Brain Advance Access first published online on June 24, 2008
This version published online on July 1, 2008
Brain, doi:10.1093/brain/awn113
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Paroxysmal exercise-induced dyskinesia and epilepsy is due to mutations in SLC2A1, encoding the glucose transporter GLUT1
1Neurogenetics Group, VIB Department of Molecular Genetics, 2Laboratory of Neurogenetics, Institute Born-Bunge, 3University of Antwerp, Antwerpen, 4Department of Neurology, 5Division of Nuclear Medicine, 6Center for Human Genetics, 7Metabolic Center, University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Leuven, Belgium, 8Neurological Clinic, 9Institute of Applied Physiology, University of Ulm, Germany, 10Department of Neurology, Tel Aviv Sourasky Medical Center, 11Sieratzki Chair of Neurology, Tel Aviv University, Jerusalem, Israel, 12Department of Medicine, University of Melbourne (Austin Health), Heidelberg West, Australia, 13Department of Neurology, Hadassah Ein Kerem University Medical Center, Jerusalem, Israel, 14Epilepsy Unit, Schneider Children's Medical Center of Israel, Petach Tikvah, Israel, 15Department of Functional Neurology and Epileptology, CTRS-INSERM IDEE, INSERM U821, Hospices Civils de Lyon and Université Claude Bernard Lyon1, Lyon, France, 16VIB Department of Molecular Genetics, Applied Molecular Genomics Group and 17Division of Neurology, University Hospital of Antwerp, Antwerpen, Belgium
Correspondence to:
Prof. Dr Wim Van Paesschen, Department of Neurology, University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Herestraat 49, BE-3000 Leuven, Belgium E-mail: wim.vanpaesschen{at}uz.kuleuven.ac.be
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.
Key Words: GLUT1; paroxysmal dyskinesia; exercise-induced; GLUT1 deficiency syndrome; ketogenic diet
Abbreviations: AED, antiepileptic drugs; FDG, 2-[18F]Fluoro-2-deoxy-D-glucose; GLUT1, facilitative glucose transporter type 1; GLUT1 DS, GLUT1 deficiency syndrome; LOD, logarithms of odds; MNI, Montreal Neurological Institute; OMG, 3-O-methyl-D-glucose; PED, paroxysmal exercise-induced dyskinesias; PHD, paroxysmal hypnogenic dyskinesias; PKD, paroxysmal kinesigenic dyskinesias; PNKD, paroxysmal non-kinesigenic dyskinesias; SPM, statistical parametric mapping
Received January 31, 2008. Revised April 4, 2008. Accepted May 12, 2008.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  W. G. Leen, J. Klepper, M. M. Verbeek, M. Leferink, T. Hofste, B. G. van Engelen, R. A. Wevers, T. Arthur, N. Bahi-Buisson, D. Ballhausen, et al. Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder Brain, February 2, 2010; (2010): awp336v1 - awp336. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Perez-Duenas, C. Prior, Q. Ma, E. Fernandez-Alvarez, X. Setoain, R. Artuch, and J. M. Pascual Childhood Chorea With Cerebral Hypotrophy: A Treatable GLUT1 Energy Failure Syndrome Arch Neurol, November 1, 2009; 66(11): 1410 - 1414. [Abstract] [Full Text] [PDF]
|
|