Hypokalemic Periodic Paralysis Research Articles

Hypokalemic Periodic Paralysis and Spectrum of Thyroid Disorders: Analysis of 7 Cases from Northern India.

Hypokalemic Periodic Paralysis and Spectrum of Thyroid Disorders: Analysis of 7 Cases from Northern India.

Secondary hypokalemic periodic paralysis: A study of a case series

Background: Periodic paralysis is a group of heterogeneous disorders of different etiologies, with episodic, short-lived, and hyporeflexic skeletal muscle weakness, with or without myotonia. There is neither sensory deficit nor loss of consciousness. They can be familial (primary) or acquired (secondary). Secondary periodic paralysis is due to demonstrably known causes. The interictal potassium level is abnormal in these cases. Hypokalemic paralysis is more common than hyperkalemic. Materials and Methods: This is a prospective observational study elucidating the clinical profile of the cases of secondary hypokalaemic periodic paralysis seen in our care over a period of 14 months. Results: In this study, we present nine patients with hypokalemic periodic paralysis, in which four were diagnosed with thyrotoxicosis and five with dengue. They were given potassium correction under judicious cardiac monitoring. Antithyroid drugs and beta-blockers were used in thyrotoxicosis. Dengue patient received adequate fluid and antipyretic cover. All the patients made complete recovery, without any neurological sequelae. Conclusion: Secondary hypokalemic periodic paralysis should always be kept in mind as a differential in the setting of acute, painless, flaccid motor paralysis, especially in young patients with no significant family history or risk factors for stroke or Guillain–Barre Syndrome. A clinician must be aware of causes of secondary periodic paralysis as recognition and diagnosis can completely prevent further attacks of periodic paralysis. Routine estimation of thyroid levels should be the initial line of investigation even if features of thyrotoxicosis are absent. In the presence of acute febrile illness, ordering serology for dengue, after ruling out thyrotoxicosis, is the preferred approach in India.

Overlap of periodic paralysis and paramyotonia congenita caused by SCN4A gene mutations two family reports and literature review

ABSTRACTObjective: To verify the diagnosis of channelopathies in two families and explore the mechanism of the overlap between periodic paralysis (PP) and paramyotonia congenita (PMC). Methods: We have studied two cases with overlapping symptoms of episodic weakness and stiffness in our clinical center using a series of assessment including detailed medical history, careful physical examination, laboratory analyses, muscle biopsy, electrophysiological evaluation, and genetic analysis. Results: The first proband and part of his family with the overlap of PMC and hyperkalemic periodic paralysis (HyperPP) has been identified as c.2111C > T (T704M) substitution of the gene SCN4A. The second proband and part of his family with the overlap of PMC and hypokalemic periodic paralysis type 2 (HypoPP2) has been identified as c.4343G > A (R1448H) substitution of the gene SCN4A. In addition, one member of the second family with overlapping symptoms has been identified as a novel mutation c.2111C > T without the mutation c.4343G > A. Conclusions: SCN4A gene mutations can cause the overlap of PMC and PP (especially the HypoPP2). The clinical symptoms of episodic weakness and stiffness could happen at a different time or temperature. Based on diagnosis assessments such as medical history and muscle biopsy, further evaluations on long-time exercise test, genetic analysis, and patch clamp electrophysiology test need to be done in order to verify the specific subtype of channelopathies. Furthermore, the improvement of one member in the pregnancy period can be used as a reference for the other female in the child-bearing period with T704M.

Thyrotoxic Periodic Paralysis with Hypokalemia in an Adult Male from Nepal: A Case Report

Thyrotoxic periodic paralysis is rare complication of hyperthyroidism characterized by the sudden onset of hypokalemia and muscle paralysis. It is typically present in young Asian males. There are very few literatures regarding the occurrence of thyrotoxic hypokalemic periodic paralysis in Nepal. We reported a case of a 35-year-old male presented with the chief complaints of weakness of all four limbs of 1 day duration. He was diagnosed as a case of hyperthyroidism in the past, received treatment for 6 months and left medications on his own 6 months ago. Evaluation during admission revealed severe hypokalemia with serum potassium level 1.3mEq/l and high serum Triiodothyronine (>20.00µg/L) and low serum Thyroid Stimulating Hormone (<0.01µg/L). Potassium supplements resolved muscle weakness and the patient was restarted with anti-thyroid drugs. Hence, hypokalemic paralysis is a reversible cause of paralysis and high index of suspicion as well as timely interventions are required to prevent potential harm. Keywords: hyperthyroidism; hypokalemia; muscle paralysis; thyrotoxic periodic paralysis.

