Leaky glucose transporters cause paroxysmal exertion-induced dyskinesia with haemolytic anaemia and epilepsy

Paroxysmal dyskinesias are characterized by attacks of involuntary movements classified as kinesiogenic, non-kinesiogenic or exertion-induced. The pathophysiology of these syndromes is still unclear. We describe a novel autosomal dominant syndrome in a three-generation family with four affected individuals presenting with a combination of paroxysmal exertion-induced dyskinesia, hemolytic anemia and epilepsy. The syndrome was characterized by extensive clinical, genetic and experimental studies. Three individuals suffer from attacks of involuntary movements with dystonic and choreoathetotic components after heavy workload since early childhood. In addition, the two sons of the index case show mild neuropsychological deficits, mild permanent motor problems and a focal epilepsy with myoclonic and atonic seizures with status epilepticus brought on by overnight fast. Affected individuals presented with decreased CSF glucose levels, hemolytic anemia, and increased intracellular sodium and decreased potassium concentrations in red blood cells, which showed an increased percentage of echinocytes.

In a candidate gene approach of SLC2A1 encoding the glucose transporter type 1 (Glut1) we identified a unique mutation in the transporter's pore region. Functional analysis in Xenopus laevis oocytes using ion-selective electrodes and uptake measurements revealed a cation leak in combination with a decreased rate of glucose uptake of the mutant transporter compared to the wild type as the crucial pathogenetic mechanism. We propose that the cation leak can be compensated under resting conditions by the Na/K pump and that the dyskinesias are caused by a local disruption of ionic homeostasis after periods of prolonged exercise when the decreased rate of glucose transport leads to an energy deficit in the respective brain region. The hemolytic anemia can be explained by a permanent cation leak of red blood cells, and the nutrition-dependent epilepsy by a decreased delivery of glucose across the blood brain barrier. The latter phenomenon is similar to symptoms of Glut1-deficiency syndrome, in which mutations of Glut1 cause a decreased glucose transport without affecting ion homeostasis.