Hypokalemic Periodic Paralysis Research Articles

Prevalence and mutation spectrum of skeletal muscle channelopathies in the Netherlands

Few reliable data exist on the prevalence of skeletal muscle channelopathies. We determined the minimum point prevalence of genetically-defined skeletal muscle channelopathies in the Netherlands and report their mutation spectrum. Minimum point prevalence rates were calculated as number of genetically-confirmed skeletal muscle channelopathy patients (CLCN1, SCN4A, CACNA1S and KCNJ2 gene mutations) in the Netherlands (1990–2015) divided by the total number of at-risk individuals. Rates were expressed as cases/100.000 and 95% confidence intervals were calculated based on Poisson distribution. Results of standardized genetic diagnostic procedures were used to analyze mutation spectra. We identified 405 patients from 234 unrelated pedigrees, resulting in a minimum point prevalence of 2.38/100.000 (95% CI 2.16–2.63) for skeletal muscle channelopathies in the Netherlands. Minimum point prevalence rates for the disease groups, non-dystrophic myotonia and periodic paralysis, were 1.70/100.000 and 0.69/100.000 respectively.Sixty-one different CLCN1 mutations (including 12 novel mutations) were detected in myotonia congenita. Twenty-eight different SCN4A missense mutations (including three novel mutations) were identified in paramyotonia congenita/sodium channel myotonia, hypokalemic periodic paralysis and hyperkalemic periodic paralysis. Four different CACNA1S missense mutations were detected in hypokalemic periodic paralysis and five KCNJ2 missense mutations in Andersen–Tawil syndrome. The minimum point prevalence rates for genetically-defined skeletal muscle channelopathies confirm their rare disease status in the Netherlands. Rates are almost twice as high as in the UK and more in line with pre-genetic prevalence estimates in parts of Scandinavia. Future diagnostic and therapeutic studies may benefit from knowledge of the mutation spectrum of skeletal muscle channelopathies.

A prospective study of clinical profile of hypokalemic periodic paralysis in paediatric patients

Background: Hypokalemic periodic paralysis is not a frequent but a cause of weakness in paediatric age group patient and it is revised after treatment. If it is not diagnosed properly it could be life threatening but if it is treated properly recovery is good. It can be primary and secondary type and it can be localized or generalized. Present study has been designed with an aim to study the clinical profile, demography, and response to treatment of hypokalemic periodic paralysis in our region.Methods: This a prospective clinical study conducted in the Department of Paediatrics and Emergency Medicine Konaseema Institute of Medical Science, Amalapuram, from November 2013 to March 2017. During this period around 42 patients with weakness and decrease serum potassium level was included in this study as per exclusion and inclusion criteria.Results: Out of 42 patients, 6 patients were between 1 to 6 years of age, 10 patients were between 6 to 12 years of age and 26 patients were 12 to 18 years of age. Sex distribution has male predominance that is 26/16. 26 patients presented with quadriperesis that is (61.9%) and 16 (38.10%) presented with paraparesis or plegia, eleven patients have serum potassium level below 2 meq/L, 26 patients having between 2-3 meq/L, 3 patients having serum potassium 3-4 meq/L and two patients having serum potassium above 4 meq/L.Conclusions: Male predominance and frequency of attack was more in second decade of life. Quadriparesis was the commonest mode of presentation. Most of the patient have had serum potassium level between 2 to 3 meq/L. ECG abnormalities has been observed in 85% of the patients most of these patients were treated with oral potassium chloride alone. Outcome was good in all patients.

Hypokalemia associated with pseudo-Cushing\u2019s syndrome and magnesium deficiency induced by chronic alcohol abuse

Hypokalemia and hypomagnesemia are frequently observed in patients with chronic alcoholism. However, the involvement of deranged cortisol regulation in patients with those conditions has not been reported. A 63-year-old Japanese male with chronic alcoholism was referred to the Department of Diabetes, Endocrinology and Metabolism for examination and treatment of hypokalemic periodic paralysis. Laboratory findings showed hypokalemia (2.3 mmol/l), as well as a high level of urinary excretion of potassium and hypomagnesemia (1.2 mg/dl), whereas urinary excretion of magnesium was undetectable. Potassium infusion treatment recovered that level in serum to 4.1 mmol/l, though it decreased to 2.2 mmol/l following discontinuation. A dexamethasone suppression test and urinary cortisol level showed corticotropin-dependent hypercortisolemia. However, gadolinium-enhanced MRI revealed no evidence of pituitary adenoma. The patient recovered from hypokalemia following an administration of magnesium in addition to potassium, which was accompanied by potassium over-excretion improvement. After being discharged, serum potassium level was maintained within a normal range with only magnesium infusion treatment. Furthermore, alcohol intake was reduced from 160 to 20 g/day and an endocrinological re-examination after that restriction showed normal cortisol regulation. The patient was diagnosed with pseudo-Cushing’s syndrome induced by alcohol abuse. Serum potassium level was maintained within a normal range even after discontinuation of magnesium supplementation. Our findings in this case indicate that pseudo-Cushing’s syndrome in conjunction with hypomagnesemia may be involved in development of hypokalemia in patients with chronic alcoholism.

