Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Immunogold electron microscopy was used to examine human brain resections to localize the GLUT1 glucose transporter. The tissue examined was obtained from a patient undergoing surgery for treatment of seizures, and the capillary profiles examined had characteristics identical to those described previously for active, epileptogenic sites (confirmed by EEG analyses). A rabbit polyclonal antiserum to the full-length human erythrocyte glucose transporter (GLUT1) was labeled with 10-nm gold particle-secondary antibody conjugates and localized immunoreactive GLUT1 molecules in human brain capillary endothelia, with < 0.25% of the particles beyond the capillary profile. Erythrocyte membranes were also highly immunoreactive, whereas macrophage membranes were GLUT1-negative. The number of immunoreactive sites per capillary profile was observed to be 10-fold greater in humans than in previous studies of rat and rabbit brain capillaries. In addition, half of the total number of immunoreactive gold particles were localized to the luminal capillary membrane. We suggest that the blood-brain barrier GLUT1 glucose transporter is up-regulated in seizures, and this elevated transporter activity is characterized by increased GLUT1 transporters, particularly on the luminal capillary membranes. In addition, acute modulation of glucose transporter activity is presumed to involve translocation of GLUT1 from cytoplasmic to luminal membrane sites, demonstrable with quantitative immunogold electron microscopy.
 ...
PMID:The human brain GLUT1 glucose transporter: ultrastructural localization to the blood-brain barrier endothelia. 826 45

Pentylenetetrazole and kainic acid, seizure-inducing agents that are known to increase glucose utilization in brain, were used to produce chronic seizures in mature rats. To test the hypothesis that increased brain glucose utilization associated with seizures may alter glucose transporter expression, polyclonal carboxyl-terminal antisera to glucose transporters (GLUT1 and GLUT3) were employed with a quantitative immunocytochemical method and immunoblots to detect changes in the regional abundances of these proteins. GLUT3 abundances in control rats were found to be correlated with published values for regional glucose utilization in normal brain. Following treatment with kainic acid and pentylenetetrazole, both GLUT3 and GLUT1 increased in abundance in a region and isoform-specific manner. GLUT3 was maximal at eight hours, whereas GLUT1 was maximal at three days. Immunoblots indicated that most of the GLUT3 increase was accounted for by the higher molecular weight component of the GLUT3 doublet. The rapid response time for GLUT3 relative to GLUT1 may be related to the rapid increase in neuronal metabolic energy demands during seizure. These observations support the hypothesis that glucose transporters may be upregulated in brain under conditions when brain glucose metabolism is elevated.
 ...
PMID:Chronic seizures increase glucose transporter abundance in rat brain. 896 98

The high metabolic requirements of the mammalian central nervous system require specialized structures for the facilitated transport of nutrients across the blood-brain barrier. Stereospecific high-capacity carriers, including those that recognize glucose, are key components of this barrier, which also protects the brain against noxious substances. Facilitated glucose transport in vertebrates is catalyzed by a family of carriers consisting of at least five functional isoforms with distinct tissue distributions, subcellular localizations and transport kinetics. Several of these transporters are expressed in the mammalian brain. GLUT-1, whose sequence was originally deduced from cDNAs cloned from human hepatoma and rat brain, is present at high levels in primate erythrocytes and brain endothelial cells. GLUT1 has been cloned and positionally mapped to the short arm of chromosome 1 (1p35-p31.3; refs 6-8). Despite substantial metabolic requirements of the central nervous system, no genetic disease caused by dysfunctional blood-brain barrier transport has been identified. Several years ago, we described two patients with infantile seizures, delayed development and acquired microcephaly who have normal circulating blood glucose, low-to-normal cerebrospinal fluid (CSF) lactate, but persistent hypoglycorrachia (low CSF glucose) and diminished transport of hexose into isolated red blood cells (RBC). These symptoms suggested the existence of a defect in glucose transport across the blood brain barrier. We now report two distinct classes of mutations as the molecular basis for the functional defect of glucose transport: hemizygosity of GLUT1 and nonsense mutations resulting in truncation of the GLUT-1 protein.
 ...
PMID:GLUT-1 deficiency syndrome caused by haploinsufficiency of the blood-brain barrier hexose carrier. 946 54

The glucose transporter protein syndrome (GTPS) is caused by defective transport of glucose across the blood-brain barrier via the glucose transporter GLUT1, resulting in hypoglycorrhachia, infantile seizures, and developmental delay. Recent reports indicated that GLUT1 is a multifunctional transporter. We investigated the transport of vitamin C in its oxidized form (dehydroascorbic acid) via GLUT1 into erythrocytes of 2 patients with GTPS. In both patients, uptake of oxidized vitamin C was 61% of the mothers' values. Our findings are consistent with recent observations that vitamin C is transported in its oxidized form via GLUT1. We speculate that impaired transport of this substrate and perhaps other substrates in GTPS might contribute to the pathophysiology of this condition.
 ...
PMID:Deficient transport of dehydroascorbic acid in the glucose transporter protein syndrome. 970 57

