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l -Arginine is required for regulating synapse formation/patterning and angiogenesis in the developing brain. We hypothesized that this requirement would be met by increased transporter-mediated supply across the blood-brain barrier (BBB). Thus, the purpose of this work was to test the idea that elevation of blood-to-brain l -arginine transport across the BBB in the postnatal period coincides with up-regulation of cationic acid transporter 1 (CAT1) expression in developing brain capillaries. We found that the apparent brain-to-plasma concentration ratio (Kp, app) of l -arginine after intravenous administration during the first and second postnatal weeks was 2-fold greater than that at the adult stage. Kp, app of l -serine was also increased at the first postnatal week. In contrast, Kp, app of d -mannitol, a passively BBB-permeable molecule, did not change, indicating that increased transport of l -arginine and l -serine is not due to BBB immaturity. Double immunohistochemical staining of CAT1 and a marker protein, glucose transporter 1, revealed that CAT1 was localized on both luminal and abluminal membranes of brain capillary endothelial cells during the developmental and adult stages. A dramatic increase in CAT1 expression in the brain was seen at postnatal day 7 (P7) and day 14 (P14) and the expression subsequently decreased as the brain matured. In accordance with this, intense immunostaining of CAT1 was observed in brain capillaries at P7 and P14. These findings strongly support our hypothesis and suggest that the supply of blood-born l -arginine to the brain via CAT1 at the BBB plays a key role in meeting the elevated demand for l -arginine in postnatal brain. [ABSTRACT FROM AUTHOR]

Glucose transporter type 1 (GLUT1) deficiency due to SLC2A1 mutations causes a wide spectrum of neurologic disorders ranging from severe encephalopathy with developmental delay, epilepsy, ataxia, and acquired microcephaly to atypical less severe variants. Early diagnosis is crucial for prompt initiation of a ketogenic diet. Recognizing GLUT1 deficiency syndrome (GLUT1DS) may be challenging and results in delayed diagnosis. Here we describe the clinical and molecular findings of patients with SLC2A1 mutations referred to our adult Epilepsy Center. Patients with a clinical history suggestive of GLUT1DS were screened for SLC2A1 mutations. Blood samples were collected from probands and first-degree relatives. A lumbar puncture was performed in two patients in fasting state, and cerebrospinal fluid and blood glucose measurement were undertaken at the same time. Since 2010, 19 GLUT1DS probands have been screened for SLC2A1 mutations. We identified four different SLC2A1 mutations in three sporadic cases and one family. Three mutations (c.130_135delTACAAC, c.342_343insA, and c.845A > G) were novel, whereas one was previously reported in the literature associated with a different phenotype (c.497_499delTCG). Here we describe a small case series of patients with sporadic and familial GLUT1DS presenting with a broad phenotypic heterogeneity which is likely to be responsible for the considerable delay in diagnosis. [ABSTRACT FROM AUTHOR]

Dissolved oxygen (DO) plays a crucial role in survival, growth, and normal physiological functions of aquatic organisms. Nevertheless, the mechanisms involved in hypoxic stress and adaptation have not been fully elucidated in Largemouth bass ( Micropterus salmoides ). To reveal the effect of acute hypoxia on Largemouth bass, we simulated acute hypoxia (DO: 1.2 ± 0.2 mg/L) in the laboratory and analyzed physiological parameters (RBCs, Hb, SOD, CAT, NA + /K + -ATPase, GPx, and MDA) and gene expression ( HIF-1alpha and GLUT-1 ) in Largemouth bass exposed to various durations of acute hypoxia (0, 1, 2, 4, 8, 12, and 24 h). Our results indicated that acute hypoxic exposure significantly increased RBCs but decreased Hb. In addition, antioxidant enzyme activity was enhanced significantly in the liver and muscles at the initial stage of acute hypoxic exposure, but decreased significantly in gills during the entire process of hypoxic exposure. Furthermore, the expression levels of HIF-1alpha and GLUT-1 mRNA were significantly up-regulated in Largemouth bass under acute hypoxic exposure. In conclusion, our study provides a valuable basis for further elucidation of hypoxic adaptation and facilitates husbandry for an economically valuable species. [ABSTRACT FROM AUTHOR]

