Sodium channel mutations in paramyotonia congenita and hyperkalemic periodic paralysis

Clinical and electrophysiological data have outlined a spectrum of similar yet distinct periodic paralyses, including potassium-sensitive (hyperkalemic periodic paralysis [HYPP]) and temperature-sensitive (paramyotonia congenita [PC]) forms. Recent work has revealed that these disorders result from allelic defects in the x-subunit of the adult, human skeletal muscle sodium channel. We report an additional mutation, a leucine - arginine substirution in the ss segment of domain 4 (L1433R), that results in the PC phenotype. Five other HYPP and PC families have been ascertained, and previously reported sodium channel mutations have been identified in each. Characterization of these mutartions and phenotypic variations in such familes will contribute to the understanding of sodium channel structure and function relationships, as well as channel malfunction in the periodic paralyses.     

Different effectiveness of tocainide and hydrochlorothiazide in paramyotonia congenita with hyperkalemic episodic paralysis

We investigated the effectiveness of tocainide and hydrochlorothiazide on muscular symptoms in a patient with paramyotonia congenita and episodic attacks of hyperkalemic paralysis. Generalized weakness was evoked by exercise and potassium loading. Myotonia and weakness were evoked by local muscle cooling. Tocainide prevented myotonia and weakness induced by cooling, but failed to prevent hyperkalemic weakness. Hydrochlorothiazide prevented hyperkalemic weakness, but did not influence symptoms evoked by cooling. These results suggest that, in this disorder, two different mechanisms cause muscular weakness.     

The anesthetic propofol modulates gating in paramyotonia congenita mutant muscle sodium channels

We examined the effects of propofol on a paramyotonia congenita mutant skeletal muscle sodium channel in vitro, because life-threatening complications resulting from severe muscle rigidity during induction of anesthesia have been observed using other anesthetics in patients with hereditary sodium channel myopathies. Our hypothesis was that propofol might interact directly with mutant channels, causing enhanced muscle excitability in affected patients. Whole-cell voltage-clamp experiments were performed on HEK 293 cells expressing R1448H mutant sodium channels. Propofol blocked sodium inward current at clinical concentrations (5 micromol/L) when depolarizing pulses were started from holding potentials close to the physiological resting potential (-70 mV). Higher propofol concentrations (>/=25 micromol/L) accelerated pathologically delayed inactivation kinetics and delayed pathologically enhanced recovery from inactivation. Our in vitro results show that inactivation-deficient sodium channels are specifically targeted and blocked by propofol. This might reduce enhanced muscle excitability experienced by affected patients in vivo.     

Hypokalemic paralysis in two patients with paramyotonia congenita (PC) and known hyperkalemic/exercise-induced weakness

Two male patients from a single family with known PC and "potassium sensitivity" developed hypokalemic paralysis following generalized anesthesia. These patients confirm previous similar observations. It's significance and management are discussed.     

Patch clamp studies of the thr1313met mutant sodium channel causing paramyotonia congenita

Paramyotonia congenita (PC) is an autosomal-dominant disorder due to a point mutation in the adult skeletal muscle Na channel gene. Muscle fibers from PC patients have normal membrane properties at 32 degrees C. At 27 degrees C, they are inexcitable, have increased Na conductance, and have a reduced resting membrane potential of -40 mV. To define the biophysical basis for the muscle membrane abnormalities, we performed patch clamp whole-cell and outside-out single Na channel studies at 22 degrees C on cultured human muscle cells from 4 control patients and 2 sisters with PC and the thr1313met mutant Na channel. The whole-cell studies showed no difference in window currents. Unlike cells transfected with the thr1313met mutant Na channel, the inactivation time constant, tau(h), for PC cells was similar to control cells. For PC recordings containing long-duration single Na channel openings, mean open time was prolonged at -60, -40, and -20 mV. The long-duration Na channel openings occurred randomly with no evidence of modal gating. The number of channel openings, occurrence of late openings, and the prolonged mean open time resulted in a sustained inward Na current at -40 mV. We suggest that the biophysical marker of the thr1313met mutant Na channel is a voltage- and temperature-dependent abnormality in mutant single Na channel behavior.     

Paramyotonia congenita and hyperkalemic periodic paralysis are linked to the adult muscle sodium channel gene.

