SLC2A1 and Its Related Epileptic Phenotypes

Abstract

Glucose transporter type 1 deficiency syndrome (GLUT1DS) is caused by heterozygous, mostly de novo, mutations in SLC2A1 gene encoding the glucose transporter GLUT1, the most relevant energy transporter in the blood–brain barrier. GLUT1DS includes a broad spectrum of neurologic disturbances, from severe encephalopathy with developmental delay, to epilepsy, movement disorders, acquired microcephaly and atypical mild forms. For diagnosis, lumbar puncture and genetic analysis are necessary and complementary; an immediate response to ketogenic diet supports the diagnosis in case of high suspicion of disease and negative exams. The ketogenic diet is the first-line treatment and should be established at the initial stages of disease.

Keywords

SLC2A1 - epilepsy - microcephaly - movement disorders - ketogenic diet

Publication History

Received: 17 September 2020

Accepted: 25 February 2021

Article published online:
01 June 2021

• References

• 1 Schneider SA, Paisan-Ruiz C, Garcia-Gorostiaga I. et al. GLUT1 gene mutations cause sporadic paroxysmal exercise-induced dyskinesias. Mov Disord 2009; 24 (11) 1684-1688
• 2 Pavone P, Praticò AD, Pavone V. et al. Ataxia in children: early recognition and clinical evaluation. Ital J Pediatr 2017; 43 (01) 6
• 3 Pavone P, Praticò AD, Falsaperla R. et al. Congenital generalized hypertrichosis: the skin as a clue to complex malformation syndromes. Ital J Pediatr 2015; 41: 55
• 4 Pavone P, Praticò AD, Ruggieri M. et al. Acquired peripheral neuropathy: a report on 20 children. Int J Immunopathol Pharmacol 2012; 25 (02) 513-517
• 5 Klepper J, Leiendecker B. Glut1 deficiency syndrome and novel ketogenic diets. J Child Neurol 2013; 28 (08) 1045-1048
• 6 Ruggieri M, Polizzi A, Marceca GP, Catanzaro S, Praticò AD, Di Rocco C. Introduction to phacomatoses (neurocutaneous disorders) in childhood. Childs Nerv Syst 2020; 36 (10) 2229-2268
• 7 Mueckler M, Caruso C, Baldwin SA. et al. Sequence and structure of a human glucose transporter. Science 1985; 229 (4717): 941-945
• 8 Adam MP, Ardinger HH, Pagon RA. et al, Eds. GeneReviews®. University of Washington; Seattle: 1993. http://www.ncbi.nlm.nih.gov/books/NBK1116/ . Accessed March 18, 2021
• 9 Klepper J, Vera JC, De Vivo DC. Deficient transport of dehydroascorbic acid in the glucose transporter protein syndrome. Ann Neurol 1998; 44 (02) 286-287
• 10 Matricardi S, Spalice A, Salpietro V. et al. Epilepsy in the setting of full trisomy 18: a multicenter study on 18 affected children with and without structural brain abnormalities. Am J Med Genet C Semin Med Genet 2016; 172 (03) 288-295
• 11 Koch H, Weber YG. The glucose transporter type 1 (Glut1) syndromes. Epilepsy Behav 2019; 91: 90-93
• 12 Ruggieri M, McShane MA. Parental view of epilepsy in Angelman syndrome: a questionnaire study. Arch Dis Child 1998; 79 (05) 423-426
• 13 Klepper J. GLUT1 deficiency syndrome in clinical practice. Epilepsy Res 2012; 100 (03) 272-277
• 14 Salpietro V, Polizzi A, Bertè LF. et al. Idiopathic intracranial hypertension: a unifying neuroendocrine hypothesis through the adrenal-brain axis. Neuroendocrinol Lett 2012; 33 (06) 569-573
• 15 Jiménez Legido M, Cortés Ledesma C, Bernardino Cuesta B. et al. Study of paediatric patients with the clinical and biochemical phenotype of glucose transporter type 1 deficiency syndrome. Neurologia 2019; S0213-4853(19)30016-7
