GLUT1 mutations are a cause of paroxysmal exertion-induced dyskinesias and induce hemolytic anemia by a cation leak.
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GLUT1 mutations are a cause of paroxysmal exertion-induced dyskinesias and induce hemolytic anemia by a cation leak. / Weber, Yvonne G; Storch, Alexander; Wuttke, Thomas V; Brockmann, Knut; Kempfle, Judith; Maljevic, Snezana; Margari, Lucia; Kamm, Christoph; Schneider, Susanne A; Huber, Stephan M; Pekrun, Arnulf; Roebling, Robert; Seebohm, Guiscard; Koka, Saisudha; Lang, Camelia; Kraft, Eduard; Blazevic, Dragica; Salvo-Vargas, Alberto; Fauler, Michael; Mottaghy, Felix M; Münchau, Alexander; Edwards, Mark J; Presicci, Anna; Margari, Francesco; Gasser, Thomas; Lang, Florian; Bhatia, Kailash P; Lehmann-Horn, Frank; Lerche, Holger.
in: J CLIN INVEST, Jahrgang 118, Nr. 6, 6, 2008, S. 2157-2168.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - GLUT1 mutations are a cause of paroxysmal exertion-induced dyskinesias and induce hemolytic anemia by a cation leak.
AU - Weber, Yvonne G
AU - Storch, Alexander
AU - Wuttke, Thomas V
AU - Brockmann, Knut
AU - Kempfle, Judith
AU - Maljevic, Snezana
AU - Margari, Lucia
AU - Kamm, Christoph
AU - Schneider, Susanne A
AU - Huber, Stephan M
AU - Pekrun, Arnulf
AU - Roebling, Robert
AU - Seebohm, Guiscard
AU - Koka, Saisudha
AU - Lang, Camelia
AU - Kraft, Eduard
AU - Blazevic, Dragica
AU - Salvo-Vargas, Alberto
AU - Fauler, Michael
AU - Mottaghy, Felix M
AU - Münchau, Alexander
AU - Edwards, Mark J
AU - Presicci, Anna
AU - Margari, Francesco
AU - Gasser, Thomas
AU - Lang, Florian
AU - Bhatia, Kailash P
AU - Lehmann-Horn, Frank
AU - Lerche, Holger
PY - 2008
Y1 - 2008
N2 - 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.
AB - 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.
M3 - SCORING: Zeitschriftenaufsatz
VL - 118
SP - 2157
EP - 2168
JO - J CLIN INVEST
JF - J CLIN INVEST
SN - 0021-9738
IS - 6
M1 - 6
ER -