Impaired glucose transport across brain tissue barriers causes infantile seizures, developmental delay and acquired microcephaly. Since the first report in 1991 (De Vivo et al, NEJM, 1991) 17 patients have been identified with the glucose transporter protein syndrome (GTPS). The diagnostic feature of the syndrome is an unexplained hypoglycorrhachia in the clinical setting of an infantile epileptic encephalopathy. We review our clinical experience by highlighting one illustrative case: a 6-year old girl who presented at age 2 months with infantile seizures and hypoglycorrhachia. The CSF/blood glucose ratio was 0.33. DNA sequencing identified a missense mutation in exon 7 (C1108T). Erythrocyte GLUT1 immunoreactivity was normal. The time course of 3-O-methyl-glucose (3OMG) uptake by erythrocytes of the patient was 46% that of mother and father. The apparent Km was similar in all cases (2-4 mmol/L), but the apparent Vmax in the patient was only 28% that of the parents (500 versus 1,766 fmol/s/10(6)RBC; p < 0.004). In addition, a 3-month trial of oral thioctic acid also benefited the patient and increased the Vmax to 935 fmol/s/10(6) RBC (p < 3 x 10(-7)). Uptake of dehydroascorbic acid by erythrocytes of the patient was impaired to the same degree as that of 3OMG (Vmax was 38% of that of the mother's), which supports previous observations of GLUT1 being multifunctional. These studies confirm the molecular basis of the GTPS and the multifunctional role of GLUT1. The need for more effective treatment is compelling.
 ...
PMID:Defective glucose transport across brain tissue barriers: a newly recognized neurological syndrome. 1022 90

The finding that epileptic seizures alter blood-brain barrier (BBB) properties has stimulated interest into the possibility that phenotypic changes in brain endothelium may constitute a pathological initiator leading to seizures. Recent evidence obtained from epileptic patients undergoing cortical resection, demonstrated abnormal expression of glucose transporter molecules (GLUT1), while [18F]deoxyglucose PET studies demonstrated regions of decreased glucose uptake and hypometabolism in seizure foci. The properties of other 'nonexcitable CNS cells' are also altered in epileptic tissue, and glial cells from epileptic brain displayed diminished capacity for ionic homeostasis; voltage-dependent mechanisms were primarily affected, increasing reliance on energy-dependent mechanisms. Diminished ion homeostasis together with increased metabolic demand of hyperactive neurons may further aggravate the neuropathological consequences of BBB loss of glucose uptake mechanisms. Since ketone bodies can provide an alternative to glucose to support brain energy requirements, it is hypothesized that one of the mechanisms of the ketogenic diet in epilepsy may relate to increased availability of beta-hydroxybutyrate, a ketone body readily transported at the BBB. This hypothesis is supported by the fact that the ketogenic diet is the treatment of choice for the glucose transporter protein syndrome and pyruvate dehydrogenase deficiency, both associated with cerebral energy failure and seizures.
 ...
PMID:Blood-brain barrier, ion homeostatis and epilepsy: possible implications towards the understanding of ketogenic diet mechanisms. 1058 72

Fifteen children presenting with infantile seizures, acquired microcephaly, and developmental delay were found to have novel heterozygous mutations in the GLUT1 (SLC2A1). We refer to this condition as the Glut-1 Deficiency Syndrome (Glut-1 DS). The encoded protein (Glut-1), which has 12 transmembrane domains, is the major glucose transporter in the mammalian blood-brain barrier. The presence of GLUT1 mutations correlates with reduced cerebrospinal fluid glucose concentrations (hypoglycorrhachia) and reduced erythrocyte glucose transporter activities in the patients. We used Florescence in situ hybridization, PCR, single-stranded DNA conformational polymorphism, and DNA sequencing to identify novel GLUT1 mutations in 15 patients. These abnormalities include one large-scale deletion (hemizygosity), five missense mutations (S66F, R126L, E146K, K256V, R333W), three deletions (266delC, 267A>T; 904delA; 1086delG), three insertions (368-369 insTCCTGCCCACCACGCTCACCACG, 741-742insC, 888-889insG), three splice site mutations (197+1G>A; 1151+1G>T; 857T>G, 858G>A, 858+1del10), and one nonsense mutation (R330X). In addition, six silent mutations were identified in exons 2, 4, 5, 9, and 10. The K256V missense mutation involved the maternally derived allele in the patient and one allele in his mother. A spontaneous R126L missense mutation also was present in the paternally derived allele of the patient. The apparent pathogenicity of these mutations is discussed in relation to the functional domains of Glut-1.
 ...
PMID:Mutational analysis of GLUT1 (SLC2A1) in Glut-1 deficiency syndrome. 1098 May 29

