Seizure Control and Acceptance of the Ketogenic Diet in GLUT1 Deficiency Syndrome: A 2- to 5-Year Follow-Up of 15 Children Enrolled Prospectively

Abstract

Background: GLUT1 deficiency syndrome is caused by impaired glucose transport into the brain resulting in an epileptic encephalopathy, developmental delay, and a complex motor disorder. A ketogenic diet provides an alternative fuel to the brain and effectively restores brain energy metabolism. Methods: Fifteen children with GLUT1 deficiency syndrome were enrolled prospectively for a 2.0 - 5.5-year follow-up of the effectiveness of a 3 : 1 LCT ketogenic diet. Eight patients enrolled were described previously, seven patients were novel. Results: Four novel heterozygous GLUT1 mutations were identified. 10/15 patients remained seizure-free on the ketogenic diet in monotherapy. In 2/15 patients seizures recurred after 2œ years despite adequate ketosis, but were controlled by add-on ethosuximide. In one patient seizures were reduced without complete seizure control. No serious adverse effects occurred and parental satisfaction with the diet was good. 2/15 patients discontinued the diet. Conclusion: GLUT1 deficiency syndrome represents a complex childhood encephalopathy that can be treated effectively by means of a ketogenic diet. The response to the diet did not correlate to clinical, biochemical, or genetic features of the disease. In contrast to previous reports, our results indicate that epilepsy is not always completely controlled by a ketogenic diet and can recur in a subset of patients.

Key words

GLUT1 - GLUT1 deficiency syndrome - epilepsy - children - glucose - ketogenic diet

