Current Neurology and Neuroscience Reports

, Volume 2, Issue 1, pp 61–69

Periodic paralysis: Understanding channelopathies

  • Frank Lehmann-Horn
  • Karin Jurkat-Rott
  • Reinhardt Rüdel
Article

Abstract

Familial periodic paralyses are typical channelopathies (ie, caused by functional disturbances of ion channel proteins). The episodes of flaccid muscle weakness observed in these disorders are due to underexcitability of sarcolemma leading to a silent electromyogram and the lack of action potentials even upon electrical stimulation. Interictally, ion channel malfunction is well compensated, so that special exogenous or endogenous triggers are required to produce symptoms in the patients. An especially obvious trigger is the level of serum potassium (K+), the ion responsible for resting membrane potential and degree of excitability. The clinical symptoms can be caused by mutations in genes coding for ion channels that mediate different functions for maintaining the resting potential or propagating the action potential, the basis of excitability. The phenotype is determined by the type of functional defect brought about by the mutations, rather than the channel effected, because the contrary phenotypes hyperkalemic periodic paralysis (HyperPP) and hypokalemic periodic paralysis (HypoPP) may be caused by point mutations in the same gene. Still, the common mechanism for inexcitability in all known episodic-weakness phenotypes is a long-lasting depolarization that inactivates sodium ion (Na+) channels, initiating the action potential.

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References and Recommended Reading