Screening of genetic mutations in a Chinese pedigree affected with hypokalemic periodic paralysis

OBJECTIVE To screen for mutations in a Chinese pedigree affected with hypokalemic periodic paralysis. METHODS The proband and nine family members were enrolled for the analysis of CACNA1S and SCN4A gene mutations. Genomic DNA was extracted from peripheral blood samples. The coding regions of the two genes were amplified with PCR and subjected to Sanger sequencing. Potential impact of suspected mutations was predicted with Bioinformatics software. The mutations were also verified among 100 healthy controls. RESULTS The proband and 5 family members (including 5 males and 1 female) had presented with episodes of flaccid paralysis accompanied by low serum potassium. Genetic testing has identified a c.664C>T (p.Arg222Trp) mutation in the proband, which has been reported previously. The same mutation was identified in other 5 affected members from the family. No mutation of the CACNA1S gene was detected. CONCLUSION The c.664C>T mutation of the SCN4A gene probably underlies the hypokalemic periodic paralysis in this family. All patients from the family have shown a complete penetrance of the disease.

Hypokalemic Periodic Paralysis Cases with Substitutions from Arginine to Lysine in the Voltage Sensor

Familial hypokalemic periodic paralysis (HypoPP) is a rare skeletal muscle disease caused by the dysregulation of excitability in salcolemma. HypoPP is characterized by repeated episodic paralytic attacks with hypokalemia and several mutations in CACNA1S gene coding Cav1.1 and SCN4A gene coding Nav1.4 have been identified as causative mutations. Most of the mutations are substitution to non-charged amino acid from the positively charged arginine (R) in segment 4 (S4) of the voltage sensor in either Cav1.1 or Nav1.4. Biophysical experiments demonstrated that the loss of the charge in S4 by the arginine-to-non-charged substitution creates a leak current called “gating pore current”. Since the discovery, “the gating pore current theory” has been suggested as the common pathogenic feature in HypoPP. However, the pathological mechanism from generation of “gating pore current” to paralytic attack is still unknown. In this report, we have identified five cases with an arginine(R)-to-lysine (K) substitution in voltage sensor, which retained positive net charge of S4 ; one is a Japanese boy with R219K mutation in SCN4A gene and the other four are one Japanese man, one French man and two French brothers with R897K mutation in CACNA1S gene. All cases presented typical paralytic episodes with hypokalemia and, in four of five cases, significant decrement in the compound action potential was observed with prolonged exercise test. From Nav1.4-R219K mutant channel expressed in vitro, we measured the ionic current by patch-clamp technique and the gating pore current by cut-open voltage clamp technique. Nav1.4-R219K revealed gating pore current, but the size of the conductance was smaller compared to that observed in other mutant HypoPP-Nav1.4 channels previously reported. Our data might provide a new insight in pathogenic mechanism of HypoPP.

Characterization of a NaV1.4 Hypokalemic Periodic Paralysis Mutation in Domain I

We characterized the clinical effects and biophysical properties of hypokalemic periodic paralysis mutation, R222W, initially identified in Korean patients. The heterozygous mutation was also found in a 52 year-old patient with weakness beginning at age 18 and associated with mild hypokalemia, and associated with myalgia. R222W muscle fibers exhibited action potentials with attenuated height, and slowed rate of rise compared to those from a control patient. Membrane potential recordings in normal potassium showed that R222W fibers exhibited a greater density of depolarized potentials (P2) compared to controls. R222W was functionally characterized with cut-open oocyte voltage clamp recordings at 20 °C. The mutation produced a depolarizing shift of the activation midpoint; this effect was shown to be indirect by comparing wild type and R222W channels in the IFM/QQQ inactivation deficient background. R222W produced several effects on inactivation consistent with hypoexcitability. Compared to wild type hNaV1.4, R222W produced a left-shift of the steady-state fast inactivation curve, accelerated entry, and slowed recovery. R222W also produced more complete slow inactivation and slowed its recovery. At hyperpolarized voltages, R222W promoted a cationic omega current, which may explain the paradoxical depolarization of muscle fibers. This work was supported by NIH 1R15NS093579-01A1 to JRG, NIH NIGMS P20GM103498 to ISU, the non-profit Else-Kroner-Fresenius Foundation, German DGM Muscle Disease Society, Taro Pharmaceuticals, and the German BMBF Ministry for IonNeurOnet project jointly to KJR and FLH.

