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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 HyperPP NormoPP Paramyotoniacongenita HypoPP Type II HypoPP Type I ThyrotoxicPP Andersen-Tawil syndrome CACNA1S KCNJ18 KCNJ2 Cav1.1 Kir2.18 Kir2.1 Dominant Dominant Dominant Gene SCN4A Protein Nav1.4 Inheritance Dominant Mutation Gain Gain (-pore) Gain Gain (-pore) Gain (-pore) Loss 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.
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.
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 fastinactivation 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, andM1592V. 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 current with reversed voltage dependence as this site is exposed to extracellular sites at stronger depolarization.[3]
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 inCACNL1A3 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 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 current to distinguish from (-) through ionconducting 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]
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]