Glucose transporter type 1 deficiency syndrome (Glut1DS): Methylxanthines potentiate GLUT1 haploinsufficiency in vitro

Methylxanthines such as caffeine and theophylline are known to inhibit gluc ose transport. We have studied such inhibition in the glucose transporter t ype I deficiency syndrome (Glut1DS) by erythrocyte glucose transport assays . Data from four patients with individual mutations in the GLUT1 gene are d iscussed: patient I (hemizygosity), 3 (S66F), 15 (368Ins23), and 17 (R333W) . Zero-trans influx of C-14-labeled 3-O-methyl glucose (3-OMG) into erythro cytes of patients is reduced (patient 1, 51%; 3, 45%; 15 31%; 17, 52%) comp ared with maternal controls. Inhibition studies on patients 1, 3, 17, and m aternal controls show an IC50 for caffeine of approximately 1.5 mM both in controls (it = 3) and patients (n = 3) at 5 mM 3-OMG concentration. In the same two groups, kinetic studies show that 3 mM caffeine significantly decr eases V-max (p < 0.005), whereas the decrease in K-m is significant (p < 0. 01) only in the three controls and one patient (patient 3). Kinetic data fr om individual patients permit us to speculate that the interactions between caffeine and Glut1 are influenced by the mutation. Three mM caffeine also inhibits the transport of dehydroascorbic acid (DHA), another substrate for Glut1. The combined effects of caffeine (3 mM) and phenobarbital (10 mM) o n glucose transport, as determined in patient 15 and the maternal control, show no additive or synergistic inhibition. These data indicate that caffei ne and phenobarbital have similar Glut1 inhibitory properties in these two subjects. Our Study suggests that Glut1DS patients may have a reduced safet y margain for methylxanthines. Consumption of methylxanthine-containing pro ducts may aggravate the neurologic symptoms associated with the Glut1DS.