Autosomal dominant Glut-1 deficiency syndrome and familial epilepsy

Glut-l deficiency syndrome was first described in 1991 as a sporadic clinic al condition, later shown to be the result of haploinsufficiency. We now re port a family with Glut-l deficiency syndrome affecting 5 members over 3 ge nerations. The syndrome behaves as an autosomal dominant condition. Affecte d family members manifested mild to severe seizures, developmental delay, a taxia, hypoglycorrhachia, and decreased erythrocyte 3-O-methyl-D-glucose up take. Seizure frequency and severity were aggravated by fasting, and respon ded to a carbohydrate load. Glut-1 immunoreactivity in erythrocyte membrane s was normal. A heterozygous R126H missense mutation was identified in the 3 patients available for testing, 2 brothers (Generation 3) and their mothe r (Generation 2). The sister and her father were clinically and genotypical ly normal. In vitro mutagenesis studies in Xenopus laevis oocytes demonstra ted significant decreases in the transport of 3-O-methyl-D-glucose and dehy droascorbic acid. Xenopus oocyte membranes expressed high amounts of the R1 26H mutant Glut-1. Kinetic analysis indicated that replacement of arginine- 126 by histidine in the mutant Glut-l resulted in a lower V-max. These stud ies demonstrate the pathogenicity of the R126H missense mutation and transm ission of Glut-1 deficiency syndrome as an autosomal dominant trait.