Autosomal dominant transmission of GLUT1 deficiency

GLUT1 deficiency is caused by a defect in the facilitative glucose transpor ter GLUT1. Impaired glucose transport across brain tissue barriers is refle cted by hypoglycorrhachia and results in an epileptic encephalopathy with d evelopmental delay and motor disorders. Recently heterozygous mutations in the GLUT1 gene (1p35-31.3) have been reported in sporadic patients. Parents and siblings carried the GLUT1 wild-type, suggesting a de novo, autosomal dominant condition resulting from GLUT1 haploinsufficiency. We report a fat her and two children from separate marriages affected by GLUT1 deficiency a nd carrying a novel heterozygous missense mutation (G272A) in the GLUT1 gen e. Mutations were identified by polymerase chain reaction and DNA sequencin g and confirmed by restriction fragment digest. The predicted amino acid ch ange (Gly91Asp) affects an Arg-X-Gly-Arg-Arg motif between helices 2 and 3 that represents a cytoplasmic anchor point and is highly conserved among tr ansporters of the major facilitator superfamily down to yeast and bacteria, GLUT1 immunoreactivity was normal, but 3-O-methyl-D-glucose uptake into er ythrocytes was significantly reduced, suggesting a quantitatively normal, b ut functionally impaired, GLUT1 protein at the cell membrane. This is the f irst report of autosomal dominant transmission of GLUT1 deficiency, confirm ing that this condition is the result of haploinsufficiency. The Gly-->Asp mutation within a highly conserved sequence highlights its importance for G LUT1 function, GLUT1 deficiency should be considered in patients with epile psy, mental retardation and motor disorders, Our observations have bearing on the identification of this treatable disorder in pediatric and adult pat ients, will modify current biochemical protocols which use parental control s and will enable genetic counseling of affected families.