Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Clin Invest
2008 Jun 01;1186:2157-68. doi: 10.1172/JCI34438.
Show Gene links
Show Anatomy links
GLUT1 mutations are a cause of paroxysmal exertion-induced dyskinesias and induce hemolytic anemia by a cation leak.
Weber YG
,
Storch A
,
Wuttke TV
,
Brockmann K
,
Kempfle J
,
Maljevic S
,
Margari L
,
Kamm C
,
Schneider SA
,
Huber SM
,
Pekrun A
,
Roebling R
,
Seebohm G
,
Koka S
,
Lang C
,
Kraft E
,
Blazevic D
,
Salvo-Vargas A
,
Fauler M
,
Mottaghy FM
,
Münchau A
,
Edwards MJ
,
Presicci A
,
Margari F
,
Gasser T
,
Lang F
,
Bhatia KP
,
Lehmann-Horn F
,
Lerche H
.
???displayArticle.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.
Auburger,
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.
1996, Pubmed
Auburger,
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.
1996,
Pubmed
Barry,
Liquid junction potentials and small cell effects in patch-clamp analysis.
1991,
Pubmed
Bentivoglio,
Phenotypic variability of DYT1-PTD: does the clinical spectrum include psychogenic dystonia?
2002,
Pubmed
Bhatia,
Familial (idiopathic) paroxysmal dyskinesias: an update.
2001,
Pubmed
Brecher,
Present status of spiculed red cells and their relationship to the discocyte-echinocyte transformation: a critical review.
1972,
Pubmed
Brockmann,
Autosomal dominant glut-1 deficiency syndrome and familial epilepsy.
2001,
Pubmed
,
Xenbase
Brown,
Control of respiration and ATP synthesis in mammalian mitochondria and cells.
1992,
Pubmed
Bruce,
Monovalent cation leaks in human red cells caused by single amino-acid substitutions in the transport domain of the band 3 chloride-bicarbonate exchanger, AE1.
2005,
Pubmed
,
Xenbase
Cannon,
Pathomechanisms in channelopathies of skeletal muscle and brain.
2006,
Pubmed
Danek,
Neuroacanthocytosis.
2005,
Pubmed
De Vivo,
Defective glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia, seizures, and developmental delay.
1991,
Pubmed
DeLong,
Circuits and circuit disorders of the basal ganglia.
2007,
Pubmed
Du,
Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder.
2005,
Pubmed
,
Xenbase
Feinberg,
Diagnostic tests for choreoacanthocytosis.
1991,
Pubmed
Friedman,
Atypical GLUT1 deficiency with prominent movement disorder responsive to ketogenic diet.
2006,
Pubmed
Guerrini,
Autosomal recessive rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp: delineation of the syndrome and gene mapping to chromosome 16p12-11.2.
1999,
Pubmed
Guizouarn,
Point mutations involved in red cell stomatocytosis convert the electroneutral anion exchanger 1 to a nonselective cation conductance.
2007,
Pubmed
,
Xenbase
Hruz,
Cysteine-scanning mutagenesis of transmembrane segment 7 of the GLUT1 glucose transporter.
1999,
Pubmed
,
Xenbase
Hruz,
Structural analysis of the GLUT1 facilitative glucose transporter (review).
2001,
Pubmed
Kamm,
New family with paroxysmal exercise-induced dystonia and epilepsy.
2007,
Pubmed
Kraft,
T2*-weighted MRI differentiates multiple system atrophy from Parkinson's disease.
2002,
Pubmed
Lang,
Mechanisms of suicidal erythrocyte death.
2005,
Pubmed
Lee,
Movement disorders following lesions of the thalamus or subthalamic region.
1994,
Pubmed
Lee,
The gene for paroxysmal non-kinesigenic dyskinesia encodes an enzyme in a stress response pathway.
2004,
Pubmed
Lerche,
Ion channel defects in idiopathic epilepsies.
2005,
Pubmed
Maher,
Glucose transporter proteins in brain.
1994,
Pubmed
Margari,
Familial paroxysmal exercise-induced dyskinesia and benign epilepsy: a clinical and neurophysiological study of an uncommon disorder.
2000,
Pubmed
Mueckler,
Analysis of transmembrane segment 8 of the GLUT1 glucose transporter by cysteine-scanning mutagenesis and substituted cysteine accessibility.
2004,
Pubmed
,
Xenbase
Münchau,
A new family with paroxysmal exercise induced dystonia and migraine: a clinical and genetic study.
2000,
Pubmed
Overweg-Plandsoen,
GLUT-1 deficiency without epilepsy--an exceptional case.
2003,
Pubmed
Pulsinelli,
Selective neuronal vulnerability: morphological and molecular characteristics.
1985,
Pubmed
Rainier,
Myofibrillogenesis regulator 1 gene mutations cause paroxysmal dystonic choreoathetosis.
2004,
Pubmed
Redman,
Effect of phosphatidylserine on the shape of McLeod red cell acanthocytes.
1989,
Pubmed
Salas-Burgos,
Predicting the three-dimensional structure of the human facilitative glucose transporter glut1 by a novel evolutionary homology strategy: insights on the molecular mechanism of substrate migration, and binding sites for glucose and inhibitory molecules.
2004,
Pubmed
Schrag,
The syndrome of fixed dystonia: an evaluation of 103 patients.
2004,
Pubmed
Seidner,
GLUT-1 deficiency syndrome caused by haploinsufficiency of the blood-brain barrier hexose carrier.
1998,
Pubmed
Storch,
Testing for acanthocytosis A prospective reader-blinded study in movement disorder patients.
2005,
Pubmed
Szepetowski,
Familial infantile convulsions and paroxysmal choreoathetosis: a new neurological syndrome linked to the pericentromeric region of human chromosome 16.
1997,
Pubmed
Wang,
Glut-1 deficiency syndrome: clinical, genetic, and therapeutic aspects.
2005,
Pubmed
Weber,
Benign familial infantile convulsions: linkage to chromosome 16p12-q12 in 14 families.
2004,
Pubmed