• 16 Brancati F, Travaglini L, Zablocka D. et al; International JSRD Study Group. RPGRIP1L mutations are mainly associated with the cerebello-renal phenotype of Joubert syndrome-related disorders. Clin Genet 2008; 74 (02) 164-170
• 17 De Vivo DC, Leary L, Wang D. Glucose transporter 1 deficiency syndrome and other glycolytic defects. J Child Neurol 2002; 17 (Suppl. 03) S15-S23 , discussion S24–S25
• 18 Dozières-Puyravel B, Zaman S, Petrou S. et al. Usefulness of diagnostic tools in a GLUT1 deficiency syndrome patient with 2 inherited mutations. Brain Dev 2019; 41 (09) 808-811
• 19 De Vivo DC, Trifiletti RR, Jacobson RI, Ronen GM, Behmand RA, Harik SI. Defective glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia, seizures, and developmental delay. N Engl J Med 1991; 325 (10) 703-709
• 20 Castellotti B, Ragona F, Freri E. et al. Screening of SLC2A1 in a large cohort of patients suspected for Glut1 deficiency syndrome: identification of novel variants and associated phenotypes. J Neurol 2019; 266 (06) 1439-1448
• 21 Üstyol A, Takahashi S, Hatipoğlu HU, Duman MA, Elevli M, Selçuk-Duru HN. A novel mutation in SLC2A1 gene causing GLUT-1 deficiency syndrome in a young adult patient. Turk J Pediatr 2019; 61 (06) 946-948
• 22 Kim H, Lee JS, Lee Y. et al. Diagnostic challenges associated with GLUT1 deficiency: phenotypic variabilities and evolving clinical features. Yonsei Med J 2019; 60 (12) 1209-1215
• 23 Ismayilova N, Hacohen Y, MacKinnon AD, Elmslie F, Clarke A. GLUT-1 deficiency presenting with seizures and reversible leukoencephalopathy on MRI imaging. Eur J Paediatr Neurol 2018; 22 (06) 1161-1164
• 24 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 (Pt 7): 1831-1844
• 25 Ruggieri M, Milone P, Pavone P. et al. Nevus vascularis mixtus (cutaneous vascular twin nevi) associated with intracranial vascular malformation of the Dyke-Davidoff-Masson type in two patients. Am J Med Genet A 2012; 158A (11) 2870-2880
• 26 Pong AW, Geary BR, Engelstad KM, Natarajan A, Yang H, De Vivo DC. Glucose transporter type I deficiency syndrome: epilepsy phenotypes and outcomes. Epilepsia 2012; 53 (09) 1503-1510
• 27 Pavone P, Falsaperla R, Ruggieri M, Praticò AD, Pavone L. West syndrome treatment: new roads for an old syndrome. Front Neurol 2013; 4: 113
• 28 Falsaperla R, Perciavalle V, Pavone P. et al. Unilateral eye blinking arising from the ictal ipsilateral occipital area. Clin EEG Neurosci 2016; 47 (03) 243-246
• 29 Incorpora G, Pavone P, Castellano-Chiodo D, Praticò AD, Ruggieri M, Pavone L. Gelastic seizures due to hypothalamic hamartoma: rapid resolution after endoscopic tumor disconnection. Neurocase 2013; 19 (05) 458-461
• 30 Arsov T, Mullen SA, Rogers S. et al. Glucose transporter 1 deficiency in the idiopathic generalized epilepsies. Ann Neurol 2012; 72 (05) 807-815
• 31 O'Connor KC, Lopez-Amaya C, Gagne D. et al. Anti-myelin antibodies modulate clinical expression of childhood multiple sclerosis. J Neuroimmunol 2010; 223 (1-2): 92-99
• 32 Hully M, Vuillaumier-Barrot S, Le Bizec C. et al. From splitting GLUT1 deficiency syndromes to overlapping phenotypes. Eur J Med Genet 2015; 58 (09) 443-454
