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DOI: 10.1055/s-0030-1248264
© Georg Thieme Verlag KG Stuttgart · New York
Autosomal Recessive Inheritance of GLUT1 Deficiency Syndrome
Publication History
received 24.07.2009
accepted 20.01.2010
Publication Date:
10 March 2010 (online)

Abstract
GLUT1 deficiency syndrome (GLUT1DS) is understood as a monogenetic disease caused by heterozygous SLC2A1 gene mutations with autosomaldominant and sporadic transmission. We report on a six-year-old girl from an inbred Arab family with moderate global developmental delay, epilepsy, ataxia, hypotonia, and hypoglycorrhachia (CSF glucose 36 mg/dL; CSF lactate 1.09 mmol/L; CSF/blood glucose ratio 0.44). Molecular analysis of the SLC2A1 gene identified a novel homozygous c1402C>T (p. Arg468Trp) mutation in exon 10 in the index patient and her asymptomatic younger sister. The mutation was absent in 120 control alleles of healthy individuals as well as in 400 alleles of other GLUT1DS patients. Arg468 represents a highly conserved, functionally important amino acid residue in the GLUT1 carboxy-terminus essential for substrate recognition and transport. Both unaffected parents were heterozygous for the mutation. A younger brother and two family members were healthy and carried the GLUT1 wild type. A ketogenic diet effectively controlled seizures in the index patient. We conclude that GLUT1DS can be transmitted as an autosomal recessive disease and provide new insights into genetic counselling for this treatable disorder.
Key words
arabs - GLUT1 - GLUT1 deficiency - blood-brain barrier - childhood epilepsy - ketogenic diet - SLC2A1 - autosomal recessive - homozygosity - paroxysmal exertion-induced dyskinesia - Qatar
References
- 1 Brockmann K, Wang D, Korenke CG. et al . Autosomal dominant glut-1 deficiency syndrome and familial epilepsy. Ann Neurol. 2001; 50 476-485
- 2 Dauterive R, Laroux S, Bunn RC. et al . C-terminal mutations that alter the turnover number for 3-O-methylglucose transport by GLUT1 and GLUT4. J Biol Chem. 1996; 271 11414-11421
- 3 De Vivo DC, Leary L, Wang D. Glucose transporter 1 deficiency syndrome and other glycolytic defects. J Child Neurol. 2002; 17 3S15-3S25
- 4 Due AD, Qu ZC, Thomas JM. et al . Role of the C-terminal tail of the GLUT1 glucose transporter in its expression and function in Xenopus laevis oocytes. Biochemistry. 1995; 25 5462-5471
- 5 Klepper J, Leiendecker B. GLUT1 deficiency syndrome − 2007 update. Dev Med Child Neurol. 2007; 49 707-716
- 6 Klepper J, Willemsen M, Verrips A. et al . Autosomal dominant transmission of GLUT1 deficiency. Hum Mol Genet. 2001; 10 63-68
- 7 Muraoka A, Hashiramoto , Clark AE. et al . Analysis of the structural features of the C-terminus of GLUT1 that are required for transport catalytic activity. Biochem J. 1995; 15 699-704
- 8 Oka Y, Asano T, Shibasaki Y. et al . C-terminal truncated glucose transporter is locked into an inward-facing form without transport activity. Nature. 1990; 7 550-553
- 9 Pascual JM, Wang DDV. Glucose transporter type 1 deficiency syndrome. Gene Reviews.
- 10 Suls A, Dedeken P, Goffin K. et al . Paroxysmal exercise-induced dyskinesia and epilepsy is due to mutations in SLC2A1, encoding the glucose transporter GLUT1. Brain. 2008; 131 183-144
- 11 Verhey KJ, Hausdorff SF, Birnbaum MJ. Identification of the carboxy terminus as important for the isoform-specific subcellular targeting of glucose transporter proteins. J Cell Biol. 1993; 123 137-147
- 12 Wang D, Kranz-Eble P, DeVivo DC. Mutational analysis of GLUT1 (SLC2A1) in Glut-1 deficiency syndrome. Hum Mutat. 2000; 16 224-231
- 13 Weber YG, Storch A, Wuttke TV. et al . GLUT1 mutations are a cause of paroxysmal exertion-induced dyskinesias and induce hemolytic anemia by a cation leak. J Clin Invest. 2008; 118 2157-2168
- 14 Zhao F-Q, Keating AF. Functional properties and genomics of glucose transporters. Current Genetics. 2007; 8 113-128
Correspondence
PD Dr. med. Joerg Klepper
Childrens’ Hospital Aschaffenburg
Am Hasenkopf
63739 Aschaffenburg
Germany
Phone: +49/6021/32 3601/3600
Fax: +49/6021/32 3699
Email: joerg.klepper@klinikum-aschaffenburg.de