, Volume 4, Issue 2, pp 258–266 | Cite as

Episodic ataxia type 1: A neuronal potassium channelopathy

  • Sanjeev Rajakulendran
  • Stephanie Schorge
  • Dimitri M. Kullmann
  • Michael G. HannaEmail author


Episodic ataxia type 1 is a paroxysmal neurological disorder characterized by short-lived attacks of recurrent midline cerebellar dysfunction and continuous motor activity. Mutations in KCN1A, the gene encoding Kv1.1, a voltage-gated neuronal potassium channel, are associated with the disorder. Although rare, the syndrome highlights the fundamental features of genetic ion-channel diseases and serves as a useful model for understanding more common paroxysmal disorders, such as epilepsy and migraine. This review examines our current understanding of episodic ataxia type 1, focusing on its clinical and genetic features, pathophysiology, and treatment.

Key Words

Episodic ataxia channelopathies myokymia potassium channel 


  1. 1.
    Ptacek LJ. Channelopathics: ion channel disorders of muscle as a paradigm for paroxysmal disorders of the nervous system. Neuromuscul Disord 1997;7: 250–255.CrossRef
  2. 2.
    Kullman DM. The neuronal channelopathies. Brain 2002;125: 1177–1195.CrossRef
  3. 3.
    Ashcroft FM. Ion channels and disease: channelopathies. San Diego: Academic Press; 2000.
  4. 4.
    Davics NP, Hanna MG. Neurological channelopathies: diagnosis and therapy in the new millennium. Ann Med 1999;31: 406–420.CrossRef
  5. 5.
    Cannon SC. Ion-channel defects and aberrant excitability in myotonia and periodic paralysis. Trends Neurosci 1996;19: 3–10.CrossRef
  6. 6.
    Kullmann DM, Rea R, Spauschus A, Jouvenceau A. The inherited episodic ataxias: how well do we understand the disease mechanisms? Neuroscientist 2001;7: 80–88.CrossRef
  7. 7.
    Griggs RC, Moxley RT 3rd, Lafrance RA, McQuillen J. Hereditary paroxysmal ataxia: response to acetazolamide. Neurology 1978; 28: 1259–1264.
  8. 8.
    Gancher ST, Nutt JG. Autosomal dominant episodic ataxia: a heterogeneous syndrome. Mov Disord 1986;1: 239–253.CrossRef
  9. 9.
    Griggs RC, Nutt JG. Episodic ataxias as channelopathies. Ann Neurol 1995;37: 285–287.CrossRef
  10. 10.
    Brunt ER, van Weerden TW. Familial paroxysmal kinesigenic ataxia and continuous myokymia. Brain 1990;113: 1361–1382.CrossRef
  11. 11.
    Browne DL, Gancher ST, Nutt JG, et al. Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene, KCNA1. Nat Genet 1994;8: 136–140.CrossRef
  12. 12.
    Browne DL, Brunt ER, Griggs RC, et al. Identification of two new KCNA1 mutations in episodic ataxia/myokymia families. Hum Mol Genet 1995;4: 1671–1672.CrossRef
  13. 13.
    Comu S, Giuliani M, Narayanan V. Episodic ataxia and myokymia syndrome: a new mutation of potassium channel gene Kv1.1. Ann Neurol 1996;40: 684–687.CrossRef
  14. 14.
    Eunson LH, Rea R, Zuberi SM, et al. Clinical, genetic, and expression studies of mutations in the potassium channel gene KCNA1 reveal new phenotypic variability. Ann Neurol 2000;48: 647–656.CrossRef
  15. 15.
    Scheffer H, Brunt ER, Mol GJ, et al. Three novel KCNA1 mutations in episodic ataxia type I families. Hum Genet 1998;102: 464–466.CrossRef
  16. 16.
    Spauschus A, Eunson L, Hanna MG, Kullmann DM. Functional characterization of a novel mutation in KCNA1 in episodic ataxia type 1 associated with epilepsy. Ann N Y Acad Sci 1999;868: 442–446.CrossRef
  17. 17.
    Zuberi SM, Eunson LH, Spauschus A, et al. A novel mutation in the human voltage-gated potassium channel gene (Kv1.1) associates with episodic ataxia type 1 and sometimes with partial epilepsy. Brain 1999;122: 817–825.CrossRef
  18. 18.
