Cause Of Hypokalemic Periodic Paralysis Research Articles

Gating pore currents occur in CaV1.1 domain III mutants associated with HypoPP.

Mutations in the voltage sensor domain (VSD) of CaV1.1, the α1S subunit of the L-type calcium channel in skeletal muscle, are an established cause of hypokalemic periodic paralysis (HypoPP). Of the 10 reported mutations, 9 are missense substitutions of outer arginine residues (R1 or R2) in the S4 transmembrane segments of the homologous domain II, III (DIII), or IV. The prevailing view is that R/X mutations create an anomalous ion conduction pathway in the VSD, and this so-called gating pore current is the basis for paradoxical depolarization of the resting potential and weakness in low potassium for HypoPP fibers. Gating pore currents have been observed for four of the five CaV1.1 HypoPP mutant channels studied to date, the one exception being the charge-conserving R897K in R1 of DIII. We tested whether gating pore currents are detectable for the other three HypoPP CaV1.1 mutations in DIII. For the less conserved R1 mutation, R897S, gating pore currents with exceptionally large amplitude were observed, correlating with the severe clinical phenotype of these patients. At the R2 residue, gating pore currents were detected for R900G but not R900S. These findings show that gating pore currents may occur with missense mutations at R1 or R2 in S4 of DIII and that the magnitude of this anomalous inward current is mutation specific.

SUN-496 A Challenging Diagnosis of Thyrotoxic Periodic Paralysis

Thyrotoxic Periodic Paralysis (TPP) is a rare but potentially lethal manifestation of hyperthyroidism which is characterized by muscular weakness due to intracellular shift of potassium and subsequent hypokalemia. The muscular weakness may range from mild weakness to complete flaccid paralysis. It is predominantly seen in Asian young men. Graves’ disease has been described as the most common cause of TPP. Other rare causes of hypokalemic periodic paralysis include inherited disorders and acquired cases due to drug abuse, specifically cocaine. It is important to recognize and diagnose TPP to provide appropriate treatment and prevent serious cardiopulmonary complications.A 26 year old Hispanic male with past medical history of cocaine abuse presented to the emergency department with profound lower extremity weakness since that morning. Laboratory studies on initial evaluation revealed hypokalemia. He was admitted to the intensive care unit (ICU) for IV potassium replacement and cardiac monitoring. Upon obtaining further history, the patient had suffered a similar episode of weakness and hypokalemia two months prior. At the time, he had a positive urine toxicology for cocaine. He was treated with IV potassium with resolution of his weakness and was told the reason for the episode was cocaine induced periodic paralysis. No further work up was done due to patient leaving Against Medical Advice. The patient stopped recreational drug abuse after this diagnosis.During current hospitalization, further laboratory studies revealed hyperthyroidism. TSI and TPO antibodies were elevated and thus patient was diagnosed with Graves’ disease. On questioning, patient was asymptomatic and clinically euthyroid. He was treated with IV potassium, methimazole and propranolol with quick resolution of weakness. He has been followed in an out-patient basis and he has had no further exacerbations.In this case, we present a case of TPP that was initially diagnosed as cocaine induced periodic paralysis which is an extremely rare disorder with only a couple of described cases in the literature. Diagnosis was initially missed as the patient was clinically euthyroid and had history of recreational drug abuse. Restoration of euthyroidism eliminates attacks of TPP. It is important to recognize and diagnose these patient to prevent further attacks.

Stac3 enhances expression of human CaV1.1 in Xenopus oocytes and reveals gating pore currents in HypoPP mutant channels.

Mutations of CaV1.1, the pore-forming subunit of the L-type Ca2+ channel in skeletal muscle, are an established cause of hypokalemic periodic paralysis (HypoPP). However, functional assessment of HypoPP mutant channels has been hampered by difficulties in achieving sufficient plasma membrane expression in cells that are not of muscle origin. In this study, we show that coexpression of Stac3 dramatically increases the expression of human CaV1.1 (plus α2-δ1b and β1a subunits) at the plasma membrane of Xenopus laevis oocytes. In voltage-clamp studies with the cut-open oocyte clamp, we observe ionic currents on the order of 1 μA and gating charge displacements of ∼0.5-1 nC. Importantly, this high expression level is sufficient to ascertain whether HypoPP mutant channels are leaky because of missense mutations at arginine residues in S4 segments of the voltage sensor domains. We show that R528H and R528G in S4 of domain II both support gating pore currents, but unlike other R/H HypoPP mutations, R528H does not conduct protons. Stac3-enhanced membrane expression of CaV1.1 in oocytes increases the throughput for functional studies of disease-associated mutations and is a new platform for investigating the voltage-dependent properties of CaV1.1 without the complexity of the transverse tubule network in skeletal muscle.

