Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.6.1.3 (ATPase)
 65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In Japan, more than 60% of hypokalemic periodic paralysis is thyrotoxic instead of familial type frequently experienced in Caucasian countries. The pathogenesis of familial hypokalemic periodic paralysis (FHPP) has been elucidated to be due to the mutation of one of the genes in either Ca(CACN1AS), Na(SCN4A) or K channel(KCNE3). Clinical features of thyrotoxic periodic paralysis (TPP) is very similar to that of FHPP and rigorous attempts have been devoted to the search of the gene mutation of ion channels in TPP. To date, however, no such an attempt has been successful except for the findings of SNiPs in those ion channel genes or in the vicinity of TRE of CACN1AS. Those SNiPs may provide a risk to the attack of TPP. In TPP, we and others reported that the serum insulin level tremendously elevated prior to the attack of paralysis. There were clinical evidences indicating that hypokalemic periodic paralysis is caused by the depolarization block of muscle cell membrane instead of hyperpolarization block once assumed previously. Otsuka reported that insulin can induce depolarization block of muscle membrane in low K concentration by increasing membrane permeability to Na. We have reported that K deficiency and thyroid hormone excess increased NaK-ATPase and may sensitize the muscle membrane to the effect of insulin to cause depolarization in an animal model. In fact, in Japan, incidence of TPP of male decreased from 8.6% in 1958 to 4.3% in 1998. During this 40 years, intake of K was increased from 43 to 65 mEq per day per person as described by the National Survey of Nutrition. The SNiPs of ion channel genes, together with K deficiency or thyroid hormone excess, may provide a risk to the occurrence of TPP.
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PMID:[Recent progress on the searchs of pathogenesis of thyrotoxic periodic paralysis]. 1715 2

Hypokalemic periodic paralysis is a rare disorder characterized by episodic attacks of muscle flaccidity associated with low serum potassium levels. We report twelve patients with normokalemic and hypokalemic periodic paralysis due to various mutations who developed hypokalemic paralytic episodes following a single dose or short-term administration of glucocorticoids. We hypothesize that glucocorticoids cause hypokalemia due to their stimulation of the Na(+)-K(+) ATPase mediated by insulin and amylin and due to their side effect of insulin resistance resulting in hyperglycemia. This report adds to the clinical description of glucocorticoids as a trigger of attacks of hypokalemic periodic paralysis indicating that glucocorticoids should be administered with caution in patients with periodic paralysis.
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PMID:Glucocorticoids may trigger attacks in several types of periodic paralysis. 1920 8

Hypokalemic periodic paralysis (HypoPP) is an ion channelopathy of skeletal muscle characterized by attacks of muscle weakness associated with low serum K+. HypoPP results from a transient failure of muscle fiber excitability. Mutations in the genes encoding a calcium channel (CaV1.1) and a sodium channel (NaV1.4) have been identified in HypoPP families. Mutations of NaV1.4 give rise to a heterogeneous group of muscle disorders, with gain-of-function defects causing myotonia or hyperkalemic periodic paralysis. To address the question of specificity for the allele encoding the NaV1.4-R669H variant as a cause of HypoPP and to produce a model system in which to characterize functional defects of the mutant channel and susceptibility to paralysis, we generated knockin mice carrying the ortholog of the gene encoding the NaV1.4-R669H variant (referred to herein as R669H mice). Homozygous R669H mice had a robust HypoPP phenotype, with transient loss of muscle excitability and weakness in low-K+ challenge, insensitivity to high-K+ challenge, dominant inheritance, and absence of myotonia. Recovery was sensitive to the Na+/K+-ATPase pump inhibitor ouabain. Affected fibers had an anomalous inward current at hyperpolarized potentials, consistent with the proposal that a leaky gating pore in R669H channels triggers attacks, whereas a reduction in the amplitude of action potentials implies additional loss-of-function changes for the mutant NaV1.4 channels.
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PMID:A sodium channel knockin mutant (NaV1.4-R669H) mouse model of hypokalemic periodic paralysis. 2188 Dec 11

