Hypokalemic periodic paralysis
- Laurie Gutmann, MD
Laurie Gutmann, MD
- Professor and Vice Chair of Clinical Research
- University of Iowa
- Robin Conwit, MD
Robin Conwit, MD
- Program Director, Division of Extramural Research
- National Institutes of Health, National Institute of Neurological Disorders and Stroke
Periodic paralysis is a rare neuromuscular disorder, related to a defect in muscle ion channels, characterized by episodes of painless muscle weakness, which may be precipitated by heavy exercise, fasting, or high-carbohydrate meals.
Periodic paralysis (PP) is classified as hypokalemic when episodes occur in association with low potassium blood levels or as hyperkalemic when episodes can be induced by elevated potassium. Most cases of periodic paralysis are hereditary, usually with an autosomal dominant inheritance pattern. Acquired cases of hypokalemic PP have been described in association with hyperthyroidism. The clinical features of these disorders are summarized in the Table (table 1).
Hypokalemic PP and the periodic paralysis associated with the Andersen syndrome will be reviewed here. Other causes of periodic paralysis are discussed separately. (See "Hyperkalemic periodic paralysis" and "Thyrotoxic periodic paralysis".)
Hypokalemic periodic paralysis (PP) is the most common of the periodic paralyses, but is still quite rare, with an estimated prevalence of 1 in 100,000 . Hypokalemic PP may be familial with autosomal dominant inheritance or may be acquired in patients with thyrotoxicosis [2-7]. (See "Thyrotoxic periodic paralysis".)
Clinical penetrance is often incomplete, especially in women [8,9]. The disorder is three to four times more commonly clinically expressed in men. Approximately one-third of cases represent new mutations [10,11].To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Fontaine B. Periodic paralysis. Adv Genet 2008; 63:3.
- Fontaine B, Lapie P, Plassart E, et al. Periodic paralysis and voltage-gated ion channels. Kidney Int 1996; 49:9.
- Ober KP. Thyrotoxic periodic paralysis in the United States. Report of 7 cases and review of the literature. Medicine (Baltimore) 1992; 71:109.
- Chan A, Shinde R, Chow CC, et al. In vivo and in vitro sodium pump activity in subjects with thyrotoxic periodic paralysis. BMJ 1991; 303:1096.
- Ko GT, Chow CC, Yeung VT, et al. Thyrotoxic periodic paralysis in a Chinese population. QJM 1996; 89:463.
- Lin SH. Thyrotoxic periodic paralysis. Mayo Clin Proc 2005; 80:99.
- Kung AW. Clinical review: Thyrotoxic periodic paralysis: a diagnostic challenge. J Clin Endocrinol Metab 2006; 91:2490.
- Elbaz A, Vale-Santos J, Jurkat-Rott K, et al. 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 1995; 56:374.
- Ke Q, Luo B, Qi M, et al. Gender differences in penetrance and phenotype in hypokalemic periodic paralysis. Muscle Nerve 2013; 47:41.
- Miller TM, Dias da Silva MR, Miller HA, et al. Correlating phenotype and genotype in the periodic paralyses. Neurology 2004; 63:1647.
- Venance SL, Cannon SC, Fialho D, et al. The primary periodic paralyses: diagnosis, pathogenesis and treatment. Brain 2006; 129:8.
- Ptácek LJ, Tawil R, Griggs RC, et al. Dihydropyridine receptor mutations cause hypokalemic periodic paralysis. Cell 1994; 77:863.
- Sillén A, Sørensen T, Kantola I, et al. Identification of mutations in the CACNL1A3 gene in 13 families of Scandinavian origin having hypokalemic periodic paralysis and evidence of a founder effect in Danish families. Am J Med Genet 1997; 69:102.
- Wang Q, Liu M, Xu C, et al. Novel CACNA1S mutation causes autosomal dominant hypokalemic periodic paralysis in a Chinese family. J Mol Med (Berl) 2005; 83:203.
- Matthews E, Labrum R, Sweeney MG, et al. Voltage sensor charge loss accounts for most cases of hypokalemic periodic paralysis. Neurology 2009; 72:1544.
- Sternberg D, Maisonobe T, Jurkat-Rott K, et al. Hypokalaemic periodic paralysis type 2 caused by mutations at codon 672 in the muscle sodium channel gene SCN4A. Brain 2001; 124:1091.
- Bulman DE, Scoggan KA, van Oene MD, et al. A novel sodium channel mutation in a family with hypokalemic periodic paralysis. Neurology 1999; 53:1932.
- Lapie P, Goudet C, Nargeot J, et al. Electrophysiological properties of the hypokalaemic periodic paralysis mutation (R528H) of the skeletal muscle alpha 1s subunit as expressed in mouse L cells. FEBS Lett 1996; 382:244.
