title: Paroxysmal exercise-induced dyskinesia and epilepsy is due to mutations in SLC2A1, encoding the glucose transporter GLUT1.
abstract: 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.
authors.affiliation: Neurogenetics Group,VIB Department of Molecular Genetics, University of Antwerp, Antwerpen, Belgium.
authors.forename: Arvid
authors.initials: A
authors.lastname: Suls
authors.forename: Peter
authors.initials: P
authors.lastname: Dedeken
authors.forename: Karolien
authors.initials: K
authors.lastname: Goffin
authors.forename: Hilde
authors.initials: H
authors.lastname: Van Esch
authors.forename: Patrick
authors.initials: P
authors.lastname: Dupont
authors.forename: David
authors.initials: D
authors.lastname: Cassiman
authors.forename: Judith
authors.initials: J
authors.lastname: Kempfle
authors.forename: Thomas V
authors.initials: TV
authors.lastname: Wuttke
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Weber
authors.forename: Holger
authors.initials: H
authors.lastname: Lerche
authors.forename: Zaid
authors.initials: Z
authors.lastname: Afawi
authors.forename: Wim
authors.initials: W
authors.lastname: Vandenberghe
authors.forename: Amos D
authors.initials: AD
authors.lastname: Korczyn
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Berkovic
authors.forename: Dana
authors.initials: D
authors.lastname: Ekstein
authors.forename: Sara
authors.initials: S
authors.lastname: Kivity
authors.forename: Philippe
authors.initials: P
authors.lastname: Ryvlin
authors.forename: Lieve R F
authors.initials: LR
authors.lastname: Claes
authors.forename: Liesbet
authors.initials: L
authors.lastname: Deprez
authors.forename: Snezana
authors.initials: S
authors.lastname: Maljevic
authors.forename: Alberto
authors.initials: A
authors.lastname: Vargas
authors.forename: Tine
authors.initials: T
authors.lastname: Van Dyck
authors.forename: Dirk
authors.initials: D
authors.lastname: Goossens
authors.forename: Jurgen
authors.initials: J
authors.lastname: Del-Favero
authors.forename: Koen
authors.initials: K
authors.lastname: Van Laere
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
authors.forename: Wim
authors.initials: W
authors.lastname: Van Paesschen
mesh_terms: 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
chemical_list: D001786:Blood Glucose; D051272:Glucose Transporter Type 1; C495677:SLC2A1 protein, human; D005947:Glucose