Skip to main content
Log in

Paroxysmal muscle weakness - the familial periodic paralyses

  • REVIEW
  • Published:
Journal of Neurology Aims and scope Submit manuscript

Abstract

The familial periodic paralyses (PP) were commonly considered to be benign diseases since frequency and severity of the paralytic attacks decrease in adulthood. However, with increasing age, a third of the patients develop permanent weakness and muscle degeneration with fatty replacement. Another complication, cardiac arrhythmia, can result from the dyskalemia during paralytic attacks. The familial PP are typical dominant ion channelopathies: the function of the mutant muscular channel is compensated in the interictal state but defective under certain conditions which then cause flaccid weakness. A triggering factor is the level of serum potassium, the extracellular ion decisive for membrane excitability. In hyper- and hypokalemic periodic paralysis, the mutations are specifically located in the voltage-gated sodium and calcium channels which are essential for action potential generation or excitation-contraction coupling. The common mechanism for the membrane inexcitability during paralytic attacks is a transient membrane depolarization that inactivates the sodium channels which are then no longer available for action potential generation. For the third PP type, the Andersen syndrome, the responsible gene is also expressed in cardiac muscle, and, independently of paralytic attacks, the hazard of ventricular arrhythmias is inherent. The gene product, an inwardly rectifying potassium channel, is responsible for maintaining the resting membrane potential, and all known mutations cause dominant–negative effects on the tetrameric channel complexes. In this article the clinical consequences of the mutations and the therapeutic strategies for all three types of PP are reported.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Abbott GW, Butler MH, Bendahhou S, Dalakas MC, Ptacek LJ, Goldstein SA (2001) MiRP2 forms potassium channels in skeletal muscle with Kv3.4 and is associated with periodic paralysis. Cell 104:217–231

    Article  CAS  PubMed  Google Scholar 

  2. Andelfinger G, Tapper AR, Welch RC, Vanoye CG, George AL Jr, Benson DW (2002) KCNJ2 mutation results in Andersens syndrome with sex-specific cardiac and skeletal muscle phenotypes. Am J Hum Genet 71:663–668

    Article  CAS  PubMed  Google Scholar 

  3. Bendahhou S, Donaldson MR, Plaster NM, Tristani-Firouzi M, Fu YH, Ptacek LJ (2003) Defective potassium channel Kir2.1 trafficking underlies Andersen-Tawil syndrome. J Biol Chem 278:51779–51785

    Article  CAS  PubMed  Google Scholar 

  4. Fontaine B, Khurana TS, Hoffman EP, Bruns GAP, Haines JL, Trofatter JA, Hanson MP, Rich J, McFarlane H, McKenna-Yacek D, Gusella JF, Brown RH (1990) Hyperkalemic periodic paralysis and the adult muscle sodium channel alpha-subunit gene. Science 250:1000–1002

    Article  CAS  PubMed  Google Scholar 

  5. Fontaine B, Vale-Santos JE, Jurkat-Rott K, Reboul J, Plassart E, Rime CS, Elbaz A, Heine R, Guimaraes J, Weissenbach J, Baumann N, Fardeau M, Lehmann-Horn F (1994). Mapping of the hypokalaemic periodic paralysis (HypoPP) locus to chromosome 1q31–32 in three European families. Nature Genet 6:267–272

    Article  CAS  PubMed  Google Scholar 

  6. Hayward LJ, Brown RH Jr, Connon SC (1996) Inactivation defects caused by myotonia-associated mutations in the sodium channel III-IV linker. J Gen Physiol 107:559–576

    Article  CAS  PubMed  Google Scholar 

  7. Jurkat-Rott K, Lehmann-Horn F, Elbaz A, Heine R, Gregg RG, Hogan K, Powers P, Lapie P, Vale-Santos JE, Weissenbach J, Fontaine B (1994) A calcium channel mutation causing hypokalemic periodic paralysis. Hum Mol Gen 3:1415–1419

    CAS  PubMed  Google Scholar 

  8. Jurkat-Rott K, Uetz U, Pika-Hartlaub U, Powell J, Fontaine B, Melzer W, Lehmann-Horn F (1998) Calcium currents and transients of native and heterologously expressed mutant skeletal muscle DHP receptor α1 subunits (R528H). FEBS Lett 423:198–204

    Article  CAS  PubMed  Google Scholar 

  9. Jurkat-Rott K, Mitrovic N, Hang C, Kuzmenkin A, Iaizzo P, Herzog J, Lerche H, Nicole N, Vale-Santos J, Chauveau D, Fontaine B, Lehmann-Horn F (2000) Voltage sensor sodium channel mutations cause hypokalemic periodic paralysis type 2 by enhanced inactivation and reduced current. Proc Natl Acad Sci USA 97:9549–9554

    Article  CAS  PubMed  Google Scholar 

  10. Jurkat-Rott K, Lehmann-Horn F (2004) Periodic paralysis mutation MiRP2-R83H in controls: interpretations and general recommendation. Neurology 62:1012–1015

    PubMed  Google Scholar 

  11. Kuzmenkin A, Muncan V, Jurkat-Rott K, Hang C, Lerche H, Lehmann-Horn F, Mitrovic N (2002) Enhanced inactivation and pH sensitivity of Na+ channel mutations causing hypokalemic periodic paralysis type II. Brain 125:835–843

