Introduction
Background
The heterogeneous group of muscle diseases known as periodic paralyses (PP) is characterized by episodes of flaccid muscle weakness occurring at irregular intervals. Most of the conditions are hereditary and are more episodic than periodic. They can be divided conveniently into primary and secondary disorders.
General characteristics of primary PP include the following: (1) they are hereditary; (2) most are associated with alteration in serum potassium levels; (3) myotonia sometimes coexists; and (4) both myotonia and PP result from defective ion channels.
Pathophysiology
A clinically useful classification of primary periodic paralyses, shown in Table 1, includes hypokalemic, hyperkalemic, and paramyotonic forms.Table 1. Primary Periodic ParalysisOpen table in new window
Table
| Sodium channel | Hyperkalemic PP (HyperPP) Hypokalemic PP (HypoPP2) Paramyotonia congenita Potassium-aggravated myotonia |
| Calcium channel | Hypokalemic PP (HypoPP1) |
| Potassium channel | Andersen-Tawil syndrome Hyperkalemic PP or hypokalemic PP* |
| Sodium channel | Hyperkalemic PP (HyperPP) Hypokalemic PP (HypoPP2) Paramyotonia congenita Potassium-aggravated myotonia |
| Calcium channel | Hypokalemic PP (HypoPP1) |
| Potassium channel | Andersen-Tawil syndrome Hyperkalemic PP or hypokalemic PP* |
*The deficit was described in 2 small families and has not been substantiated by others.1,2
The physiologic basis of flaccid weakness is inexcitability of the muscle membrane (ie, sarcolemma). Alteration of serum potassium level is not the principal defect in primary PP; the altered potassium metabolism is a result of the PP. In primary and thyrotoxic PP, flaccid paralysis occurs with relatively small changes in the serum potassium level, whereas in secondary PP, serum potassium levels are markedly abnormal.
No single mechanism is responsible for this group of disorders. Thus, they are heterogeneous but share some common traits. The weakness usually is generalized but may be localized. Cranial musculature and respiratory muscles usually are spared. Stretch reflexes are either absent or diminished during the attacks. The muscle fibers are electrically inexcitable during the attacks. Muscle strength is normal between attacks but, after a few years, some degree of fixed weakness develops in certain types of PP (especially primary PP). All forms of primary PP (except Becker myotonia congenita [MC]) are either autosomal dominant inherited or sporadic (most likely arising from point mutations).
Voltage-sensitive ion channels closely regulate generation of action potentials (brief and reversible alterations of the voltage of cellular membranes). These are selectively and variably permeable ion channels. Energy-dependent ion transporters maintain concentration gradients. During the generation of action potentials, sodium ions move across the membrane through voltage-gated ion channels. The resting muscle fiber membrane is polarized primarily by the movement of chloride through chloride channels and is repolarized by movement of potassium. Sodium, chloride, and calcium channelopathies, as a group, are associated with myotonia and PP. The functional subunits of sodium, calcium, and potassium channels are homologous. Sodium channelopathies are better understood than calcium or chloride channelopathies. All forms of familial PP show the final mechanistic pathway involving aberrant depolarization, inactivating sodium channels, and muscle fiber inexcitability.
Discussion in this article primarily addresses the sodium, calcium, and potassium channelopathies as well as secondary forms of periodic paralyses (PP). Chloride channelopathies are not associated with episodic weakness and are discussed in more detail in the articles on myotonic disorders.
Muscle sodium channel gene
The sodium channel has an alpha subunit and a beta subunit. The alpha subunit of the sodium channel is a 260-kd glycoprotein comprising about 1800-2000 amino acids. This channel is highly conserved evolutionarily from Drosophila to human. It has 4 homologous domains (I-IV) that fold to form a central pore, each with 225-325 amino acids. Each domain consists of 6 hydrophobic segments (S1-S6) traversing the cell membrane. The main functions of the channel include voltage-sensitive gating, inactivation, and ion selectivity. The extracellular loop between S5 and S6 dips into the plasma membrane and participates in the formation of the pore. The S4 segment contains positively charged amino acids at every third position and functions as a voltage sensor. Conformation changes may occur during depolarization, resulting in activation and inactivation of the channel. The cellular loop between domain III-S6 and domain IV-S1 acts as an inactivating gate.