- Morrill JA, Brown RH Jr, Cannon SC. Gating of the L-type Ca channel in human skeletal myotubes: an activation defect caused by the hypokalemic periodic paralysis mutation R528H. J Neurosci 1998; 18:10320.
- Tanabe T, Beam KG, Powell JA, Numa S. Restoration of excitation-contraction coupling and slow calcium current in dysgenic muscle by dihydropyridine receptor complementary DNA. Nature 1988; 336:134.
- Tricarico D, Servidei S, Tonali P, et al. Impairment of skeletal muscle adenosine triphosphate-sensitive K+ channels in patients with hypokalemic periodic paralysis. J Clin Invest 1999; 103:675.
- Ruff RL. Insulin acts in hypokalemic periodic paralysis by reducing inward rectifier K+ current. Neurology 1999; 53:1556.
- Francis DG, Rybalchenko V, Struyk A, Cannon SC. Leaky sodium channels from voltage sensor mutations in periodic paralysis, but not paramyotonia. Neurology 2011; 76:1635.
- Sokolov S, Scheuer T, Catterall WA. Gating pore current in an inherited ion channelopathy. Nature 2007; 446:76.
- Tucker C, Villanueva L. Acute hypokalemic periodic paralysis possibly precipitated by albuterol. Am J Health Syst Pharm 2013; 70:1588.
- Links TP, Zwarts MJ, Wilmink JT, et al. Permanent muscle weakness in familial hypokalaemic periodic paralysis. Clinical, radiological and pathological aspects. Brain 1990; 113 ( Pt 6):1873.
- Gold R, Reichmann H. Muscle pathology correlates with permanent weakness in hypokalemic periodic paralysis: a case report. Acta Neuropathol 1992; 84:202.
- Griggs RC, Engel WK, Resnick JS. Acetazolamide treatment of hypokalemic periodic paralysis. Prevention of attacks and improvement of persistent weakness. Ann Intern Med 1970; 73:39.
- Dalakas MC, Engel WK. Treatment of "permanent" muscle weakness in familial Hypokalemic Periodic Paralysis. Muscle Nerve 1983; 6:182.
- Links TP, Smit AJ, Molenaar WM, et al. Familial hypokalemic periodic paralysis. Clinical, diagnostic and therapeutic aspects. J Neurol Sci 1994; 122:33.
- Cheng CJ, Chen YH, Chau T, Lin SH. A hidden cause of hypokalemic paralysis in a patient with prostate cancer. Support Care Cancer 2004; 12:810.
- Fujimoto T, Shiiki H, Takahi Y, Dohi K. Primary Sjögren's syndrome presenting as hypokalaemic periodic paralysis and respiratory arrest. Clin Rheumatol 2001; 20:365.
- Chang YC, Huang CC, Chiou YY, Yu CY. Renal tubular acidosis complicated with hypokalemic periodic paralysis. Pediatr Neurol 1995; 13:52.
- Agarwal AK, Wadhwa S, Wali M. Hypokalaemic periodic paralysis associated with thyrotoxicosis. J Assoc Physicians India 1994; 42:261.
- Ahlawat SK, Sachdev A. Hypokalaemic paralysis. Postgrad Med J 1999; 75:193.
- Lin SH, Lin YF, Chen DT, et al. Laboratory tests to determine the cause of hypokalemia and paralysis. Arch Intern Med 2004; 164:1561.
- Lin SH, Lin YF, Halperin ML. Hypokalaemia and paralysis. QJM 2001; 94:133.
- Liu PY, Jeng CY. Severe hypophosphatemia in a patient with diabetic ketoacidosis and acute respiratory failure. J Chin Med Assoc 2004; 67:355.
- Ng HY, Lin SH, Hsu CY, et al. Hypokalemic paralysis due to Gitelman syndrome: a family study. Neurology 2006; 67:1080.
- Phakdeekitcharoen B, Ruangraksa C, Radinahamed P. Hypokalaemia and paralysis in the Thai population. Nephrol Dial Transplant 2004; 19:2013.
- Cannon SC, George AL. Pathophysiology of myotonia and periodic paralysis. In: Diseases of the Nervous System, 3rd, Asbury AK, McKhann GM, McDonald WI, et al (Eds), Cambridge University Press, Cambridge 2002. p.1183.
- Streeten DH, Speller PJ, Fellerman H. Use of corticotropin-induced potassium changes in the diagnosis of both hypo- and hyperkalemic periodic paralysis. Eur Neurol 1993; 33:103.
- Sharma CM, Nath K, Parekh J. Reversible electrophysiological abnormalities in hypokalemic paralysis: Case report of two cases. Ann Indian Acad Neurol 2014; 17:100.
- McManis PG, Lambert EH, Daube JR. The exercise test in periodic paralysis. Muscle Nerve 1986; 9:704.
- Tengan CH, Antunes AC, Gabbai AA, Manzano GM. The exercise test as a monitor of disease status in hypokalaemic periodic paralysis. J Neurol Neurosurg Psychiatry 2004; 75:497.