Biophysical Characterization of Two NaV1.4 Mutations Making a Clinical Overlap between the Myotonia-Hyperkalemic and Hypokalemic Periodic Paralysis Clusters of Disorders

We report here the functional characterization of two dominant SCN4A missense mutations targeting the R1451 residue located in transmembrane segment S4 of DIV. The R1451L is a novel mutation found in two unrelated patients. The first patient was diagnosed with SMC, and the second with a mixed hyperPP-hypoPP phenotypes. The R1451C mutation was previously reported by our group in one patient with a single attack of PP induced by glucocorticoids. To elucidate the mechanism underlying the phenotypes caused by the R1451C/L mutations and their roles in different types of sodium channelopathies, we used the whole-cell patch-clamp technique to study tsA201 cells expressing WT, R1451C or R1451L channels. Our results showed that both mutations shifted the steady-state inactivation to hyperpolarized potentials, reduced the current density, slowed the recovery from slow inactivation and exhibited a slow of the overall kinetics of fast inactivation. Cooling further enhances the abnormalities of fast inactivation kinetics in R1451L channels. Homology modeling revealed a dissimilar disruption of hydrogen bonds in the VSD of R1451C/L mutant channels.The altered biophysical properties of R1451C/L channels account for the clinical phenotypes seen in our patients but that additional factors are likely to play a role in the diversity of symptoms.

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.

Etiological Search and Epidemiological Profile in Patients Presenting with Hypokalemic Paresis: An Observational Study.

Introduction:Hypokalemia is associated with increased morbidity and at times mortality. “Hypokalemic paralysis”, particularly if recurrent, has often been considered synonymous with “hypokalemic periodic paralysis (HPP)”; however, diseases such as Gitelman syndrome (GS), Bartter syndrome (BS), and renal tubular acidosis (RTA) can have identical presentation. We have tried to explore the etiological spectrum along with epidemiological and certain clinical, biochemical, and electrophysiological features in patients with hypokalemic paralysis.Materials and Methods:In this observational study, 200 appropriate patients with hypokalemic paralysis (serum K+ <3.5 mmol/L) were evaluated for transcellular shift, extra-renal or renal loss of K+ as the underlying etiology of hypokalemia. We took urinary potassium >25 mmol/day as the cutoff for inappropriate renal loss of potassium in presence of hypokalemia. Serum and urinary osmolality along with arterial blood gas analysis were performed in all patients with renal loss of potassium. Serum and urinary sodium, potassium, calcium, magnesium, chloride, and creatinine were measured in normotensive patients with metabolic alkalosis. Hypertensive patients were evaluated with plasma aldosterone and renin activity.Results:Probable GS topped the list involving 28% individuals of the entire cohort while probable BS, distal RTA, and HPP were diagnosed in 20%, 22%, and 19% cases, respectively. Rural tribal population (61%) and age group of 30–40 years suffered the most (48%) with concentration of cases in hot and humid summer months.Conclusions:We suggest that patients with hypokalemic paresis should be evaluated thoroughly to unmask the underlying etiology that may have a different therapeutic and prognostic connotations and not to use the term “periodic” in cases of recurrent hypokalemic paralysis.

Anesthetic Management of a Pediatric Patient with Hypokalemic Periodic Paralysis - A Case Report

We report on the anesthetic management of an 11-yearold girl with hypokalemic periodic paralysis who underwent left radius plate removal surgery. This patient’s course was complicated early in the postoperative period by an episode of bilateral lower limb paralysis. She presented with hypokalemia after general anesthesia; however, she recovered well after taking a potassium supplement. Patients with this disorder, who are apparently normal, can develop sudden paralysis when they are exposed to predisposing factors peri-operatively. Complications related to this rare genetic disorder, the factors that can precipitate these, and preventive measures are discussed.

