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)

Glut-1 deficiency syndrome was first described in 1991 as a sporadic clinical condition, later shown to be the result of haploinsufficiency. We now report a family with Glut-1 deficiency syndrome affecting 5 members over 3 generations. The syndrome behaves as an autosomal dominant condition. Affected family members manifested mild to severe seizures, developmental delay, ataxia, hypoglycorrhachia, and decreased erythrocyte 3-O-methyl-D-glucose uptake. Seizure frequency and severity were aggravated by fasting, and responded to a carbohydrate load. Glut-1 immunoreactivity in erythrocyte membranes was normal. A heterozygous R126H missense mutation was identified in the 3 patients available for testing, 2 brothers (Generation 3) and their mother (Generation 2). The sister and her father were clinically and genotypically normal. In vitro mutagenesis studies in Xenopus laevis oocytes demonstrated significant decreases in the transport of 3-O-methyl-D-glucose and dehydroascorbic acid. Xenopus oocyte membranes expressed high amounts of the R126H mutant Glut-1. Kinetic analysis indicated that replacement of arginine-126 by histidine in the mutant Glut-1 resulted in a lower Vmax. These studies demonstrate the pathogenicity of the R126H missense mutation and transmission of Glut-1 deficiency syndrome as an autosomal dominant trait.
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PMID:Autosomal dominant glut-1 deficiency syndrome and familial epilepsy. 1160 79

Rasmussen's syndrome is a chronic encephalitis characterized by intractable focal epilepsy and progressive neurologic deterioration with lateralized brain destruction. In the early stages of the disease, the diagnosis can be difficult to make, and brain biopsy is often performed. We evaluated the patterns of cerebral glucose metabolism using 2-deoxy-2-[18F]-fluoro-D-glucose positron emission tomography (PET) in 15 children (age range 2.9-15.4 years, mean age 8.7 +/- 4.3 years) with Rasmussen's syndrome. In 6 patients evaluated early (< or = 1 year of onset of seizures), the PET scan showed areas of abnormal metabolism restricted mostly to the frontal and temporal regions, whereas the posterior cortex was preserved. Pathologic changes seen in the resected cortex were more pronounced in cortical areas of abnormal metabolism than in regions showing normal metabolism. In 9 patients evaluated later (>1 year after onset of seizures), the PET scan showed more diffuse hemispheric metabolic abnormalities including the occipital cortex, but the abnormalities remained highly lateralized. These patterns of glucose metabolic abnormalities in the early and late stages of the disease may facilitate the diagnosis of Rasmussen's syndrome and assist guidance of biopsy in early cases, when structural neuroimaging is still normal.
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PMID:Patterns of cerebral glucose metabolism in early and late stages of Rasmussen's syndrome. 1173 64

We describe a new congenital disorder of glycosylation, CDG-If. The patient has severe psychomotor retardation, seizures, failure to thrive, dry skin and scaling with erythroderma, and impaired vision. CDG-If is caused by a defect in the gene MPDU1, the human homologue of hamster Lec35, and is the first disorder to affect the use, rather than the biosynthesis, of donor substrates for lipid-linked oligosaccharides. This leads to the synthesis of incomplete and poorly transferred precursor oligosaccharides lacking both mannose and glucose residues. The patient has a homozygous point mutation (221T-->C, L74S) in a semiconserved amino acid of MPDU1. Chinese hamster ovary Lec35 cells lack a functional Lec35 gene and synthesize truncated lipid-linked oligosaccharides similar to the patient's. They lack glucose and mannose residues donated by Glc-P-Dol and Man-P-Dol. Transfection with the normal human MPDU1 allele nearly completely restores normal glycosylation, whereas transfection with the patient's MPDU1 allele only weakly restores normal glycosylation. This work provides a new clinical picture for another CDG that may involve synthesis of multiple types of glycoconjugates.
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PMID:A mutation in the human MPDU1 gene causes congenital disorder of glycosylation type If (CDG-If). 1173 52

