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: Arvid Suls, Peter Dedeken, Karolien Goffin, Hilde Van Esch, Patrick Dupont, David Cassiman, Judith Kempfle, Thomas V Wuttke, Yvonne Weber, Holger Lerche, Zaid Afawi, Wim Vandenberghe, Amos D Korczyn, Samuel F Berkovic, Dana Ekstein, Sara Kivity, Philippe Ryvlin, Lieve R F Claes, Liesbet Deprez, Snezana Maljevic, Alberto Vargas, Tine Van Dyck, Dirk Goossens, Jurgen Del-Favero, Koen Van Laere, Peter De Jonghe, Wim Van Paesschen
• Journal: Brain : a journal of neurology (Brain) Vol. 131 Issue Pt 7 Pg. 1831-44 (Jul 2008) ISSN: 1460-2156 [Electronic] England
• PMID: 18577546 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Glucose
• Glucose Transporter Type 1
• SLC2A1 protein, human
• Glucose

Topics

• Adolescent
• Adult
• Blood Glucose (metabolism)
• Chorea (complications, diagnostic imaging, diet therapy, genetics)
• Chromosome Mapping
• DNA Mutational Analysis (methods)
• Electroencephalography
• Epilepsy (complications, diagnostic imaging, diet therapy, genetics)
• Exercise
• Female
• Glucose (cerebrospinal fluid)
• Glucose Transporter Type 1 (genetics)
• Humans
• Lod Score
• Magnetic Resonance Imaging
• Male
• Middle Aged
• Mutation
• Pedigree
• Phenotype
• Positron-Emission Tomography