Facilitative type-1 glucose transporter (GLUT1) deficiency syndrome is caused by a defect of glucose transport into brain, resulting in an epileptic encephalopathy. Seizures respond effectively to a ketogenic diet, but a subgroup of patients require add-on anticonvulsant therapy or do not tolerate the diet. With the exception of barbiturates, which have been shown to inhibit GLUT1 function, no anticonvulsants have been investigated for possible interactions with GLUT1. Kinetic analyses of (14)C-labeled 3-O-methyl glucose (3OMG) uptake into erythroctes were performed in 11 patients and 30 controls. For in vitro inhibition studies, zero-trans influx of 3OMG (5 mmol/L) into erythrocytes was determined following preincubation with diazepam, carbamazepine, phenytoin, and chloralhydrate. In addition, the effects of ethanol on cell lysis and 3OMG transport into erythrocytes were determined. In patients, mean 3OMG influx was 53% of controls. Ethanol, diazepam, and chloralhydrate significantly inhibited GLUT1 function. Erythrocyte cell lysis was evident at concentrations of 2.5% ethanol. Diazepam, chloralhydrate, and ethanol are inhibitors of GLUT1 function in vitro and might potentiate the effects of GLUT1-mediated glucose transport in patients with GLUT1 deficiency syndrome. In contrast, no inhibitory effects were observed for carbamazepine and phenytoin, indicating that these substances might be preferable for additional seizure control in this disorder.
 ...
PMID:Effects of anticonvulsants on GLUT1-mediated glucose transport in GLUT1 deficiency syndrome in vitro. 1254 83

The ketogenic diet is a rational treatment for pyruvate dehydrogenase complex deficiency (McKusick 312170) and GLUT1 deficiency syndrome (McKusick 138140). An increasing number of patients are diagnosed in early infancy, but few data are available on the introduction of a ketogenic diet in this age group. GLUT1 deficiency syndrome was suspected in four infants presenting with seizures and unexplained hypoglycorrhachia. A ketogenic diet was introduced at 6-28 weeks of age. Ketosis was initiated by fasting, monitored by bedside blood glucose and 3-hydroxybutyrate determinations, and was maintained successfully using supplemented carbohydrate-free infant formula and emulgated triglycerides. All patients developed ketosis within 24 h. 3-Hydroxybutyrate concentrations available at the bedside correlated inversely with the base excess. At glucose levels < or = 40 mg/dl patients remained asymptomatic in the presence of ketones. The ketogenic formula was tolerated well, parental compliance was good, and all patients remained seizure-free on the diet. GLUT1 deficiency was confirmed in two patients; the diet was discontinued in the other two patients. In one infant, failure to thrive on medium-chain triglycerides was effectively reversed using long-chain triglycerides. Urine dipstick analyses failed to detect ketosis in another infant. Adverse effects of the diet were limited to renal stones in one patient. The ketogenic diet can be introduced and maintained successfully in young infants using long-chain fat emulsion. Monitoring 3-hydroxybutyrate at the bedside was useful for metabolic control and superior to urine dipstick analysis. Seizure control was effective and adverse effects were limited, but evaluation of the long-term effects of the ketogenic diet in this age group must await ongoing studies.
 ...
PMID:Introduction of a ketogenic diet in young infants. 1255 38

A ketogenic diet suppresses seizure activity in children and in juvenile rats. To investigate whether alteration in brain IGF activity could be involved in the beneficial effects of the ketogenic diet, we examined the effects of this diet on IGF system gene expression in the rat brain. Juvenile rats were fed one of three different diets for 7 d: ad libitum standard rat chow (AL-Std), calorie-restricted standard chow (CR-Std), or a calorie-restricted ketogenic diet (CR-Ket). The calorie-restricted diets contained 90% of the rats' calculated energy requirements. The AL-Std diet group increased in weight, whereas the two CR groups merely maintained their weight during the 7-d diet. Glucose levels were significantly reduced in both CR groups compared with the AL-Std group, but only the CR-Ket group developed ketonemia. IGF1 mRNA levels were reduced by 30-50% in most brain regions in both CR groups. IGF1 receptor (IGF1R) mRNA levels were decreased in the CR-Std group but were increased in the CR-Ket diet group. Brain IGF binding protein (IGFBP)-2 and -5 mRNA levels were not altered by diet, but IGFBP-3 mRNA levels were markedly increased by the ketogenic diet while not altered by calorie restriction alone. Brain glucose transporter expression was also investigated in this study. Glucose transporter (GLUT) 4 mRNA levels were quite low and not appreciably altered by the different diets. Parenchymal GLUT1 mRNA levels were increased by the CR-Ket diet, but endothelial GLUT1 mRNA levels were not affected. Neuronal GLUT3 expression was decreased with the CR-Std diet and increased with the CR-Ket diet, in parallel with the IGF1R pattern. These observations reveal divergent effects of dietary caloric content and macronutrient composition on brain IGF system and GLUT expression. In addition, the data may be consistent with a role for enhanced IGF1R and GLUT expression in ketogenic diet-induced seizure suppression.
 ...
PMID:A ketogenic diet increases brain insulin-like growth factor receptor and glucose transporter gene expression. 1274 32


1 2 3 4 5 Next >>