Periodic Paralyses 

  • Author: Naganand Sripathi, MD; Chief Editor: Nicholas Lorenzo, MD   more...
 
Updated: Nov 25, 2010
 

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 (Open Table in a new window)

Sodium channelHyperkalemic PP (HyperPP)



Hypokalemic PP (HypoPP2)



Paramyotonia congenita



Calcium channelHypokalemic PP (HypoPP1)
Potassium channelAndersen-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 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.

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Epidemiology

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%.

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Contributor Information and Disclosures
Author

Naganand Sripathi, MD  Director, Neuromuscular Clinic, Department of Neurology, Henry Ford Hospital

Naganand Sripathi, MD is a member of the following medical societies: American Academy of Neurology, American Medical Association, Michigan State Medical Society, and New York Academy of Sciences

Disclosure: Nothing to disclose.

Specialty Editor Board

Paul E Barkhaus, MD  Professor, Department of Neurology, Medical College of Wisconsin; Director of Neuromuscular Diseases, Milwaukee Veterans Administration Medical Center

Paul E Barkhaus, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Neurological Association

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Senior Pharmacy Editor, eMedicine

Disclosure: eMedicine Salary Employment

Glenn Lopate, MD  Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University School of Medicine; Director of Neurology Clinic, St Louis ConnectCare; Consulting Staff, Department of Neurology, Barnes-Jewish Hospital

Glenn Lopate, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Selim R Benbadis, MD  Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital

Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association

Disclosure: UCB Pharma Honoraria Speaking, consulting; Lundbeck Honoraria Speaking, consulting; Cyberonics Honoraria Speaking, consulting; Glaxo Smith Kline Honoraria Speaking, consulting; Ortho McNeil Honoraria Speaking, consulting; Pfizer Honoraria Speaking, consulting; Sleepmed/DigiTrace Speaking, consulting

Chief Editor

Nicholas Lorenzo, MD  Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants

Nicholas Lorenzo, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Neurology

Disclosure: Nothing to disclose.

References
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Table 1. Primary Periodic Paralysis
Sodium channelHyperkalemic PP (HyperPP)



Hypokalemic PP (HypoPP2)



Paramyotonia congenita



Calcium channelHypokalemic PP (HypoPP1)
Potassium channelAndersen-Tawil syndrome



Hyperkalemic PP or hypokalemic PP*



*The deficit was described in 2 small families and has not been substantiated by others.[1, 2]
Table 2. Distinguishing Features Among the Common Forms of Periodic Paralyses
SyndromeAge of OnsetDuration of AttackPrecipitating



Factors



Severity of AttacksAssociated



Features



Hyper-kalemic periodic paralysesFirst decade of lifeFew minutes to less than 2 h (mostly less than 1 h)Low carbohydrate intake (fasting)



Cold



Rest following exercise



Alcohol



Infection



Emotional stress



Trauma



Menstrual period



Rarely severePerioral and limb paresthesias



Myotonia frequent



Occasional pseudo-hypertrophy of muscles



Hypo-kalemic periodic paralysesVariable -Childhood to third decade



Majority of cases before 16 years



Few hours to almost a week



Typically no longer than 72 h



Early morning attacks after previous day physical activity



High-carbohydrate meal, Chinese food, alcohol



Cold, change in barometric pressure or humidity



Fever, upper respiratory tract infections



Lack of sleep,



fatigue



Menstrual cycle



Severe



Complete paralysis



Occasional myotonic lid lag



Myotonia between attacks rare



Unilateral, partial, monomelic



Fixed muscle weakness late in disease



Potassium- associated myotoniaFirst decadeNo weaknessCold



Rest after exercise



Attacks of stiffness can be mild to severeMuscle hypertrophy
Para-myotonia congenitaFirst decade2-24 hColdRarely severePseudo-hypertrophy of muscles



Paradoxical myotonia



Fixed weakness rare



Thyrotoxic periodic paralysesThird and fourth decadesFew hours to 7 dSame as hypokalemic PP



Hyper-insulinemia



Same as hypokalemic PPFixed muscle weakness may develop



Hypokalemia during attacks



Table 3. Differential Diagnosis of Secondary Periodic Paralyses
HypokalemicHyperkalemic
Urinary potassium-wasting syndromes
  • Hyperaldosteronism
  • Conn syndrome
  • Bartter syndrome
  • Licorice intoxication
AlcoholAddison disease



Chronic renal failure



Hyporeninemic



Hypoaldosteronism



Drugs - Amphotericin B, bariumIleostomy with tight stoma
Renal tubular acidosisPotassium load
GI potassium-wasting syndromes
  • Laxative abuse
  • Severe diarrhea
Potassium-sparing diuretics
Table 4. Differential Diagnosis of Other Entities Causing Acute Generalized Weakness
DisorderPattern and



Distribution of



Weakness



Transient ischemic attacksFollow CNS distribution (ie, hemiparetic)



May have sensory symptoms and signs



Sleep attacksOccur at onset or termination of sleep



Last only minutes



Myelopathy
  • Traumatic
  • Transverse myelitis
  • Ischemic
Sensory symptoms



Presence of a sensory level



Sphincter involvement



Myasthenia gravis



Lambert-Eaton myasthenic syndrome



Subacute in onset



Associated autonomic symptoms in LEMS



Hyporeflexia in LEMS



Abnormal repetitive nerve stimulation



Presence of distinct antibodies



Peripheral neuropathy of acute onset
  • Acute inflammatory
  • demyelinating poly-radiculoneuropathy
  • Porphyria
Pattern of weakness



Absent stretch reflexes



Toxins
  • Ciguatera
  • Tetrodotoxin
Clinical presentation
Table 5. Medical Conditions Associated With Hypokalemia
Urine K/C RatioAcid Base StatusOther Associated FeaturesMedical



Conditions



< 1.5Metabolic acidosisLower GI loss – Laxative abuse, diarrhea
< 1.5Metabolic alkalosisNormal BPSurreptitious vomiting
>1.5Metabolic acidosisDKA, type 1 or type 2 distal RTA
>1.5Metabolic alkalosisNormal BPDiuretic use, Bartter syndrome, Gitelman syndrome
≥1.5Metabolic alkalosisHypertensionPrimary aldosteronism, Cushing syndrome, renal artery stenosis, congenital adrenal hyperplasia, apparent mineralocorticoid excess, Liddle syndrome
Table 6. Diagnostic Studies of Hypokalemic and Hyperkalemic Periodic Paralyses
Hypokalemic PPHyperkalemic PP
Serum potassiumMildly depressed; may reach 1-5 mEq/LIncreases from baseline but may not increase beyond normal range
Serum CPKModerately elevated during attacksMildly elevated during attacks
ECGBradycardia



Flat T waves, U waves, ST-segment depression



Tall T waves
Table 7. Electrophysiological Patterns to Exercise Testing
Para-



myotonia



Congenita



Hyper-



kalemic



Periodic Paralysis



Hypo-



kalemic



Periodic Paralysis



Electrophysiological



pattern



IIVV
Channel mutationsSodium T1313M, R1448CSodium T704MCalcium R528H
Short Exercise Test:
Post exercise myotonic potentialsYesNoNo
CMAP amplitude



change after First trial



Increase or



decrease



IncreaseNo
CMAP amplitude



change after second



and third trial



Gradual



increase



Gradual



increase



No
Long Exercise Test:
Immediate change of



CMAP amplitude



DecreaseIncreaseNo
Late change of CMAP amplitudeDecreaseDecreaseDecrease
Modified from Fournier et al, 2004.[9]
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