The sodium channel has 2 gates (activation and inactivation) and can exist in 3 states. At rest with the membrane polarized, the activation gate is closed and the inactivation gate is opened. With depolarization, the activation gate opens, allowing sodium ions to pass through the ion channel and also exposing a docking site for the inactivation gate. With continued depolarization, the inactivation gate closes, blocking the entry of sodium into the cell and causing the channel to enter the fast-inactivation state. This inactivation of the channel allows the membrane to become repolarized, resulting in a return to the resting state with the activation gate closed and the inactivation gate opened. Two inactivation processes occur in mammalian skeletal muscle: Fast inactivation involves terminating the action potential and acts on a millisecond time scale. Slow inactivation takes seconds to minutes and can regulate the population of excitable sodium channels.
Sodium channel mutations that disrupt fast and slow inactivation are usually associated with a phenotype of HyperPP and myotonia, where as mutations that enhance slow or fast inactivation producing loss of sodium channel function cause HypoPP.
Mutations of the sodium channel gene (SCN4A) have several general features. Most of the mutations are in the "inactivating" linker between repeats III and IV, in the "voltage-sensing" segment S4 of repeat IV or at the inner membrane where they could impair the docking site for the inactivation gate. The clinical phenotype differs by specific amino acid substitution and, while some overlap may occur between hyperkalemic PP, paramyotonia congenita (PC), and potassium-aggravated myotonias (PAM), the 3 phenotypes are generally distinct (as described below). Nearly all mutant channels have impaired fast-inactivation of sodium current. Most patients are sensitive to systemic potassium or to cold temperature.
Two populations of channels exist, mutant and wild-type; the impaired fast-inactivation results in prolonged depolarization of the mutant muscle fiber membranes and can explain the 2 cardinal symptoms of these disorders, myotonia and weakness. In hyperkalemic PP, a gain of function occurs in mutant channel gating, resulting in an increased sodium current excessively depolarizing the affected muscle. Mild depolarization (5-10 mV) of the myofiber membrane, which may be caused by increased extracellular potassium concentrations, results in the mutant channels being maintained in the noninactivated mode. The persistent inward sodium current causes repetitive firing of the wild-type sodium channels, which is perceived as stiffness (ie, myotonia).
If a more severe depolarization (20-30 mV) is present, both normal and abnormal channels are fixed in a state of inactivation, causing weakness or paralysis. Thus, subtle differences in severity of membrane depolarization may make the difference between myotonia and paralysis. Temperature sensitivity is a hallmark of PC. Cold exacerbates myotonia and induces weakness. A number of mutations are associated with this condition, 3 of them at the same site (1448) in the S4 segment. These mutations replace arginine with other amino acids and neutralize this highly conserved S4 positive charge. Mutations of these residues are the most common cause of PC. Some of the possible mechanisms responsible for temperature sensitivity include the following:
- Temperature may differentially affect the conformational change in the mutant channel.
- Lower temperatures may stabilize the mutant channels in an abnormal state.
- Mutations may alter the sensitivity of the channel to other cellular processes, such as phosphorylation or second messengers.
Most cases of hyperkalemic PP are due to 2 mutations in SCN4A, T704M, and M1592V. Mutations in the sodium channel, especially at residues 1448 and 1313, are responsible for paramyotonia congenita. A small proportion of hypokalemic periodic paralysis cases are associated with mutations at codons 669 and 672 (HypoPP2). In HypoPP2, sodium channel mutations enhance inactivation to produce a net loss of function defect.
