Summary
Rare diseases have attracted little attention in the past from physicians and researchers. The situation has recently changed for several reasons. First, patient associations have successfully advocated their cause to institutions and governments. They were able to argue that, taken together, rare diseases affect approximately 10% of the population in developed countries. Second, almost 80% of rare diseases are of genetic origin. Advances in genetics have enabled the identification of the causative genes. Unprecedented financial support has been dedicated to research on rare diseases, as well as to the development of referral centers aimed at improving the quality of care. This expenditure of resources is justified by the experience in cystic fibrosis, which demonstrated that improved care delivered by specialized referral centers resulted in a dramatic increase of life expectancy. Moreover, clinical referral centers offer the unique possibility of developing high quality clinical research studies, not otherwise possible because of the geographic dispersion of patients. This is the case in France where national referral centers for rare diseases were created, including one for muscle channelopathies. The aim of this center is to develop appropriate care, clinical research, and teaching on periodic paralysis and myotonia. In this review, we plan to demonstrate how research has improved our knowledge of hypokalemic periodic paralysis and the way we evaluate, advise, and treat patients. We also advocate for the establishment of international collaborations, which are mandatory for the follow-up of cohorts and conduct of definitive therapeutic trials in rare diseases.
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Buruma OJS, Schipperheyn JJ. Periodic paralysis. In: Vinken PJ, Bruyn GW, eds. Handbook of clinical neurology. Amsterdam: North Holland Publishing; 1979: 147–174.
Venance SL, Cannon SC, Fialho D, et al. The primary periodic paralyses: diagnosis, pathogenesis and treatment. Brain 2006;129: 8–17.
Lin SH, Lin YF, Chen DT, Chu P, Hsu CW, Halperin ML. Laboratory tests to determine the cause of hypokalemia and paralysis. Arch Intern Med 2004;164: 1561–1566.
Kung AW. Clinical review: thyrotoxic periodic paralysis: a diagnostic challenge. J Clin Endocrinol Metab 2006;91: 2490–2495.
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: 374–380.
Links TP. Familial hypokalemic periodic paralysis. Groningen: Rijksuniversiteit Groningen; 1992.
Caciotti A, Morrone A, Domenici R, Donati MA, Zammarchi E. Severe prognosis in a large family with hypokalemic periodic paralysis. Muscle Nerve 2003;27: 165–169.
Tawil R, Ptacek LJ, Pavlakis SG, et al. Andersen’s syndrome: potassium-sensitive periodic paralysis, ventricular ectopy, and dysmorphic features. Ann Neurol 1994;35: 326–330.
Links TP, Zwarts MJ, Wilmink JT, Molenaar WM, Oosterhuis HJ. Permanent muscle weakness in familial hypokalemic periodic paralysis. Clinical, radiological and pathological aspects. Brain 1990; 113: 1873–1889.
Dalakas MC, Engel WK. Treatment of “permanent” muscle weakness in familial hypokalemic periodic paralysis. Muscle Nerve 1983;6: 182–186.
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: 39–48.
Links TP, Zwarts MJ, Oosterhuis HJ. Improvement of muscle strength in familial hypokalemic periodic paralysis with acetazolamide. J Neurol Neurosurg Psychiatry 1988;51: 1142–1145.
Buruma OJ, Bots GT. Myopathy in familial hypokalemic periodic paralysis independent of paralytic attacks. Acta Neurol Scand 1978;57: 171–179.
Engel AG. Electron microscopic observations in primary hypokalemic and thyrotoxic periodic paralyses. Mayo Clin Proc 1966;41: 797–808.
Engel AG. Evolution and content of vacuoles in primary hypokalemic periodic paralysis. Mayo Clin Proc 1970;45: 774–814.
Links TP, Smit AJ, Molenaar WM, Zwarts MJ, Oosterhuis HJ. Familial hypokalemic periodic paralysis. Clinical, diagnostic and therapeutic aspects. J Neurol Sci 1994;122: 33–43.
Rudel R, Lehmann-Horn F, Ricker K, Kuther G. Hypokalemic periodic paralysis: in vitro investigation of muscle fiber membrane parameters. Muscle Nerve 1984;7: 110–120.
