Letter to the Editor 235 Absence of SLC2A1 Mutations Does Not Exclude Glut1 Deficiency Syndrome Joerg Klepper1 Aschaffenburg, Aschaffenburg, Germany Neuropediatrics 2013;44:235–236. Abstract Keywords ► glut1 deficiency ► SLC2A1 ► ketogenic diet Increasingly, the absence of SLC2A1 mutations causes pediatricians to abandon the diagnosis of Glut1 deficiency. For several reasons this is not justified. Potential disease mechanisms in SLC2A1-negative Glut1 deficiency are discussed. Dear Editors, The diagnosis of Glut1 deficiency syndrome (Glut1DS) is suspected on clinical grounds presenting as an early-onset epileptic encephalopathy and/or a complex movement disorder. Subtypes of this entity in patients with early-onset absence epilepsy, paroxysmal exertion-induced dystonia, and myoclonic astatic epilepsy (Doose syndrome) have been identified. The diagnosis is confirmed by (1) a lumbar puncture showing low cerebrospinal fluid glucose (hypoglycorrhachia) in the setting of normoglycemia and low-to-normal cerebrospinal fluid lactate, (2) mutations in the SLC2A1 gene, and (3) a positive glucose uptake assay (not available on a commercial basis).1,2 A positive response to the ketogenic diet further supports the diagnosis. However, in individual patients confirmed with Glut1DS each diagnostic “gold standard” has eventually failed without sufficient explanation: • Mullen et al describe normoglycorrhachia in a case with early-onset absence epilepsy and an SLC2A1 missense mutation.3 • Fujii et al report a case of hypoglycorrhachia, an SLC2A1 missense mutation, but normal glucose uptake.4 • Yang et al report hypoglycorrhachia, an SLC2A1 missense mutation, but normal glucose uptake in 1 of 109 patients suspected of Glut1DS; they also report hypoglycorrhachia and impaired glucose uptake with negative SLC2A1 mutation analysis in 4 of 109 in the same series.2 Increasingly, the absence of SLC2A1 mutations causes pediatricians to abandon the diagnosis of Glut1DS. For several reasons this is not justified. SLC2A1-negative Glut1DS is seen in about 5 to 10% of cases1,2,5 (Joerg Klepper, personal received September 17, 2012 accepted after revision January 8, 2013 published online March 12, 2013 Address for correspondence Prof. Joerg Klepper, MD, Department of Pediatrics and Neuropediatrics, Childrens’ Hospital Aschaffenburg, Am Hasenkopf 1, Aschaffenburg D-63739, Germany (e-mail: joerg.klepper@klinikum-aschaffenburg.de). communications). Missing evidence for nongenetic mechanisms does not mean they do not exist but rather may simply mean they not have been investigated yet. Potential mechanisms could be as follows6: 1. Defects in other genes associated with Glut1DS but currently unidentified may contribute to Glut1DS. 2. The pathophysiologic basis for the Glut1 defect in these patients may not the genetic “blueprint” of the transporter at all. Rather, the process of generating a fully functional Glut1 transporter includes transcription of DNA into RNA, translation into amino acids, generating the secondary and tertiary structure of the protein, transportation to intracellular pools, and finally activation from these pools and expression on the cell membrane. 3. Several regulating processes are involved to ensure glucose transport across tissue barriers. These include ATP binding to activate/inactivate Glut1-mediated glucose transport according to the energy demand of the cell, hormonal control mechanisms, and the fact that the Glut1 protein is a functional dimer, meaning that two Glut1 molecules have to work together effectively to ensure glucose transport. 4. Glut1DS may also be an acquired disease: The Glut1 transporter is particularly sensitive to drugs, toxins, trauma, and inflammation. SLC2A1-negative patients remain a particular challenge. Next-generation sequencing might help to identify associated genes; proteomic methods might provide a novel approach to investigate Glut1 assembly, processing, and regulation; and eventually acquired Glut1DS may be identified. © 2013 Georg Thieme Verlag KG Stuttgart · New York DOI http://dx.doi.org/ 10.1055/s-0033-1336015. ISSN 0174-304X. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 1 Department of Pediatrics and Neuropediatrics, Childrens’ Hospital Letter to the Editor Klepper In summary, in the absence of SLC2A1 mutations, the combination of clinical signs and otherwise unexplained hypoglycorrhachia appears per se sufficient to establish the diagnosis and to initiate a ketogenic diet. References 1 Klepper J, Leiendecker B. GLUT1 deficiency syndrome—2007 update. Dev Med Child Neurol 2007;49(9):707–716 2 Yang H, Wang D, Engelstad K, et al. Glut1 deficiency syndrome and erythrocyte glucose uptake assay. Ann Neurol 2011;70(6): 996–1005 3 Mullen SA, Suls A, De Jonghe P, Berkovic SF, Scheffer IE. Absence epilepsies with widely variable onset are a key feature of familial GLUT1 deficiency. Neurology 2010;75(5):432–440 4 Fujii T, Morimoto M, Yoshioka H, et al. T295M-associated Glut1 deficiency syndrome with normal erythrocyte 3-OMG uptake. Brain Dev 2011;33(4):316–320 5 Wang D, Pascual JM, De Vivo D. Glucose transporter type deficiency syndrome. In: Pagon RA, Bird TC, Dolan CR, Stephens K, eds. Gene Reviews. Seattle, WA: University of Washington, Seattle, Washington; 1993–2013 6 Carruthers A, DeZutter J, Ganguly A, Devaskar SU. Will the original glucose transporter isoform please stand up! Am J Physiol Endocrinol Metab 2009;297(4):E836–E848 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 236 Neuropediatrics Vol. 44 No. 4/2013 Copyright of Neuropediatrics is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.