The hyperkalemic periodic paralyses are a clinically heterogeneous group of autosomal dominant syndromes characterized by episodic paralysis associated with an elevated serum potassium level. Affected individuals in the same family tend to have homogeneous symptom complexes, although phenotypic variation is present among different families. For example, myotonia is absent in some pedigrees, present in others, and, in a third variant, paramyotonia congenita, myotonia coexists with cold-induced paralysis. Electrophysiological studies have demonstrated variant-specific abnormalities in skeletal muscle membrane sodium conductance. We tested the hypothesis that hyperkalemic periodic paralysis (without myotonia) and paramyotonia congenita are tightly linked to the tetrodotoxin-sensitive adult skeletal muscle sodium channel gene on chromosome 17q23-25 in two large pedigrees. The DNA polymorphisms detected in the growth hormone skeletal muscle sodium channel complex (GH1-SCN4A) and by flanking polymorphic markers (D17S74 and D17S40) demonstrated no recombinants between the disease phenotypes and this complex. Phenotypic variation in the hereditary hyperkalemic periodic paralyses may result from allelic heterogeneity at the tetrodotoxin-sensitive adult skeletal muscle sodium channel locus.     

Different gene loci for hyperkalemic and hypokalemic periodic paralysis

The periodic paralyses are dominantly inherited disorders in which patients acutely develop muscle weakness in association with changes in the level of blood potassium. We recently reported genetic linkage of hyperkalemic periodic paralysis (HIKPP) to the gene encoding the adult form of the skeletal muscle sodium channel on the long arm of chromosome 17. In this paper, we exclude genetic linkage between hypokalemic periodic paralysis (HOKPP) and this sodium channel gene, demonstrating that there is non-allelic genetic heterogeneity among different forms of periodic paralysis. Electrophysiological abnormalities in muscle sodium conductance have been reported for both HIKPP and HOKPP as well as other muscle disorders characterized by membrane hyperexcitability or myotonia (myotonia congenita, paramyotonia congenita and the Schwartz-Jampel syndrome). The possibility that there may be a family of human muscle diseases arising from mutations in the sodium channel suggests these disorders may be classified by categories of mutations within this critical voltage-sensitive membrane protein.     

beta-Adrenergic treatment of hyperkalemic periodic paralysis

In a patient with hyperkalemic periodic paralysis, metaproterenol prevented muscular weakness and hyperkalemia in periods of rest after exercise. During a severe attack, the drug rapidly corrected hyperkalemia and seemed to enhance the return of strength. The action of metaproterenol may involve a beta-adrenergic-mediated increase of potassium transport via the sodium-potassium pump.     

正常血钾型周期性麻痹与高钾型周期性麻痹关系的基因研究

目的 探讨正常血钾型周期性麻痹(normoPP)的临床特点并在基因水平上研究normoPP与高钾型周期性麻痹(hyperPP)的关系。方法 研究患有normoPP。的2个家系及2例散发病例的临床特点，并应用聚合酶链反应—单链构象多态性分析(PCR—SSCP)方法检测其中18例患者及其亲属的SCN4A基因，并对发现异常构象的单链进行测序。为了确保试验结果可靠，每个家庭中至少1例患者进行了测序。结果 18例患者常规实验室检查未见异常，肌电图正常。散发病例2在发作间期行肌肉活检，光镜下未见异常，电镜下示局灶性肌纤维变性。基因研究发现：(1)家系1发生Metl592Val突变；(2)散发病例2及其父亲的SCN4A基因出现点突变G2418A，引起氨基酸序列的改变Val781Ile。(3)家系2和散发病例1未发生已知的可导致hyperPP的突变(Thr704Met、Alall56Thr、Met1360Val、Ilel495Phe、Met1592Val)。结论 NormoPP与hyperPP在临床表现方面有一定的相似性，二者可有共同的突变位点。     

Exercise and rest in hyperkalemic periodic paralysis

The effect of muscle immobility, with and without prior vigorous exercise, on amplitude and area of the compound muscle action potential (CMAP) to supramaximal nerve stimulation was studied in a family with hyperkalemic periodic paralysis. Amplitude and area of different CMAPs were measured during basal state, sustained immobility, and after brief maximal voluntary exercise of these muscles. Sustained immobility reduced the amplitude and area of the CMAP, with maximal effect occurring after 30 minutes. Though brief intense exercise seemed to minimally accentuate these effects of subsequent immobility at certain times, serial CMAP monitoring over 60 minutes did not reveal major differences between exercised and nonexercised muscles. Muscle immobility in itself can alter the CMAP in hyperkalemic periodic paralysis. Prior intense muscle exercise may accentuate this to some degree. This appears to be the electrophysiologic correlate of the characteristic symptom of focal weakness induced by rest after exercise.     