A case is presented of a rare complication of hyperthyroidism, known as thyrotoxic hypokalaemic periodic paralysis, in a man from Nepal. A 26-year-old Nepalese man, with known hypokalaemia, was referred to the clinical laboratory services for electrolyte analysis. Results showed Na(+) 120 mmol/l and K(+) 2.8 mmol/l, and he was prescribed potassium chloride. In fact, he had previously been receiving potassium supplementation periodically and his history revealed that he had experienced the same type of attack and was hospitalised 6 months earlier. He had profound tremor and was agitated and irritable during his visit to this hospital. Thyroid function testing showed high T3 (tri-iodothyronine) and T4 (thyroxine) with low thyroid stimulating hormone (TSH) concentration in the serum, indicating thyrotoxic hypokalaemic periodic paralysis. Treatment with neomercazole resulted in an improvement during the follow up visit. Hypokalaemia is believed to be a consequence of a massive shift due to increased sodium-potassium-adenosine triphosphatase (Na(+)K(+)ATPase ) pump activity in the presence of elevated thyroid hormones.
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PMID:Thyrotoxic hypokalaemic periodic paralysis in a man from Nepal. 2189 47

The pathogenesis of thyrotoxic periodic paralysis has long been thought related to increased Na(+)-K(+) ATPase activity stimulated by thyroid hormone and/or hyperadrenergic activity and hyperinsulinemia. This mechanism alone, however, cannot adequately explain how hypokalemia occurs during acute attacks or the associated paradoxical depolarization of the resting membrane potential. Recent findings that loss of function mutations of the skeletal muscle-specific inward rectifying K(+) (Kir) channel, Kir2.6, associate with thyrotoxic periodic paralysis provide new insights into how reduced outward K(+) efflux in skeletal muscle, from either channel mutations or inhibition by hormones (adrenalin or insulin), can lead to a vicious cycle of hypokalemia and paradoxical depolarization, which in turn, inactivates Na(+) channels and causes muscle unexcitability and paralysis.
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PMID:Mechanism of thyrotoxic periodic paralysis. 2246 May 32

Extracellular potassium makes up only about 2% of the total body's potassium store. The majority of the body potassium is distributed in the intracellular space, of which about 80% is in skeletal muscle. Movement of potassium in and out of skeletal muscle thus plays a pivotal role in extracellular potassium homeostasis. The exchange of potassium between the extracellular space and skeletal muscle is mediated by specific membrane transporters. These include potassium uptake by Na(+), K(+)-adenosine triphosphatase and release by inward-rectifier K(+) channels. These processes are regulated by circulating hormones, peptides, ions, and by physical activity of muscle as well as dietary potassium intake. Pharmaceutical agents, poisons, and disease conditions also affect the exchange and alter extracellular potassium concentration. Here, we review extracellular potassium homeostasis, focusing on factors and conditions that influence the balance of potassium movement in skeletal muscle. Recent findings that mutations of a skeletal muscle-specific inward-rectifier K(+) channel cause hypokalemic periodic paralysis provide interesting insights into the role of skeletal muscle in extracellular potassium homeostasis. These recent findings are reviewed.
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PMID:Extracellular potassium homeostasis: insights from hypokalemic periodic paralysis. 2395 1

A 40-year-old Japanese man who had a medical history of hypokalemic periodic paralysis 4 months prior was hospitalized to undergo a cholecystectomy. Hypokalemia, nephrocalcinosis and alkaluria suggesting distal renal tubular acidosis (dRTA) were detected, but metabolic acidosis was not evident. An ammonium chloride/furosemide-fludrocortisone/bicarbonate loading test demonstrated a remarkable disability in urinary H(+) excretion. A novel heterozygous mutation in the ATP6V0A4 gene encoding the vacuolar H(+)-ATPase (V-ATPase) a4 subunit p.S544L was detected. Among cases of V-ATPase a4 mutations, this is the first case in which a heterozygous mutation developed to an incomplete or latent form of dRTA.
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PMID:A novel heterozygous mutation in the ATP6V0A4 gene encoding the V-ATPase a4 subunit in an adult patient with incomplete distal renal tubular acidosis. 2799 69

