Phenotypic Spectrum of Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS)
- 1.8k Downloads
Glut1 deficiency syndrome (Glut1 DS) was originally described in 1991 as a developmental encephalopathy characterized by infantile onset refractory epilepsy, cognitive impairment, and mixed motor abnormalities including spasticity, ataxia, and dystonia. The clinical condition is caused by impaired glucose transport across the blood brain barrier. The past 5 years have seen a dramatic expansion in the range of clinical syndromes that are recognized to occur with Glut1 DS. In particular, there has been greater recognition of milder phenotypes. Absence epilepsy and other idiopathic generalized epilepsy syndromes may occur with seizure onset in childhood or adulthood. A number of patients present predominantly with movement disorders, sometimes without any accompanying seizures. In particular, paroxysmal exertional dyskinesia is now a well-documented clinical feature that occurs in individuals with Glut1 DS. A clue to the diagnosis in patients with paroxysmal symptoms may be the triggering of episodes during fasting or exercise. Intellectual impairment may range from severe to very mild. Awareness of the broad range of potential clinical phenotypes associated with Glut1 DS will facilitate earlier diagnosis of this treatable neurologic condition. The ketogenic diet is the mainstay of treatment and nourishes the starving symptomatic brain during development.
KeywordsSeizures Intellectual disability Movement disorders Hypoglycorrhachia SLC2A1 mutations Glucose transporter
The authors are grateful for the support of the Colleen Giblin Foundation, the Will Foundation, Milestones for Children, and USPHS grant 5R01NS37949 (NINDS, dcd).
Toni S. Pearson declares no conflict of interest. Cigdem Akman declares no conflict of interest. Veronica J. Hinton declares no conflict of interest. Kristin Engelstad declares no conflict of interest. Darryl C. De Vivo declares no conflict of interest.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 3.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):703–9. doi: 10.1056/NEJM199109053251006.PubMedCrossRefGoogle Scholar
- 6.•• Rotstein M, Engelstad K, Yang H, Wang D, Levy B, Chung WK, et al. Glut1 deficiency: inheritance pattern determined by haploinsufficiency. Ann Neurol. 2010;68(6):955–8. doi: 10.1002/ana.22088. This article describes 2 patients with Glut1 DS as an autosomal recessive trait, demonstrating that the severity of the clinical syndrome was determined by the relative pathogenicity of the mutations and the resulting degree of haploinsufficiency. This illustrates an important principle that applies to all patients with Glut1DS.PubMedCrossRefGoogle Scholar
- 7.•• Leen WG, Klepper J, Verbeek MM, Leferink M, Hofste T, van Engelen BG, et al. Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder. Brain. 2010;133(Pt 3):655–70. doi: 10.1093/brain/awp336. This articles describes the genetic and clinical features of a series of 57 patients with Glut1 DS, outlining the broad range of possible clinical syndromes, including patients with seizure onset at an older age and patients without epilepsy.PubMedCrossRefGoogle Scholar
- 8.•• Yang H, Wang D, Engelstad K, Bagay L, Wei Y, Rotstein M, et al. Glut1 deficiency syndrome and erythrocyte glucose uptake assay. Ann Neurol. 2011;70(6):996–1005. doi: 10.1002/ana.22640. This study validated the erythrocyte glucose uptake assay as a confirmatory functional diagnostic test, and as a surrogate marker of residual Glut1 activity which correlates with clinical severity.PubMedCrossRefGoogle Scholar
- 11.• 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(9):1503–10. doi: 10.1111/j.1528-1167.2012.03592.x. This retrospective study details the epilepsy phenotypes and treatment response to the ketogenic diet and anticonvulsant mediations in 87 patients with Glut1 DS. Also found was a significant lag in diagnosis, with mean age at seizure onset of 8 months to mean age at diagnosis of 5 years.PubMedCrossRefGoogle Scholar
- 13.•• 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):432–40. doi: 10.1212/WNL.0b013e3181eb58b4. The authors describe the variety of epilepsy syndromes observed in 2 kindreds (12 individuals) with SLC2A1 mutations, including idiopathic generalized epilepsy with absence, myoclonic-astatic, and focal seizures. These represent milder forms of epilepsy than were previously associated with Glut1 DS.PubMedCrossRefGoogle Scholar
- 21.Schreckenberger M, Lange-Asschenfeldt C, Lochmann M, Mann K, Siessmeier T, Buchholz HG, et al. The thalamus as the generator and modulator of EEG alpha rhythm: a combined PET/EEG study with lorazepam challenge in humans. Neuroimage. 2004;22(2):637–44. doi: 10.1016/j.neuroimage.2004.01.047.PubMedCrossRefGoogle Scholar
- 38.•• Weber YG, Storch A, Wuttke TV, 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(6):2157–68. doi: 10.1172/JCI34438. The authors identified a SLC2A1 mutation in members of a family with paroxysmal exertional dyskinesia (PED), epilepsy, mild developmental delay, and hemolytic anemia, and demonstrated that a cation leak in the red cell membrane caused by the mutant Glut1 protein was the mechanism underlying the hemolytic anemia. They also identified SLC2A1 mutations in 2 other families with PED and epilepsy.PubMedGoogle Scholar
- 39.Bovi T, Fasano A, Juergenson I, Gellera C, Castellotti B, Fontana E, et al. Paroxysmal exercise-induced dyskinesia with self-limiting partial epilepsy: a novel GLUT-1 mutation with benign phenotype. Parkinsonism Relat Disord. 2011;17(6):479–81. doi: 10.1016/j.parkreldis.2011.03.015.PubMedCrossRefGoogle Scholar
- 41.Auburger G, Ratzlaff T, Lunkes A, Nelles HW, 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(1):90–4. doi: 10.1006/geno.1996.0013.PubMedCrossRefGoogle Scholar
- 45.Urbizu A, Cuenca-Leon E, Raspall-Chaure M, Gratacos M, Conill J, Redecillas S, et al. 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. 2010;295(1–2):110–3. doi: 10.1016/j.jns.2010.05.017.PubMedCrossRefGoogle Scholar
- 48.Klepper J, Scheffer H, Leiendecker B, Gertsen E, Binder S, Leferink M, et al. 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. 2005;36(5):302–8. doi: 10.1055/s-2005-872843.PubMedCrossRefGoogle Scholar
- 55.• Levy B, Wang D, Ullner PM, Engelstad K, Yang H, Nahum O, et al. Uncovering microdeletions in patients with severe Glut-1 deficiency syndrome using SNP oligonucleotide microarray analysis. Mol Genet Metab. 2010;100(2):129–35. doi: 10.1016/j.ymgme.2010.03.007. The authors describe 7 children with Glut-1 DS caused by microdeletions in the SLC2A1 region, who all had a severe clinical syndrome.PubMedCrossRefGoogle Scholar
- 61.Konrad D, Somwar R, Sweeney G, Yaworsky K, Hayashi M, Ramlal T, et al. The antihyperglycemic drug alpha-lipoic acid stimulates glucose uptake via both GLUT4 translocation and GLUT4 activation: potential role of p38 mitogen-activated protein kinase in GLUT4 activation. Diabetes. 2001;50(6):1464–71.PubMedCrossRefGoogle Scholar