title: GLUT1 mutations are a cause of paroxysmal exertion-induced dyskinesias and induce hemolytic anemia by a cation leak.
abstract: Paroxysmal dyskinesias are episodic movement disorders that can be inherited or are sporadic in nature. The pathophysiology underlying these disorders remains largely unknown but may involve disrupted ion homeostasis due to defects in cell-surface channels or nutrient transporters. In this study, we describe a family with paroxysmal exertion-induced dyskinesia (PED) over 3 generations. Their PED was accompanied by epilepsy, mild developmental delay, reduced CSF glucose levels, hemolytic anemia with echinocytosis, and altered erythrocyte ion concentrations. Using a candidate gene approach, we identified a causative deletion of 4 highly conserved amino acids (Q282_S285del) in the pore region of the glucose transporter 1 (GLUT1). Functional studies in Xenopus oocytes and human erythrocytes revealed that this mutation decreased glucose transport and caused a cation leak that alters intracellular concentrations of sodium, potassium, and calcium. We screened 4 additional families, in which PED is combined with epilepsy, developmental delay, or migraine, but not with hemolysis or echinocytosis, and identified 2 additional GLUT1 mutations (A275T, G314S) that decreased glucose transport but did not affect cation permeability. Combining these data with brain imaging studies, we propose that the dyskinesias result from an exertion-induced energy deficit that may cause episodic dysfunction of the basal ganglia, and that the hemolysis with echinocytosis may result from alterations in intracellular electrolytes caused by a cation leak through mutant GLUT1.
authors.affiliation: Neurologische Klinik and Institut für Anatomie und Zellbiologie, Universität Ulm, Ulm, Germany.
authors.forename: Yvonne G
authors.initials: YG
authors.lastname: Weber
authors.forename: Alexander
authors.initials: A
authors.lastname: Storch
authors.forename: Thomas V
authors.initials: TV
authors.lastname: Wuttke
authors.forename: Knut
authors.initials: K
authors.lastname: Brockmann
authors.forename: Judith
authors.initials: J
authors.lastname: Kempfle
authors.forename: Snezana
authors.initials: S
authors.lastname: Maljevic
authors.forename: Lucia
authors.initials: L
authors.lastname: Margari
authors.forename: Christoph
authors.initials: C
authors.lastname: Kamm
authors.forename: Susanne A
authors.initials: SA
authors.lastname: Schneider
authors.forename: Stephan M
authors.initials: SM
authors.lastname: Huber
authors.forename: Arnulf
authors.initials: A
authors.lastname: Pekrun
authors.forename: Robert
authors.initials: R
authors.lastname: Roebling
authors.forename: Guiscard
authors.initials: G
authors.lastname: Seebohm
authors.forename: Saisudha
authors.initials: S
authors.lastname: Koka
authors.forename: Camelia
authors.initials: C
authors.lastname: Lang
authors.forename: Eduard
authors.initials: E
authors.lastname: Kraft
authors.forename: Dragica
authors.initials: D
authors.lastname: Blazevic
authors.forename: Alberto
authors.initials: A
authors.lastname: Salvo-Vargas
authors.forename: Michael
authors.initials: M
authors.lastname: Fauler
authors.forename: Felix M
authors.initials: FM
authors.lastname: Mottaghy
authors.forename: Alexander
authors.initials: A
authors.lastname: Münchau
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Edwards
authors.forename: Anna
authors.initials: A
authors.lastname: Presicci
authors.forename: Francesco
authors.initials: F
authors.lastname: Margari
authors.forename: Thomas
authors.initials: T
authors.lastname: Gasser
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
authors.forename: Kailash P
authors.initials: KP
authors.lastname: Bhatia
authors.forename: Frank
authors.initials: F
authors.lastname: Lehmann-Horn
authors.forename: Holger
authors.initials: H
authors.lastname: Lerche
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000743:Anemia, Hemolytic / Q000209:etiology* / Q000235:genetics*; D000818:Animals; D002412:Cations; D002819:Chorea / Q000235:genetics* / Q000473:pathology; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D008297:Male; D008954:Models, Biological; D008969:Molecular Sequence Data; D005082:Physical Exertion; D014981:Xenopus
chemical_list: D002412:Cations; D051272:Glucose Transporter Type 1; C495677:SLC2A1 protein, human; D005947:Glucose