• 33 Suls A, Mullen SA, Weber YG. et al. Early-onset absence epilepsy caused by mutations in the glucose transporter GLUT1. Ann Neurol 2009; 66 (03) 415-419
• 34 Ruggieri M, Tigano G, Mazzone D, Tiné A, Pavone L. Involvement of the white matter in hypomelanosis of Ito (incontinentia pigmenti achromiens). Neurology 1996; 46 (02) 485-492
• 35 Pavone P, Falsaperla R, Ruggieri M. et al. Clinical course of N-methyl-D-aspartate receptor encephalitis and the effectiveness of cyclophosphamide treatment. J Pediatr Neurol 2017; 15: 84-89
• 36 Pavone P, Praticò AD, Vitaliti G. et al. Hydranencephaly: cerebral spinal fluid instead of cerebral mantles. Ital J Pediatr 2014; 40: 79
• 37 Arsov T, Mullen SA, Damiano JA. et al. Early onset absence epilepsy: 1 in 10 cases is caused by GLUT1 deficiency. Epilepsia 2012; 53 (12) e204-e207
• 38 Thouin A, Crompton DE. Glut1 deficiency syndrome: absence epilepsy and La Soupe du Jour. Pract Neurol 2016; 16 (01) 50-52
• 39 Soto-Insuga V, López RG, Losada-Del Pozo R. et al; Grupo Español de Genética de las Epilepsias de la Infancia (GEGEI). Glut1 deficiency is a rare but treatable cause of childhood absence epilepsy with atypical features. Epilepsy Res 2019; 154: 39-41
• 40 Zenzola A, De Mari M, De Blasi R, Carella A, Lamberti P. Paroxysmal dystonia with thalamic lesion in multiple sclerosis. Neurol Sci 2001; 22 (05) 391-394
• 41 Lionetti E, Francavilla R, Maiuri L. et al. Headache in pediatric patients with celiac disease and its prevalence as a diagnostic clue. J Pediatr Gastroenterol Nutr 2009; 49 (02) 202-207
• 42 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 (06) 2157-2168
• 43 Ruggieri M. Cutis tricolor: congenital hyper- and hypopigmented lesions in a background of normal skin with and without associated systemic features: further expansion of the phenotype. Eur J Pediatr 2000; 159 (10) 745-749
• 44 Mongin M, Mezouar N, Dodet P, Vidailhet M, Roze E. Paroxysmal exercise-induced dyskinesias caused by GLUT1 deficiency syndrome. Tremor Other Hyperkinet Mov (N Y) 2016; 6: 371
• 45 Juozapaite S, Praninskiene R, Burnyte B, Ambrozaityte L, Skerliene B. Novel mutation in a patient with late onset GLUT1 deficiency syndrome. Brain Dev 2017; 39 (04) 352-355
• 46 Ruggieri M. Mosaic (segmental) neurofibromatosis type 1 (NF1) and type 2 (NF2): no longer neurofibromatosis type 5 (NF5). Am J Med Genet 2001; 101 (02) 178-180
• 47 Ruggieri M, Polizzi A, Spalice A. et al. The natural history of spinal neurofibromatosis: a critical review of clinical and genetic features. Clin Genet 2015; 87 (05) 401-410
• 48 Striano P, Weber YG, Toliat MR. et al; EPICURE Consortium. GLUT1 mutations are a rare cause of familial idiopathic generalized epilepsy. Neurology 2012; 78 (08) 557-562
• 49 Larsen J, Johannesen KM, Ek J. et al; MAE working group of EuroEPINOMICS RES Consortium. The role of SLC2A1 mutations in myoclonic astatic epilepsy and absence epilepsy, and the estimated frequency of GLUT1 deficiency syndrome. Epilepsia 2015; 56 (12) e203-e208
• 50 Mullen SA, Marini C, Suls A. et al. Glucose transporter 1 deficiency as a treatable cause of myoclonic astatic epilepsy. Arch Neurol 2011; 68 (09) 1152-1155
• 51 Ruggieri M, Praticò AD, Evans DG. Diagnosis, management, and new therapeutic options in childhood neurofibromatosis type 2 and related forms. Semin Pediatr Neurol 2015; 22 (04) 240-258
