title: Defective glucose transport across brain tissue barriers: a newly recognized neurological syndrome.
abstract: 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.
authors.affiliation: Division of Pediatric Neurology, Columbia University, New York, NY 10032, USA.
authors.forename: J
authors.initials: J
authors.lastname: Klepper
authors.forename: D
authors.initials: D
authors.lastname: Wang
authors.forename: J
authors.initials: J
authors.lastname: Fischbarg
authors.forename: J C
authors.initials: JC
authors.lastname: Vera
authors.forename: I T
authors.initials: IT
authors.lastname: Jarjour
authors.forename: K R
authors.initials: KR
authors.lastname: O'Driscoll
authors.forename: D C
authors.initials: DC
authors.lastname: De Vivo
mesh_terms: D019325:3-O-Methylglucose / Q000097:blood; D001692:Biological Transport / Q000502:physiology; D001921:Brain / Q000378:metabolism*; D002648:Child; D003683:Dehydroascorbic Acid / Q000097:blood; D002658:Developmental Disabilities / Q000209:etiology* / Q000235:genetics; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1; D006801:Humans; D015151:Immunoblotting; D008831:Microcephaly / Q000209:etiology* / Q000235:genetics; D009004:Monosaccharide Transport Proteins / Q000235:genetics / Q000502:physiology; D009154:Mutation / Q000502:physiology; D013036:Spasms, Infantile / Q000209:etiology* / Q000235:genetics; D013577:Syndrome
chemical_list: D051272:Glucose Transporter Type 1; D009004:Monosaccharide Transport Proteins; C495677:SLC2A1 protein, human; D019325:3-O-Methylglucose; D005947:Glucose; D003683:Dehydroascorbic Acid