Channel Surfing

Louis J. Ptácek

Howard Hughes Medical Institute, Departments of Neurology and Human Genetics, University of Utah, Salt Lake City, Utah 84112

Address all correspondence and requests for reprints to: Louis J. Ptácek, M.D., Associate Investigator, Howard Hughes Medical Institute, University of Utah, 4420 Eccles Institute of Human Genetics, 15 North 2030 East, Salt Lake City, Utah 84112. E-mail: ptacek{at}genetics.utah.edu.

The study by Dias Da Silva et al. (1), in this issue of JCEM, reports an interesting approach to a challenging problem and to understanding the pathophysiological basis of a relatively common metabolic muscle disorder. Thyrotoxic hypokalemic periodic paralysis (TPP) is seen in individuals of all races and manifests as attacks of episodic weakness with hypokalemia during thyrotoxicosis. TPP is seen most commonly in young Latin American or Asian men where up to 10% of thyrotoxic patients may have periodic paralysis. In such patients thyrotoxicosis has often been overlooked for many months. TPP generally occurs as a sporadic disease, and the periodic paralysis resolves completely with treatment of the thyrotoxicosis, although the muscle phenotype returns if the patient becomes thyrotoxic again later.

Clinically, TPP shares significant similarities with the familial form of hypokalemic periodic paralysis (HypoKPP). Several differences help differentiate these two conditions. Familial HypoKPP can occur as a sporadic disorder (these often represent de novo mutations in the HypoKPP gene that subsequently can be passed down in an autosomal dominant manner). TPP is usually sporadic. However, rare familial TPP cases have been recognized. Although serum potassium levels tend to be low during attacks in familial HypoKPP (in the range of 2.3–3.1, typically), the serum potassiums are often even lower in TPP (less than 2 mM).

It is interesting to speculate that TPP might have an underlying genetic basis. If this is the case, it is possible that a single gene mutation is segregating in a Mendelian fashion in families but that the disorder only shows up as a clinically manifesting disease with coincident thyrotoxicosis. Another possibility is that multiple genetic components are required to predispose to TPP and, again, that the disorder is only manifest during thyrotoxicosis. An alternative hypothesis is that TPP is a purely secondary disorder due to the extremely low serum potassium levels seen in many of these patients. Rare familial clusterings have helped to support the former two possibilities.

As noted above, TPP is seen in a wide variety of ethnic populations although its highest incidence is in Latin American and Asian populations. If genetic factors contribute significantly to TPP predisposition, it could be that the frequencies of predisposing alleles are higher in these ethnic groups. Another possibility is that the allele frequencies are similar across all ethnic groups but expressed more frequently because the requisite environmental factor is more common in these populations. Asians have among the highest rate of thyrotoxicosis, and, therefore, it would not be surprising that such a predisposition would lead to a much more frequent phenotype in this population.

Interestingly, the genetics of the familial periodic paralyses have been worked out to a significant degree over the last 11 yr. The first voltage-gated ion channel disorder recognized in humans was first reported in 1991 (2, 3). At that time, these discoveries suggested the possibility that this rare muscle disease might serve as a model for other episodic and electrical muscle disorders as well as other electrical and episodic phenomena such as cardiac arrhythmias, epilepsy, and even migraine headache (2). Subsequently, a large family of clinically overlapping but distinct episodic muscle disorders have been recognized, resulting in mutations in this and other ion channel genes (4, 5, 6, 7).

Subsequently, a growing number of disorders have been shown to result from ion channel mutations. These include long QT syndrome with cardiac arrhythmias, episodic ataxias, seizure disorders, and headache (8).

In the current report, these investigators hypothesize that perhaps variants in these aforementioned ion channels might, in fact, be targets for genetic variants that predispose to periodic paralysis that can be uncovered by thyrotoxicosis. In this model, the thyrotoxicosis may have a very direct effect on thyroid-responsive elements in some of these ion channel genes or, alternatively, might change the general metabolic milieu sufficiently to uncover functional consequences of a mutation whose effect is relatively small under basal conditions.