Fontaine B, Khurana TS, Hoffman EP, et al. Hyperkalemic periodic paralysis and the adult muscle sodium channel alpha-subunit gene. Science 1990;250: 1000–1002.
Ptacek LJ, George AL Jr, Griggs RC, Tawil R, Kallen RG, Barchi RL, Robertson M, Leppert MF. Identification of a mutation in the gene causing hyperkalemic periodic paralysis. Cell 1991;67: 1021–1027.
Rojas CV, Wang JZ, Schwartz LS, Hoffman EP, Powell BR, Brown RH Jr. A Met-to-Val mutation in the skeletal muscle Na+ channel alpha-subunit in hyperkalaemic periodic paralysis. Nature 1991;354: 387–389.
Fontaine B, Vale-Santos J, Jurkat-Rott K, et al. Mapping of the hypokalemic periodic paralysis (HypoPP) locus to chromosome lq31-32 in three European families. Nat Genet 1994;6: 267–272.
Jurkat-Rott K, Lehmann-Horn F, Elbaz A, et al. A calcium channel mutation causing hypokalemic periodic paralysis. Hum Mol Genet 1994;3: 1415–1419.
Ptácek LJ, Tawil R, Griggs RC, et al. Dihydropyridine receptor mutations cause hypokalemic periodic paralysis. Cell 1994;77: 863–868.
Wang Q, Liu M, Xu C, et al. Novel CACNA1S mutation causes autosomal dominant hypokalemic periodic paralysis in a Chinese family. J Mol Med 2005;83: 203–208.
Fouad G, Dalakas M, Servidei S, et al. Genotype-phenotype correlations of DHP receptor alpha 1-subunit gene mutations causing hypokalemic periodic paralysis. Neuromuscul Disord 1997;7: 33–38.
Ikeda Y, Abe B, Watanabe M, et al. A Japanese family of autosomal dominant hypokalemic periodic paralysis with a CACNL1A3 gene mutation. Eur J Neurol 1996;3: 441–445.
Kawamura S, Ikeda Y, Tomita K, Watanabe N, Seki K. A family of hypokalemic periodic paralysis with CACNA1S gene mutation showing incomplete penetrance in women. Intern Med 2004;43: 218–222.
Miller TM, Dias da Silva MR, Miller HA, et al. Correlating phenotype and genotype in the periodic paralyses. Neurology 2004; 63: 1647–1655.
Sillen A, Sorensen T, Kantola I, Friis ML, Gustavson KH, Wadelius C. 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: 102–106.
Boerman RH, Ophoff RA, Links TP, et al. Mutation in DHP receptor alpha 1 subunit (CACLN1A3) gene in a Dutch family with hypokalemic periodic paralysis. J Med Genet 1995;32: 44–47.
Grosson CL, Esteban J, McKenna-Yasek D, Gusella JF, Brown RH Jr. Hypokalemic periodic paralysis mutations: confirmation of mutation and analysis of founder effect. Neuromuscul Disord 1996; 6: 27–31.
Wang W, Jiang L, Ye L, et al. Mutation screening in Chinese hypokalemic periodic paralysis patients. Mol Genet Metab 2006; 87: 359–363.
Dias da Silva MR, Cerutti JM, Tengan CH, et al. Mutations linked to familial hypokalemic periodic paralysis in the calcium channel alphal subunit gene (Cav1.1) are not associated with thyrotoxic hypokalemic periodic paralysis. Clin Endocrinol (Oxf) 2002;56: 367–375.
Engel AG, Lambert EH. Calcium activation of electrically inexcitable muscle fibers in primary hypokalemic periodic paralysis. Neurology 1969;19: 851–858.
Ruff RL. Calcium-tension relationships of muscle fibers from patients with periodic paralysis. Muscle Nerve 1991;14: 838–844.
Lapie P, Goudet C, Nargeot J, Fontaine B, Lory P. Electrophysiological properties of the hypokalemic periodic paralysis mutation (R528H) of the skeletal muscle alpha 1s subunit as expressed in mouse L cells. FEBS Lett 1996;382: 244–248.
