Hypokalemic Periodic Paralysis Mutation in CACNA1S

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Hypokalemic Periodic ParalysisMutation in
CACNA1S

• Gloria Ho
• Ren Shuoh Kuo
• Lisa Lehmann
• Ki Cheon Park

http//www.sinc.stonybrook.edu/Stu/glho/
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What is Hypokalemic Periodic Paralysis ?

• A channelopathy
• Mutation at the calcium channel gene, CACNA1S
  (HypoKPP type1)
• 43 of HypoKPP are caused by mutation at domain 2
  and 53 of HypoKPP are caused by mutation at
  domain 4. 1
• The mutation affect the calcium ions
  voltage-gated channel and DHP receptor.

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Genetic Picture

• CACNA1S located at 1q31-32
• Mutation causes change in skeletal muscle Ca2
  channel a-1 subunit
• Arg528-to-His in DIIS4
• Arg1239-to-His in DIVS4 (common)
• Arg1239-to-Gly in DIVS4
• Missense mutations that change arginine into
  histidine or glycine 2

Figure 1.
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L-type Calcium Channel

• Mutations are only in S4 (voltage sensor)3

Figure 2.
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L-type Calcium Channel

• Mutation is dominant, passed on to offspring 3
• Mutation is active in all males however it is
  reduced in females (50) 4
• Disorder can also be caused by mutations in the
  CACNL1A3 and SCN4A gene 5
• Recovery time does not change with mutation 2

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• Voltage dependence of steady-state inactivation
  does not change with mutation

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• Conduction shifted by -5.7mV in Arg528His, 10mV
  in Arg1239His and 6.5 in Arg1239Gly

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• Activation time much slower with increasing
  depolarization

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• Current reduced by 40 in Arg528His and 60-70 in
  Arg1239His and Arg1239Gly 6

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Genotype to Phenotype

• Mutation causes attacks of weakness (paralysis)
  and low extracellular K levels 4
• CACNA1S releases local intracellular Ca2 due to
  an influx of Ca2, causing muscle contraction
• HOKPP changes the KATP channel, perhaps caused by
  low intracellular Ca2
• Low KATP current may cause HOKPP symptoms 7,8

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Prevalence

• In US, HypoKPP has a prevalence of 1100,000
  9,10
• 65 of HypoKPP patients have showed their first
  symptoms before the age of 16 11

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Symptoms

• Muscle weakness
• Cranial nerve spared
• Myotonia
• Rhabdomolysis
• Myalgias
• The duration of the symptoms may varies from a
  few hours to days and the disease may causes the
  permanent weakness.

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What triggers HypoKPP?

• High glucose/insulin level in the bloodstream
• Stress
• Infections
• Menstruation
• Medications (beta-agonists, adrenaline and
  contriosteroids)

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Diagnosis

• Urine test
• Muscle biopsy
• Electrodiagnostic - Long exercise test
• Sequence analysis or mutation scanning

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Treatments

• Acetazolamide
• Gene therapy (trial)

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References

• Fouad G, Dalakas M, Servidei S, Mendell JR, Van
  den Bergh P, Angelini C, Alderson K, Griggs RC,
  Tawil R, Gregg R, Hogan K, Powers PA, Weinberg N,
  Malonee W, Ptacek LJ. Genotype-phenotype
  correlations of DHP receptor alpha 1-subunit gene
  mutations causing hypokalemic periodic paralysis.
  Neuromuscul Disord. 199773338
• 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.
  1998181032010334.
• Wang Q, Liu M, Xu C, Tang Z, Liao Y, Du R, Li W,
  Wu X, Wang X, Liu P, Zhang X, Zhu J, Ren X, Ke T,
  Wang Q, Yang J 2005 Novel CACNA1S mutation causes
  autosomal dominant hypokalemic periodic paralysis
  in a Chinese family. J Mol Med. 83(3), 203208.
• http//www.neuro.wustl.edu/neuromuscular/mtime/mep
  isodic.htmlhopp
• http//www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id
  170400
• 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.
  1999520321336
• Tricarico D, Servidei S, Tonali P, Jurkat-Rott K,
  Camerino DC. Impairment of skeletal muscle
  adenosine triphosphate-sensitive K channels in
  patients w/ hypokalemic periodic paralysis. J
  Clin Ivest 1999, 103 675-82.

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References

• Kageyama K, Terui K, Tsutaya S, Matsuda E, Shoji
  M, Sakihara S, Nigawara T, Takayasu S, Moriyama
  T, Yasujima M, Suda T. Gene analysis of the
  calcium channel 1 subunit and clinical studies
  for two patienets with hypokalemic periodic
  paralysis. J Endocrinol Invest 2006, 29 928-33.
• http//www.emedicine.com/NEURO/topic308.htm
• Lehmann-Horn, F. Jurkat-Rott, K. Voltage-gated
  ion channels and hereditary disease.
  Physiological Reviews, Vo. 79, N0, October 1999
• http//hkpp.org/faq/hypokalemic_periodic_paralysis
  .html
• Figure 1 Lehmann-Horn F, Sipos I, Jurkat-Rott K,
  Heine R, Brinkmeier H, Fontaine B, Kovaks L,
  Melzer W. Altered calcium currents in human
  hypokalemic periodic paralysis myotubes
  expressing mutant L-type calcium channels. Ion
  Channels and Diseases 1995, 50 101-113.
• Figure 2 Sternberg D, Maisonobe T, Jurkat-Rott
  K, Nicole S, Launay E, Chauveau D, Tabti N,
  Lehmann-Horn F, Hainque B, Fontaine B. 2001
  Hypokalaemic periodic paralysis type 2 caused by
  mutations at codon 672 in the muscle sodium
  channel gene SCN4A. Brain 124(6), 1091-1099.