2-deoxy-2-[18F] fluoro-D-glucose (18FDG) was developed in 1976 in a collaboration between scientists at the National Institutes of Health, the University of Pennsylvania, and Brookhaven National Laboratory. It was developed for the specific purpose of mapping brain glucose metabolism in living humans, thereby serving as a tool in the basic human neurosciences. With 18FDG it was possible for the first time to measure regional glucose metabolism in the living human brain. Around the same time, the use of 18FDG for studies of myocardial metabolism and as a tracer for tumor metabolism were reported. After the first synthesis of 18FDG via an electrophilic fluorination with 18F gas (produced via the 20Ne(d,alpha)18F reaction), small volume enriched water targets were developed that made it possible to produce large quantities of [18F]fluoride ion via the high-yield 18(p,n)18F reaction. This was followed by a major milestone, the development of a nucleophilic fluorination method that produced 18FDG in very high yield. These advances and the remarkable properties of 18FDG have largely overcome the limitations of the 110-minute half-life of 18F so that 18FDG is now available to most regions of the United States from a number of central production sites. This avoids the need for an on-site cyclotron and chemistry laboratory and has opened up the use of 18FDG to institutions that have a positron emission tomography (PET) scanner (or other imaging device) but no cyclotron or chemistry infrastructure. Currently, 18FDG is used by many hospitals as an off the shelf radiopharmaceutical for clinical diagnosis in heart disease, seizure disorders, and oncology, the area of most rapid growth. However, it remains an important tool in human neuroscience and in drug research and development.
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PMID:Initial and subsequent approach for the synthesis of 18FDG. 1183 70

The relationship between positron emission tomography (PET) findings and developmental or seizure outcome was examined in 17 infants (11 males, six females; mean age at onset of spasms 7 months, range 3 to 26 months) with newly diagnosed cryptogenic West syndrome. The predictive value of PET in these infants was assessed. PET was performed in the infants at the onset of spasms and 3 months after initial therapy using 18F-labelled 2-deoxy-2-fluoro-D-glucose. A third PET was performed at 18 months of age if the second scan was abnormal. All infants were followed up until at least 3 years of age. Cortical hypometabolism was detected in 11 infants on the first PET and in five infants on the second. Rate of developmental delay at the last follow-up was significantly higher in infants with hypometabolism on the second PET than in those without PET abnormalities (p<0.05). Rate of seizure occurrence after initial treatment was higher in infants with cortical hypometabolism on the second PET, but the difference was not statistically significant. Results suggest that when PET after the initial treatment shows no abnormalities, even though the first PET shows hypometabolism, infants with cryptogenic West syndrome may have a favourable developmental or seizure outcome. PET may be a useful tool in evaluating the prognosis in infants with cryptogenic West syndrome.
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PMID:Prognostic value of positron emission tomography in cryptogenic West syndrome. 1184 6

Hyperinsulinism is a rare cause of severe persistent hypoglycaemia in the neonatal period. It is associated with a high incidence of brain damage and mental retardation as a consequence of repeated episodes of hypoglycaemia. Subtotal to near total pancreatectomy is indicated as a matter of urgency to decrease the amount of circulating insulin. The perioperative management of a 45-day-old, 5 kg male infant with hyperinsulinaemia (nesidioblastosis) is described. He had a history of generalized tonic clonic seizures 4 h after birth. The blood sugar at that time was 0.66 mmol x l(-1) (12 mg x dl(-1)) and serum calcium was 2.4 mmol x l(-1) (9.82 mg x dl(-1)). The insulin : glucose ratio was 1.6 (normal < 0.4). Occasional episodes of hypoglycaemia persisted in spite of medical line of management with intravenous dextrose 12%, 2 h gastric tube feeds, hydrocortisone (5 mg x kg(-1) x day(-1) i.v.) and oral diazoxide 10 mg x kg(-1), 8 h for 3 weeks. A CT scan and USG did not reveal any abnormality of the pancreas. However, the EEG varied from one of abnormally low amplitude to an isoelectric record. Renal, liver function tests and coagulation profile were normal. The patient was scheduled for elective subtotal pancreatectomy. The anaesthetic management with emphasis on glucose homeostasis and fluid balance is discussed.
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PMID:Anaesthetic management of a case of nesidioblastosis for subtotal pancreatectomy. 1184 82

