Periodic Paralyses

Updated: May 18, 2017
  • Author: Naganand Sripathi, MD; Chief Editor: Nicholas Lorenzo, MD, MHA, CPE  more...
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Overview

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.

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Pathophysiology

A clinically useful classification of primary periodic paralyses, shown in Table 1, includes hypokalemic, hyperkalemic, and paramyotonic forms.

Table 1. Primary Periodic Paralysis (modified from Jurkat-Rott and Lehmann-Horn [1] ) (Open Table in a new window)

Disease Gene Protein Inheritance Mutation
HyperPP SCN4A Nav1.4 Dominant Gain
NormoPP       Gain (ω-pore)
Paramyotoniacongenita Gain
HypoPP Type II Gain (ω-pore)
HypoPP Type I CACNA1S Cav1.1 Dominant Gain (ω-pore)
ThyrotoxicPP KCNJ18 Kir2.18 Dominant Loss
Andersen-Tawil syndrome KCNJ2 Kir2.1 Dominant Loss

 

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 PP. Chloride channelopathies are not associated with episodic weakness and are discussed in more detail in the articles on myotonic disorders.

Summary of channel dysfunction in various types of PP

With HyperPP fast channel inactivation, mutations are usually situated in the inner parts of transmembrane segments or in the intracellular loops affecting the docking sites for the fast inactivating particle, thus impairing fast channel inactivation leading to persistent Na+ current.

With HypoPP hyperpolarization-activated cation leak counteracting K+ -rectifying current, mutations cause outermost arginine or lysine substitution.

With NormoPP depolarization-activated cation leak, mutations are in deeper locations of voltage sensor of domain II at codon R675. [1, 2]

Ion channel dysfunction is usually well compensated with normal excitation, and additional triggers are often necessary to produce muscle inexcitability owing to sustained membrane depolarization.

Glucose and potassium intake has the opposite effects in these disorders. In HyperPP, potassium intake triggers the attack, whereas glucose ameliorates it. In contrast, glucose provokes hypokalemic attacks and potassium is the treatment for the attack. [2]

Note the image below.

Mutations in periodic paralysis. Mutations in periodic paralysis.

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.

Normokalemic PP resembles both HyperPP (potassium sensitivity) and HypoPP (duration of attacks) and is caused by SCN4A mutations at a deeper location of voltage sensor DII at codon 675. R675 mutations differ from HypoPP in that these mutations result in depolarization-activated gating pore generating ω-current with reversed voltage dependence as this site is exposed to extracellular sites at stronger depolarization. [3]

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. [4]

Voltage sensor charge loss accounts for most cases of HypoPP. Sodium and calcium channels have homologous pore-forming α subunits. Almost all of the mutations in Cav1.1 (HypoPP-1) and Nav1.4 (HypoPP-2) neutralize a positively charged amino acid in one of the outermost arginines or lysines of voltage sensors. The Nav1.4 mutations are most commonly situated in the voltage sensors of I, II, and III repeats, causing a cation leak.

Substitution of outermost arginine with a smaller amino acid such as glycine opens a conductive pathway at hyperpolarized potential, resulting in an inward cation current (cation leak or ω current to distinguish from (ω-) through ion–conducting pore, is a hyperpolarization-activated current of monovalent cations through S4 gating pore counteracting rectifying K+ currents) depolarizing or destabilizing the resting potential.

S4 segment moves outward during depolarization closing the conductive pathway. Muscle fibers with severe voltage sensor mutations are depolarized not only during hypokalemia but also at potassium levels in the normal range, explaining interictal and permanent weakness. Severe myopathy with fatty replacement of muscle tissue is commonly found in patients with Cav1.1 R1239H (DIV mutations). [1]

Glucocorticosteroids cause HypoPP by stimulating Na+ K+ ATPase mediated by insulin and amylin. [5]

Potassium channel gene

Inward rectification is an important property of Kir channels. Rectification involves voltage-dependent conduction-pore blockage of pore with polyamines and Mg++ during depolarization, and this blockage is removed during potential gradient during hyperpolarization. Potassium channel mutations are seen in Andersen-Tawil syndrome and thyrotoxic PP.

The triad of dysmorphic features, periodic paralysis, and cardiac arrhythmias characterizes Andersen-Tawil syndrome. This syndrome is associated with mutations in the KCNJ2 gene. [6] 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.

Mutations in Kir2.6 cause susceptibility to thyrotoxic PP. Episodic weakness seen in thyrotoxic PP is similar to that seen in HypoPP and Andersen-Tawil syndrome. This disorder is most prevalent in Asians and Latin American men. Thyrotoxic PP is a genetic disorder unmasked by thyrotoxicosis. Kir2.6 is primarily expressed in skeletal muscle. Triiodothyronine enhances KCNJ18 transcription, which may drive enhanced expression of Kir2.6. PKC is activated during thyrotoxicosis because of increased PIP2 turnover and Kir channels directly interact with PIP2 during normal gating. In Andersen-Tawil syndrome, there is decreased PIP2 affinity. In thyrotoxic PP, none of the mutations alters Kir2.6 rectification. [7]

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Epidemiology

Frequency

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.

Thyrotoxic PP is most common in males (85%) of Asian descent with a frequency of approximately 2%.

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