Hypokalemic Periodic Paralysis With Reversible Electrophysiological Abnormalities: A Case Report

Hypokalemic periodic paralysis (HPP) is a reasonably rare condition, presenting complains being those associated with acute systemic weakness and hypokalemia. Majority of the cases are characterized as familial or primary, whereas sporadic cases are associated with various other conditions such as barium poisoning, hyperthyroidism, renal disorders, endocrinopathies and gastrointestinal potassium losses. We report a unique case in a 5-year-old female child following gastrointestinal losses (vomiting and diarrhea). According to the patient’s mother, for the past 2 days, she was lethargic, unable to walk and hold the neck. She underwent pyelolithotomy for recurrent kidney stones 5 years back. Her neurologic examination revealed diminished bulk overall, decreased tone, power and reflexes in lower limbs with down-going plantars. Labs (except potassium) and electrocardiography were normal. Nerve conduction studies (NCS) favored the diagnosis of Guillain-Barre syndrome. Intravenous immunoglobulin and potassium replacement was started. After a week, patient’s condition had a remarkable improvement. We did a repeat NCS which came out to be normal. Potassium serum values were normal too. We turned back to the other differential diagnosis of HPP. Our case report highlights several important factors. Firstly, it states that the NCS can be deceptive in patients with flaccid paralysis, especially when we are not suspecting hypokalemia. It further explains the importance of suspecting a diagnosis of HPP in a patient presenting with features of Guillain-Barre syndrome following an NCS. J Med Cases. 2018;9(6):177-178 doi: https://doi.org/10.14740/jmc3058w

Thyrotoxic hypokalemic periodic paralysis (THPP) A case report and review of literature

Thyrotoxic hypokalemic periodic paralysis (THPP) A case report and review of literature

Thyrotoxic hypokalemic periodic paralysis

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.

Accidental intravenous bolus infusion of potassium chloride in a young man with hypokalemic periodic paralysis

Hypokalemic periodic paralysis is anautosomal dominantdisease characterized by muscle weakness or paralysis with a matching fall in blood potassium levels. Paralysis attacks often occur in adolescence and are induced by strenuous exercise followed by rest, high carbohydrateor high sodiummeal content, sudden changes in temperature, and even excitement, noise, flashing lights and cold temperatures. Despite global daily use of intravenous and oral potassium in the treatment of patients, data about intravenous bolus potassium is rare. Here we report a 29-year-old man complaining of weakness in the upper and lower limbs. By initial diagnosis of periodic hypokalemic paralysis, potassium chloride was ordered by oral route. After a few minutes, we heard patient screaming in pain. He complained of severe acute pain in peripheral intravenous line, palpitation and dyspnea. We noticed that potassium chloride vial was infused directly via cubital vein in few minutes erroneously. Physical exam revealed sinus tachycardia and hypertension. We began hyperkalemia treatment immediately. With appropriate treatment,the patient was discharged with good condition after 12 hours of admission.

An atypical CaV1.1 mutation reveals a common mechanism for hypokalemic periodic paralysis.

Cannon reviews new evidence supporting a key role for anomalous inward currents in the etiology of hypokalemic periodic paralysis.

Na leak with gating pore properties in hypokalemic periodic paralysis V876E mutant muscle Ca channel.

Type 1 hypokalemic periodic paralysis (HypoPP1) is a poorly understood genetic neuromuscular disease characterized by episodic attacks of paralysis associated with low blood K+ The vast majority of HypoPP1 mutations involve the replacement of an arginine by a neutral residue in one of the S4 segments of the α1 subunit of the skeletal muscle voltage-gated Ca2+ channel, which is thought to generate a pathogenic gating pore current. The V876E HypoPP1 mutation has the peculiarity of being located in the S3 segment of domain III, rather than an S4 segment, raising the question of whether such a mutation induces a gating pore current. Here we successfully transfer cDNAs encoding GFP-tagged human wild-type (WT) and V876E HypoPP1 mutant α1 subunits into mouse muscles by electroporation. The expression profile of these WT and V876E channels shows a regular striated pattern, indicative of their localization in the t-tubule membrane. In addition, L-type Ca2+ current properties are the same in V876E and WT fibers. However, in the presence of an external solution containing low-Cl- and lacking Na+ and K+, V876E fibers display an elevated leak current at negative voltages that is increased by external acidification to a higher extent in V876E fibers, suggesting that the leak current is carried by H+ ions. However, in the presence of Tyrode's solution, the rate of change in intracellular pH produced by external acidification was not significantly different in V876E and WT fibers. Simultaneous measurement of intracellular Na+ and current in response to Na+ readmission in the external solution reveals a rate of Na+ influx associated with an inward current, which are both significantly larger in V876E fibers. These data suggest that the V876E mutation generates a gating pore current that carries strong resting Na+ inward currents in physiological conditions that are likely responsible for the severe HypoPP1 symptoms associated with this mutation.

