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The glucose transporter type 1 (Glut1) syndromes

  • Henner Koch
    Affiliations
    Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
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  • Yvonne G. Weber
    Correspondence
    Corresponding author at: Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, 72072 Tübingen, Germany.
    Affiliations
    Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
    Search for articles by this author
Published:August 01, 2018DOI:https://doi.org/10.1016/j.yebeh.2018.06.010

      Highlights

      • SLC2A1 codes the glucose transporter type 1 (Glut1).
      • Glut1 is expressed at the blood–brain barrier.
      • Glut1 is associated with a broad spectrum of epilepsies and movement disorders.
      • Additional diagnostics are lumbar puncture and genetic analysis.
      • Ketogenic diet is the precision therapy for Glut1 defects.

      Abstract

      The glucose transporter type 1 (Glut1) is the most important energy carrier of the brain across the blood–brain barrier. In the early nineties, the first genetic defect of Glut1 was described and known as the Glut1 deficiency syndrome (Glut1-DS). It is characterized by early infantile seizures, developmental delay, microcephaly, and ataxia. Recently, milder variants have also been described. The clinical picture of Glut1 defects and the understanding of the pathophysiology of this disease have significantly grown. A special form of transient movement disorders, the paroxysmal exertion-induced dyskinesia (PED), absence epilepsies particularly with an early onset absence epilepsy (EOAE) and childhood absence epilepsy (CAE), myoclonic astatic epilepsy (MAE), episodic choreoathetosis and spasticity (CSE), and focal epilepsy can be based on a Glut1 defect. Despite the rarity of these diseases, the Glut1 syndromes are of high clinical interest since a very effective therapy, the ketogenic diet, can improve or reverse symptoms especially if it is started as early as possible. The present article summarizes the clinical features of Glut1 syndromes and discusses the underlying genetic mutations, including the available data on functional tests as well as the genotype–phenotype correlations.
      This article is part of the Special Issue "Individualized Epilepsy Management: Medicines, Surgery and Beyond".

