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Nationwide survey of glucose transporter-1 deficiency syndrome (GLUT-1DS) in Japan

Published:December 05, 2014DOI:https://doi.org/10.1016/j.braindev.2014.11.006

      Abstract

      Objectives

      We conducted a nationwide survey of glucose transporter type-1 deficiency syndrome (GLUT-1DS) in Japan in order to clarify its incidence as well as clinical and laboratory information.

      Subjects and methods

      A questionnaire to survey the number of genetically and clinically confirmed cases of GLUT-1DS was sent to 1018 board-certified pediatric neurologists, which resulted in 57 patients being reported. We obtained the clinical and laboratory data of 33 patients through a secondary questionnaire.

      Results

      The age of the 33 patients (male: 15, female: 18) at the time of the study ranged between 3 and 35 years (mean: 13.5 years). The age of these patients at the onset of initial neurological symptoms ranged between the neonatal period and 48 months (mean: 9.4 months). GLUT-1DS was diagnosed at a mean age of 8.4 years (range: 1 year to 33 years). The initial symptom was convulsive seizures, which occurred in 15 cases, and was followed by abnormal eye movements in 7 cases and apneic or cyanotic attacks in 4 cases. The latter two symptoms most frequently occurred early in infancy. Thirty-two patients (97%) exhibited some type of epileptic seizure. Neurological findings revealed that most patients had muscle hypotonia, cerebellar ataxia, dystonia, and spastic paralysis. Mild to severe mental retardation was detected in all 33 cases. Furthermore, paroxysmal episodes of ataxia, dystonia/dyskinesia, and motor paralysis were described in approximately 1/3 of all patients. The factors that frequently aggravated these events were hunger, exercise, fever, and fatigue, in that order. The mean CSF/blood glucose ratio was 0.36 (0.28–0.48). Pathological mutations in the SLC2A1 gene were identified in 28 out of 32 cases (87.5%).

      Conclusion

      The results described herein provided an insight into the early diagnosis of GLUT1-DS, including unexplained paroxysmal abnormal eye movements, apneic/cyanotic attacks, and convulsive seizures in infancy, as well as uncommon paroxysmal events (ataxia, atonia, and motor paralysis) in childhood.