Calcium channel gene
The calcium channel gene (CACNL1A3) is a complex of 5 subunits (alpha-1, alpha-2, beta, gamma, and delta). The skeletal muscle dihydropyridine (DHP) receptor is located primarily in the transverse tubular membrane. The alpha-1 subunit has binding sites for DHP drugs and conducts the slow L-type calcium current. It also participates in excitation-contraction (EC) coupling and acts as a voltage sensor through its linkage with the ryanodine receptor of sarcoplasmic reticulum (ie, calcium release channel). Any changes in the membrane potential are linked to intracellular calcium release, enabling EC coupling. Point mutations in DHP receptor/calcium channel alpha-1 subunit cause hypokalemic PP (HypoPP1). Two mutations of CACNA1S gene, R528H and R1239H, are responsible for most cases of hypokalemic PP.
The physiological basis of disease is still not understood, but is more likely due to a failure of excitation rather than a failure of EC coupling. However, hypokalemia-induced depolarization may reduce calcium release, affecting the voltage control of the channel directly or indirectly through inactivation of the sodium channel. Insulin and adrenaline may act in a similar manner. Mutations of the calcium channel gene have some similarities to SCN4A mutations. Mutations modify channel inactivation but not voltage-dependent activation. Recordings from myotube cultures from affected patients revealed a 30% reduction in the DHP-sensitive L-type calcium current. Channels are inactivated at low membrane potentials.
Calcium channel mutations cause a loss of function manifested as a reduced current density and slower inactivation. How this inactivation is related to hypokalemia-induced attacks is not understood. At least in R528H mutation, a possible secondary channelopathy occurs, tied to a reduction in the ATP-sensitive potassium current from altered calcium homeostasis. The lower currents associated with CACNL1A3 mutations could slightly alter intracellular calcium homeostasis, which could affect the properties and expression of K+ channels, particularly KATP (ATP-sensitive potassium channel) belonging to inward rectifier class of channels. Insulin also acts in HypoPP by reducing this inward rectifier K+ current.
Voltage sensor charge loss accounts for most cases of HypoPP. Sodium and calcium channels have homologous pore-forming alfa subunits. Point mutations in CACNL1A3 and SCN4A affect argentine residues in the S4 voltage sensors of these channels. Arginine mutations in S4 segments are responsible for 90% of HypoPP cases.3
Glucocorticosteroids cause HypoPP by stimulating Na+ K+ ATPase mediated by insulin and amylin.4
Potassium channel gene
Potassium channel mutations are seen in Andersen-Tawil syndrome. The triad of dysmorphic features, periodic paralysis, and cardiac arrhythmias characterizes Andersen-Tawil syndrome. This syndrome is associated with mutations in the KCNJ2 gene.5 The KCNJ2 gene encodes the inward-rectifying potassium channel Kir2.1. Potassium channel mutations in KCNE3 are reported to cause hypokalemic PP, but this has not been substantiated.
Frequency
United States
The frequencies of hyperkalemic periodic paralysis, paramyotonia congenita (PC), and potassium-aggravated myotonias (PAM) are not known. Hypokalemic periodic paralysis has a prevalence of 1 case per 100,000 population.
International
Not known
Race
Thyrotoxic PP is most common in males (85%) of Asian descent with a frequency of approximately 2%.
Clinical
History
All periodic paralyses (PPs) are characterized by episodic weakness. Strength is normal between attacks. Fixed weakness may develop later in some forms. Most patients with primary PP develop symptoms before the third decade.
- Hyperkalemic periodic paralyses
- Age at onset is younger than 10 years. Patients usually describe a sense of heaviness or stiffness in the muscles. Weakness starts in the thighs and calves, which then spreads to arms and neck. Proximal weakness predominates; distal muscles may become involved after vigorous exercise.
- In children, a myotonic lid lag (lagging of upper eyelid on downward gaze) may be the earliest symptom. Complete paralysis is rare and some residual mobility remains. Respiratory muscle involvement is rare. The attacks last less than 4 hours and in the majority of cases, less than 1 hour. Sphincters are not involved; any bowel and bladder dysfunction is due to abdominal muscle weakness.
