Paroxysmal exercise-induced dyskinesia and epilepsy is due to mutations in SLC2A1, encoding the glucose transporter GLUT1.
Paroxysmal exercise-induced dyskinesia (PED) can occur in isolation or in association with epilepsy, but the genetic causes and pathophysiological mechanisms are still poorly understood. We performed a clinical evaluation and genetic analysis in a five-generation family with co-occurrence of PED and epilepsy (n = 39), suggesting that this combination represents a clinical entity. Based on a whole genome linkage analysis we screened SLC2A1, encoding the glucose transporter of the blood-brain-barrier, GLUT1 and identified heterozygous missense and frameshift mutations segregating in this and three other nuclear families with a similar phenotype. PED was characterized by choreoathetosis, dystonia or both, affecting mainly the legs. Predominant epileptic seizure types were primary generalized. A median CSF/blood glucose ratio of 0.52 (normal >0.60) in the patients and a reduced glucose uptake by mutated transporters compared with the wild-type as determined in Xenopus oocytes confirmed a pathogenic role of these mutations. Functional imaging studies implicated alterations in glucose metabolism in the corticostriate pathways in the pathophysiology of PED and in the frontal lobe cortex in the pathophysiology of epileptic seizures. Three patients were successfully treated with a ketogenic diet. In conclusion, co-occurring PED and epilepsy can be due to autosomal dominant heterozygous SLC2A1 mutations, expanding the phenotypic spectrum associated with GLUT1 deficiency and providing a potential new treatment option for this clinical syndrome.
Suls
Arvid
A
Neurogenetics Group,VIB Department of Molecular Genetics, University of Antwerp, Antwerpen, Belgium.
Dedeken
Peter
P
Goffin
Karolien
K
Van Esch
Hilde
H
Dupont
Patrick
P
Cassiman
David
D
Kempfle
Judith
J
Wuttke
Thomas V
TV
Weber
Yvonne
Y
Lerche
Holger
H
Afawi
Zaid
Z
Vandenberghe
Wim
W
Korczyn
Amos D
AD
Berkovic
Samuel F
SF
Ekstein
Dana
D
Kivity
Sara
S
Ryvlin
Philippe
P
Claes
Lieve R F
LR
Deprez
Liesbet
L
Maljevic
Snezana
S
Vargas
Alberto
A
Van Dyck
Tine
T
Goossens
Dirk
D
Del-Favero
Jurgen
J
Van Laere
Koen
K
De Jonghe
Peter
P
Van Paesschen
Wim
W
D000293:Adolescent; D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D002819:Chorea / Q000150:complications / Q000000981:diagnostic imaging / Q000178:diet therapy / Q000235:genetics*; D002874:Chromosome Mapping; D004252:DNA Mutational Analysis / Q000379:methods; D004569:Electroencephalography; D004827:Epilepsy / Q000150:complications / Q000000981:diagnostic imaging / Q000178:diet therapy / Q000235:genetics*; D015444:Exercise; D005260:Female; D005947:Glucose / Q000134:cerebrospinal fluid; D051272:Glucose Transporter Type 1 / Q000235:genetics*; D006801:Humans; D008126:Lod Score; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D049268:Positron-Emission Tomography
D001786:Blood Glucose; D051272:Glucose Transporter Type 1; C495677:SLC2A1 protein, human; D005947:Glucose