Idiopathic hypokalemic periodic paralysis: A series of cases clustered in a part of Eastern India

Background: Most of the studies on hypokalemic periodic paralysis (HOPP) in India and abroad had described secondary causes as the origin of the disease. We had observed a series of HOPP cases clustered within 40 kilometers around Bankura, a district town of West Bengal, Eastern India. The aim of our study was to probe into the clinical, biochemical and electrophysiological details of the cases, which were found to be idiopathic. Material and Methods: 32 idiopathic HOPP cases, attending the neurology OPD or admitted in Bankura Sammilani Medical College & Hospital (BSMCH), were selected from October 2006 to May 2008. All the secondary causes of HOPP were excluded. The patients were evaluated and the data was analyzed. Results: Cases were clustered within a 40-kilometer radius from Bankura town, location of BSMCH. Male: female = 4.3:1. Median age of onset was 23.5 years (4-50 years). Median number of attacks was 2.5, (1 to 70); duration 3 hours - 6 days, median 3 days. Strenous physical activity was most common precipitating factor. 25% had bulbar symptoms, 9.4% had bladder dysfunction and 46.9% had diminished to absent deep tendon reflexes. Mean serum potassium = 2.45 mEq/L (1.4 – 3.1 mEq/L). Conclusion: We had observed a group of idiopathic HOPP cases within a relatively small area in a short span of time in contrast to most other Indian studies, where the share of idiopathic aetiology is comparatively smaller. This underscores the importance of a larger study with genetic analysis on the aetiology of the idiopathic HOPP in this area.DOI: http://dx.doi.org/10.3126/ajms.v6i6.12482 Asian Journal of Medical Sciences Vol.6(6) 2015 83-87

Hypokalemic Periodic Paralysis Due To Distal Renal Tubular Acidosis

Hypokalemic periodic paralysis (HPP) is a disorder that characterized by attacks of skeletal muscle paralysis depending on the changes in serum potassium levels, and can occur due to primary and secondary causes. One of the secondary causes of HPP is distal renal tubular acidosis (DRTA). DRTA is a disorder that characterized by hypokalemia or hyperkalemia hypercalciuria, metabolic acidosis and alkaline urine. DRTA's clinical symptoms are listed as constipation, nausea, vomiting, kidney and skeletal muscle complications, nephrocalcinosis, urolithiasis and severe hypokalemia crisis. In this case report, we reported a patient who admitted to emergency department with complains of nausea, vomiting, and periodic muscle weakness and was diagnosed with hypokalemic periodic paralysis due to DRTA was presented.

Hypokalemic periodic paralysis: Three rare secondary causes

Periodic paralysis is a rare neuromuscular disorder, related to a defect in muscle ion channels, characterized by episodes of painless muscle weakness, which may be precipitated by heavy exercise, fasting, or high-carbohydrate meals. Hypokalemic periodic paralysis may be familial (primary) or secondary. Here, we report three cases of secondary causes of hypokalemic periodic paralysis. On evaluation, case 1 had distal renal tubular acidosis (RTA) due to Sjogren's syndrome, case 2 had drug induced proximal RTA (Fanconi's syndrome) and case 3 had thyrotoxicosis. Clinician must be aware of causes of secondary PP as recognition and diagnosis can completely prevent further attacks of periodic paralysis. Each of the above case is rare, but completely treatable if diagnosed. Low dose steroids with bicarbonate replacement in case 1, stopping tenofovir in case 2 and carbimazole therapy in case 3 prevented further attacks of periodic paralysis and cardiopulmonary complications.

Disrupted coupling of gating charge displacement to Na+ current activation for DIIS4 mutations in hypokalemic periodic paralysis.