- Weakness occurs during rest after a period of strenuous exercise or during fasting. It also may be provoked by potassium, cold, ethanol, or stress. It may be relieved by mild prolonged exercise or carbohydrate intake. Patients also may report muscle pains and paresthesias. Between attacks, clinical and electrical myotonia is present in the majority of patients. Some families have no myotonia. Clinically apparent myotonia is seen less than 20% of patients, but electrical myotonia may be found in 50-75%. Interictal weakness, if present, is not as severe as in hypokalemic PP.
- Hypokalemic periodic paralyses
- Severe cases present in early childhood and mild cases may present as late as the third decade. A majority of cases present before age 16 years. Weakness may range from slight transient weakness of an isolated muscle group to severe generalized weakness. Severe attacks begin in the morning, often with strenuous exercise or a high carbohydrate meal on the preceding day. Sometimes, the time between premonitory symptoms to full-blown attack is in order of minutes. Attacks may also be provoked by stress, including infections, menstruation, lack of sleep, and certain medications (eg, beta-agonists, insulin, corticosteroids). Patients wake up with severe symmetrical weakness, often with truncal involvement.
- Mild attacks are frequent and involve only a particular group of muscles, and may be unilateral, partial, or monomelic. This may affect predominantly legs; sometimes, extensor muscles are affected more than flexors. Duration varies from a few hours to almost 8 days but seldom exceeds 72 hours. The attacks are intermittent and infrequent in the beginning but may increase in frequency until attacks occur almost daily. The frequency starts diminishing by age 30 years; it rarely occurs after age 50 years.
- Urinary output is decreased during the attack because water accumulates intracellularly in muscles. In HypoPP1 patients, the age of onset is earlier (10 y), the symptoms lasts longer (20 h), and the fixed proximal weakness is more frequent (about 70%), compared with HypoPP2 patients (16 y, 1 h, none).
- Permanent muscle weakness may be seen later in the course of the disease and may become severe. Hypertrophy of the calves has been observed. Proximal muscle wasting, rather than hypertrophy, may be seen in patients with permanent weakness.
- Potassium-aggravated myotonia
- These autosomal dominant inherited disorders have been divided into 3 categories, myotonia fluctuans, myotonia permanens, and acetazolamide-responsive MC.
- Weakness is rare in these disorders, but episodic muscle pain and stiffness due to myotonia is present in myotonia fluctuans and acetazolamide-responsive MC, while it is continuous in myotonia permanens.
- Attacks begin at rest soon after exercise in myotonia fluctuans but are more common with exercise in acetazolamide-responsive MC. Potassium and cold aggravate the myotonia in all 3 disorders.
- Paramyotonia congenita
- In this autosomal dominant inherited disorder, myotonia worsens with activity (paradoxical myotonia) or cold temperatures.
- Symptoms are most pronounced in the face.
- Episodic weakness also may develop after exercise or cold temperatures and usually lasts only a few minutes, but may last as long as days.
- Potassium loading usually worsens the symptoms, but in some cases, lowering the serum potassium level precipitates the attacks.
- Thyrotoxic periodic paralyses
- Thyrotoxicosis periodic paralyses (TPP) are the most common secondary hypokalemic PP. TPP is most common in adults aged 20-40 years. Hyperinsulinemia, a carbohydrate load, and exercise are important in precipitating paralytic attacks. Weakness is proximal and, if severe, may involve respiratory or bulbar muscles. Attacks last hours to days.
- The prevalence of TPP in patients with thyrotoxicosis is estimated to be 0.1-0.2% in Caucasians and 13-14% in Chinese. Ninety-five percent of TPP cases are sporadic. As TPP is more common in Asians, a genetic predisposition is strongly suspected. Familial clustering of TPP indicates unmasking of an inherited disease (which is sporadic) by thyrotoxicosis. A mutation in KCNE3 potassium channel gene was identified in one series.6
- Andersen-Tawil syndrome
- Andersen-Tawil syndrome is characterized by variable expression of the triad of dysmorphic features, periodic paralysis, and cardiac arrhythmias. Patients may have short stature, hypertelorism, low-set ears, micrognathia, fifth finger clinodactyly, and scoliosis. Episodic weakness lasting a few hours to several days may arise spontaneously but usually follows physical activity. The periodic paralysis is not associated with myotonia.
