GLUT1 mutations are a cause of paroxysmal exertion-induced dyskinesias and induce hemolytic anemia by a cation leak.
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.
Weber
Yvonne G
YG
Neurologische Klinik and Institut für Anatomie und Zellbiologie, Universität Ulm, Ulm, Germany.
Storch
Alexander
A
Wuttke
Thomas V
TV
Brockmann
Knut
K
Kempfle
Judith
J
Maljevic
Snezana
S
Margari
Lucia
L
Kamm
Christoph
C
Schneider
Susanne A
SA
Huber
Stephan M
SM
Pekrun
Arnulf
A
Roebling
Robert
R
Seebohm
Guiscard
G
Koka
Saisudha
S
Lang
Camelia
C
Kraft
Eduard
E
Blazevic
Dragica
D
Salvo-Vargas
Alberto
A
Fauler
Michael
M
Mottaghy
Felix M
FM
Münchau
Alexander
A
Edwards
Mark J
MJ
Presicci
Anna
A
Margari
Francesco
F
Gasser
Thomas
T
Lang
Florian
F
Bhatia
Kailash P
KP
Lehmann-Horn
Frank
F
Lerche
Holger
H
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
D002412:Cations; D051272:Glucose Transporter Type 1; C495677:SLC2A1 protein, human; D005947:Glucose