Missense mutations at arginine residues in the S4 voltage-sensor domains of NaV1.4 are an established cause of hypokalemic periodic paralysis, an inherited disorder of skeletal muscle involving recurrent episodes of weakness in conjunction with low serum K(+). Expression studies in oocytes have revealed anomalous, hyperpolarization-activated gating pore currents in mutant channels. This aberrant gating pore conductance creates a small inward current at the resting potential that is thought to contribute to susceptibility to depolarization in low K(+) during attacks of weakness. A critical component of this hypothesis is the magnitude of the gating pore conductance relative to other conductances that are active at the resting potential in mammalian muscle: large enough to favor episodes of paradoxical depolarization in low K(+), yet not so large as to permanently depolarize the fiber. To improve the estimate of the specific conductance for the gating pore in affected muscle, we sequentially measured Na(+) current through the channel pore, gating pore current, and gating charge displacement in oocytes expressing R669H, R672G, or wild-type NaV1.4 channels. The relative conductance of the gating pore to that of the pore domain pathway for Na(+) was 0.03%, which implies a specific conductance in muscle from heterozygous patients of ∼ 10 µS/cm(2) or 1% of the total resting conductance. Unexpectedly, our data also revealed a substantial decoupling between gating charge displacement and peak Na(+) current for both R669H and R672G mutant channels. This decoupling predicts a reduced Na(+) current density in affected muscle, consistent with the observations that the maximal dV/dt and peak amplitude of the action potential are reduced in fibers from patients with R672G and in a knock-in mouse model of R669H. The defective coupling between gating charge displacement and channel activation identifies a previously unappreciated mechanism that contributes to the reduced excitability of affected fibers seen with these mutations and possibly with other R/X mutations of S4 of NaV, CaV, and KV channels associated with human disease.

Thyrotoxic periodic paralysis triggered by β2- adrenergic bronchodilators

ABSTRACT Hypokalemic periodic paralysis is the most common form of periodic paralysis and is characterized by attacks of muscle paralysis associated with a low serum potassium (K+) level due to an acute intracellular shifting. Thyrotoxic periodic paralysis (TPP), characterized by the triad of muscle paralysis, acute hypokalemia, and hyperthyroidism, is one cause of hypokalemic periodic paralysis. The triggering of an attack of undiagnosed TPP by β2-adrenergic bronchodilators has, to our knowledge, not been reported previously. We describe two young men who presented to the emergency department with the sudden onset of muscle paralysis after administration of inhaled β2-adrenergic bronchodilators for asthma. In both cases, the physical examination revealed an enlarged thyroid gland and symmetrical flaccid paralysis with areflexia of lower extremities. Hypokalemia with low urine K+ excretion and normal blood acid-base status was found on laboratory testing, suggestive of an intracellular shift of K+, and the patients' muscle strength recovered at serum K+ concentrations of 3.0 and 3.3 mmol/L. One patient developed hyperkalemia after a total potassium chloride supplementation of 110mmol. Thyroid function testing was diagnostic of primary hyperthyroidism due to Graves disease in both cases. These cases illustrate that β2-adrenergic bronchodilators should be considered a potential precipitant of TPP.

Hypokalemic Periodic Paralysis Case Accompanied with Cardiac Arrhythmia

Introduction: Hypokalemic periodic paralysis (HPP) is a disease characterized by intermittent attacks of muscle weakness occurring at irregular intervals and accompanied by episodic hypokalemia. The most common cause of HPP is familial periodic paralysis, which is an autosomal dominantly inherited congenital disease. The serum potassium level is low during the attack due to the shift of potassium into muscle cells, but it is normal between attacks. Attacks of muscle weakness may be triggered or enhanced by high carbohydrate food consumption, emotional stress, cold, resting after strenuous exercise, drugs (such as glucocorticosteroids), insulin and diuretics, preceding infections, and pregnancy.Case Report: We hereby present a 31-year-old male patient admitted to emergency services who had suddenly developed muscle weakness in his upper and lower extremities. Hypopotassemia was observed on the blood test, the electrocardiography was a Mobitz type I atrioventricular block, and the patient was diagnosed with familial periodic paralysis (PP).Conclusion: Familial HPP is diagnosed if there are recurrent attacks of paralysis that are reversible with potassium replacement and hypopotassemia, without any apparent cause of hypopotassemia