      Keywords

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      References

        • Wang D.
        • Pascual J.M.
        • De Vivo D.
        Glucose Transporter Type 1 Deficiency Syndrome.
        in: Pagon R.A. Adam M.P. Ardinger H.H. Bird T.D. Dolan C.R. Fong C.T. GeneReviews® Seattle (WA): University of Washington, 1993
        • 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
        • Brockmann K.
        The expanding phenotype of GLUT1-deficiency syndrome.
        Brain Dev. 2009; 31: 545-552
        • 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
        • Verrotti A.
        • D’Egidio C.
        • Agostinelli S.
        • Gobbi G.
        Glut1 deficiency: when to suspect and how to diagnose?.
        Eur J Paediatr Neurol. 2012; 16: 3-9
        • Rotstein M.
        • Engelstad K.
        • Yang H.
        • Wang D.
        • Levy B.
        • Chung W.K.
        • et al.
        Glut1 deficiency: inheritance pattern determined by haploinsufficiency.
        Ann Neurol. 2010; 68: 955-958
        • Klepper J.
        • Scheffer H.
        • Elsaid M.F.
        • Kamsteeg E.J.
        • Leferink M.
        • Ben-Omran T.
        Autosomal recessive inheritance of GLUT1 deficiency syndrome.
        Neuropediatrics. 2009; 40: 207-210
        • 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
        • Leen W.G.
        • Klepper J.
        • Verbeek M.M.
        • Leferink M.
        • Hofste T.
        • van Engelen B.G.
        • et al.
        Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder.
        Brain. 2010; 133: 655-670
        • 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
        • Gokben S.
        • Yilmaz S.
        • Klepper J.
        • Serdaroglu G.
        • Tekgul H.
        Video/EEG recording of myoclonic absences in GLUT1 deficiency syndrome with a hot-spot R126C mutation in the SLC2A1 gene.
        Epilepsy Behav. 2011; 21: 200-202
        • 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.
        . 2011; 68: 1152-1155
        • Perez-Duenas B.
        • Prior C.
        • Ma Q.
        • Fernandez-Alvarez E.
        • Setoain X.
        • Artuch R.
        • et al.
        Childhood chorea with cerebral hypotrophy: a treatable GLUT1 energy failure syndrome.
        Arch Neurol. 2009; 66: 1410-1414
        • Roubergue A.
        • Apartis E.
        • Mesnage V.
        • Doummar D.
        • Trocello J.M.
        • Roze E.
        • et al.
        Dystonic tremor caused by mutation of the glucose transporter gene GLUT1.
        J Inherit Metab Dis. 2011; 34: 483-488
        • Schneider S.A.
        • Paisan-Ruiz C.
        • Garcia-Gorostiaga I.
        • Quinn N.P.
        • Weber Y.G.
        • Lerche H.
        • et al.
        GLUT1 gene mutations cause sporadic paroxysmal exercise-induced dyskinesias.
        Mov Disord. 2009; 24: 1684-1688
        • 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.
        GLUT1 deficiency syndrome in clinical practice.
        Epilepsy Res. 2012; 100: 272-277
        • Ito Y.
        • Gertsen E.
        • Oguni H.
        • Nakayama T.
        • Matsuo M.
        • Funatsuka M.
        • et al.
        Clinical presentation, EEG studies, and novel mutations in two cases of GLUT1 deficiency syndrome in Japan.
        Brain Dev. 2005; 27: 311-317
        • Fujii T.
        • Morimoto M.
        • Yoshioka H.
        • Ho Y.Y.
        • Law P.P.
        • Wang D.
        • et al.
        T295M-associated Glut1 deficiency syndrome with normal erythrocyte 3-OMG uptake.
        Brain Dev. 2011; 33: 316-320
        • Hashimoto N.
        • Kagitani-Shimono K.
        • Sakai N.
        • Otomo T.
        • Tominaga K.
        • Nabatame S.
        • et al.
        SLC2A1 gene analysis of Japanese patients with glucose transporter 1 deficiency syndrome.
        J Hum Genet. 2011; 56: 846-851
        • Takahashi S.
        • Ohinata J.
        • Suzuki N.
        • Amamiya S.
        • Kajihama A.
        • Sugai R.
        • et al.
        Molecular analysis and anticonvulsant therapy in two patients with glucose transporter 1 deficiency syndrome: a successful use of zonisamide for controlling the seizures.
        Epilepsy Res. 2008; 80: 18-22
        • 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
        • Klepper J.
        Glucose transporter deficiency syndrome (GLUT1DS) and the ketogenic diet.
        Epilepsia. 2008; 49: 46-49
        • Ito Y.
        • Oguni H.
        • Ito S.
        • Oguni M.
        • Osawa M.
        A modified Atkins diet is promising as a treatment for glucose transporter type 1 deficiency syndrome.
        Dev Med Child Neurol. 2011; 53: 658-663
        • Akman C.I.
        • Engelstad K.
        • Hinton V.J.
        • Ullner P.
        • Koenigsberger D.
        • Leary L.
        • et al.
        Acute hyperglycemia produces transient improvement in glucose transporter type 1 deficiency.
        Ann Neurol. 2010; 67: 31-40
        • Pong A.W.
        • Geary B.R.
        • Engelstad K.M.
        • Natarajan A.
        • Yang H.
        • De Vivo D.C.
        Glucose transporter type I deficiency syndrome: epilepsy phenotypes and outcomes.
        Epilepsia. 2012; 53: 1503-1510
        • Hirano Y.
        • Oguni H.
        • Funatsuka M.
        • Imai K.
        • Osawa M.
        Differentiation of myoclonic seizures in epileptic syndromes: a video-polygraphic study of 26 patients.
        Epilepsia. 2009; 50 (in eng): 1525-1535
        • Leen W.G.
        • Wevers R.A.
        • Kamsteeg E.J.
        • Scheffer H.
        • Verbeek M.M.
        • Willemsen M.A.
        Cerebrospinal fluid analysis in the workup of GLUT1 deficiency syndrome: a systematic review.
        JAMA Neurol. 2013; 70: 1440-1444
        • Anand G.
        • Padeniya A.
        • Hanrahan D.
        • Scheffer H.
        • Zaiwalla Z.
        • Cox D.
        • et al.
        Milder phenotypes of glucose transporter type 1 deficiency syndrome.
        Dev Med Child Neurol. 2011; 53: 664-668
        • Arsov T.
        • Mullen S.A.
        • Rogers S.
        • Phillips A.M.
        • Lawrence K.M.
        • Damiano J.A.
        • et al.
        Glucose transporter 1 deficiency in the idiopathic generalized epilepsies.
        Ann Neurol. 2012; 72: 807-815
        • Koy A.
        • Assmann B.
        • Klepper J.
        • Mayatepek E.
        Glucose transporter type 1 deficiency syndrome with carbohydrate-responsive symptoms but without epilepsy.
        Dev Med Child Neurol. 2011; 53: 1154-1156
        • 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
        • 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
        • Klepper J.
        Absence of SLC2A1 mutations does not exclude Glut1 deficiency syndrome.
        Neuropediatrics. 2013; 44: 235-236
        • Klepper J.
        • Leiendecker B.
        GLUT1 deficiency syndrome–2007 update.
        Dev Med Child Neurol. 2007; 49: 707-716
        • Wang D.
        • Yang H.
        • Shi L.
        • Ma L.
        • Fujii T.
        • Engelstad K.
        • et al.
        Functional studies of the T295M mutation causing Glut1 deficiency: glucose efflux preferentially affected by T295M.
        Pediatr Res. 2008; 64: 538-543