- Prolonged QT interval and ventricular arrhythmias are the most common cardiac manifestations. Other ECG abnormalities include PVCs, ventricular bigeminy, supraventricular and ventricular tachycardias, prominent U waves, and torsades de pointes. Bidirectional ventricular tachycardia, which is characterized by beat-to-beat alternating QRS axis polarity, is unique to a subset of patients. Patients may be completely asymptomatic. Patients may experience palpitations, syncopal episodes, and cardiac arrest. Sudden cardiac death is less frequent in ATS when compared with the other long QT syndromes.
Physical
Most of the patients with a periodic paralysis (PP) have similar clinical features, which are as follows:
- Interictal lid lag and eyelid myotonia - May be the only clinical signs in hyperkalemic PP
- Normal sensation
- Fixed proximal weakness - May develop in patients with either hyperkalemic or hypokalemic PP
- Diminished stretch reflexes during attacks
Open table in new window
Table
| Syndrome | Age of Onset | Duration of Attack | Precipitating Factors | Severity of Attacks | Associated Features |
| Hyperkalemic periodic paralyses | First decade of life | Few minutes to less than 2 h (mostly less than 1 h) |
| Rarely severe |
|
| Hypokalemic periodic paralyses |
|
|
|
|
|
| Potassium- associated myotonia | First decade | No weakness |
| Attacks of stiffness can be mild to severe | Muscle hypertrophy |
| Paramyotonia congenita | First decade | 2-24 h | Cold | Rarely severe |
|
| Thyrotoxic periodic paralyses | Third and fourth decades | Few hours to 7 d |
| Same as hypokalemic PP |
|
| Syndrome | Age of Onset | Duration of Attack | Precipitating Factors | Severity of Attacks | Associated Features |
| Hyperkalemic periodic paralyses | First decade of life | Few minutes to less than 2 h (mostly less than 1 h) |
| Rarely severe |
|
| Hypokalemic periodic paralyses |
|
|
|
|
|
| Potassium- associated myotonia | First decade | No weakness |
| Attacks of stiffness can be mild to severe | Muscle hypertrophy |
| Paramyotonia congenita | First decade | 2-24 h | Cold | Rarely severe |
|
| Thyrotoxic periodic paralyses | Third and fourth decades | Few hours to 7 d |
| Same as hypokalemic PP |
|
Causes
Refer to Pathophysiology and Table 2 and Table 3.
More on Periodic Paralyses |
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| Differential Diagnoses & Workup: Periodic Paralyses |
| Treatment & Medication: Periodic Paralyses |
| Follow-up: Periodic Paralyses |
| References |
| Next Page » |
References
Miller TM, Dias da Silva MR, Miller HA, et al. Correlating phenotype and genotype in the periodic paralyses. Neurology. Nov 9 2004;63(9):1647-55. [Medline].
Venance SL, Cannon SC, Fialho D, et al. The primary periodic paralyses: diagnosis, pathogenesis and treatment. Brain. Jan 2006;129(Pt 1):8-17. [Medline].
Matthews E, Labrum R, Sweeney MG, Sud R, Haworth A, Chinnery PF, et al. Voltage sensor charge loss accounts for most cases of hypokalemic periodic paralysis. Neurology. May 5 2009;72(18):1544-7. [Medline].
Arzel-Hezode M, McGoey S, Sternberg D, Vicart S, Eymard B, Fontaine B. Glucocorticoids may trigger attacks in several types of periodic paralysis. Neuromuscul Disord. Mar 2009;19(3):217-9. [Medline].
Donaldson MR, Yoon G, Fu YH, Ptacek LJ. Andersen-Tawil syndrome: a model of clinical variability, pleiotropy, and genetic heterogeneity. Ann Med. 2004;36 Suppl 1:92-7. [Medline].
