser(820)Phe) in the calcium-sensing receptor. 1205 Feb 33

Over 20 years have elapsed since aspartame was approved by regulatory agencies as a sweetener and flavor enhancer. The safety of aspartame and its metabolic constituents was established through extensive toxicology studies in laboratory animals, using much greater doses than people could possibly consume. Its safety was further confirmed through studies in several human subpopulations, including healthy infants, children, adolescents, and adults; obese individuals; diabetics; lactating women; and individuals heterozygous (PKUH) for the genetic disease phenylketonuria (PKU) who have a decreased ability to metabolize the essential amino acid, phenylalanine. Several scientific issues continued to be raised after approval, largely as a concern for theoretical toxicity from its metabolic components--the amino acids, aspartate and phenylalanine, and methanol--even though dietary exposure to these components is much greater than from aspartame. Nonetheless, additional research, including evaluations of possible associations between aspartame and headaches, seizures, behavior, cognition, and mood as well as allergic-type reactions and use by potentially sensitive subpopulations, has continued after approval. These findings are reviewed here. The safety testing of aspartame has gone well beyond that required to evaluate the safety of a food additive. When all the research on aspartame, including evaluations in both the premarketing and postmarketing periods, is examined as a whole, it is clear that aspartame is safe, and there are no unresolved questions regarding its safety under conditions of intended use.
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PMID:Aspartame: review of safety. 1218 Apr 94

A study on phenylketonuria (PKU) has been carried out in China-Japan Friendship Hospital since 1984. The results revealed that: (1) Totally 603 patients with PKU were diagnosed and treated in the hospital from October 1984 to September 2002. Among which 136 cases were identified by neonatal screening and treated within 3 months. One hundred and ninety-five cases were treated when the children were 3-12 months of age. Another 272 PKU children were diagnosed when they were more than 1 year old. All of these late-treated cases had some signs and symptoms of PKU. Mental retardation was found in 467 cases and various patterns of seizures in 119 cases. After treatment with low-phenylalanine diet, the follow-up for early-treated patients revealed that their physical and mental developments were normal. In late-treated patients, abnormal behaviour was significantly improved and their developmental quotient were elevated. Prenatal gene diagnosis of PKU risk foetus in 22 PKU families was successfully performed. (2) Urinary pterins obtained from 369 HPA patients were measured by HPLC. Twenty two patients with BH4 deficiency have been recognized. Six single base mutations were detected in 18 unrelated northern Chinese BH4 deficiency families, and the mutations at nucleotides 259C-->T and 286G-->A were common mutations. Eighteen BH4 deficient patients were treated with BH4, L-dopa and 5-hydroxytryptophan, and the results were satisfactory. (3) The abnormal rate of EEG was high in untreated patients with PKU, mainly showing epileptiform discharges and partly showing background activity abnormality. The most frequent finding was patchy areas of increased signal intensity in white matter on MRI in the brain of PKU patients, while delayed myelination and brain agenesis were often detected. After dietary treatment, follow-ups with EEG and MRI revealed that the abnormalities were decreased significantly. (4) The relationship between genotype and intellectual phenotype was examined in 29 late-treated patients with classical PKU. It was found that the genotype of 22 patients were compatible with intellectual phenotype and not well matched in 7 cases. The result indicate that the genotype was well matched with intellectual phenotype in classical PKU patients.
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PMID:[An eighteen-year study on phenylketonuria]. 1290 26

Mutations in the coding region of the angiotensin II type 2 receptor gene (AGTR2) were recently identified to cause X-linked recessive mental retardation. We report a mutation screening of the AGTR2 gene in 57 Finnish male patients with non-syndromic mental retardation. We identified two mutations, a 62G-->T transversion, which leads to a substitution of glycine for valine (G21V) and a 157A-->T transversion, which causes a substitution of isoleucine for phenylalanine (I53F). The patients with AGTR2 sequence variants had severe/profound mental retardation, epileptic seizures, restlessness, hyperactivity, and disturbed development of speech.
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PMID:Identification of two AGTR2 mutations in male patients with non-syndromic mental retardation. 1472 54


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