Introduction Glucose transporter type 1 deficiency syndrome (GLUT1-DS) is a rare metabolic encephalopathy with a wide variation of clinical phenotypes. Familial variants are often milder than de novo cases, and may therefore remain undiagnosed. The aim of this study was to characterize the clinical course of GLUT1-DS in a four-generation Norwegian family where the oldest generations had never received any treatment. Method Through interviews and clinical investigations, we characterized a family of 26 members, where 11 members had symptoms strongly suggesting GLUT1-DS. All members were offered genetic testing of the SLC2A1 gene. Affected members were offered treatment with ketogenic diet, and the effect of the treatment was registered. Results We sequenced the SLC2A1 gene in 13 members, and found that 10, all with symptoms, had the c.823G > A ( p.Ala275Thr ) variant. All affected members had experienced early-onset epilepsy, paroxysmal exercise-induced dyskinesias, and most had mild learning disability. Moreover, some had symptoms and signs of a distal neuropathy in addition to reduced sense of orientation and excessive daytime sleep. Their load of symptoms had decreased over the years, although that they never had received any treatment. Nevertheless, those who started dietary treatment all experienced an improved quality of life. Conclusion We report a four-generation family with GLUT1-DS where the disease has a mild course, even when untreated. In addition to classical GLUT1-DS features, we also describe symptoms which have never been reported in GLUT1-DS previously. As such, this family extends the phenotypic spectrum of GLUT1-DS and underlines the importance of diagnosing also relatively mildly affected patients, even in adult life, as they also seem to benefit from dietary treatment. [ABSTRACT FROM AUTHOR]

Objective We investigated a correlation between a mutation in the SLC2A1 gene and functional disorders in Glucose transporter I deficiency syndrome (GLUT1DS). Methods We performed direct sequence analysis of SLC2A1 in a severe GLUT1DS patient and identified a novel frame shift mutation, c.906_907insG, p.V303fs. We created a plasmid vector carrying the c.906_907insG mutation, as well as A405D or R333W in the SLC2A1 , which are found in patients with mild and moderate GLUT1DS severity, respectively. We transiently expressed these mutants and wild type SLC2A1 plasmids in a human embryonic kidney cell line (HEK293), and performed immunoblotting, immunofluorescence, and enzymatic photometric 2-deoxyglucose (2DG) uptake assays. Results GLUT1 was not detected after transient expression of the SLC2A1 plasmid carrying c.906_907insG by either immunoblotting or immunofluorescence. The degree of glucose transport reduction as determined by enzymatic photometric 2DG assay uptake correlated with disease severity. Conclusions Enzymatic photometric 2DG uptake study appears to be a suitable functional assay to predict the effect of SLC2A1 mutations on GLUT1 transport. [ABSTRACT FROM AUTHOR]

