TY - JOUR
T1 - A novel ATP1A2 mutation in a patient with hypokalaemic periodic paralysis and CNS symptoms
AU - Sampedro Castañeda, Marisol
AU - Zanoteli, Edmar
AU - Scalco, Renata S.
AU - Scaramuzzi, Vinicius
AU - Marques Caldas, Vitor
AU - Conti Reed, Umbertina
AU - da Silva, Andre Macedo Serafim
AU - O'Callaghan, Benjamin
AU - Phadke, Rahul
AU - Bugiardini, Enrico
AU - Sud, Richa
AU - McCall, Samuel
AU - Hanna, Michael G.
AU - Poulsen, Hanne
AU - Männikkö, Roope
AU - Matthews, Emma
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
KW - Hypokalaemic periodic paralysis
KW - Na /K -ATPase
KW - Na /K -pump
UR - http://www.scopus.com/inward/record.url?scp=85057521191&partnerID=8YFLogxK
U2 - 10.1093/brain/awy283
DO - 10.1093/brain/awy283
M3 - Journal article
C2 - 30423015
AN - SCOPUS:85057521191
SN - 0006-8950
VL - 141
SP - 3308
EP - 3318
JO - Brain : a journal of neurology
JF - Brain : a journal of neurology
IS - 12
ER -