    Knight MA, Storey E, McKinlay Gardner RJ, Hand P, Forrest SM. Identification of a novel missense mutation L329I in the episodic ataxia type 1 gene KCNA1: a challenging problem. Hum Mutat 2000;16: 374.CrossRef
  19. 19.
    Yue Q, Jen JC, Nelson SF, Baloh RW. Progressive ataxia due to a missense mutation in a calcium-channel gene. Am J Hum Genet 1997;61: 1078–1087.CrossRef
  20. 20.
    Jen J, Yue Q, Nelson SF, et al. A novel nonsense mutation in CACNA1A causes episodic ataxia and hemiplegia. Neurology 1999;53: 34–37.
  21. 21.
    Ophoff RA, Terwindt GM, Vergouwe MN, et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 1996;87: 543–552.CrossRef
  22. 22.
    Denier C, Ducros A, Vahedi K, et al. High prevalence of CACNA1A truncations and broader clinical spectrum in episodic ataxia type 2. Neurology 1999;52: 1816–1821.
  23. 23.
    Denier C, Ducros A, Durr A, Eymard B, Chassande B, Toumier-Lasserve E. Missense CACNA1A mutation causing episodic ataxia type 2. Arch Neurol 2001;58: 292–295.CrossRef
  24. 24.
    Battistini S, Stenirri S, Piatti M, et al. A new CACNA1A gene mutation in acetazolamide-responsive familial hemiplegic migraine and ataxia. Neurology 1999;53: 38–43.
  25. 25.
    Jouvenceau A, Eunson LH, Spauschus A, et al. Human epilepsy associated with dysfunction of the brain P/Q-type calcium channel. Lancet 2001;358: 801–807.CrossRef
  26. 26.
    Vahedi K, Joutel A, Van Bogaert P, et al. A gene for hereditary paroxysmal cerebellar ataxia maps to chromosome 19p. Ann Neurol 1995;37: 289–293.CrossRef
  27. 27.
    Van Dyke DH, Griggs RC, Murphy MJ, Goldstein MN. Hereditary myokymia and periodic ataxia. J Neurol Sci 1975;25: 109–118.CrossRef
  28. 28.
    Hanson PA, Martinez LB, Cassidy R. Contractures, continuous muscle discharges, and titubation. Ann Neurol 1977;1: 120–124.CrossRef
  29. 29.
    Vaamonde J, Artieda J, Obeso JA. Hereditary paroxysmal ataxia with neuromyotonia. Mov Disord 1991;6: 180–182.CrossRef
  30. 30.
    Hand PJ, Gardner RJ, Knight MA, Forrest SM, Storey E. Clinical features of a large Australian pedigree with episodic ataxia type 1. Mov Disord 2001;16: 938–939.CrossRef
  31. 31.
    Van Bogaert P, Van Nechel C, Goldman S, Szliwowski HB. Acetazolamide-responsive hereditary paroxysmal ataxia: report of a new family. Acta Neurol Belg 1993;93: 268–275.
  32. 32.
    Jen J, Kim GW, Baloh RW. Clinical spectrum of episodic ataxia type 2. Neurology 2004;62: 17–22.
  33. 33.
    Baloh RW, Yue Q, Furman JM, Nelson SF. Familial episodic ataxia: clinical heterogeneity in four families linked to chromosome 19p. Ann Neurol 1997;41: 8–16.CrossRef
  34. 34.
    Hans M, Luvisetto S, Williams ME, et al. Functional consequences of mutations in the human α1A calcium channel subunit linked to familial hemiplegic migraine. J Neurosci 1999;19: 1610–1619.
  35. 35.
    Ducros A, Denier C, Joutel A, et al. The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal calcium channel. N Engl J Med 2001;345: 17–24.CrossRef
  36. 36.
    Vighetto A, Froment JC, Trillet M, Aimard G. Magnetic resonance imaging in familial paroxysmal ataxia. Arch Neurol 1988;45: 547–549.
  37. 37.
    Lee H, Wang H, Jen JC, Sabatti C, Baloh RW, Nelson SF. A novel mutation in KCNA1 causes episodic ataxia without myokymia. Hum Mutat 2004;24: 536.CrossRef
  38. 38.
    Kinali M, Jungbluth H, Eunson LH, et al. Expanding the phenotype of potassium channelopathy: severe neuromyotonia and skeletal deformities without prominent episodic ataxia. Neuromuscul Disord 2004;14: 689–693.CrossRef
  39. 39.
    Klein A, Boltshauser E, Jen J, Baloh RW. Episodic ataxia type 1 with distal weakness: a novel manifestation of a potassium channelopathy. Neuropediatrics 2004;35: 147–149.CrossRef
  40. 40.