Morrill JA, Cannon SC. Effects of mutations causing hypokaelemic periodic paralysis on the skeletal muscle L-type Ca2+ channel expressed in Xenopus laevis oocytes. J Physiol 1999;520: 321–336.
Ruff RL. Insulin acts in hypokalemic periodic paralysis by reducing inward rectifier K+ current. Neurology 1999;53: 1556–1563.
Tricarico D, Servidei S, Tonali P, Jurkat-Rott K, Camerino DC. Impairment of skeletal muscle adenosine triphosphate-sensitive K+ channels in patients with hypokalemic periodic paralysis. J Clin Invest 1999;103: 675–682.
Cannon SC. Pathomechanisms in channelopathies of skeletal muscle and brain. Annu Rev Neurosci 2006;29: 387–415.
Bulman DE, Scoggan KA, van Oene MD, et al. A novel sodium channel mutation in a family with hypokalemic periodic paralysis. Neurology 1999;53: 1932–1936.
Jurkat-Rott K, Mitrovic N, Hang C, et al. Voltage-sensor sodium channel mutations cause hypokalemic periodic paralysis type 2 by enhanced inactivation and reduced current. Proc Natl Acad Sci U S A 2000;97: 9549–9554.
Sugiura Y, Makita N, Li L, et al. Cold induces shifts of voltage dependence in mutant SCN4A, causing hypokalemic periodic paralysis. Neurology 2003;61: 914–918.
Vicart S, Sternberg D, Founder E, et al. New mutations of SCN4A cause a potassium-sensitive normokalemic periodic paralysis. Neurology 2004;63: 2120–2127.
Steinberg D, Maisonobe T, Jurkat-Rott K, et al. Hypokalemic periodic paralysis type 2 caused by mutations at codon 672 in the muscle sodium channel gene SCN4A. Brain 2001;124: 1091–1099.
Carle T, Lhuillier L, Luce S, et al. Gating defects of a novel Na(+) channel mutant causing hypokalemic periodic paralysis. Biochem Biophys Res Commun 2006;348: 653–661.
Davies NP, Eunson LH, Samuel M, Hanna MG. Sodium channel gene mutations in hypokalemic periodic paralysis: an uncommon cause in the UK. Neurology 2001;57: 1323–1325.
Kim MK, Lee SH, Park MS, et al. Mutation screening in Korean hypokalemic periodic paralysis patients: a novel SCN4A Arg672Cys mutation. Neuromuscul Disord 2004;14: 727–731.
Bendahhou S, Cummins TR, Griggs RC, Fu YH, Ptacek LJ. Sodium channel inactivation defects are associated with acetazolamide-exacerbated hypokalemic periodic paralysis. Ann Neurol 2001;50: 417–420.
Kuzmenkin A, Muncan V, Jurkat-Rott K, et al. Enhanced inactivation and pH sensitivity of Na(+) channel mutations causing hypokalemic periodic paralysis type II. Brain 2002; 125: 835–843.
Struyk AF, Scoggan KA, Bulman DE, Cannon SC. The human skeletal muscle Na channel mutation R669H associated with hypokalemic periodic paralysis enhances slow inactivation. J Neurosci 2000;20: 8610–8617.
Plaster NM, Tawil R, Tristani-Firouzi M, et al. Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen’s syndrome. Cell 2001;105: 511–519.
Abbott GW, Butler MH, Bendahhou S, Dalakas MC, Ptacek LJ, Goldstein SA. MiRP2 forms potassium channels in skeletal muscle with Kv3.4 and is associated with periodic paralysis. Cell 2001; 104: 217–231.
Dias Da Silva MR, Cerutti JM, Amaldi LA, Maciel RM. A mutation in the KCNE3 potassium channel gene is associated with susceptibility to thyrotoxic hypokalemic periodic paralysis. J Clin Endocrinol Metab 2002;87: 4881–4884.
Tang NL, Chow CC, Ko GT, et al. No mutation in the KCNE3 potassium channel gene in Chinese thyrotoxic hypokalemic periodic paralysis patients. Clin Endocrinol (Oxf) 2004;61: 109–112.
