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

ABSTRACT: 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 ?2 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.

SUBMITTER: Sampedro Castaneda M

PROVIDER: S-EPMC6262219 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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

Sampedro Castañeda Marisol M Zanoteli Edmar E Scalco Renata S RS Scaramuzzi Vinicius V Marques Caldas Vitor V Conti Reed Umbertina U da Silva Andre Macedo Serafim AMS O'Callaghan Benjamin B Phadke Rahul R Bugiardini Enrico E Sud Richa R McCall Samuel S Hanna Michael G MG Poulsen Hanne H Männikkö Roope R Matthews Emma E

Brain : a journal of neurology 20181201 12

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 k ...[more]

PMID: 30423015

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Project description:Hypokalaemic periodic paralysis is typically associated with mutations of voltage sensor residues in calcium or sodium channels of skeletal muscle. To date, causative sodium channel mutations have been studied only for the two outermost arginine residues in S4 voltage sensor segments of domains I to III. These mutations produce depolarization of skeletal muscle fibres in response to reduced extracellular potassium, owing to an inward cation-selective gating pore current activated by hyperpolarization. Here, we describe mutations of the third arginine, R3, in the domain III voltage sensor i.e. an R1135H mutation which was found in two patients in separate families and a novel R1135C mutation identified in a third patient in another family. Muscle fibres from a patient harbouring the R1135H mutation showed increased depolarization tendency at normal and reduced extracellular potassium compatible with the diagnosis. Additionally, amplitude and rise time of action potentials were reduced compared with controls, even for holding potentials at which all NaV1.4 are fully recovered from inactivation. These findings may be because of an outward omega current activated at positive potentials. Expression of R1135H/C in mammalian cells indicates further gating defects that include significantly enhanced entry into inactivation and prolonged recovery that may additionally contribute to action potential inhibition at the physiological resting potential. After S4 immobilization in the outward position, mutant channels produce an inward omega current that most likely depolarizes the resting potential and produces the hypokalaemia-induced weakness. Gating current recordings reveal that mutations at R3 inhibit S4 deactivation before recovery, and molecular dynamics simulations suggest that this defect is caused by disrupted interactions of domain III S2 countercharges with S4 arginines R2 to R4 during repolarization of the membrane. This work reveals a novel mechanism of disrupted S4 translocation for hypokalaemic periodic paralysis mutations at arginine residues located below the gating pore constriction of the voltage sensor module.

Project description:Familial hypokalaemic periodic paralysis is a rare skeletal muscle disease caused by the dysregulation of sarcolemmal excitability. Hypokalaemic periodic paralysis is characterized by repeated episodes of paralytic attacks with hypokalaemia, and several variants in CACNA1S coding for CaV1.1 and SCN4A coding for NaV1.4 have been established as causative mutations. Most of the mutations are substitutions to a non-charged residue, from the positively charged arginine (R) in transmembrane segment 4 (S4) of a voltage sensor in either CaV1.1 or NaV1.4. Mutant channels have aberrant leak currents called 'gating pore currents', and the widely accepted consensus is that this current is the essential pathological mechanism that produces susceptibility to anomalous depolarization and failure of muscle excitability during a paralytic attack. Here, we have identified five hypokalaemic periodic paralysis cases from two different ethnic backgrounds, Japanese and French, with charge-preserving substitutions in S4 from arginine, R, to lysine, K. An R to K substitution has not previously been reported for any other hypokalaemic periodic paralysis families. One case is R219K in NaV1.4, which is located at the first charge in S4 of Domain I. The other four cases all have R897K in CaV1.1, which is located at the first charge in S4 of Domain III. Gating pore currents were not detected in expression studies of CaV1.1-R897K. NaV1.4-R219K mutant channels revealed a distinct, but small, gating pore current. Simulation studies indicated that the small-amplitude gating pore current conducted by NaV1.4-R219K is not likely to be sufficient to be a risk factor for depolarization-induced paralytic attacks. Our rare cases with typical hypokalaemic periodic paralysis phenotypes do not fit the canonical view that the essential defect in hypokalaemic periodic paralysis mutant channels is the gating pore current and raise the possibility that hypokalaemic periodic paralysis pathogenesis might be heterogeneous and diverse.

Project description:BackgroundAcute hypokalaemic paralysis is characterised by acute flaccid muscle weakness and has a complex aetiological spectrum. Herein we report, for the first time, a case of unilateral adrenal hyperplasia accompanied by hypokalaemic periodic paralysis type I resulting from a novel dominant mutation in CACNA1S. We present the clinical features and prognosis after adrenalectomy in this case.Case presentationA 43-year-old Han Chinese male presented with severe hypokalaemic paralysis that remitted after taking oral potassium. The patient had suffered from periodic attacks of hypokalaemic paralysis for more than 20 years. A computed tomography (CT) scan of the abdomen showed a nodular mass on the left adrenal gland, although laboratory examination revealed the patient had not developed primary aldosteronism. The patient underwent a left adrenalectomy 4 days after admission, and the pathological examination further confirmed a 1.1 cm benign nodule at the periphery of the adrenal gland. Three months after the adrenalectomy, a paralytic attack recurred and the patient asked for assistance from the Department of Medical Genetics. His family history showed that two uncles, one brother, and a nephew also had a history of periodic paralysis, although their symptoms were milder. The patient's CACNA1S and SCN4A genes were sequenced, and a novel missense mutation, c.1582C > T (p.Arg528Cys), in CACNA1S was detected. Detection of the mutation in five adult male family members, including three with periodic paralysis and two with no history of the disease, indicated that this mutation caused hypokalaemic periodic paralysis type I in his family. Follow-up 2 years after adrenalectomy showed that the serum potassium concentration was increased between paralyses and the number and severity of paralytic attacks were significantly decreased.ConclusionWe identified a novel dominant mutation, c.1582C > T (p.Arg528Cys), in CACNA1S that causes hypokalaemic periodic paralysis. The therapeutic effect of adrenalectomy indicated that unilateral adrenal hyperplasia might make paralytic attacks more serious and more frequent by decreasing serum potassium. This finding suggests that the surgical removal of hyperplastic tissues might relieve the symptoms of patients with severe hypokalaemic paralysis caused by other incurable diseases, even if the adrenal lesion does not cause primary aldosteronism.

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

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

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