  1. 1.
    Lehmann-Horn F, Küther G, Ricker K, et al.: Adynamia episodica hereditaria with myotonia: a non-inactivating sodium current and the effect of extracellular pH. Muscle Nerve 1987, 10:363–374.PubMedCrossRefGoogle Scholar
  2. 2.
    Fontaine B, Khurana TS, Hoffman EP, et al.: Hyperkalemic periodic paralysis and the adult muscle sodium channel alpha-subunit gene. Science 1990, 250:1000–1003.PubMedCrossRefGoogle Scholar
  3. 3.
    Lehmann-Horn F, Jurkat-Rott K: Voltage-gated ion channels and hereditary disease. Physiol Rev 1999, 79:1317–1372. Introduction to the structure, function, isoforms, encoding genes, and pharmacology of voltage-gated ion channels followed by a description of most hereditary channelopathies in neurology, myology, nephrology, and cardiology; parallels in disease mechanisms are emphasized.PubMedGoogle Scholar
  4. 4.
    Lehmann-Horn F, Engel AG, Ricker K, Rüdel R: The periodic paralyses and paramyotonia congenita. In Myology, edn 2. Edited by Engel AG, Franzini-Armstrong C. New York: McGraw-Hill; 1994:1303–1334.Google Scholar
  5. 5.
    Yang N, George AL Jr, Horn R: Molecular basis of charge movement in voltage-gated sodium channels. Neuron 1996, 16:113–122.PubMedCrossRefGoogle Scholar
  6. 6.
    Cha A, Snyder GE, Selvin PR, Bezanilla F: Atomic scale movement of the voltage-sensing region in a potassium channel measured via spectroscopy. Nature 1999, 402:809–813. Distance changes measured by lanthanide-based resonance energy transfer suggest that the region associated with the S4 segment undergoes a rotation and possible tilt, rather than a large transmembrane movement, in response to voltage.PubMedCrossRefGoogle Scholar
  7. 7.
    Stühmer W, Conti F, Suzuki H, et al.: Structural parts involved in activation and inactivation of the sodium channel. Nature 1989, 339:597–603.PubMedCrossRefGoogle Scholar
  8. 8.
    Patton DE, West JW, Catterall WA, Goldin AL: A peptide segment critical for sodium channel inactivation functions as an inactivation gate in a potassium channel. Neuron 1993, 11:967–974.PubMedCrossRefGoogle Scholar
  9. 9.
    Fontaine B, Vale Santos JM, Jurkat-Rott K, et al.: Mapping of hypokalemic periodic paralysis (HypoPP) to chromosome 1q31-q32 by a genome-wide search in three European families. Nature Genet 1994, 6:267–272.PubMedCrossRefGoogle Scholar
  10. 10.
    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.PubMedCrossRefGoogle Scholar
  11. 11.
    Pté_ek LJ, Tawil R, Griggs RC, et al.: Dihydropyridine receptor mutations cause hypokalemic periodic paralysis. Cell 1994, 77:863–868.CrossRefGoogle Scholar
  12. 12.
    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.PubMedGoogle Scholar
  13. 13.
    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. Identifies in five families not linked to the Ca2+ channel the skeletal muscle Na+ channel é subunit as being responsible for 1) the disease slowing and the smaller size of action potentials recorded intracellularly in native muscle fibers; and 2) Na+ current reduction and enhanced channel inactivation determined in an expression system are in agreement that HypoPP-2 represents the first Na+ channel disease caused by reduced function.PubMedCrossRefGoogle Scholar
  14. 14.
    Bendahhou S, Cummins TR, Griggs RC, et al.: Sodium channel inactivation defects are associated with acetazolamide-exacerbated hypokalemic periodic paralysis. Ann Neurol 2001, 50:417–420. A new HypoPP mutation is described that reacts contrarily to medication and shows the same functional defects of stabilization of the inactivated state.PubMedCrossRefGoogle Scholar
  15. 15.
    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, 124:1091–1099.PubMedCrossRefGoogle Scholar
  16. 16.
    Ptécek LJ, George AL Jr, Griggs RC, et al.: Identification of a mutation in the gene causing hyperkalemic periodic paralysis. Cell 1991, 7:1021–1027.Google Scholar
  17. 17.
    Rojas CV, Wang J, Schwartz L, et al.: A Met-to-Val mutation in the skeletal muscle sodium channel a-subunit in hyperkalemic periodic paralysis. Nature 1991, 354:387–389.PubMedCrossRefGoogle Scholar
  18. 18.
    McClatchey AI, McKenna-Yasek D, Cros D, et al.: Novel mutations in families with unusual and variable disorders of the skeletal muscle sodium channel. Nature Genet 1992, 2:148–152.PubMedCrossRefGoogle Scholar
  19. 19.
    Wagner S, Lerche H, Mitrovic N, et al.: A novel sodium channel mutation causing a hyperkalemic paralytic and paramyotonic syndrome with reduced penetrance. Neurology 1997, 49:1018–1025.PubMedGoogle Scholar
  20. 20.
    Bendahhou S, Cummins TR, Tawil R, et al.: Activation and inactivation of the voltage-gated sodium channel: role of segment S5 revealed by a novel hyperkalaemic periodic paralysis mutation. J Neurosci 1999, 19:4762–4771. New structure-function relationships of the Na+ channel for the reader interested in electrophysiology.PubMedGoogle Scholar
  21. 21.
    Lehmann-Horn F, Iaizzo PA, Hatt H, Franke C: Altered gating and reduced conductance of single sodium channels in hyperkalemic periodic paralysis. Pflügers Arch 1991, 418:297–299.PubMedCrossRefGoogle Scholar
  22. 22.