Muscle Disease

On the basis of strong research evidence, Duchenne muscular dystrophy (DMD), the most common severe childhood form of muscular dystrophy, is an X-linked recessive disorder caused by out-of-frame mutations of the dystrophin gene. Thus, it is classified asa dystrophinopathy. The disease onset is before age 5 years. Patients with DMD present with progressive symmetrical limb-girdle muscle weakness and become wheelchair dependent after age 12 years. (2)(3). On the basis of some research evidence,cardiomyopathy and congestive heart failure are usually seen in the late teens in patients with DMD. Progressive scoliosis and respiratory in sufficiency often develop once wheelchair dependency occurs. Respiratory failure and cardiomyopathy are common causes of death, and few survive beyond the third decade of life. (2)(3)(4)(5)(6)(7). On the basis of some research evidence, prednisone at 0.75 mg/kg daily (maximum dose, 40 mg/d) or deflazacort at 0.9 mg/kg daily (maximum dose, 39 mg/d), a derivative of prednisolone (not available in the United States), as a single morning dose is recommended for DMD patients older than 5 years, which may prolong independent walking from a few months to 2 years. (2)(3)(16)(17). Based on some research evidence, treatment with angiotensin-converting enzyme inhibitors, b-blockers, and diuretics has been reported to be beneficial in DMD patients with cardiac abnormalities. (2)(3)(5)(18). Based on expert opinion, children with muscle weakness and increased serum creatine kinase levels may be associated with either genetic or acquired muscle disorders (Tables 1 and 3). (14)(15)

A Case of Thyrotoxic Hypokalemia Periodic Paralysis

Hypokalemic periodic paralysis is a rare disease characterized by reversible attacks of muscle weakness accompanied by episodic hypokalemia. The most common causes of Hypokalemic periodic paralysis are familial periodic paralysis, thyrotoxic periodic paralysis and sporadic periodic paralysis, respectively. There are generally some precipitating factors such as stress, vigorous exercise and high carbohydrate food consumption which all ease the occurrence of attacks. The duration of attacks range from 2-36 hours and can be shortened by K+ supplementation in appropriate situations. 28 years old male, admitted to our clinic with severe weakness at his legs and arms, on laboratory examination severe hypocalemia due to overt thyrotoksicosis detected. After antithyroid drug therapy his symptoms and hypocalemia resolved. After three months of therapy he underwent total thyroidectomy because of incompliance to medical therapy. Here we present the case, because of its rarely seen and difficult diagnose if not suspect.

Genotype and Phenotype Analysis of Patients With Sporadic Periodic Paralysis

IntroductionSporadic periodic paralysis (SPP), the second leading cause of hypokalemic periodic paralysis (HPP) in Asia, has a presentation similar to that of familial periodic paralysis (FPP) and is caused by gene mutations in the calcium (Ca2+)(CACNA1S)and sodium (Na+)(SCN4A)channels of skeletal muscle. The authors determined whether SPP shares similar genotype and phenotype with FPP. MethodsSixty SPP patients who did not have a family history of paralysis, abnormal thyroid function tests and other identifiable causes of HPP, and 8 FPP patients were enrolled. Genomic DNA was isolated from blood leukocytes of all SPP and FPP patients. Genetic analysis of whole S4 segment inCACNA1SandSCN4Awas performed. Phenotypic analysis included clinical presentations, laboratory data and precipitating events. ResultsAll FPP patients had mutations in eitherCACNA1SorSCN4A,but only 4 SPP patients hadde novomutations inCACNA1S(R1239H) andSCN4A(R669×2, R1135H). SPP patients withde novomutations manifested a phenotype indistinguishable from that of FPP patients except a later age of onset. SPP patients without mutations also had a later age of onset, significantly fewer attacks of paralysis than FPP patients, and unidentifiable precipitating factors. ConclusionA minority of SPP patients hadde novo CACNA1SorSCN4Amutations and may have a variant of FPP. The majority of SPP patients, those without mutations inCACNA1SandSCN4A,represent a unique subgroup of HPP patients, and this form of SPP usually manifests at a later age, is associated with fewer attacks and lacks apparent triggering factors.

Hypokalemic Quadriparesis due to Use of Tetracosactide

Hypokalemic periodic paralysis (HPP) is a rare disease characterized by reversible attacks of muscle weakness accompanied by episodic hypokalemia. The most common causes of HPP are familial periodic paralysis (FPP), thyrotoxic periodic paralysis (TPP) and sporadic periodic paralysis (SPP). A male patient admitted to our emergency services had weakness in his upper and lower extremities due to using tetracosactide. Patient was diagnosed as hypokalemic paralysis based upon laboratory examination and history. The epidemiology, pathophysiology, clinical presentation and therapy of this relatively rare disease were reviewed.

