Medicine (Austin & Northern Health) - Research Publications

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Author: Berkovic, Samuel × Start date: 2007 × End date: 2009 ×

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    Paroxysmal exercise-induced dyskinesia and epilepsy is due to mutations in SLC2A1, encoding the glucose transporter GLUT1
    Suls, A ; Dedeken, P ; Goffin, K ; Van Esch, H ; Dupont, P ; Cassiman, D ; Kempfle, J ; Wuttke, TV ; Weber, Y ; Lerche, H ; Afawi, Z ; Vandenberghe, W ; Korczyn, AD ; Berkovic, SF ; Ekstein, D ; Kivity, S ; Ryvlin, P ; Claes, LRF ; Deprez, L ; Maljevic, S ; Vargas, A ; Van Dyck, T ; Goossens, D ; Del-Favero, J ; Van Laere, K ; De Jonghe, P ; Paesschen, W (OXFORD UNIV PRESS, 2008-07)
    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.
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    Reduced cortical inhibition in a mouse model of familial childhood absence epilepsy
    Tan, HO ; Reid, CA ; Single, FN ; Davies, PJ ; Chiu, C ; Murphy, S ; Clarke, AL ; Dibbens, L ; Krestel, H ; Mulley, JC ; others, (National Acad Sciences, 2007)
    Mutations in the GABA(A) receptor gamma2 subunit are associated with childhood absence epilepsy and febrile seizures. To understand better the molecular basis of absence epilepsy in man, we developed a mouse model harboring a gamma2 subunit point mutation (R43Q) found in a large Australian family. Mice heterozygous for the mutation demonstrated behavioral arrest associated with 6-to 7-Hz spike-and-wave discharges, which are blocked by ethosuximide, a first-line treatment for absence epilepsy in man. Seizures in the mouse showed an abrupt onset at around age 20 days corresponding to the childhood nature of this disease. Reduced cell surface expression of gamma2(R43Q) was seen in heterozygous mice in the absence of any change in alpha1 subunit surface expression, ruling out a dominant-negative effect. GABA(A)-mediated synaptic currents recorded from cortical pyramidal neurons revealed a small but significant reduction that was not seen in the reticular or ventrobasal thalamic nuclei. We hypothesize that a subtle reduction in cortical inhibition underlies childhood absence epilepsy seen in humans harboring the R43Q mutation.