The pathogenesis of hypokalemic periodic paralysis (HypoPP) remains unclear. Though some mutations in skeletal muscle ion channels were revealed previously, the exact mechanism remains to be fully elucidated. Increased Na+/K+-ATPase activity in skeletal muscle is postulated to contribute to attacks of HypoPP. Before the link between Na+/K+-ATPase dysfunction and these ion channel mutations is established, mutations in Na+/K+-ATPase and their regulators are the first to be excluded. Phospholemman, which is a protein encoded by the FXYD domain-containing ion transport regulator 1 (FXYD1) gene, is predominantly expressed in skeletal muscle and is the major regulator of Na+/K+-ATPase. Therefore, the aim of the present study was to determine the genetic involvement of phospholemman in HypoPP development. Genomic DNA was extracted from the peripheral blood of five HypoPP probands with typical manifestations. The coding exons of FXYD1, exons 2-7, were polymerase chain reaction (PCR)-amplified and sequenced. No mutations were detected in FXYD1 in any of the subjects studied. To conclude, mutations in phospholemman encoding genes may not be involved with HypoPP and the relationship between phospholemman and Na+/K+-ATPase dysfunction in attacks of HypoPP requires further study.
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PMID:Phospholemman, a major regulator of skeletal muscle Na+/K+-ATPase, is not mutated in probands with hypokalemic periodic paralysis. 2891 73

Thyrotoxic periodic paralysis is a rare complication of hyperthyroidism where increased influx of potassium into skeletal muscle cells leads to profound hypokalaemia and paralysis. Most cases arise sporadically in Asians; however, it is being increasingly reported in Caucasians. It is regarded as a channelopathy where a genetic and/or acquired defect in the sodium-potassium (Na/K-ATPase) pump renders it more sensitive to excess thyroid hormone in susceptible individuals. Because the clinical presentation is similar to familial hypokalaemic periodic paralysis, genes implicated in this autosomal-dominant condition became candidates for thyrotoxic periodic paralysis, particularly if they were known to have thyroid hormone-responsive elements. These include the voltage-gated calcium (CACNA1S) and sodium (SCN4A) channel genes, KCNJ18 which encodes the inwardly rectifying potassium channel Kir2.6, and subunits of the Na/K-ATPase genes. Although no single pathogenetic mutation has been identified in thyrotoxic periodic paralysis, several single-nucleotide polymorphisms in these genes have been associated with it. We describe a 27-year-old Caucasian Irish male who presented with acute onset limb paralysis and severe hypokalaemia. He was diagnosed as having thyrotoxic periodic paralysis secondary to Graves' disease based on clinical presentation, biochemical findings and rapid response to intravenous potassium. Genetic analysis identified heterozygous variants in three candidate genes: KCNJ18 (c.576G>C), SCN4A (c.2341G>A) and CACNA1S (c.1817G>A). Since these variants are not disease causing and occur at high prevalences of 50%, 2-3% and 1%, respectively, in the normal population, they do not explain the clinical phenotype in our patient suggesting that acquired environmental triggers or as-yet unidentified gene mutations remain as leading pathogenetic co-factors in thyrotoxic periodic paralysis.
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PMID:Does thyrotoxic periodic paralysis have a genetic predisposition? A case report. 2988 59

Hypokalemia is a serious and life-threatening clinical condition. We present a case of a 45-year-old male, with known hyperthyroidism presenting with profound tremor, irritability, quadriparesis, and labored breathing since morning, on the day of admission. Arterial blood gas analysis showed severe hypokalemia. Patient's vital was stabilized and patient's oxygen saturation was maintained on oxygen inhalation. Intravenous potassium chloride infusion was administered with regular monitoring of vitals and electrolytes. Patient's symptoms improved. Thyroid function testing showed high free T3 (tri-iodothyronine) and free T4 (thyroxine) with low thyroid-stimulating hormone concentration in the serum, indicating thyrotoxic hypokalemic periodic paralysis. Treatment with antithyroid drug carbimazole resulted in an improvement during the follow-up visit. Hypokalemia is believed to be a consequence of a massive shift due to increased sodium-potassium-adenosine triphosphatase (Na+K+ATPase) pump activity in the presence of elevated thyroid hormones.
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PMID:Thyrotoxic Hypokalemic Periodic Paralysis. 2991 May 53


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