The huge demand of mitochondria as the quantitatively most important sources of ROS in the majority of heterotrophic cells for vitamin C is indisputable. The reduced form of the vitamin, l -ascorbic acid, is imported by an active mechanism requiring two sodium-dependent vitamin C transporters (SVCT1 and SVCT2). The oxidized form, dehydroascorbate is taken up by different members of the GLUT family. Because of the controversial experimental results the picture on mitochondrial vitamin C transport became quite obscure by the spring of 2014. Thus in silico prediction tools were applied in aid of the support of in vitro and in vivo results. The role of GLUT1 as a mitochondrial dehydroascorbate transporter could be reinforced by in silico predictions however the mitochondrial presence of GLUT10 is not likely since this transport protein got far the lowest mitochondrial localization scores. Furthermore the possible roles of GLUT9 and 11 in mitochondrial vitamin C transport can be proposed leastwise on the base of their computational localization analysis. In good concordance with the newest experimental observations on SVCT2 the mitochondrial presence of this transporter could also be supported by the computational prediction tools. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the effects of ketogenic diet (KD) on cognitive function in patients with glucose transporter protein 1 deficiency syndrome (GLUT1-DS). Six patients with GLUT1-DS who were referred to the National Centre for Epilepsy in Norway during the period of November 2011–September 2013 were included. They were diagnosed with GLUT1-DS on the basis of early-onset seizures and developmental delay (with or without movement disorders or microcephaly) in addition to CSF-to-blood glucose ratio below 0.5. They were all treated with either classical KD or modified Atkins diet (MAD). The effect of the diet with > 90% reduction in the seizure frequency was, in retrospect, considered as a support for the diagnosis. The patients underwent standardized neuropsychological assessment before the diet was initiated, and they were reassessed after a minimum of six months on the diet. The neuropsychological tests were individually selected for each patient in order to match their cognitive level. The main finding was a considerable improvement in several aspects of neuropsychological functioning after 6–17 months of dietary treatment in all the six patients. The greatest progress was seen in the youngest children. Our findings suggest that early diagnosis and dietary treatment are important in order to prevent developmental delay. However, also adults with GLUT1-DS may profit from dietary treatment by improving alertness, setting the stage for enhanced learning capacity, as well as physical endurance and quality of life. [ABSTRACT FROM AUTHOR]

Abstract: The aim of this study was to determine whether endogenous GLUT1 induction and the increased glucose utilization that accompanies pressure overload hypertrophy (POH) are required to maintain cardiac function during hemodynamic stress, and to test the hypothesis that lack of GLUT1 will accelerate the transition to heart failure. To determine the contribution of endogenous GLUT1 to the cardiac adaptation to POH, male mice with cardiomyocyte-restricted deletion of the GLUT1 gene (G1KO) and their littermate controls (Cont) were subjected to transverse aortic constriction (TAC). GLUT1 deficiency reduced glycolysis and glucose oxidation by 50%, which was associated with a reciprocal increase in fatty acid oxidation (FAO) relative to controls. Four weeks after TAC, glycolysis increased and FAO decreased by 50% in controls, but were unchanged in G1KO hearts relative to shams. G1KO and controls exhibited equivalent degrees of cardiac hypertrophy, fibrosis, and capillary density loss after TAC. Following TAC, in vivo left ventricular developed pressure was decreased in G1KO hearts relative to controls, but+dP/dt was equivalently reduced in Cont and G1KO mice. Mitochondrial function was equivalently impaired following TAC in both Cont and G1KO hearts. GLUT1 deficiency in cardiomyocytes alters myocardial substrate utilization, but does not substantially exacerbate pressure-overload induced contractile dysfunction or accelerate the progression to heart failure. [Copyright &y& Elsevier]

Abstract: Glucose transporter 1 deficiency syndrome (GLUT1-DS) is a treatable metabolic encephalopathy caused by a mutation in the SLC2A1 gene. This mutation causes a compromised transport of glucose across the blood–brain barrier. The treatment of choice is ketogenic diet, with which most patients become seizure-free. At the National Centre for Epilepsy, we have, since 2005, offered treatment with ketogenic diet (KD) and modified Atkins diet (MAD) to children with difficult-to-treat epilepsy. As we believe many children with GLUT1-DS are unrecognized, the aim of this study was to search for patients with GLUT1-DS among those who had been responders (>50% reduction in seizure frequency) to KD or MAD. Of the 130 children included, 58 (44%) were defined as responders. Among these, 11 were already diagnosed with GLUT1-DS. No mutations in the SLC2A1 gene were detected in the remaining patients. However, the clinical features of these patients differed considerably from the patients diagnosed with GLUT1-DS. While 9 out of 10 patients with GLUT1-DS became seizure-free with dietary treatment, only 3 out of the 33 remaining patients were seizure-free with KD or MAD treatment. We therefore conclude that a seizure reduction of >50% following dietary treatment is not a suitable criterion for identifying patients with GLUT1-DS, as these patients generally achieve complete seizure freedom shortly after diet initiation. [Copyright &y& Elsevier]