Hypokalemic periodic paralysis; two different genes responsible for similar clinical manifestations

Primary hypokalemic periodic paralysis (HOKPP) is an autosomal dominant disorder manifesting as recurrent periodic flaccid paralysis and concomitant hypokalemia. HOKPP is divided into type 1 and type 2 based on the causative gene. Although 2 different ion channels have been identified as the molecular genetic cause of HOKPP, the clinical manifestations between the 2 groups are similar. We report the cases of 2 patients with HOKPP who both presented with typical clinical manifestations, but with mutations in 2 different genes (CACNA1Sp.Arg528His and SCN4A p.Arg672His). Despite the similar clinical manifestations, there were differences in the response to acetazolamide treatment between certain genotypes of SCN4A mutations and CACNA1S mutations. We identified p.Arg672His in the SCN4A gene of patient 2 immediately after the first attack through a molecular genetic testing strategy. Molecular genetic diagnosis is important for genetic counseling and selecting preventive treatment.

Mutation screening in Chinese hypokalemic periodic paralysis patients

Thyrotoxic periodic paralysis (TPP), familial periodic paralysis (FPP), and sporadic periodic paralysis (SPP) are the most common causes of hypokalemic periodic paralysis (hypoKPP). The patients present with similar clinical features characterized by episodic attacks of muscle weakness and a decrease in blood potassium. Mutations in the gene encoding the voltage-sensor coding regions of the skeletal muscle sodium channel gene ( SCN4A) and the α-1 subunit of the skeletal muscle calcium channel gene were analyzed in 23 Chinese hypoKPP patients, including 1 FPP pedigree, 14 TPP patients, and 8 SPP patients. In addition, R83H mutation of the potassium channel subunit gene which was originally published as periodic paralysis mutation was also analyzed. A heterozygous CGT-TGT mutation at codon 672 in SCN4A gene was identified to segregate with the disease in the FPP family. Mutations in these regions were excluded in those patients with SPP and TPP. The results suggest that a likely genetic basis for FPP does not contribute to TPP and SPP, despite close similarities among FPP, TPP, and SPP.

Skeletal Muscle Dihydropyridine-Sensitive Calcium Channel (CACNA1S) Gene Mutations in Chinese Patients with Hypokalemic Periodic Paralysis

Thyrotoxic periodic paralysis (TPP), familial periodic paralysis (FPP), and sporadic periodic paralysis (SPP) are common causes of hypokalemic periodic paralysis and have similar clinical presentations, thus possibly sharing the identical mutations. We analyzed the role of the three known CACNA1S gene mutations (R528H, R1239H, and R1239G) in Chinese patients, including two FPP families, 36 TPP patients, 12 SPP patients, and their relatives. Fifty unrelated healthy subjects were also studied. Genomic DNA was prepared from the peripheral blood of all patients, their family members, and healthy subjects. Mutations of the CACNA1S gene were screened using polymerase chain reaction-based restriction analysis. Two FPP families had the R528H point mutation, but with incomplete penetrance occurring more commonly in men than in women. Only one SPP patient had a de novo mutation (R528H). None of the TPP patients had mutations in the three hot spots. Patients with FPP have R528H mutations in the CACNA1S gene. Only a few patients with SPP may share similar mutations with FPP. TPP patients do not carry any of the three known gene mutations.

Diagnosing thyrotoxic periodic paralysis in the ED

Thyrotoxic periodic paralysis (TPP) and sporadic periodic paralysis (SPP) are the most common causes of hypokalemic periodic paralysis (HPP) in EDs in Asia. Their neuromuscular presentations are almost indistinguishable. We conducted this study to identify clinical clues that can help EPs distinguish between TPP and SPP. Thirty-four patients presenting to the ED with HPP were enrolled during a 3-year period. They did not have known hyperthyroidism before the attack and no family history of paralysis. They all had low K + excretion rates. Vital signs and blood biochemistry, including acid-base and electrolytes, were measured. TPP was subsequently established by thyroid function tests. Twenty patients had TPP and 14 patients had SPP. There was no significant difference in age and sex distribution between them. Systolic (SBP) but not diastolic blood pressure (SBP 145 ± 4 vs 128 ± 4 mm Hg, P < 0.001) and heart rate (106 ± 3 vs 73 ± 3 beats/min, P < 0.001) were significantly higher in those experiencing TPP than SPP. Among the biochemical factors, only plasma phosphate concentration (2.2 ± 0.2 vs 3.2 ± 0.2 mg/dL, P < 0.001) was significantly lower in those experiencing TPP than SPP. Systolic hypertension, tachycardia, and hypophosphatemia are clinical clues favoring the diagnosis of TPP.