The etiology of various age-related neurological diseases remains unknown. Sporadic forms ofAlzheimer's, Parkinson's and Lou Gehrig's disease have been linked to environmental factors that cause neuronal cell death either by excitotoxicity or by inducing oxidative stress. Our recent studies have demonstrated that various compounds not previously associated with these diseases, i.e. methionine sulfoximine (MSO), originally isolated from 'agenized' flour, and sitosterol glucoside (BSSG), isolated from the seed of the cycad, appear to be neurotoxins, likely acting by excitotoxic mechanisms. For these compounds, the primary excitotoxic effect appears to involve glutamate release followed by NMDA receptor activation. Lactate dehydrogenase assays demonstrate that both compounds cause rapid cell death in vitro. In addition, both compounds appear to alter antioxidant defense mechanisms, acting particularly on levels of reduced glutathione (GSH). In vivo application of MSO has historically been linked to behavioral abnormalities, including seizures, in various species. Our recent experiments have demonstrated that mice fed cycad flour containing sitosterol glucoside have severe behavioral abnormalities of motor and cognitive function, as well as significant levels of neurodegeneration in cortex, hippocampus, spinal cord and other CNS regions measured post mortem. The combined weight of excitotoxic action, in concert to a decline in antioxidant defenses, induced by molecules such as methionine sulfoximine and sitosterol glucoside is hypothesized to be causal to neuronal degeneration in various neurological diseases. Understanding the mechanisms of action of these and functionally related molecules may serve to focus attention on potential neurotoxins present in the human environment. Only once such molecules have been identified, can we begin to design appropriate pharmaceutical strategies to prevent or halt the progression of the age-related neurological diseases.
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PMID:Synergistic versus antagonistic actions of glutamate and glutathione: the role of excitotoxicity and oxidative stress in neuronal disease. 1199 Apr 49

In response to a question on how to avoid the rare, inadvertent intravascular or ip injection of hypertonic saline solution during therapeutic abortion, 3 consultants replied. According to Reid and Frigoletto, to avoid intravascular or ip infusion, place a small indwelling polyethylene catheter in the amniotic sac rather than a metal needle. This virtually precludes the possibility of inadvertent iv injection. When and if necessary, correct catheter placement may be confirmed by the use of fluoroscopy and amniography prior to the injection of hypertonic saline solution. The chemical imbalances associated with this accident are those encountered in severe hypernatremia with resultant brain edema and hemorrhagic softening. Bizarre paresthesia, pyrexia, altered consciousness, and, eventually, convulsions preceded the fatal cases. Peritoneal dialysis may be life saving in the event of ip injection. Naturiuretics, appropriate parenteral fluid administration, and possibly exchange transfusion might be indicated for intravascular accidents. In Goodlin's hospital there have been no cases of acute hypernatremia in the last 500 therapeutic abortions done with hypertonic saline solution. This is believed to be related to 2 changes in technique: 1) not losing the amniotic space by removing only as much amniotic fluid as can easily be obtained and 2) using a simple gravity infusion technique for the instillation of the hypertonic saline solution. During infusion it is essential that the patient be alert, for the first symptoms of intravascular injection are a slight pain, burning, or a feeling of warmth in the pelvis. If these minor symptoms are ignored and the procedure is continued, a sensation of flushing occurs throughout the body with tingling in the scalp and ringing in the ears followed finally by seizures, apnea, or coma or both. Late symptoms are those of hemolytic anemia and renal failure. From experience, serum sodium levels during these events are as high as 185 mEq/1. Along with occurrence of acute hypernatremia the contents of the amniotic cavity are sometimes extruded extraovularly through the fallopian tube into the peritoneal cavity when labor begins. Cases with serum sodium levels of 170 mEq/1 some 6-7 hours after saline instillation were observed, but by contrast these patients' only symptoms were extreme thirst and peritoneal discomfort (Lancet 1: 305, 1968). The treatment of hypernatremia is to force fluids either by mouth or iv. Since most commercial 5% dextrose in water solutions are actually 4.5% (regulations permit a 10% error), such hypotonic fluids are useful for treating hypernatremia.
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PMID:Hypernatremia from intravascular saline infusion during therapeutic abortion. 1230 84