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

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 α2 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.

The study of exercise tests in paroxysmal kinesigenic dyskinesia

ObjectiveTo unravel if there was muscular ion channel dysfunction in paroxysmal kinesigenic dyskinesia (PKD) patients using the exercises tests (ET). MethodsSixty PKD patients including 28 PRRT2 mutations carriers were enrolled in this study, as well as 19 hypokalaemic periodic paralysis (HypoPP) patients as the positive controls and 45 healthy subjects as the negative controls. ET including long exercise test (LET) and short exercise test (SET) was performed in the corresponding subjects. ResultsIn the LET, both the overall PKD patients and HypoPP patients had greater CMAP amplitude and area increments during exercise than healthy controls. At most 25% of PKD patients were identified from the normality with greater amplitude increment than the area. On the contrary, 50% of HypoPP patients were differentiated with greater area increment than the amplitude. More percentage of PRRT2− patients than PRRT2+ patients had abnormal average amplitude increment. Unexpectedly, five PKD patients had abnormal maximum CMAP amplitude decrements after exercise in the LET, and one had abnormal maximum immediate amplitude decrement in the SET. ConclusionsDistinct ET manifestations were found in PKD patients compared to normal controls and HypoPP patients. SignificanceAbnormal muscle membrane excitability might be involved in the mechanisms responsible for PKD.

Does thyrotoxic periodic paralysis have a genetic predisposition? A case report.

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.

NaV1.4 DI-S4 periodic paralysis mutation R222W enhances inactivation and promotes leak current to attenuate action potentials and depolarize muscle fibers

Hypokalemic periodic paralysis is a skeletal muscle disease characterized by episodic weakness associated with low serum potassium. We compared clinical and biophysical effects of R222W, the first hNaV1.4 domain I mutation linked to this disease. R222W patients exhibited a higher density of fibers with depolarized resting membrane potentials and produced action potentials that were attenuated compared to controls. Functional characterization of the R222W mutation in heterologous expression included the inactivation deficient IFM/QQQ background to isolate activation. R222W decreased sodium current and slowed activation without affecting probability. Consistent with the phenotype of muscle weakness, R222W shifted fast inactivation to hyperpolarized potentials, promoted more rapid entry, and slowed recovery. R222W increased the extent of slow inactivation and slowed its recovery. A two-compartment skeletal muscle fiber model revealed that defects in fast inactivation sufficiently explain action potential attenuation in patients. Molecular dynamics simulations showed that R222W disrupted electrostatic interactions within the gating pore, supporting the observation that R222W promotes omega current at hyperpolarized potentials. Sodium channel inactivation defects produced by R222W are the primary driver of skeletal muscle fiber action potential attenuation, while hyperpolarization-induced omega current produced by that mutation promotes muscle fiber depolarization.

Hypokalaemic periodic paralysis and myotonia in a patient with homozygous mutation p.R1451L in NaV1.4

Dominantly inherited channelopathies of the skeletal muscle voltage-gated sodium channel NaV1.4 include hypokalaemic and hyperkalaemic periodic paralysis (hypoPP and hyperPP) and myotonia. HyperPP and myotonia are caused by NaV1.4 channel overactivity and overlap clinically. Instead, hypoPP is caused by gating pore currents through the voltage sensing domains (VSDs) of NaV1.4 and seldom co-exists clinically with myotonia. Recessive loss-of-function NaV1.4 mutations have been described in congenital myopathy and myasthenic syndromes. We report two families with the NaV1.4 mutation p.R1451L, located in VSD-IV. Heterozygous carriers in both families manifest with myotonia and/or hyperPP. In contrast, a homozygous case presents with both hypoPP and myotonia, but unlike carriers of recessive NaV1.4 mutations does not manifest symptoms of myopathy or myasthenia. Functional analysis revealed reduced current density and enhanced closed state inactivation of the mutant channel, but no evidence for gating pore currents. The rate of recovery from inactivation was hastened, explaining the myotonia in p.R1451L carriers and the absence of myasthenic presentations in the homozygous proband. Our data suggest that recessive loss-of-function NaV1.4 variants can present with hypoPP without congenital myopathy or myasthenia and that myotonia can present even in carriers of homozygous NaV1.4 loss-of-function mutations.

Evaluation of mutant muscle Ca2+ channel properties using two different expression systems.

Allard appraises recent studies investigating the pathological mechanism of hypokalemic periodic paralysis mutations.