Effects of phenytoin in two myotonic horses with hyperkalemic periodic paralysis.

The effects of phenytoin treatment were evaluated in 2 myotonic horses with hyperkalemic periodic paralysis (HPP). Phenytoin treatment abolished the clinical signs of muscle fasciculations following oral potassium challenge and decreased or abolished repetitive firing and myotonic discharges found on electromyographic examination. In both horses, an abnormally low threshold for calcium-induced calcium release was measured in heavy sarcoplasmic reticulum fractions from skeletal muscle, and this threshold increased with phenytoin treatment. Results suggest phenytoin is useful in modifying disordered ion regulation in the sarcolemma and sarcoplasmic reticulum of skeletal muscle in equine hyperkalemic periodic paralysis.     

Paramyotonia congenita or hyperkalemic periodic paralysis? Clinical and electrophysiological features of each entity in one family

The nosological distinction between paramyotonia congenita (PC) and hyperkalemic periodic paralysis (HPP) continues to generate debate. Recently, electrophysiological signs thought to be specific for each entity have been described and have been used to bolster the argument that the two disorders are distinct. We report a particularly instructive family wherein individual members had clinical features of either PC or HPP and electrophysiological features of both. We suggest that PC and HPP represent part of the spectrum of a single genetic disorder. Evoked response testing, with exercise and cold provocation, may be useful in determining the physiologic pattern that predominates in any one individual.     

Potentially fatal cardiac dysrhythmia and hyperkalemic periodic paralysis

An 11-year-old boy was evaluated for mild periodic muscular weakness exacerbated on separate occasions by disopyramide phosphate and procainamide. He and his mother both had bidirectional ventricular tachydysrhythmia (BVT), short stature, microcephaly, and clinodactyly. The mother, but not the child, had lingual myotonia. The two antiarrhythmic drugs worsened the muscular weakness without benefiting the cardiac dysrhythmia. Potassium loading produced skeletal muscle weakness and transient conversion of the BVT to normal sinus rhythm. Hypokalemia aggravated the BVT without causing weakness. Acetazolamide had no effect. The patient suffered a nonfatal cardiac arrest after several days of increased carbohydrate intake. Imipramine controlled the dysrhythmia without inducing weakness. Periodic paralysis should be considered as the diagnosis in children with BVT, a potentially fatal condition.     

Lack of cold sensitivity in hyperkalemic periodic paralysis

The nosologic distinction between paramyotonia congenita and hyperkalemic periodic paralysis is somewhat blurred. Muscle membrane inexcitability induced by cooling seems to be characteristic of paramyotonia congenita. The effect of cooling on the maximal compound muscle action potential (CMAP) in patients with paramyotonia congenita was compared to that in patients with hyperkalemic periodic paralysis. Diminution in CMAP amplitude and area, which was observed in paramyotonia congenita, did not occur in hyperkalemic periodic paralysis. We suggest that this effect of cooling on the CMAP can be utilized in the differentiation of these two syndromes.     

Regulation of plasma potassium in hyperkalemic periodic paralysis

Hyperkalemic periodic paralysis is frequently considered a disorder in which episodes of weakness and an attendant rise in plasma potassium interrupt a baseline of normal strength and potassium. We studied venous potassium throughout a 36-hour period in two patients with hyperkalemic periodic paralysis and in nine normals under rigidly controlled conditions. At no time did the patients with periodic paralysis have an attack of weakness, but their mean potassium concentrations were above the normal range for 33 to 36 hours. In hyperkalemic periodic paralysis, the postprandial change in potassium relative to insulin release exceeded normal. There appears to be a continuous alteration in potassium regulation in our patients with hyperkalemic periodic paralysis.     

Long-term effectiveness of acetazolamide on permanent weakness in hyperkalemic periodic paralysis

Acetazolamide is commonly used as an empirical treatment for inherited periodic paralyses although some patients may develop deleterious effects. We report a 65 year-old man with hyperkalemic periodic paralysis and late-onset permanent weakness in association with the common T704M mutation in α-subunit, skeletal muscle voltage-gated sodium channel gene. He rapidly recovered from weakness after acetazolamide treatment. Magnetic resonance imaging of thighs comparing pre- and post-treatment revealed a significant increase in muscle bulk. The patient has been without any type of weakness for over 6 years. This data show the remarkable benefit of acetazolamide on permanent weakness of hyperkalemic periodic paralysis in association with the T704M mutation.