• 52 Ruggieri M, Gabriele AL, Polizzi A. et al. Natural history of neurofibromatosis type 2 with onset before the age of 1 year. Neurogenetics 2013; 14 (02) 89-98
• 53 Ruggieri M, Praticò AD, Serra A. et al. Childhood neurofibromatosis type 2 (NF2) and related disorders: from bench to bedside and biologically targeted therapies. Acta Otorhinolaryngol Ital 2016; 36 (05) 345-367
• 54 Salafia S, Praticò AD, Pizzo E, Greco F, Di Bella D. Hemiconvulsion-hemiplegia-epilepsy syndrome. Magnetic resonance findings in a 3-year-old boy. Neurol Neurochir Pol 2013; 47 (06) 584-589
• 55 Ruggieri M, Iannetti P, Pavone L. Delineation of a newly recognized neurocutaneous malformation syndrome with “cutis tricolor”. Am J Med Genet A 2003; 120A [phone]
• 56 Lee HH, Hur YJ. Glucose transport 1 deficiency presenting as infantile spasms with a mutation identified in exon 9 of SLC2A1 . Korean J Pediatr 2016; 59 (Suppl. 01) S29-S31
• 57 Ruggieri M, Polizzi A. Segmental neurofibromatosis. J Neurosurg 2000; 93 (03) 530-532
• 58 Wolking S, Becker F, Bast T. et al. Focal epilepsy in glucose transporter type 1 (Glut1) defects: case reports and a review of literature. J Neurol 2014; 261 (10) 1881-1886
• 59 De Giorgis V, Varesio C, Baldassari C. et al. Atypical manifestations in Glut1 deficiency syndrome. J Child Neurol 2016; 31 (09) 1174-1180
• 60 Pavone V, Signorelli SS, Praticò AD. et al. Total hemi-overgrowth in pigmentary mosaicism of the (hypomelanosis of) Ito type: eight case reports. Medicine (Baltimore) 2016; 95 (10) e2705
• 61 Pavone P, Briuglia S, Falsaperla R. et al. Wide spectrum of congenital anomalies including choanal atresia, malformed extremities, and brain and spinal malformations in a girl with a de novo 5.6-Mb deletion of 13q12.11-13q12.13. Am J Med Genet A 2014; 164A [phone]
• 62 Reis S, Matias J, Machado R, Monteiro JP. Paroxysmal ocular movements - an early sign in Glut1 deficiency syndrome. Metab Brain Dis 2018; 33 (04) 1381-1383
• 63 Akman CI, Yu J, Alter A, Engelstad K, De Vivo DC. Diagnosing glucose transporter 1 deficiency at initial presentation facilitates early treatment. J Pediatr 2016; 171: 220-226
• 64 Messana T, Russo A, Vergaro R, Boni A, Santucci M, Pini A. Glucose transporter type 1 deficiency syndrome: developmental delay and early-onset ataxia in a novel mutation of the SLC2A1 gene. J Pediatr Neurosci 2018; 13 (04) 496-499
• 65 Ruggieri M, Huson SM. The neurofibromatoses. An overview. Ital J Neurol Sci 1999; 20 (02) 89-108
• 66 Praticò AD, Falsaperla R, Ruggieri M, Corsello G, Pavone P. Prognostic challenges of SCN1A genetic mutations: report on two children with mild features. J Pediatr Neurol 2016; 14: 82-88
• 67 Klepper J, Fischbarg J, Vera JC, Wang D, De Vivo DC. GLUT1-deficiency: barbiturates potentiate haploinsufficiency in vitro. Pediatr Res 1999; 46 (06) 677-683
• 68 Flatt JF, Guizouarn H, Burton NM. et al. Stomatin-deficient cryohydrocytosis results from mutations in SLC2A1: a novel form of GLUT1 deficiency syndrome. Blood 2011; 118 (19) 5267-5277
• 69 Leen WG, Klepper J, Verbeek MM. et al. Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder. Brain 2010; 133 (Pt 3): 655-670
• 70 De Giorgis V, Teutonico F, Cereda C. et al. Sporadic and familial glut1ds Italian patients: a wide clinical variability. Seizure 2015; 24: 28-32
