Glucose Transporter Type 1 Deficiency Syndrome (Glut1DS): Methylxanthines Potentiate GLUT1 Haploinsufficiency In Vitro

Ho, Yu‐Ling; Yang, Hong; Klepper, Jörg; Fischbarg, Jorge; Wang, Dong; Vivo, Darryl C. De

doi:10.1203/00006450-200108000-00015

Cited by 56 publications

(31 citation statements)

References 25 publications

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“…Reported Glut1 inhibitors include methylxanthine, barbiturates, tyrosine kinase inhibitors, Genistein, GTP analogs, tricyclic antidepressants, general anesthetics, and ethanol [Motais et al, 1980;Salah et al, 1982;Wellner et al, 1993;Krauss et al, 1994;Honkanen et al, 1995;Vera et al, 1996Vera et al, , 2001Klepper et al, 1999Klepper et al, , 2003Pinkofsky et al, 2000;Stephenson et al, 2000;Ho et al, 2001;Johannessen et al, 2001]. Consistent with the in vitro studies, clinical observations have found barbiturates ineffective in controlling Glut1DS-associated seizures and methylxanthines exacerbating haploinsufficiency in Glut1DS patients [Klepper et al, 1999;Ho et al, 2001]. It is conceivable that avoiding the consumption of Glut1-inhibiting compounds would facilitate seizure control in Glut1DS patients.…”

Section: Discussionmentioning

confidence: 99%

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Sodium valproate inhibits glucose transport and exacerbates Glut1‐deficiency in vitro

Wong

Chu

Lai

et al. 2005

J of Cellular Biochemistry

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Anticonvulsant sodium valproate interferes with brain glucose metabolism. The mechanism underlying such metabolic disturbance is unclear. We tested the hypothesis that sodium valproate interferes with cellular glucose transport with a focus on Glut1 since glucose transport across the blood-brain barrier relies on this transporter. Cell types enriched with Glut1 expression including human erythrocytes, human skin fibroblasts, and rat astrocytes were used to study the effects of sodium valproate on glucose transport. Sodium valproate significantly inhibited Glut1 activity in normal and Glut1-deficient erythrocytes by 20%-30%, causing a corresponding reduction of Vmax of glucose transport. Similarly, in primary astrocytes as well as in normal and Glut1-deficient fibroblasts, sodium valproate inhibited glucose transport by 20%-40% (P < 0.05), accompanied by an up to 60% downregulation of GLUT1 mRNA expression (P < 0.05). In conclusion, sodium valproate inhibits glucose transport and exacerbates Glut1 deficiency in vitro. Our findings imply the importance of prudent use of sodium valproate for patients with compromised Glut1 function.

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Section: Discussionmentioning

confidence: 99%

“…The previously established model measures Glut1-mediated glucose transport into erythrocytes at 48C. We have adopted the lowtemperature assay system to evaluate the effects of sodium valproate on Glut1 activity [Klepper et al, 1999a[Klepper et al, ,b, 2003Ho et al, 2001; Fig. 1.…”

Section: Discussionmentioning

confidence: 99%

Sodium valproate inhibits glucose transport and exacerbates Glut1‐deficiency in vitro

Wong

Chu

Lai

et al. 2005

J of Cellular Biochemistry

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“…These substances are: ethanol, methylxanthines, caffeine and green tea catechins, tyrosin kinase inhibitors, genistein, guanosin triphosphate analogs, dioxine, ethanol, androgens, tricyclic antidepressants, general anaesthetics, and anticonvulsants such as phenobarbital, chloralhydrate, diazepam, and valproate. 9,80,81 PROGNOSIS In the data currently available for GLUT1DS there is no evidence that life expectancy is limited. Children clearly benefit from the ketogenic diet.…”

Section: Treatmentmentioning

confidence: 99%

GLUT1 deficiency syndrome – 2007 update

Klepper

Leiendecker

2007

Develop Med Child Neuro

222

216

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GLUT1 deficiency syndrome (GLUT1DS, OMIM 606777) is a treatable epileptic encephalopathy resulting from impaired glucose transport into the brain. The essential biochemical finding is a low glucose concentration in the cerebrospinal fluid (CSF; hypoglycorrhachia; mean 1.7 [SD 0.3mmol/L]) in the setting of normoglycaemia. CSF lactate is normal. Patients present with an early‐onset epilepsy resistant to anticonvulsants, developmental delay, and a complex movement disorder. Hypotonic, ataxic, and dystonic features are most prominent. Speech is often severely affected. Some patients develop spasticity and secondary microcephaly. The phenotype is highly variable ranging from severe impairment to children without seizures. Electroencephalography (EEG) may show 2.5‐4Hz spike‐waves improving on food intake. Neuroimaging is uninformative. Most patients carry heterozygous de novo mutations in the GLUT1 gene (OMIM 138140, gene map locus 1p35‐31.3). Autosomal dominant transmission and several mutational hot spots have been identified, but phenotype‐genotype correlations are not yet apparent. Homozygous GLUT1 mutations presumably are lethal. The ketogenic diet is the treatment of choice as it provides an alternative fuel to the brain. It should be introduced early and maintained into puberty. Seizures are effectively controlled with the onset of ketosis, but might recur and require comedication. The effect on neurodevelopment appears less impressive. The increasing number of patients, molecular and biochemical analysis, recent research into ketogenic diet mechanisms, and the development of animal models for GLUT1DS have brought substantial insights in disease manifestations and mechanisms. This review summarizes data on 84 published cases and highlights recent advances in understanding this entity.

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“…Inhibitors of GLUT1 function include ethanol [34,49], methylxanthines [33], tyrosine kinase inhibitors [79], Genistein [78], GTP analogues [82], toxins such as dioxine [56], tricyclic antidepressants [63], and general anaesthetics [72]. Avoidance of these substances in patients with GLUT1 deficiency syndrome is important in order to preserve already impaired GLUT1 function.…”

Section: Laboratory Diagnosismentioning

confidence: 99%

Facilitated glucose transporter protein type 1 (GLUT1) deficiency syndrome: impaired glucose transport into brain – a review

2002

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Glucose Transporter Type 1 Deficiency Syndrome (Glut1DS): Methylxanthines Potentiate GLUT1 Haploinsufficiency In Vitro

Cited by 56 publications

References 25 publications

Sodium valproate inhibits glucose transport and exacerbates Glut1‐deficiency in vitro

Sodium valproate inhibits glucose transport and exacerbates Glut1‐deficiency in vitro

GLUT1 deficiency syndrome – 2007 update

Facilitated glucose transporter protein type 1 (GLUT1) deficiency syndrome: impaired glucose transport into brain – a review

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