Glucose transporter type 1 deficiency syndrome (Glut1 DS) is a rare neurological disorder caused by impaired glucose delivery to the brain. The clinical spectrum of Glut1 DS mainly includes epilepsy, paroxysmal dyskinesia (PD), developmental delay and microcephaly. Glut1 DS diagnosis is based on the identification of hypoglycorrhachia and pathogenic mutations of the SLC2A1 gene. Here, we report the molecular screening of SLC2A1 in 354 patients clinically suspected for Glut1 DS. From this cohort, we selected 245 patients for whom comprehensive clinical and laboratory data were available. Among them, we identified 19 patients carrying nucleotide variants of pathological significance, 5 of which were novel. The symptoms of onset, which varied from neonatal to adult age, included epilepsy, PD or non-epileptic paroxysmal manifestations. The comparison of the clinical features between the 19 SLC2A1 mutated and the 226 non-mutated patients revealed that the onset of epilepsy within the first year of life (when associated with developmental delay or other neurological manifestations), the association of epilepsy with PD and acquired microcephaly are more common in mutated subjects. Taken together, these data confirm the variability of expression of the phenotypes associated with mutation of SLC2A1 and provide useful clinical tools for the early identification of subjects highly suspected for the disease.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
De Vivo DC, Trifiletti RR, Jacobson RI, Ronen GM, Behmand RA, Harik SI (1991) Defective glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia, seizures, and developmental delay. N Engl J Med 325(10):703–709
Seidner G, Alvarez MG, Yeh JI, O’Driscoll KR, Klepper J, Stump TS et al (1998) GLUT-1 deficiency syndrome caused by haploinsufficiency of the blood-brain barrier hexose carrier. Nat Genet 18(2):188–191. https://doi.org/10.1038/ng0298-188
Brockmann K (2009) The expanding phenotype of GLUT1 -deficiency syndrome. Brain Dev 7:545–552. https://doi.org/10.1016/j.braindev.2009.02.008
Weber YG, Storch A, Wuttke TV, Brockmann K, Kempfle J, Maljevic S et al (2008) GLUT1 mutations are a cause of paroxysmal exertion-induced dyskinesias and induce hemolytic anemia by a cation leak. J Clin Invest 118 6:2157–2168. https://doi.org/10.1172/JCI34438
Pong AW, Geary BR, Engelstad KM, Natarajan A, Yang H, De Vivo DC (2012) Glucose transporter type I deficiency syndrome: epilepsy phenotypes and outcomes. Epilepsia 53(9):1503–1510. https://doi.org/10.1111/j.1528-1167.2012.03592.x
Arsov T, Mullen SA, Damiano JA, Lawrence KM, Huh LL, Nolan M et al (2012) Early onset absence epilepsy: 1 in 10 cases is caused by GLUT1 deficiency. Epilepsia 53(12):e204–e207. https://doi.org/10.1111/epi.12007
Suls A, Mullen SA, Weber YG, Verhaert K, Ceulemans B, Guerrini R et al (2009) Early-onset absence epilepsy caused by mutations in the glucose transporter GLUT1. Ann Neurol 66 3:415–419. https://doi.org/10.1002/ana.21724
Mullen SA, Marini C, Suls A, Mei D, Della Giustina E, Buti D et al (2011) Glucose transporter 1 deficiency as a treatable cause of myoclonic astatic epilepsy. Arch Neurol 68 9:1152–1155. https://doi.org/10.1001/archneurol.2011.102
Arsov T, Mullen SA, Rogers S, Phillips AM, Lawrence KM, Damiano JA et al (2012) Glucose transporter 1 deficiency in the idiopathic generalized epilepsies. Ann Neurol 72 5:807–815. https://doi.org/10.1002/ana.23702
Agostinelli S, Traverso M, Accorsi P, Beccaria F, Belcastro V, Capovilla G et al (2013) Early-onset absence epilepsy: SLC2A1 gene analysis and treatment evolution. Eur J Neurol 20 5:856–859. https://doi.org/10.1111/j.1468-1331.2012.03871
Larsen J, Johannesen KM, Ek J, Tang S, Marini C, Blichfeldt S et al (2015) The role of SLC2A1 mutations in myoclonic astatic epilepsy and absence epilepsy, and the estimated frequency of GLUT1 deficiency syndrome. Epilepsia 56(12):e203–e208. https://doi.org/10.1111/epi.13222
Leen WG, Wevers RA, Kamsteeg EJ, Scheffer H, Verbeek MM, Willemsen MA (2013) Cerebrospinal fluid analysis in the workup of GLUT1 deficiency syndrome: a systematic review. JAMA Neurol 70 11:1440–1444. https://doi.org/10.1001/jamaneurol.2013.3090