• 71 Ramm-Pettersen A, Nakken KO, Haavardsholm KC, Selmer KK. GLUT1-deficiency syndrome: Report of a four-generation Norwegian family with a mild phenotype. Epilepsy Behav 2017; 70 (Pt A): 1-4
• 72 Di Vito L, Licchetta L, Pippucci T. et al. Phenotype variability of GLUT1 deficiency syndrome: description of a case series with novel SLC2A1 gene mutations. Epilepsy Behav 2018; 79: 169-173
• 73 Wang D, Pascual JM, Yang H. et al. A mouse model for Glut-1 haploinsufficiency. Hum Mol Genet 2006; 15 (07) 1169-1179
• 74 Caltabiano R, Magro G, Polizzi A. et al. A mosaic pattern of INI1/SMARCB1 protein expression distinguishes Schwannomatosis and NF2-associated peripheral schwannomas from solitary peripheral schwannomas and NF2-associated vestibular schwannomas. Childs Nerv Syst 2017; 33 (06) 933-940
• 75 Ruggieri M, Praticò AD, Caltabiano R, Polizzi A. Early history of the different forms of neurofibromatosis from ancient Egypt to the British Empire and beyond: first descriptions, medical curiosities, misconceptions, landmarks, and the persons behind the syndromes. Am J Med Genet A 2018; 176 (03) 515-550
• 76 Barbagallo M, Ruggieri M, Incorpora G. et al. Infantile spasms in the setting of Sturge-Weber syndrome. Childs Nerv Syst 2009; 25 (01) 111-118
• 77 Ruggieri M, Praticò AD, Serra A. et al. Early history of neurofibromatosis type 2 and related forms: earliest descriptions of acoustic neuromas, medical curiosities, misconceptions, landmarks and the pioneers behind the eponyms. Childs Nerv Syst 2017; 33 (04) 549-560
• 78 Ruggieri M, Praticò AD, Scuderi A, Sorge G, Polizzi A. The multiple faces of artwork diagnoses. Lancet Neurol 2017; 16 (06) 417-418
• 79 Pratico AD, Longo L, Mansueto S. et al. Off-label use of drugs and adverse drug reactions in pediatric units: a prospective, multicenter study. Curr Drug Saf 2018; 13 (03) 200-207
• 80 Praticò AD, Pavone P, Scuderi MG. et al. Symptomatic hypocalcemia in an epileptic child treated with valproic acid plus lamotrigine: a case report. Cases J 2009; 2: 7394
• 81 Pratico AD, Ruggieri M, Falsaperla R, Pavone P. A probable topiramate-induced limbs paraesthesia and rigid fingers flexion. Curr Drug Saf 2018; 13 (02) 131-136
• 82 Friedman JR, Thiele EA, Wang D. et al. Atypical GLUT1 deficiency with prominent movement disorder responsive to ketogenic diet. Mov Disord 2006; 21 (02) 241-245
• 83 Schwantje M, Verhagen LM, van Hasselt PM, Fuchs SA. Glucose transporter type 1 deficiency syndrome and the ketogenic diet. J Inherit Metab Dis 2020; 43 (02) 216-222
• 84 Brockmann K. The expanding phenotype of GLUT1-deficiency syndrome. Brain Dev 2009; 31 (07) 545-552
• 85 Gramer G, Wolf NI, Vater D. et al. Glucose transporter-1 (GLUT1) deficiency syndrome: diagnosis and treatment in late childhood. Neuropediatrics 2012; 43 (03) 168-171
• 86 van der Louw E, van den Hurk D, Neal E. et al. Ketogenic diet guidelines for infants with refractory epilepsy. Eur J Paediatr Neurol 2016; 20 (06) 798-809
• 87 Falsaperla R, D'Angelo G, Praticò AD. et al. Ketogenic diet for infants with epilepsy: a literature review. Epilepsy Behav 2020; 112: 107361
• 88 Mochel F, Hainque E, Gras D. et al. Triheptanoin dramatically reduces paroxysmal motor disorder in patients with GLUT1 deficiency. J Neurol Neurosurg Psychiatry 2016; 87 (05) 550-553