    Cannon SC, Brown RH Jr, Corey DP: A sodium channel defect in hyperkalemic periodic paralysis: potassium-induced failure of inactivation. Neuron 1991, 6:619–626.PubMedCrossRefGoogle Scholar
  23. 23.
    Hayward LJ, Sandoval GM, Cannon SC: Defective slow inactivation of sodium channels contributes to familial periodic paralysis. Neurology 1999, 52:1447–1453.PubMedGoogle Scholar
  24. 24.
    Bendahhou S, Cummins TR, Hahn AF, et al.: A double mutation in families with periodic paralysis defines new aspects of sodium channel slow inactivation. J Clin Invest 2000, 106:431–438. Explains the mechanism of how defects of Na+ channel slow inactivation contributes to attacks of paralysis.PubMedGoogle Scholar
  25. 25.
    Ruff RL, Cannon SC: Defective slow inactivation of sodium channels contributes to familial periodic paralysis. Neurology 2000, 54:2190–2192.PubMedGoogle Scholar
  26. 26.
    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.PubMedGoogle Scholar
  27. 27.
    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, 103:675–682.PubMedCrossRefGoogle Scholar
  28. 28.
    Ruff RL: Insulin acts in hypokalemic periodic paralysis by reducing inward rectifier K+ current. Neurology 1999, 53:1556–1563.PubMedGoogle Scholar
  29. 29.
    Clausen T, Overgaard K: The role of K+ channels in the force recovery elicited by Na+K+ pump stimulation in Ba2+-paralysed rat skeletal muscle. J Physiol 2000, 527:325–332.PubMedCrossRefGoogle Scholar
  30. 30.
    Tricarico D, Barbieri M, Conte-Camerino D: 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. Hypothesis of acetazolamide interaction with K+ channels that could explain depolarization and hypokalemia in hypokalemic periodic paralysis.PubMedCrossRefGoogle Scholar
  31. 31.
    Lapie P, Goudet C, Nargeot J, et al.: 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.PubMedCrossRefGoogle Scholar
  32. 32.
    Lerche H, Klugbauer N, Lehmann-Horn F, et al.: Expression and functional characterization of the cardiac L-type calcium channel carrying a skeletal muscle DHP-receptor mutation causing hypokalaemic periodic paralysis. Pflügers Arch 1996, 431:461–463.PubMedCrossRefGoogle Scholar
  33. 33.
    Jurkat-Rott K, Uetz U, Pika-Hartlaub U, et al.: Calcium currents and transients of native and heterologously expressed mutant skeletal muscle DHP receptor α 1 subunits (R528H). FEBS Lett 1998, 423:198–204.PubMedCrossRefGoogle Scholar
  34. 34.
    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, 18:10320–10334.PubMedGoogle Scholar
  35. 35.
    Morrill JA, Cannon SC: Effects of mutations causing hypokalaemic periodic paralysis on the skeletal muscle L-Type Ca2+ channel expressed in Xenopus laevis oocytes. J Physiol 1999, 2:321–336. Heterologous expression of the skeletal muscle dihydropyridine receptor reveals reduced L-type current amplitude for all three mutations causing hypokalemic periodic paralysis similarly to previous reports; the IVS4 mutations slow current activation at depolarized membrane.CrossRefGoogle Scholar
  36. 36.
    Links TP, Vanderhoeven JH, Zwarts MJ: Surface EMG and muscle fiber conduction during attacks of hypokalaemic periodic paralysis. J Neurol Neurosurg Psychiatry 1994, 57:632–634.PubMedCrossRefGoogle Scholar
  37. 37.
    Rüdel R, Lehmann-Horn F, Ricker K, Küther G: Hypokalemic periodic paralysis: in vitro investigation of muscle fiber membrane parameters. Muscle Nerve 1984, 7:110–120.PubMedCrossRefGoogle Scholar
  38. 38.
    Abbott GW, Butler MH, Bendahhou S, et al.: Mirp2 forms potassium channels in skeletal muscle with Kv3.4 and is associated with periodic paralysis. Cell 2001, 104:217–231. Shows that the Shaw-like voltage-gated K+ channel Kv3.4 (_ subunit) and the b subunit MiRP2, the latter encoded by KCNE3, form a channel complex that sets the resting membrane potential of skeletal muscle. A kcne3 mutation predicting R83H was identified in two periodic paralysis families.PubMedCrossRefGoogle Scholar
  39. 39.
    Tawil R, Ptá_ek LJ, Pavlakis SG, et al.: Andersen’s syndrome: potassium-sensitive periodic paralysis, ventricular ectopy, and dysmorphic features. Ann Neurol 1994, 35:326–330.PubMedCrossRefGoogle Scholar
  40. 40.
    Sansone V, Griggs RC, Meola G, et al.: Andersen’s syndrome: a distinct periodic paralysis. Ann Neurol 1997, 42:305–312.PubMedCrossRefGoogle Scholar
  41. 41.
    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, 105:511–5199. First description of gene, mutations, and functional consequences in Andersen’s syndrome.PubMedCrossRefGoogle Scholar
  42. 42.
    Cannon SC, Strittmatter SM: Functional expression of sodium channel mutations identified in families with periodic paralysis. Neuron 1993, 10:317–326.PubMedCrossRefGoogle Scholar
  43. 43.
    Ryan MM, Taylor P, Donald JA, et al.: A novel syndrome of episodic muscle weakness maps to Xp22.3. Am J Hum Genet 1999, 65:1104–1113.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc 2002

Authors and Affiliations

  • Frank Lehmann-Horn
    • 1
  • Karin Jurkat-Rott
    • 1
  • Reinhardt Rüdel
    • 1
  1. 1.Department of PhysiologyUlm UniversityUlmGermany

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