    Lubbers WJ, Brunt ER, Scheffer H, et al. Hereditary myokymia and paroxysmal ataxia linked to chromosome 12 is responsive to acetazolamide. J Neurol Neurosurg Psychiatry 1995;59: 400–405.CrossRef
  41. 41.
    Smart SL, Lopantsev V, Zhang CL, et al. Deletion of the Kv1.1 potassium channel causes epilepsy in mice. Neuron 1998;20: 809–819.CrossRef
  42. 42.
    Biervert C, Schroeder BC, Kubisch C, et al. A potassium channel mutation in neonatal human epilepsy. Science 1998;279: 403–406.CrossRef
  43. 43.
    Charlier C, Singh NA, Ryan SG, et al. A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family. Nat Genet 1998;18: 53–55.CrossRef
  44. 44.
    Singh NA, Charlier C, Stauffer D, et al. A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nat Genet 1998;18: 25–29.CrossRef
  45. 45.
    Lee WL, Biervert C, Hallmann K, Tay A, Dean JC, Steinlein OK. A KCNQ2 splice site mutation causing benign neonatal convulsions in a Scottish family. Neuropediatrics 2000;31: 9–12.CrossRef
  46. 46.
    Schroeder BC, Kubisch C, Stein V, Jentsch TJ. Moderate loss of function of cyclic-AMP-modulated KCNQ2/KCNQ3 K+ channels causes epilepsy. Nature 1998;396: 687–690.CrossRef
  47. 47.
    Bagetta G, Nistico G, Dolly JO. Production of seizures and brain damage in rats by α-dendrotoxin, a selective K+ channel blocker. Neurosci Lett 1992;139: 34–40.CrossRef
  48. 48.
    Juhng KN, Kokate TG, Yamaguchi S, et al. Induction of seizures by the potent K+ channel-blocking scorpion venom peptide toxins tityustoxin-Kα and pandinustoxin-Kα. Epilepsy Res 1999;34: 177–186.CrossRef
  49. 49.
    Schulte U, Thumfart JO, Klocker N, et al. The epilepsy-linked Lgi1 protein assembles into presynaptic Kv1 channels and inhibits inactivation by Kvβ1. Neuron 2006;49: 697–706.CrossRef
  50. 50.
    Fukata Y, Adesnik H, Iwanaga T, Bredt DS, Nicoll RA, Fukata M. Epilepsy-related ligand/receptor complex LGI1 and ADAM22 regulate synaptic transmission. Science 2006;313: 1792–1795.CrossRef
  51. 51.
    Litt M, Kramer P, Browne D, et al. A gene for episodic ataxia/myokymia maps to chromosome 12p13. Am J Hum Genet 1994; 55: 702–709.
  52. 52.
    Yu FH, Yarov-Yarovoy V, Gutman GA, Catterall WA. Overview of molecular relationships in the voltage-gated ion channel superfamily. Pharmacol Rev 2005;57: 387–395.CrossRef
  53. 53.
    Long SB, Campbell EB, Mackinnon R. Crystal structure of a mammalian voltage-dependent Shaker family K+ channel. Science 2005;309: 897–903.CrossRef
  54. 54.
    Rettig J, Heinemann SH, Wunder F, et al. Inactivation properties of voltage-gated K+ channels altered by presence of beta-subunit. Nature 1994;369: 289–294.CrossRef
  55. 55.
    Wang H, Kunkel DD, Martin TM, Schwartzkroin PA, Tempel BL. Heteromultimeric K+ channels in terminal and juxtaparanodal regions of neurons. Nature 1993;365: 75–79.CrossRef
  56. 56.
    Wang H, Kunkel DD, Schwartzkroin PA, Tempel BL. Localization of Kv1.1 and Kv1.2, two K channel proteins, to synaptic terminals, somata, and dendrites in the mouse brain. J Neurosci 1994;14: 4588–4599.
  57. 57.
    Coleman SK, Newcombe J, Pryke J, Dolly JO. Subunit composition of Kv1 channels in human CNS. J Neurochem 1999;73: 849–858.CrossRef
  58. 58.
    Adelman JP, Bond CT, Pessia M, Maylie J. Episodic ataxia results from voltage-dependent potassium channels with altered functions. Neuron 1995;15: 1449–1454.CrossRef
  59. 59.
    D’Adamo MC, Liu Z, Adelman JP, Maylie J, Pessia M. Episodic ataxia type-1 mutations in the hKv1.1 cytoplasmic pore region alter the gating properties of the channel. EMBO J 1998;17: 1200–1207.CrossRef
  60. 60.
    Boland LM, Rice DL, Jackson KA. Episodic ataxia/myokymia mutations functionally expressed in the Shaker potassium channel. Neuroscience 1999;91: 1557–1564.CrossRef