Dias Da Silva MR, Cerutti JM, Arnaldi LA, Maciel RM. A mutation in the KCNE3 potassium channel gene is associated with susceptibility to thyrotoxic hypokalemic periodic paralysis. J Clin Endocrinol Metab. Nov 2002;87(11):4881-4. [Medline].
Assadi F. Diagnosis of hypokalemia: a problem-solving approach to clinical cases. Iran J Kidney Dis. Jul 2008;2(3):115-22. [Medline].
Streib EW. AAEE minimonograph #27: Differential diagnosis of myotonic syndromes. Muscle Nerve. Sep 1987;10(7):603-15. [Medline].
Fournier E, Arzel M, Sternberg D, et al. Electromyography guides toward subgroups of mutations in muscle channelopathies. Ann Neurol. Nov 2004;56(5):650-61. [Medline].
Levitt JO. Practical aspects in the management of hypokalemic periodic paralysis. J Transl Med. Apr 21 2008;6:18. [Medline].
Elbaz A, Vale-Santos J, Jurkat-Rott K. Hypokalemic periodic paralysis and the dihydropyridine receptor (CACNL1A3): genotype/phenotype correlations for two predominant mutations and evidence for the absence of a founder effect in 16 caucasian families. Am J Hum Genet. Feb 1995;56(2):374-80. [Medline].
Engel AG, Lambert EH, Rosevear JW, Tauxe WN. Clinical and electromyographic studies in a patient with primary hypokalemic periodic paralysis. Am J Med. Apr 1965;38:626-40. [Medline].
Griggs RC. Evaluation and Treatment of Myopathies. 1995. Philadelphia: FA Davis; 318-354.
Hoffman EP, Lehmann-Horn F, Rudel R. Overexcited or inactive: ion channels in muscle disease. Cell. Mar 10 1995;80(5):681-6. [Medline].
Junker J, Haverkamp W, Schulze-Bahr E, et al. Amiodarone and acetazolamide for the treatment of genetically confirmed severe Andersen syndrome. Neurology. Aug 13 2002;59(3):466. [Medline].
Koch MC, Steinmeyer K, Lorenz C. The skeletal muscle chloride channel in dominant and recessive human myotonia. Science. Aug 7 1992;257(5071):797-800. [Medline].
Lin SH, Lin YF, Chen DT, et al. Laboratory tests to determine the cause of hypokalemia and paralysis. Arch Intern Med. Jul 26 2004;164(14):1561-6. [Medline].
McManis PG, Lambert EH, Daube JR. The exercise test in periodic paralysis. Muscle Nerve. Oct 1986;9(8):704-10. [Medline].
Meola G, Sansone V. Treatment in myotonia and periodic paralysis. Rev Neurol (Paris). May 2004;160(5 Pt 2):S55-69. [Medline].
Ptacek L. The familial periodic paralyses and nondystrophic myotonias. Am J Med. Jul 1998;105(1):58-70. [Medline].
Ptacek LJ, Johnson KJ, Griggs RC. Genetics and physiology of the myotonic muscle disorders. N Engl J Med. Feb 18 1993;328(7):482-9. [Medline].
Ruff RL. Slow inactivation: slow but not dull. Neurology. Mar 4 2008;70(10):746-7. [Medline].
Tricarico D, Barbieri M, Mele A, et al. Carbonic anhydrase inhibitors are specific openers of skeletal muscle BK channelof K+-deficient rats. FASEB J. Apr 2004;18(6):760-1. [Medline].
Zhang J, George AL, Griggs RC. Mutations in the human skeletal muscle chloride channel gene (CLCN1) associated with dominant and recessive myotonia congenita. Neurology. Oct 1996;47(4):993-8. [Medline].
Further Reading
Keywords
periodic paralysis, hypokalemia, hyperkalemia, myotonia, paramyotonia congenita, potassium-aggravated myotonia, voltage-sensitive ion channels, voltage-gated ion channels, channelopathy, calcium channels, sodium channels, chloride channels, thyrotoxicosis, periodic paralyses, PP
