title: Autosomal dominant glut-1 deficiency syndrome and familial epilepsy.
abstract: Glut-1 deficiency syndrome was first described in 1991 as a sporadic clinical condition, later shown to be the result of haploinsufficiency. We now report a family with Glut-1 deficiency syndrome affecting 5 members over 3 generations. The syndrome behaves as an autosomal dominant condition. Affected family members manifested mild to severe seizures, developmental delay, ataxia, hypoglycorrhachia, and decreased erythrocyte 3-O-methyl-D-glucose uptake. Seizure frequency and severity were aggravated by fasting, and responded to a carbohydrate load. Glut-1 immunoreactivity in erythrocyte membranes was normal. A heterozygous R126H missense mutation was identified in the 3 patients available for testing, 2 brothers (Generation 3) and their mother (Generation 2). The sister and her father were clinically and genotypically normal. In vitro mutagenesis studies in Xenopus laevis oocytes demonstrated significant decreases in the transport of 3-O-methyl-D-glucose and dehydroascorbic acid. Xenopus oocyte membranes expressed high amounts of the R126H mutant Glut-1. Kinetic analysis indicated that replacement of arginine-126 by histidine in the mutant Glut-1 resulted in a lower Vmax. These studies demonstrate the pathogenicity of the R126H missense mutation and transmission of Glut-1 deficiency syndrome as an autosomal dominant trait.
authors.affiliation: Department of Pediatrics and Neuropediatrics, Children's Hospital, University of Goettingen, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Brockmann
authors.forename: D
authors.initials: D
authors.lastname: Wang
authors.forename: C G
authors.initials: CG
authors.lastname: Korenke
authors.forename: A
authors.initials: A
authors.lastname: von Moers
authors.forename: Y Y
authors.initials: YY
authors.lastname: Ho
authors.forename: J M
authors.initials: JM
authors.lastname: Pascual
authors.forename: K
authors.initials: K
authors.lastname: Kuang
authors.forename: H
authors.initials: H
authors.lastname: Yang
authors.forename: L
authors.initials: L
authors.lastname: Ma
authors.forename: P
authors.initials: P
authors.lastname: Kranz-Eble
authors.forename: J
authors.initials: J
authors.lastname: Fischbarg
authors.forename: F
authors.initials: F
authors.lastname: Hanefeld
authors.forename: D C
authors.initials: DC
authors.lastname: De Vivo
mesh_terms: D019325:3-O-Methylglucose / Q000493:pharmacokinetics; D000595:Amino Acid Sequence; D000818:Animals; D002648:Child; D002658:Developmental Disabilities / Q000235:genetics; D004827:Epilepsy / Q000235:genetics*; D004912:Erythrocytes / Q000378:metabolism; D005192:Family Health; D005260:Female; D005799:Genes, Dominant; D051272:Glucose Transporter Type 1; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009004:Monosaccharide Transport Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D009865:Oocytes; D010375:Pedigree; D014982:Xenopus laevis
chemical_list: D051272:Glucose Transporter Type 1; D009004:Monosaccharide Transport Proteins; C495677:SLC2A1 protein, human; D019325:3-O-Methylglucose