  61. 61.
    Zerr P, Adelman JP, Maylie J. Characterization of three episodic ataxia mutations in the human Kv1.1 potassium channel. FEBS Lett 1998;431: 461–464.CrossRef
  62. 62.
    Zerr P, Adelman JP, Maylie J. Episodic ataxia mutations in Kv1.1 alter potassium channel function by dominant negative effects or haploinsufficiency. J Neurosci 1998;18: 2842–2848.
  63. 63.
    Imbrici P, Cusimano A, D’Adamo MC, De Curtis A, Pessia M. Functional characterization of an episodic ataxia type-1 mutation occurring in the S1 segment of hKv1.1 channels. Pflugers Arch 2003;446: 373–379.
  64. 64.
    Rea R, Spauschus A, Eunson LH, Hanna MG, Kullmann DM. Variable K+ channel subunit dysfunction in inherited mutations of KCNA1. J Physiol 2002;538: 5–23.CrossRef
  65. 65.
    Maylie B, Bissonnette E, Virk M, Adelman JP, Maylie JG. Episodic ataxia type 1 mutations in the human Kv1.1 potassium channel alter hKvβ1-induced N-type inactivation. J Neurosci 2002;22: 4786–4793.
  66. 66.
    Imbrici P, D’Adamo MC, Kullmann DM, Pessia M. Episodic ataxia type 1 mutations in the KCNA1 gene impair the fast inactivation properties of the human potassium channels Kv1.4-1.1/Kv/31.1 and Kv1.4-1.1/Kv/31.2. Eur J Neurosci 2006;24: 3073–3083.CrossRef
  67. 67.
    Trimmer JS, Rhodes KJ. Localization of voltage-gated ion channels in mammalian brain. Annu Rev Physiol 2004;66: 477–519.CrossRef
  68. 68.
    Herson PS, Virk M, Rustay NR, et al. A mouse model of episodic ataxia type-1. Nat Neurosci 2003;6: 378–383.CrossRef
  69. 69.
    Hisama F, Chen H, Von Hehn C, et al. Novel potassium channel (KCNA1) mutation in hereditary myokymia. Soc Neurosci Abstr 2006; Program no. 234.26/D64 (abstract).
  70. 70.
    Zhou L, Zhang CL, Messing A, Chiu SY. Temperature-sensitive neuromuscular transmission in Kv1.1 null mice: role of potassium channels under the myelin sheath in young nerves. J Neurosci 1998;18: 7200–7215.
  71. 71.
    Veh RW, Lichtinghagen R, Sewing S, Wunder F, Grumbach IM, Pongs O. Immunohistochemical localization of five members of the Kv1 channel subunits: contrasting subcellular locations and neuron-specific co-localizations in rat brain. Eur J Neurosci 1995; 7: 2189–2205.CrossRef
  72. 72.
    Benatar M. Neurological potassium channelopathies. QJM 2000; 93: 787–797.CrossRef
  73. 73.
    Zhang CL, Messing A, Chiu SY. Specific alteration of spontaneous GABAergic inhibition in cerebellar Purkinje cells in mice lacking the potassium channel Kv1.1. J Neurosci 1999;19: 2852–2564.
  74. 74.
    Chen G, Gao W, Reinert KC, et al. Involvement of Kv1 potassium channels in spreading acidification and depression in the cerebellar cortex. J Neurophysiol 2005;94: 1287–1298.CrossRef
  75. 75.
    Bain PG, O’Brien MD, Keevil SF, Porter DA. Familial periodic cerebellar ataxia: a problem of cerebellar intracellular pH homeostasis. Ann Neurol 1992;31: 147–154.CrossRef
  76. 76.
    Sappey-Marinier D, Vighetto A, Peyron R, Broussolle E, Bonmartin A. Phosphorus and proton magnetic resonance spectroscopy in episodic ataxia type 2. Ann Neurol 1999;46: 256–259.CrossRef

Copyright information

© Springer New York 2007

Authors and Affiliations

  • Sanjeev Rajakulendran
    • 1
  • Stephanie Schorge
    • 1
  • Dimitri M. Kullmann
    • 2
  • Michael G. Hanna
    • 1
    Email author
  1. 1.Centre for Neuromuscular Disease, Department of Molecular Neuroscience, Institute of NeurologyUniversity College LondonLondonUK
  2. 2.Department of Clinical and Experimental Epilepsy, Institute of NeurologyUniversity College LondonLondonUK

Personalised recommendations

viagra ordinare on-line

generico de viagra