    Article  PubMed  Google Scholar 

  12. Lehmann-Horn F, Kuther G, Ricker K, Grafe P, Ballanyi K, Rüdel R (1987) Adynamia episodica hereditaria with myotonia: A non-inactivating sodium current and the effect of extracellular pH. Muscle Nerve 10:363–374

    Article  CAS  PubMed  Google Scholar 

  13. Lehmann-Horn F, Jurkat-Rott K (1999) Voltage-gated ion channels and hereditary disease. Physiol Rev 79:1317–1371

    CAS  PubMed  Google Scholar 

  14. Lehmann-Horn F, Rüdel R, Jurkat-Rott K (2004) Chapter 46: Nondystrophic myotonias and periodic paralyses. In: Engel AG, Franzini-Armstrong C (ed) Myology. McGraw-Hill, New York, 3rd edition, pp 1257–1300

  15. Morrill JA, Cannon SC (1999) Effects of mutations causing hypokalaemic periodic paralysis on the skeletal muscle L-Type Ca2+ channel expressed in Xenopus laevis oocytes. J Physiol (London) 520:321–336

    Article  CAS  Google Scholar 

  16. Plaster NM, Tawil R, Tristani-Firouzi M, Canun S, Bendahhou S, Tsunoda A, Donaldson MR, Iannaccone ST, Brunt E, Barohn R, Clark J, Deymeer F, George AL Jr, Fish FA, Hahn A, Nitu A, Özdemir C, Serdaroglu P, Subramony SH, Wolfe G, Fu YH, Ptáček LJ (2001) Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen’s syndrome. Cell 105:511–519

    Article  CAS  PubMed  Google Scholar 

  17. Rojas CV, Wang J, Schwartz L, Hoffman EP, Powell BR, Brown RH Jr (1991) A Met-to-Val mutation in the skeletal muscle sodium channel -subunit in hyperkalemic periodic paralysis. Nature 354:387–389

    Article  CAS  PubMed  Google Scholar 

  18. Rüdel R, Lehmann-Horn F, Ricker K, Küther G (1984) Hypokalemic periodic paralysis: in vitro investigation of muscle fiber membrane parameters. Muscle Nerve 7:110–120

    Article  PubMed  Google Scholar 

  19. Ruff RL (1999) Insulin acts in hypokalemic periodic paralysis by reducing inward rectifier K+ current. Neurology 53:1556–1563

    CAS  PubMed  Google Scholar 

  20. Sansone V, Griggs RC, Meola G, Ptáček LJ, Barohn R, Iannaccone S, Bryan W, Baker N, Janas SJ, Scott W, Ririe D, Tawil R (1997) Andersens syndrome: a distinct periodic paralysis. Ann Neurol 42:305–312

    Article  CAS  PubMed  Google Scholar 

  21. Sternberg D, Tabti N, Fournier E, Hainque B, Fontaine B (2003) Lack of association of the potassium channel-associated peptide MiRP2-R83H variant with periodic paralysis. Neurology 61:857–859

    CAS  PubMed  Google Scholar 

  22. Struyk AF, Scoggan KA, Bulman DE, Cannon SC (2000) The human skeletal muscle Na channel mutation R669H associated with hypokalemic periodic paralysis enhances slow inactivation. J Neurosci 20:8610–8617

    CAS  PubMed  Google Scholar 

  23. Tawil R, Ptáček LJ, Pavlakis SG, DeVivo DC, Penn AS, Özdemir C, Griggs RC (1994) Andersens’s syndrome: potassium-sensitive periodic paralysis, ventricular ectopy, and dysmorphic features. Ann Neurol 35:326–330

    Article  CAS  PubMed  Google Scholar 

  24. Tristani-Firouzi M, Jensen JL, Donaldson MR, Sansone V, Meola G, Hahn A, Bendahhou S, Kwiecinski H, Fidzianska A, Plaster N, Fu YH, Ptáček LJ, Tawil R (2002) Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersens syndrome). J Clin Invest 110:381–388

    Article  CAS  PubMed  Google Scholar 

  25. Venance SL, Cannon SC, Fialho D, Fontaine B, Hanna MG, Ptacek LJ, Tristani-Firouzi M, Tawil R, Griggs RC, CINCH investigators (2006) The primary periodic paralyses: diagnosis, pathogenesis and treatment. Brain 129:8–17

    Article  CAS  PubMed  Google Scholar 

  26. Vicart S, Sternberg D, Fournier E, Ochsner F, Laforet P, Kuntzer T, Eymard B, Hainque B, Fontaine B (2004) New mutations of SCN4A cause a potassium-sensitive normokalemic periodic paralysis. Neurology 63:2120–2127

    CAS  PubMed  Google Scholar 

  27. Wagner S, Lerche H, Mitrovic N, Heine R, George AL, Lehmann-Horn F (1997) A novel sodium channel mutation causing a hyperkalemic paralytic and paramyotonic syndrome with variable clinical expressivity. Neurology 49:1018–1025

    CAS  PubMed  Google Scholar 

  28. Weber M-A, Nielles-Vallespin S, Essig M, Jurkat-Rott K, Kauczor H-U, Lehmann-Horn F (2006) Muscle Na+ channelopathies: MR1 detects intracellular 23Na accumulation during episodic weakness. Neurology 67:1151–1158

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Frank Lehmann-Horn.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jurkat-Rott, K., Lehmann-Horn, F. Paroxysmal muscle weakness - the familial periodic paralyses. J Neurol 253, 1391–1398 (2006). https://doi.org/10.1007/s00415-006-0339-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00415-006-0339-0

Keywords

Navigation