Steinberg D, Tabti N, Founder E, Hainque B, Fontaine B. Lack of association of the potassium channel-associated peptide MiRP2-R83H variant with periodic paralysis. Neurology 2003;61: 857–859.
Jurkat-Rott K, Lehmann-Horn F. Periodic paralysis mutation MiRP2-R83H in controls: interpretations and general recommendation. Neurology 2004;62: 1012–1015.
Abbott GW, Butler MH, Goldstein SA. Phosphorylation and protonation of neighboring MiRP2 sites: function and pathophysiology of MiRP2-Kv3.4 potassium channels in periodic paralysis. FASEB J 2006;20: 293–301.
Links TP, van der Hoeven JH, Zwarts MJ. Surface EMG and muscle fibre conduction during attacks of hypokalemic periodic paralysis. J Neurol Neurosurg Psychiatry 1994;57: 632–634.
Zwarts MJ, van Weerden TW, Links TP, Haenen HT, Oosterhuis HJ. The muscle fiber conduction velocity and power spectra in familial hypokalemic periodic paralysis. Muscle Nerve 1988;11: 166–173.
Links TP, van der Hoeven JH. Muscle fiber conduction velocity in argl239his mutation in hypokalemic periodic paralysis. Muscle Nerve 2000;23: 296.
McManis PG, Lambert EH, Daube JR. The exercise test in periodic paralysis. Muscle Nerve 1986;9: 704–710.
Kuntzer T, Flocard F, Vial C, et al. Exercise test in muscle channelopathies and other muscle disorders. Muscle Nerve 2000;23: 1089–1094.
Founder E, Arzel M, Sternberg D, et al. Electromyography guides toward subgroups of mutations in muscle channelopathies. Ann Neurol 2004;56: 650–661.
Bendahhou S, Founder E, Sternberg D, et al. In vivo and in vitro functional characterization of Andersen’s syndrome mutations. J Physiol 2005;565: 731–741.
Resnick JS, Engel WK, Griggs RC, Stam AC. Acetazolamide prophylaxis in hypokalemic periodic paralysis. N Engl J Med 1968;278: 582–586.
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: 304–312.
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: 46–53.
Tones CF, Griggs RC, Moxley RT, Bender AN. Hypokalemic periodic paralysis exacerbated by acetazolamide. Neurology 1981; 31: 1423–1428.
Venance SL, Jurkat-Rott K, Lehmann-Horn F, Tawil R. SCN4A-associated hypokalemic periodic paralysis merits a trial of acetazolamide. Neurology 2004;63: 1977.
Lehmann-Horn F, Iaizzo PA. Are myotonias and periodic paralyses associated with susceptibility to malignant hyperthermia? Br J Anaesth 1990;65: 692–697.
Hogan K. The anesthetic myopathies and malignant hyperthermias. Curr Opin Neurol 1998;11: 469–476.
Monnier N, Procaccio V, Stieglitz P, Lunardi J. Malignant-hyperthermia susceptibility is associated with a mutation of the alpha 1-subunit of the human dihydropyridine-sensitive L-type voltage-dependent calcium-channel receptor in skeletal muscle. Am J Hum Genet 1997;60: 1316–1325.
Klingler W, Lehmann-Horn F, Jurkat-Rott K. Complications of anaesthesia in neuromuscular disorders. Neuromuscul Disord 2005;15: 195–206.
Naguib M, Flood P, McArdle JJ, Brenner HR. Advances in neurobiology of the neuromuscular junction: implications for the anesthesiologist. Anesthesiology 2002;96: 202–231.
Hecht ML, Valtysson B, Hogan K. Spinal anesthesia for a patient with a calcium channel mutation causing hypokalemic periodic paralysis. Anesth Analg 1997;84: 461–464.
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Fontaine, B., Fournier, E., Sternberg, D. et al. Hypokalemic periodic paralysis: A model for a clinical and research approach to a rare disorder. Neurotherapeutics 4, 225–232 (2007). https://doi.org/10.1016/j.nurt.2007.01.002
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DOI: https://doi.org/10.1016/j.nurt.2007.01.002