Defective glucose transport across brain tissue barriers: A newly recognized neurological syndrome

Impaired glucose transport across brain tissue barriers causes infantile se izures, developmental delay and acquired microcephaly. Since the first repo rt in 1991 (De Vivo et al, NEJM, 1991) 17 patients have been identified wit h the glucose transporter protein syndrome (GTPS). The diagnostic feature o f 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 g lucose ratio was 0.33. DNA sequencing identified a missense mutation in exo n 7 (C1108T). Erythrocyte GLUT1 immunoreactivity was normal. The time cours e of 3-O-methylglucose (3OMG) uptake by erythrocytes of the patient was 46% that of mother and father. The apparent K-m was similar in all cases (2-4 mmol/L), but the apparent V-max in the patient was only 28% that of the par ents (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 V- max to 935 fmol/s/10(6) RBC (p < 3 x 10(-7)). Uptake of dehydroascorbic aci d by erythrocytes of the patient was impaired to the same degree as that of 3OMG (V-max was 38% of that of the mother's), which supports previous obse rvations of GLUT1 being multifunctional. These studies confirm the molecula r basis of the GTPS and the multifunctional role of GLUT1. The need for mor e effective treatment is compelling.