- Kuntzer T, Flocard F, Vial C, et al. Exercise test in muscle channelopathies and other muscle disorders. Muscle Nerve 2000; 23:1089.
- Fournier E, Arzel M, Sternberg D, et al. Electromyography guides toward subgroups of mutations in muscle channelopathies. Ann Neurol 2004; 56:650.
- Sugiura Y, Makita N, Li L, et al. Cold induces shifts of voltage dependence in mutant SCN4A, causing hypokalemic periodic paralysis. Neurology 2003; 61:914.
- Rose BD, Post TW. Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th, McGraw-Hill, New York 2001. p.836.
- Manoukian MA, Foote JA, Crapo LM. Clinical and metabolic features of thyrotoxic periodic paralysis in 24 episodes. Arch Intern Med 1999; 159:601.
- Tassone H, Moulin A, Henderson SO. The pitfalls of potassium replacement in thyrotoxic periodic paralysis: a case report and review of the literature. J Emerg Med 2004; 26:157.
- Lu KC, Hsu YJ, Chiu JS, et al. Effects of potassium supplementation on the recovery of thyrotoxic periodic paralysis. Am J Emerg Med 2004; 22:544.
- Loh KC, Pinheiro L, Ng KS. Thyrotoxic periodic paralysis complicated by near-fatal ventricular arrhythmias. Singapore Med J 2005; 46:88.
- Griggs RC, Resnick J, Engel WK. Intravenous treatment of hypokalemic periodic paralysis. Arch Neurol 1983; 40:539.
- Caciotti A, Morrone A, Domenici R, et al. Severe prognosis in a large family with hypokalemic periodic paralysis. Muscle Nerve 2003; 27:165.
- Layzer RB. Periodic paralysis and the sodium-potassium pump. Ann Neurol 1982; 11:547.
- Resnick JS, Engel WK, Griggs RC, Stam AC. Acetazolamide prophylaxis in hypokalemic periodic paralysis. N Engl J Med 1968; 278:582.
- Tawil R, McDermott MP, Brown R Jr, et al. Randomized trials of dichlorphenamide in the periodic paralyses. Working Group on Periodic Paralysis. Ann Neurol 2000; 47:46.
- Sansone V, Meola G, Links TP, et al. Treatment for periodic paralysis. Cochrane Database Syst Rev 2008; :CD005045.
- Links TP, Arnoldus EP, Wintzen AR, et al. The calcium channel blocker verapamil in hypokalemic periodic paralysis. Muscle Nerve 1998; 21:1564.
- Matthews E, Portaro S, Ke Q, et al. Acetazolamide efficacy in hypokalemic periodic paralysis and the predictive role of genotype. Neurology 2011; 77:1960.
- Fiore DM, Strober JB. Treatment of hypokalemic periodic paralysis with topiramate. Muscle Nerve 2011; 43:127.
- Tricarico D, Barbieri M, Camerino DC. Acetazolamide opens the muscular KCa2+ channel: a novel mechanism of action that may explain the therapeutic effect of the drug in hypokalemic periodic paralysis. Ann Neurol 2000; 48:304.
- Tricarico D, Barbieri M, Mele A, et al. Carbonic anhydrase inhibitors are specific openers of skeletal muscle BK channel of K+-deficient rats. FASEB J 2004; 18:760.
- Ligtenberg JJ, Van Haeften TW, Van Der Kolk LE, et al. Normal insulin release during sustained hyperglycaemia in hypokalaemic periodic paralysis: role of the potassium channel opener pinacidil in impaired muscle strength. Clin Sci (Lond) 1996; 91:583.
- Kim JB, Lee KY, Hur JK. A Korean family of hypokalemic periodic paralysis with mutation in a voltage-gated calcium channel (R1239G). J Korean Med Sci 2005; 20:162.
- Torres CF, Griggs RC, Moxley RT, Bender AN. Hypokalemic periodic paralysis exacerbated by acetazolamide. Neurology 1981; 31:1423.
- Bendahhou S, Cummins TR, Griggs RC, et al. Sodium channel inactivation defects are associated with acetazolamide-exacerbated hypokalemic periodic paralysis. Ann Neurol 2001; 50:417.
- Tristani-Firouzi M, Jensen JL, Donaldson MR, et al. Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome). J Clin Invest 2002; 110:381.
- Sansone V, Griggs RC, Meola G, et al. Andersen's syndrome: a distinct periodic paralysis. Ann Neurol 1997; 42:305.
- Tawil R, Ptacek LJ, Pavlakis SG, et al. Andersen's syndrome: potassium-sensitive periodic paralysis, ventricular ectopy, and dysmorphic features. Ann Neurol 1994; 35:326.
- Davies NP, Imbrici P, Fialho D, et al. Andersen-Tawil syndrome: new potassium channel mutations and possible phenotypic variation. Neurology 2005; 65:1083.