Deficiency of GDP-Man:Man1GlcNAc2-PP-dolichol mannosyltransferase (hALG2), is the cause of a new type of congenital disorders of glycosylation (CDG) designated CDG-Ii. The patient presented normal at birth but developed in the 1st year of life a multisystemic disorder with mental retardation, seizures, coloboma of the iris, hypomyelination, hepatomegaly, and coagulation abnormalities. An accumulation of Man1GlcNAc2-PP-dolichol and Man2GlcNAc2-PP-dolichol was observed in skin fibroblasts of the patient. Incubation of patient fibroblast extracts with Man1GlcNAc2-PP-dolichol and GDP-mannose revealed a severely reduced activity of the mannosyltransferase elongating Man1GlcNAc2-PP dolichol. Because the Saccharomyces cerevisiae mutant alg2-1 was known to accumulate the same shortened dolichol-linked oligosaccharides as the patient, the yeast ALG2 sequence was used to identify the human ortholog. Genetic analysis revealed that the patient was heterozygous for a single nucleotide deletion and a single nucleotide substitution in the human ortholog of yeast ALG2. Expression of wild type but not of mutant hALG2 cDNA restored the mannosyltransferase activity and the biosynthesis of dolichol-linked oligosaccharides both in patient fibroblasts and in the alg2-1 yeast cells. hALG2 was shown to act as an alpha1,3-mannosyltransferase. The resulting Manalpha1,3-ManGlcNAc2-PP dolichol is further elongated by a yet unknown alpha1,6-mannosyltransferase.
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PMID:A new type of congenital disorders of glycosylation (CDG-Ii) provides new insights into the early steps of dolichol-linked oligosaccharide biosynthesis. 1268 7

This study was designed to determine whether a secondary increase in neuronal activity induced by a low dose of kainic acid (KA), a glutamate analogue, exacerbates the anatomical damage in hippocampal regions following a mild lateral fluid percussion (LFP) brain injury. KA (9 mg/kg) was injected intraperitoneally in LFP-injured rats (n = 16) 1 h post-trauma. The neuronal loss in the CA3, CA4, and hilar regions at 7 days was quantified by two-dimensional cell counts. Hippocampal activation 15 min following KA injection was assessed by measuring local glucose metabolic rates (lCMR(glc)). Following LFP + KA, the ipsilateral side exhibited a 62.7%, 75.7%, and 52.1% decrease in the number of CA3, CA4 and hilar neurons, respectively, compared to naive rats (n = 3). These CA3 and CA4 neuronal counts were also significantly decreased compared to LFP + saline (n = 5) and sham + KA (n = 9) groups. The median Racine Score, used to rate the severity of behavioral seizures, was 4 in LFP + KA and 2 in sham + KA groups (p < 0.015), suggesting a reduction in seizure threshold following injury. lCMRglc in CA3 following LFP + KA was 121.8 +/- 2.0 (mean +/- SE) ipsilaterally and 71.5 +/- 5.4 contralaterally (p < 0.0012). No changes were found in the BBB permeability as measured by [(14)C]aminoisobutyric acid in CA3, CA4, and hilar regions. We conclude that the presence of low-level KA 1 h after LFP dramatically increases the extent of hippocampal activation and induces a striking loss of ipsilateral CA3 and CA4 pyramidal neurons. Neuronal excitation during a time of cellular vulnerability may trigger or amplify the cycle of secondary damage in functionally impaired, but potentially viable, tissue.
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PMID:Increased hippocampal CA3 vulnerability to low-level kainic acid following lateral fluid percussion injury. 1280 74


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