Hypokalemic periodic paralysis: an unusual presentation of primary hyperparathyroidism

Primary hyperparathyroidism is an endocrine condition characterized by hyper secretion of parathyroid hormone (PTH). It has a wide varied clinical presentation from mild nonspecific symptoms to classical disease. We herein report two cases of primary hyperparathyroidism who were presented as hypokalemic periodic paralysis. The aim of this case report is to highlight this unusual presentation of primary hyperparathyroidism. Patients presenting with hypokalemic periodic paralysis should be evaluated for the possibility of primary hyperparathyroidism. Surgeons should be aware of this unusual presentation of primary hyperparathyroidism thereby it can be detected earlier, and prompt treatment can be offered before the disease progresses.

Structural basis for gating pore current in periodic paralysis.

Potassium-sensitive Hypokalemic and Normokalemic Periodic Paralysis (HypoPP, NormoPP) are inherited skeletal muscle diseases characterized by episodes of flaccid muscle weakness1,2. They are caused by mutations in one gating charge in an S4 transmembrane segment in the voltage sensor (VS) of voltage-gated sodium channel Nav1.4 or calcium channel Cav1.11,2. Mutations of the outermost arginine gating charges (R1 and R2) cause HypoPP1,2 by creating a pathogenic gating pore in the VS through which cations leak in the resting state3,4. Mutations of the third arginine gating charge (R3) cause NormoPP5 owing to cationic leak in activated/inactivated states6. Here we present high-resolution structures of these pathogenic gating pores in the model bacterial sodium channel NaVAb7,8. Mutation of R2 in NaVAb gives gating pore current in resting states, whereas mutation of R3 gives gating pore current in activated/inactivated states. Mutations R2G and R3G have no effect on backbone structures of VS, but create aqueous space near the hydrophobic constriction site (HCS) that controls gating charge movement through VS. The R3G mutation extends the extracellular aqueous cleft completely through the activated VS. Although the R2G mutation does not create a continuous aqueous pathway in the activated state, molecular modeling of the resting state reveals a complete water-accessible pathway. Crystal structures of NaVAb/R2G in complex with guanidinium define a potential drug target site. Molecular dynamics simulations illustrate the mechanism of Na+ permeation through the mutant gating pore in concert with conformational fluctuations of gating charge R4. Our results reveal pathogenic mechanisms of periodic paralysis at the atomic level and suggest designs of drugs that may prevent ionic leak and provide symptomatic relief from these episodic diseases.

Managing Bipolar Affective Disorder in a Tribal District of Odisha.

Background:Managing any chronic illness in marginalized communities in resource-poor settings is always a challenge. Lack of facility to monitor lithium and the common morbidity of hypokalemic periodic paralysis and chronic renal failure among tribals of northern part of Odisha pose unique challenges in managing bipolar disorder.Methodology:This is a cross-sectional study done in a district-level hospital catering to predominantly tribal population. A part of the data was collected by a psychiatrist prospectively and analyzed. Historical data were obtained from medical records.Results:Out of 18 patients who had been diagnosed of bipolar/mania, 12 had received treatment with carbamazepine in the range of 400–600 mg. All but one person showed improvement. One person developed rash and had to stop the treatment.Conclusion:Carbamazepine may be used relatively safely in resource-poor settings in high-risk groups.

A Mixed Periodic Paralysis & Myotonia Mutant, P1158S, Imparts pH-Sensitivity in Skeletal Muscle Voltage-gated Sodium Channels

Skeletal muscle channelopathies, many of which are inherited as autosomal dominant mutations, include myotonia and periodic paralysis. Myotonia is defined by a delayed relaxation after muscular contraction, whereas periodic paralysis is defined by episodic attacks of weakness. One sub-type of periodic paralysis, known as hypokalemic periodic paralysis (hypoPP), is associated with low potassium levels. Interestingly, the P1158S missense mutant, located in the third domain S4-S5 linker of the “skeletal muscle”, Nav1.4, has been implicated in causing both myotonia and hypoPP. A common trigger for these conditions is physical activity. We previously reported that Nav1.4 is relatively insensitive to changes in extracellular pH compared to Nav1.2 and Nav1.5. Given that intense exercise is often accompanied by blood acidosis, we decided to test whether changes in pH would push gating in P1158S towards either phenotype. Our results suggest that, unlike in WT-Nav1.4, low pH depolarizes the voltage-dependence of activation and steady-state fast inactivation, decreases current density, and increases late currents in P1185S. Thus, P1185S turns the normally pH-insensitive Nav1.4 into a proton-sensitive channel. Using action potential modeling we predict a pH-to-phenotype correlation in patients with P1158S. We conclude that activities which alter blood pH may trigger the noted phenotypes in P1158S patients.

