Paroxysmal exercise-induced dyskinesia and epilepsy is due to mutations in SLC2A1, encoding the glucose transporter GLUT1

被引：234

作者：

Suls, Arvid ^{[2
,3
,4
]}

Dedeken, Peter ^{[1
]}

Goffin, Karolien ^{[5
]}

Van Esch, Hilde ^{[6
]}

Dupont, Patrick ^{[5
]}

Cassiman, David ^{[7
]}

Kempfle, Judith ^{[8
,9
]}

Wuttke, Thomas V. ^{[8
,9
]}

Weber, Yvonne ^{[8
]}

Lerche, Holger ^{[8
,9
]}

Afawi, Zaid ^{[10
]}

Vandenberghe, Wim ^{[1
]}

Korczyn, Amos D. ^{[11
]}

Berkovic, Samuel F. ^{[12
]}

Ekstein, Dana ^{[13
]}

Kivity, Sara ^{[14
]}

Ryvlin, Philippe ^{[15
]}

Claes, Lieve R. F. ^{[2
,3
,4
]}

Deprez, Liesbet ^{[2
,3
,4
]}

Maljevic, Snezana ^{[8
,9
]}

Vargas, Alberto ^{[8
,9
]}

Van Dyck, Tine ^{[2
,3
,4
]}

Goossens, Dirk ^{[4
,16
]}

Del-Favero, Jurgen ^{[4
,16
]}

Van Laere, Koen ^{[5
]}

De Jonghe, Peter ^{[2
,3
,4
,17
]}

Paesschen, WimVan ^{[1
]}

机构：

[1] Katholieke Univ Leuven, Univ Hosp Gasthuisberg, Dept Neurol, BE-3000 Louvain, Belgium

[2] VIB, Dept Mol Genet, Neurogenet Grp, Antwerp, Belgium

[3] Inst Born Bunge, Neurogenet Lab, Antwerp, Belgium

[4] Univ Antwerp, B-2020 Antwerp, Belgium

[5] Katholieke Univ Leuven, Univ Hosp Gasthuisberg, Div Nucl Med, BE-3000 Louvain, Belgium

[6] Katholieke Univ Leuven, Univ Hosp Gasthuisberg, Ctr Human Genet, BE-3000 Louvain, Belgium

[7] Katholieke Univ Leuven, Univ Hosp Gasthuisberg, Metab Ctr, BE-3000 Louvain, Belgium

[8] Univ Ulm, Neurol Clin, D-89069 Ulm, Germany

[9] Univ Ulm, Inst Appl Physiol, D-89069 Ulm, Germany

[10] Tel Aviv Sourasky Med Ctr, Dept Neurol, Jerusalem, Israel

[11] Tel Aviv Univ, Sieratzki Chair Neurol, Jerusalem, Israel

[12] Univ Melbourne Austin Hlth, Dept Med, Heidelberg West, Vic, Australia

[13] Hadassah Ein Kerem Univ Med Ctr, Dept Neurol, Jerusalem, Israel

[14] Schneider Childrens Med Ctr Israel, Epilepsy Unit, Petah Tiqwa, Israel

[15] Hospices Civils Lyon, INSERM, CTRS IDEE,U821, Dept Funct Neurol & Epileptol, Lyon, France

[16] VIB, Dept Mol Genet, Appl Mol Genom Grp, Antwerp, Belgium

[17] Univ Antwerp Hosp, Div Neurol, Antwerp, Belgium

来源：

BRAIN | 2008年 / 131卷

关键词：

GLUT1; paroxysmal dyskinesia; exercise-induced; GLUT1 deficiency syndrome; ketogenic diet;

D O I：

10.1093/brain/awn113

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

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.

引用

页码：1831 / 1844

页数：14

共 53 条

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