A novel ATP1A2 mutation in a patient with hypokalaemic periodic paralysis and CNS symptoms

Marisol Sampedro Castañeda, Edmar Zanoteli, Renata S. Scalco, Vinicius Scaramuzzi, Vitor Marques Caldas, Umbertina Conti Reed, Andre Macedo Serafim da Silva, Benjamin O'Callaghan, Rahul Phadke, Enrico Bugiardini, Richa Sud, Samuel McCall, Michael G. Hanna, Hanne Poulsen, Roope Männikkö, Emma Matthews

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Hypokalaemic periodic paralysis is a rare genetic neuromuscular disease characterized by episodes of skeletal muscle paralysis associated with low serum potassium. Muscle fibre inexcitability during attacks of paralysis is due to an aberrant depolarizing leak current through mutant voltage sensing domains of either the sarcolemmal voltage-gated calcium or sodium channel. We report a child with hypokalaemic periodic paralysis and CNS involvement, including seizures, but without mutations in the known periodic paralysis genes. We identified a novel heterozygous de novo missense mutation in the ATP1A2 gene encoding the a2 subunit of the Na +/K +-ATPase that is abundantly expressed in skeletal muscle and in brain astrocytes. Pump activity is crucial for Na + and K + homeostasis following sustained muscle or neuronal activity and its dysfunction is linked to the CNS disorders hemiplegic migraine and alternating hemiplegia of childhood, but muscle dysfunction has not been reported. Electrophysiological measurements of mutant pump activity in Xenopus oocytes revealed lower turnover rates in physiological extracellular K + and an anomalous inward leak current in hypokalaemic conditions, predicted to lead to muscle depolarization. Our data provide important evidence supporting a leak current as the major pathomechanism underlying hypokalaemic periodic paralysis and indicate ATP1A2 as a new hypokalaemic periodic paralysis gene.

TidsskriftBrain : a journal of neurology
Sider (fra-til)3308-3318
Antal sider11
StatusUdgivet - 1 dec. 2018


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