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      References

        • Thorens B.
        • Mueckler M.
        Glucose transporters in the 21st century.
        Am J Physiol Endocrinol Metab. 2010; 298: E141-E145
        • 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
        • Weber Y.G.
        • Storch A.
        • Wuttke T.V.
        • Brockmann K.
        • Kempfle J.
        • Maljevic S.
        • 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
        • Suls A.
        • Mullen S.A.
        • Weber Y.G.
        • Verhaert K.
        • Ceulemans B.
        • Guerrini R.
        • et al.
        Early-onset absence epilepsy caused by mutations in the glucose transporter GLUT1.
        Ann Neurol. 2009; 66: 415-419
        • Mueckler M.
        • Makepeace C.
        Analysis of transmembrane segment 8 of the GLUT1 glucose transporter by cysteine-scanning mutagenesis and substituted cysteine accessibility.
        J Biol Chem. 2004; 279: 10494-10499
        • 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
        • 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
        • 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
        • Scheffer I.E.
        • Berkovic S.
        • Capovilla G.
        • Connolly M.B.
        • French J.
        • Guilhoto L.
        • et al.
        ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology.
        Epilepsia. 2017; 58: 512-521
        • Zenzola A.
        • De Mari M.
        • De Blasi R.
        • Carella A.
        • Lamberti P.
        Paroxysmal dystonia with thalamic lesion in multiple sclerosis.
        Neurol Sci. 2001; 22: 391-394
        • Schubert J.
        • Paravidino R.
        • Becker F.
        • Berger A.
        • Bebek N.
        • Bianchi A.
        • et al.
        PRRT2 mutations are the major cause of benign familial infantile seizures.
        Hum Mutat. 2012; 33: 1439-1443
        • Gardella E.
        • Becker F.
        • Møller R.S.
        • Schubert J.
        • Lemke J.R.
        • Larsen L.H.
        • et al.
        Benign infantile seizures and paroxysmal dyskinesia caused by an SCN8A mutation.
        Ann Neurol. 2016; 79: 428-36.14
        • Lee H.Y.
        • Xu Y.
        • Huang Y.
        • Ahn A.H.
        • Auburger G.W.
        • Pandolfo M.
        • et al.
        The gene for paroxysmal non-kinesigenic dyskinesia encodes an enzyme in a stress response pathway.
        Hum Mol Genet. 2004; 13: 3161-3170
        • Rainier S.
        • Thomas D.
        • Tokarz D.
        • Ming L.
        • Bui M.
        • Plein E.
        • et al.
        Myofibrillogenesis regulator 1 gene mutations cause paroxysmal dystonic choreoathetosis.
        Arch Neurol. 2004; 61: 1025-1029
        • Shen Y.
        • Lee H.Y.
        • Rawson J.
        • Ojha S.
        • Babbitt P.
        • Fu Y.H.
        • et al.
        Mutations in PNKD causing paroxysmal dyskinesia alters protein cleavage and stability.
        Hum Mol Genet. 2011; 20: 2322-2332
        • Du W.
        • Bautista J.F.
        • Yang H.
        • Diez-Sampedro A.
        • You S.A.
        • Wang L.
        • et al.
        Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder.
        Nat Genet. 2005; 37: 733-738
        • Arsov T.
        • Mullen S.A.
        • Damiano J.A.
        • Lawrence K.M.
        • Huh L.L.
        • Nolan M.
        • et al.
        Early onset absence epilepsy: 1 in 10 cases is caused by GLUT1 deficiency.
        Epilepsia. 2012; 53: e204-e207
        • Muhle H.
        • Helbig I.
        • Frøslev T.G.
        • Suls A.
        • von Spiczak S.
        • Klitten L.L.
        • et al.
        The role of SLC2A1 in early onset and childhood absence epilepsies.
        Epilepsy Res. 2013; 105: 229-233
        • Larsen J.
        • Johannesen K.M.
        • Ek J.
        • Tang S.
        • Marini C.
        • Blichfeldt S.
        • et al.
        The role of SLC2A1 mutations in myoclonic astatic epilepsy and absence epilepsy, and the estimated frequency of GLUT1 deficiency syndrome.
        Epilepsia. 2015; 56: e203-e208
        • Striano P.
        • Weber Y.G.
        • Toliat M.R.
        • Schubert J.
        • Leu C.
        • Chaimana R.
        • et al.
        GLUT1 mutations are a rare cause of familial idiopathic generalized epilepsy.
        Neurology. 2012; 78: 557-562
        • Mullen S.A.
        • Marini C.
        • Suls A.
        • Mei D.
        • Della Giustina E.
        • Buti D.
        • et al.
        Glucose transporter 1 deficiency as a treatable cause of myoclonic astatic epilepsy.
        Arch Neurol. 2011; 68: 1152-1155
        • Weber Y.G.
        • Kamm C.
        • Suls A.
        • Kempfle J.
        • Kotschet K.
        • Schule R.
        • et al.
        Paroxysmal choreoathetosis/spasticity (DYT9) is caused by a GLUT1 defect.
        Neurology. 2011; 77: 959-964
        • Auburger G.
        • Ratzlaff T.
        • Lunkes A.
        • Nelles H.W.
        • Leube B.
        • Binkofski F.
        • et al.
        A gene for autosomal dominant paroxysmal choreoathetosis/spasticity (CSE) maps to the vicinity of a potassium channel gene cluster on chromosome 1p, probably within 2 cM between D1S443 and D1S197.
        Genomics. 1996; 31: 90-94
        • Wolking S.
        • Becker F.
        • Bast T.
        • Wiemer-Kruel A.
        • Mayer T.
        • Lerche H.
        • et al.
        Focal epilepsy in glucose transporter type 1 (Glut1) defects: case reports and a review of literature.
        J Neurol. 2014; 261: 1881-1886
        • Wang D.
        • Pascual J.M.
        • Yang H.
        • Engelstad K.
        • Jhung S.
        • Sun R.P.
        • et al.
        Glut1 deficiency syndrome: clinical, genetic, and therapeutic aspects.
        Ann Neurol. 2005; 57: 111-118
        • Liu Y.C.
        • Lee J.W.
        • Bellows S.T.
        • Damiano J.A.
        • Mullen S.A.
        • Berkovic S.F.
        • et al.
        Evaluation of non-coding variation in GLUT1 deficiency.
        Dev Med Child Neurol. 2016; 58: 1295-1302
        • Klepper J.
        • Engelbrecht V.
        • Scheffer H.
        • van der Knaap M.S.
        • Fiedler A.
        GLUT1 deficiency with delayed myelination responding to ketogenic diet.
        Pediatr Neurol. 2007; 37: 130-133
        • Gras D.
        • Cousin C.
        • Kappeler C.
        • Fung C.W.
        • Auvin S.
        • Essid N.
        • et al.
        A simple blood test expedites the diagnosis of glucose transporter type 1 deficiency syndrome.
        Ann Neurol. 2017; 82: 133-138
        • Brockmann K.
        The expanding phenotype of GLUT1-deficiency syndrome.
        Brain Dev. 2009; 31: 545-552
        • 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
        • Suls A.
        • Dedeken P.
        • Goffin K.
        • Van Esch H.
        • Dupont P.
        • Cassiman D.
        • et al.
        Paroxysmal exercise-induced dyskinesia and epilepsy is due to mutations in SLC2A1, encoding the glucose transporter GLUT1.
        Brain. 2008; 131: 1831-1844
        • 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
        • Friedman J.R.
        • Thiele E.A.
        • Wang D.
        • Levine K.B.
        • Cloherty E.K.
        • Pfeifer H.H.
        • et al.
        Atypical GLUT1 deficiency with prominent movement disorder responsive to ketogenic diet.
        Mov Disord. 2006; 21: 241-245
        • Thouin A.
        • Crompton D.E.
        Glut1 deficiency syndrome: absence epilepsy and La Soupe du Jour.
        Pract Neurol. 2016; 16: 50-52
        • Leary L.D.
        • Wang D.
        • Nordli Jr., D.R.
        • Engelstad K.
        • De Vivo D.C.
        Seizure characterization and electroencephalographic features in Glut1 deficiency syndrome.
        Epilepsia. 2003; 44: 701-707
        • Wilder R.M.
        The effect on ketonemia on the course of epilepsy.
        Mayo Clin Bull. 1921; 2: 307
        • Hartman A.L.
        • Gasior M.
        • Vining E.P.
        • Rogawski M.A.
        The neuropharmacology of the ketogenic diet.
        Pediatr Neurol. 2007; 36: 281-292
        • Neal E.G.
        • Chaffe H.
        • Schwartz R.H.
        • Lawson M.S.
        • Edwards N.
        • Fitzsimmons G.
        • et al.
        The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial.
        Lancet Neurol. 2008; 7: 500-506
        • Klepper J.
        • Diefenbach S.
        • Kohlschütter A.
        • Voit T.
        Effects of the ketogenic diet in the glucose transporter 1 deficiency syndrome.
        Prostaglandins Leukot Essent Fatty Acids. 2004; 70: 321-327
        • Nakamura S.
        • Muramatsu S.I.
        • Takino N.
        • Ito M.
        • Jimbo E.F.
        • Shimazaki K.
        • et al.
        Gene therapy for Glut1-deficient mouse using an adeno-associated virus vector with the human intrinsic GLUT1 promoter.
        J Gene Med. 2018; 20e3013