When muscle Ca2+ channels carry monovalent cations through gating pores: insights into the pathophysiology of type 1 hypokalaemic periodic paralysis.

Patients suffering from type 1 hypokalaemic periodic paralysis (HypoPP1) experience attacks of muscle paralysis associated with hypokalaemia. The disease arises from missense mutations in the gene encoding the α1subunit of the dihydropyridine receptor (DHPR), a protein complex anchored in the tubular membrane of skeletal muscle fibres which controls the release of Ca2+ from sarcoplasmic reticulum and also functions as a Ca2+ channel. The vast majority of mutations consist of the replacement of one of the outer arginines in S4 segments of the α1subunit by neutral residues. Early studies have shown that muscle fibres from HypoPP1 patients are abnormally depolarized at rest in low K+ to the point of inducing muscle inexcitability. The relationship between HypoPP1 mutations and depolarization has long remained unknown. More recent investigations conducted in the closely structurally related voltage-gated Na+ and K+ channels have shown that comparable S4 arginine substitutions gave rise to elevated inward currents at negative potentials called gating pore currents. Experiments performed in muscle fibres from different models revealed such an inward resting current through HypoPP1 mutated Ca2+ channels. In mouse fibres transfected with HypoPP1 mutated channels, the elevated resting current was found to carry H+ for the R1239H arginine-to-histidine mutation in a S4 segment and Na+ for the V876E HypoPP1 mutation, which has the peculiarity of not being located in S4 segments. Muscle paralysis probably results from the presence of a gating pore current associated with hypokalaemia for both mutations, possibly aggravated by external acidosis for the R1239H mutation.

Spider toxin inhibits gating pore currents underlying periodic paralysis

Gating pore currents through the voltage-sensing domains (VSDs) of the skeletal muscle voltage-gated sodium channel NaV1.4 underlie hypokalemic periodic paralysis (HypoPP) type 2. Gating modifier toxins target ion channels by modifying the function of the VSDs. We tested the hypothesis that these toxins could function as blockers of the pathogenic gating pore currents. We report that a crab spider toxin Hm-3 from Heriaeus melloteei can inhibit gating pore currents due to mutations affecting the second arginine residue in the S4 helix of VSD-I that we have found in patients with HypoPP and describe here. NMR studies show that Hm-3 partitions into micelles through a hydrophobic cluster formed by aromatic residues and reveal complex formation with VSD-I through electrostatic and hydrophobic interactions with the S3b helix and the S3-S4 extracellular loop. Our data identify VSD-I as a specific binding site for neurotoxins on sodium channels. Gating modifier toxins may constitute useful hits for the treatment of HypoPP.

NMJ&C03 - RCT of bumetanide in hypokalaemic periodic paralysis (HypoPP) using abductor digiti minimi compound muscle action potential (CMAP) as an objective outcome measure

NMJ&C03 - RCT of bumetanide in hypokalaemic periodic paralysis (HypoPP) using abductor digiti minimi compound muscle action potential (CMAP) as an objective outcome measure

Abstract #1061 Gravely Paralyzed: A Case of Hypokalemic Periodic Paralysis in a Patient with Graves’ Disease

Abstract #1061 Gravely Paralyzed: A Case of Hypokalemic Periodic Paralysis in a Patient with Graves’ Disease

276 Hypokalemic Periodic Paralysis with Mutations in WASHC5 and ANKH Genes

276 Hypokalemic Periodic Paralysis with Mutations in WASHC5 and ANKH Genes

HIPOKALEMIK PERIODIK PARALISIS

A 7-year-old boy of Java origin, visited the doctor with progressive weakness everytime he ate food containing Monosodium Glutamat (MSG). Progressive weakness began from his legs and spreaded to the arms as well (sometimes also to the neck). He could neither walk nor do anything for 5–6 hours then began to resolve spontaneously.. We suspected the diagnosis of hypokalaemic periodic paralysis upon the history of episodes of flacid paralysis and low serum concentration of potassium (&lt; 3,5 mmol/L) during the attacts. The clinical examination showed that this boy is in good general and nutritional conditions; electrocardiogram, laboratory blood count, urinalisis, thyroid, liver, kidney function, and ANA test were normal as well. The family history of flacid paralysis was negative. We have promptly administered potassium orally and his condition was improved progressively including less degree of flacid paralysis (the weakness). A genetic testing, electromyography (EMG), muscle biopsy and another examination has not performed.