Klepper J, Scheffer H, Leiendecker B, Gertsen E, Binder S, Leferink M et al (2005) Seizure control and acceptance of the ketogenic diet in GLUT1 deficiency syndrome: a 2- to 5-year follow-up of 15 children enrolled prospectively. Neuropediatrics 36 5:302–308. https://doi.org/10.1055/s-2005-872843
Kass HR, Winesett SP, Bessone SK, Turner Z, Kossoff EH (2016) Use of dietary therapies amongst patients with GLUT1 deficiency syndrome. Seizure 35:83–87. https://doi.org/10.1016/j.seizure.2016.01.011
Ragona F, Matricardi S, Castellotti B, Patrini M, Freri E, Binelli S et al (2014) Refractory absence epilepsy and Glut1 deficiency syndrome: a new case report and literature review. Neuropediatrics 45 5:328–332. https://doi.org/10.1055/s-0034-1378130
Zorzi G, Castellotti B, Zibordi F, Gellera C, Nardocci N (2008) Paroxysmal movement disorders in GLUT1 deficiency syndrome. Neurology 71 2:146–148. https://doi.org/10.1212/01.wnl.0000316804.10020
Koch H, Weber YG (2018) The glucose transporter type 1 (Glut1) syndromes. Epilepsy Behav. https://doi.org/10.1016/j.yebeh.2018.06.010
De Giorgis V, Varesio C, Baldassari C, Piazza E, Olivotto S, Macasaet J et al (2016) Atypical manifestations in Glut1 deficiency syndrome. J Child Neurol 31 9:1174–1180. https://doi.org/10.1177/0883073816650033
Mullen SA, Suls A, De Jonghe P, Berkovic SF, Scheffer IE (2010) Absence epilepsies with widely variable onset are a key feature of familial GLUT1 deficiency. Neurology 75(5):432–440. https://doi.org/10.1212/WNL.0b013e3181eb58b4
Striano P, Weber YG, Toliat MR, Schubert J, Leu C, Chaimana R, Baulac S, Guerrero R, LeGuern E, Lehesjoki AE, Polvi A, Robbiano A, Serratosa JM, Guerrini R, Nürnberg P, Sander T, Zara F, Lerche H, Marini C; EPICURE Consortium (2012) GLUT1 mutations are a rare cause of familial idiopathic generalized epilepsy. Neurology 78(8):557–562. https://doi.org/10.1212/WNL.0b013e318247ff54
Verrotti A, D’Egidio C, Agostinelli S, Gobbi G (2012) Glut1 deficiency: when to suspect and how to diagnose? Eur J Paediatr Neurol 16(1):3–9. https://doi.org/10.1016/j.ejpn.2011.09.005 (Epub 2011 Oct 1. Review. PMID: 21962875)
Urbizu A, Cuenca-León E, Raspall-Chaure M, Gratacòs M, Conill J, Redecillas S, Roig-Quilis M, Macaya A (2010) Paroxysmal exercise-induced dyskinesia, writer's cramp, migraine with aura and absence epilepsy in twin brothers with a novel SLC2A1 missense mutation. J Neurol Sci 295(1–2):110–113. https://doi.org/10.1016/j.jns.2010.05.017
Liu Y, Bao X, Wang D, Fu N, Zhang X, Cao G, Song F, Wang S, Zhang Y, Qin J, Yang H, Engelstad K, De Vivo DC, Wu X (2012) Allelic variations of glut-1 deficiency syndrome: the chinese experience. Pediatr Neurol 47(1):30–34. https://doi.org/10.1016/j.pediatrneurol.2012.04.010
Schneider SA, Paisan-Ruiz C, Garcia-Gorostiaga I, Quinn NP, Weber YG, Lerche H, Hardy J, Bhatia KP (2009) GLUT1 gene mutations cause sporadic paroxysmal exercise-induced dyskinesias. Mov Disord 24(11):1684–1688. https://doi.org/10.1002/mds.22507
Wang D, Pascual JM, Yang H, Engelstad K, Jhung S, Sun RP, De Vivo DC (2005) Glut-1 deficiency syndrome: clinical, genetic, and therapeutic aspects. Ann Neurol 57(1):111–118. https://doi.org/10.1002/ana.20331
The authors are deeply grateful to: Drs Francesca Darra (Child Neuropsychiatry, University of Verona), Stefania Bergamoni (Azienda Ospedaliera Ospedale Niguarda Ca’ Granda, Milano), Monica Lodi (Centro Regionale per l’Epilessia, Asst Fatebenefratelli Sacco, Milano) and Carmen Bonino (Torino) for referring patients and to Dr. Sara Matricardi (Department of Neuropsychiatry, Children’s Hospital “G. Salesi”, Ospedali Riuniti, Ancona) for her help with statistical analysis.
The present work was supported by the Bando Cariplo 2010 per la ricerca Biomedica no. 2010.0759, the Italian Ministry of Health Ricerca Finalizzata Giovani Ricercatori 2010 (Project GR-2010-2304834 to JCD) and Ricerca Finalizzata Giovani Ricercatori 2016 (Project GR-2016-02363337 to JCD), and Grants from the Pierfranco and Luisa Mariani Foundation (to TG).
Conflicts of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
Electronic supplementary material
Below is the link to the electronic supplementary material.
About this article
Cite this article
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 266, 1439–1448 (2019). https://doi.org/10.1007/s00415-019-09280-6
- Glut1 deficiency
- Movement disorder
- Intellectual disability
- Developmental delay