Arginine-to-lysine mutations in the voltage sensor are associated with hypokalemic periodic paralysis

Arginine-to-lysine mutations in the voltage sensor are associated with hypokalemic periodic paralysis

Mechanisms Responsible for ω-Pore Currents in Cav Calcium Channel Voltage-Sensing Domains

Mutations of positively charged amino acids in the S4 transmembrane segment of a voltage-gated ion channel form ion-conducting pathways through the voltage-sensing domain, named ω-current. Here, we used structure modeling and MD simulations to predict pathogenic ω-currents in CaV1.1 and CaV1.3 Ca2+ channels bearing several S4 charge mutations. Our modeling predicts that mutations of CaV1.1-R1 (R528H/G, R897S) or CaV1.1-R2 (R900S, R1239H) linked to hypokalemic periodic paralysis type 1 and of CaV1.3-R3 (R990H) identified in aldosterone-producing adenomas conducts ω-currents in resting state, but not during voltage-sensing domain activation. The mechanism responsible for the ω-current and its amplitude depend on the number of charges in S4, the position of the mutated S4 charge and countercharges, and the nature of the replacing amino acid. Functional characterization validates the modeling prediction showing that CaV1.3-R990H channels conduct ω-currents at hyperpolarizing potentials, but not upon membrane depolarization compared with wild-type channels.

Fixed muscle weakness with overlying hypokalemic periodic paralysis in Sjogren syndrome: Report of six case

Background: Sjögren’s syndrome is the most common autoimmune cause of distal renal tubular acidosis (RTA). In distal RTA, the collecting tubules of kidney fail to excrete net titrable acid thereby producing metabolic acidosis. It also produce potassium loss from collecting tubules secondary to proton loss in order to maintain apical membrane neutrality. Despite potassium loss, majority of patients maintain normal potassium due to shift of intracellular potassium to extracellular fluid. However, rarely these patients may develop severe hypokalemia resulting in hypokalemic paralysis. Despite reports of hypokalemic periodic paralysis, progressive or fixed muscle weakness in these patients is seldom described.

Elevated resting H+ current in the R1239H type 1 hypokalaemic periodic paralysis mutated Ca2+ channel.

Missense mutations in the gene encoding the α1 subunit of the skeletal muscle voltage-gated Ca2+ channel induce type 1 hypokalaemic periodic paralysis, a poorly understood neuromuscular disease characterized by episodic attacks of paralysis associated with low serum K+ . Acute expression of human wild-type and R1239H HypoPP1 mutant α1 subunits in mature mouse muscles showed that R1239H fibres displayed Ca2+ currents of reduced amplitude and larger resting leak inward current increased by external acidification. External acidification also produced intracellular acidification at a higher rate in R1239H fibres and inhibited inward rectifier K+ currents. These data suggest that the R1239H mutation induces an elevated leak H+ current at rest flowing through a gating pore and could explain why paralytic attacks preferentially occur during the recovery period following muscle exercise. Missense mutations in the gene encoding the α1 subunit of the skeletal muscle voltage-gated Ca2+ channel induce type 1 hypokalaemic periodic paralysis, a poorly understood neuromuscular disease characterized by episodic attacks of paralysis associated with low serum K+ . The present study aimed at identifying the changes in muscle fibre electrical properties induced by acute expression of the R1239H hypokalaemic periodic paralysis human mutant α1 subunit of Ca2+ channels in a mature muscle environment to better understand the pathophysiological mechanisms involved in this disorder. We transferred genes encoding wild-type and R1239H mutant human Ca2+ channels into hindlimb mouse muscle by electroporation and combined voltage-clamp and intracellular pH measurements on enzymatically dissociated single muscle fibres. As compared to fibres expressing wild-type α1 subunits, R1239H mutant-expressing fibres displayed Ca2+ currents of reduced amplitude and a higher resting leak inward current that was increased by external acidification. External acidification also produced intracellular acidification at a higher rate in R1239H fibres and inhibited inward rectifier K+ currents. These data indicate that the R1239H mutation induces an elevated leak H+ current at rest flowing through a gating pore created by the mutation and that external acidification favours onset of muscle paralysis by potentiating H+ depolarizing currents and inhibiting resting inward rectifier K+ currents. Our results could thus explain why paralytic attacks preferentially occur during the recovery period following intense muscle exercise.