References

• 1 Cremer J E. Substrate utilization and brain development.  J Cerebr Blood Flow Metab. 1982;  2 394-407
• 2 Fukumoto H, Seino S, Imura H, Seino Y, Bell G I. Characterization and expression of human HepG2/erythrocyte glucose-transporter gene.  Diabetes. 1988;  37 657-661
• 3 Maher F, Vannucci S J, Simpson I A. Glucose transporter proteins in brain.  Faseb J. 1994;  8 1003-1011
• 4 De Vivo D C, Trifiletti R R, Jacobson R I, Ronen G M, Behmand R A, Harik S I. Defective glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia, seizures, and developmental delay.  N Engl J Med. 1991;  325 703-709
• 5 Klepper J. Impaired glucose transport into the brain: the expanding spectrum of glucose transporter type 1 deficiency syndrome.  Curr Opin Neurol. 2004;  17 193-196
• 6 Wang D, Pascual J M, Yang H, Engelstad K, Jhung S, Sun R P. et al . Glut-1 deficiency syndrome: Clinical, genetic, and therapeutic aspects.  Ann Neurol. 2005;  57 111-118
• 7 Wang D, Kranz-Eble P, De Vivo D C. Mutational analysis of GLUT1 (SLC2A1) in Glut-1 deficiency syndrome.  Hum Mutat. 2000;  16 224-231
• 8 Seidner G, Alvarez M G, Yeh J I, O'Driscoll K R, Klepper J, Stump T S. et al . GLUT‐1 deficiency syndrome caused by haploinsufficiency of the blood-brain barrier hexose carrier.  Nat Genet. 1998;  18 188-191
• 9 Klepper J, Willemsen M, Verrips A, Guertsen E, Herrmann R, Kutzick C. et al . Autosomal dominant transmission of GLUT1 deficiency.  Hum Mol Genet. 2001;  10 63-68
• 10 Leary L D, Wang D, Nordli D R, Engelstad K, De Vivo D C. Seizure characterization and electroencephalographic features in glut-1 deficiency syndrome.  Epilepsia. 2003;  44 701-707
• 11 von Moers A, Brockmann K, Wang D, Korenke C G, Huppke P, De Vivo D C. et al . EEG features of glut-1 deficiency syndrome.  Epilepsia. 2002;  43 941-945
• 12 Pascual J M, Van Heertum R L, Wang D, Engelstad K, De Vivo D C. Imaging the metabolic footprint of Glut1 deficiency on the brain.  Ann Neurol. 2002;  52 458-464
• 13 Wong H Y, Chu T S, Chan Y W, Fok T F, Fung L W, Fung K P. et al . The effects of phenytoin and its metabolite 5-(4-hydroxyphenyl)-5-phenylhydantoin on cellular glucose transport.  Life Sci. 2005;  76 1859-1872
• 14 Klepper J, Florcken A, Fischbarg J, Voit T. Effects of anticonvulsants on GLUT1-mediated glucose transport in GLUT1 deficiency syndrome in vitro.  Eur J Pediatr. 2003;  162 84-89
• 15 Klepper J, Fischbarg J, Vera J C, Wang D, De Vivo D C. GLUT1-deficiency: barbiturates potentiate haploinsufficiency in vitro.  Pediatr Res. 1999;  46 677-683
• 16 Ho Y Y, Yang H, Klepper J, Fischbarg J, Wang D, De Vivo D C. Glucose transporter type 1 deficiency syndrome (Glut1DS): methylxanthines potentiate GLUT1 haploinsufficiency in vitro.  Pediatr Res. 2001;  50 254-260
• 17 Iserovich P, Wang D, Ma L, Yang H, Zuniga F A, Pascual J M. et al . Changes in glucose transport and water permeability resulting from the T310I pathogenic mutation in Glut1 are consistent with two transport channels per monomer.  J Biol Chem. 2002;  277 30991-30997
• 18 Klepper J, Monden I, Guertsen E, Voit T, Willemsen M, Keller K. Functional consequences of the autosomal dominant G272A mutation in the human GLUT1 gene.  FEBS Lett. 2001;  498 104-109
• 19 Lange P, Gertsen E, Monden I, Klepper J, Keller K. Functional consequences of an in vivo mutation in exon 10 of the human GLUT1 gene.  FEBS Lett. 2003;  555 274-278
• 20 Wang D, Pascual J M, Iserovich P, Yang H, Ma L, Kuang K. et al . Functional studies of threonine 310 mutations in Glut1: T310I is pathogenic, causing Glut1 deficiency.  J Biol Chem. 2003;  278 49015-49021
• 21 Klepper J, Voit T. Facilitated glucose transporter protein type 1 (GLUT1) deficiency syndrome: impaired glucose transport into brain - a review.  Eur J Pediatr. 2002;  161 295-304
• 22 De Vivo D C, Leary L, Wang D. Glucose transporter 1 deficiency syndrome and other glycolytic defects.  J Child Neurol. 2002;  17 15-25
• 23 Klepper J, Leiendecker B, Bredahl R, Athanassopoulos S, Heinen F, Gertsen E. et al . Introduction of a ketogenic diet in young infants.  J Inherit Metab Dis. 2002;  25 449-460
• 24 Klepper J, Diefenbach S, Kohlschutter A, Voit T. Effects of the ketogenic diet in the glucose transporter 1 deficiency syndrome.  Prostaglandins Leukot Essent Fatty Acids. 2004;  70 321-327
• 25 Willemsen M A, Verrips A, Verbeek M M, Voit T, Klepper J. Hypoglycorrhachia: a simple clue, simply missed.  Ann Neurol. 2001;  49 685-686
• 26 Klepper J, Garcia-Alvarez M, O'Driscoll K R, Parides M K, Wang D, Ho Y Y. et al . Erythrocyte 3-O-methyl-D-glucose uptake assay for diagnosis of glucose-transporter-protein syndrome.  J Clin Lab Anal. 1999;  13 116-121
• 27 Kielb S, Koo H P, Bloom D A, Faerber G J. Nephrolithiasis associated with the ketogenic diet.  J Urol. 2000;  164 464-466
• 28 Stewart W A, Gordon K, Camfield P. Acute pancreatitis causing death in a child on the ketogenic diet.  J Child Neurol. 2001;  16 682
• 29 Best T H, Franz D N, Gilbert D L, Nelson D P, Epstein M R. Cardiac complications in pediatric patients on the ketogenic diet.  Neurology. 2000;  54 2328-2330
• 30 Berry-Kravis E, Booth G, Taylor A, Valentino L A. Bruising and the ketogenic diet: evidence for diet-induced changes in platelet function.  Ann Neurol. 2001;  49 98-103
• 31 Hoyt C S, Billson F A. Optic neuropathy in ketogenic diet.  Br J Ophthalmol. 1979;  63 191-194
• 32 De Vivo D C, Wang D, Pascual J M, Ho Y Y. Glucose transporter protein syndromes.  Int Rev Neurobiol. 2002;  51 259-288
• 33 Scriver C R. Why mutation analysis does not always predict clinical consequences: Explanations in the era of genomics.  J Pediatr. 2004;  140 502-506
• 34 Brockmann K, Wang D, Korenke C G, von Moers A, Ho Y Y, Pascual J M. et al . Autosomal dominant glut-1 deficiency syndrome and familial epilepsy.  Ann Neurol. 2001;  50 476-485
• 35 Monden I, Olsowski A, Krause G, Keller K. The large cytoplasmic loop of the glucose transporter GLUT1 is an essential structural element for function.  Biol Chem. 2001;  382 1551-1558
• 36 Olsowski A, Monden I, Krause G, Keller K. Cysteine scanning mutagenesis of helices 2 and 7 in GLUT1 identifies an exofacial cleft in both transmembrane segments.  Biochemistry. 2000;  39 2469-2474
• 37 Schwartzkroin P A. Mechanisms underlying the anti-epileptic efficacy of the ketogenic diet.  Epilepsy Res. 1999;  37 171-180
• 38 Freeman J M, Vining E P, Pillas D J, Pyzik P L, Casey J C, Kelly L M. The efficacy of the ketogenic diet-1998: a prospective evaluation of intervention in 150 children.  Pediatrics. 1998;  102 1358-1363
• 39 Heilig C W, Saunders T. Brosius FC 3rd . Glucose transporter-1-deficient mice exhibit impaired development and deformities that are similar to diabetic embryopathy.  Proc Natl Acad Sci USA. 2003;  100 15613-15618
• 40 Brown G K. Glucose transporters: structure, function and consequences of deficiency.  J Inherit Metab Dis. 2000;  23 237-246