The familial HypoKPP phenotype has been attributed to calcium, sodium, and potassium channel mutations (8). A search for familial HypoKPP calcium channel mutations in TPP patients revealed negative results (9, 10). Furthermore, sodium channel mutations causing the HypoKPP phenotype were also not found in this cohort of TPP patient DNAs.

Interestingly, however, a rare mutation that was identified rarely in hyperkalemic periodic paralysis or HypoKPP families was noted in 1 of the 14 TPP patients examined in this study. This was a gene encoding an auxiliary subunit for a potassium channel {alpha}-subunit that was shown to decrease the outward flux of potassium, leading to a less negative resting membrane potential.

The results identifying KCNE3 mutations in periodic paralysis patients (1, 5) must be viewed with caution. To date, they have only been recognized in a very small number of probands; however, a search through a large number of control subjects has not yet identified this variant as a polymorphism.

It is fascinating to speculate that TPP, a secondary form of periodic paralysis, is really a genetic predisposition due to ion channel variants that ultimately lead to clinical manifestations with an environmental exposure (i.e. thyrotoxicosis). Much work remains to be done in examining this hypothesis further in larger TPP patient cohorts and other channel genes that are expressed in skeletal muscle. Nonetheless, this serves as an exciting example of how understanding in rare Mendelian disorders can open up avenues for investigating complex genetics (presumably multiple genes plus environmental factors) in a sporadic disorder like TPP.

There are a large number of proteins that contribute to the excitability of muscle membranes including the channels but also other proteins important for the processing, trafficking, and regulation of ion channels. The summation of all of the normal variations that exist in these genes and their encoded proteins are likely to contribute not only to normal variations in muscle function but also to different susceptibilities to disorders such as TPP.

Acknowledgments

Footnotes

Abbreviations: HypoKPP, Hypokalemic periodic paralysis; TPP, thyrotoxic hypokalemic periodic paralysis.

Received September 17, 2002.

Accepted September 17, 2002.

References

  1. Dias Da Silva MR, Cerutti JM, Arnaldi LAT, Maciel RMB 2002 A mutation in the KCNE3 potassium channel gene is associated with susceptibility to thyrotoxic hypokalemic periodic paralysis. J Clin Endocrinol Metab 87:4881–4884[Abstract/Free Full Text]
  2. Ptácek LJ, George AL, Griggs RC, Tawil R, Kallen RG, Barchi RL, Robertson M, Leppert MF 1991 Identification of a mutation in the gene causing hyperkalemic periodic paralysis. Cell 67:1021–1027[Medline]
  3. Rojas CV, Wang JZ, Schwartz LS, Hoffman EP, Powell BR, Brown Jr RH 1991 A Met-to-Val mutation in the skeletal muscle Na+ channel {alpha}-subunit in hyperkalaemic periodic paralysis. Nature 354:387–389[CrossRef][Medline]
  4. Koch MC, Steinmeyer K, Lorenz C, Ricker K, Wolf F, Otto M, Zoll B, Lehmann-Horn F, Grzeschik KH, Jentsch TJ 1992 The skeletal muscle chloride channel in dominant and recessive human myotonia. Science 257:797–800[Medline]
  5. Ptácek LJ, Tawil R, Griggs RC, Engel AG, Layzer RB, Kwiecinski H, McManis P, Santiago F, Moore M, Fouad G, Bradley P, Leppert MF 1994 Dihydropyridine receptor mutations cause hypokalemic periodic paralysis. Cell 77:863–868[Medline]
  6. Abbott GW, Butler MH, Bendahhou S, Dalakas M, Ptácek LJ, Goldstein L 2001 Mirp2 forms potassium channels in skeletal muscle with Kv3.4 and is associated with periodic paralysis. Cell 104:217–231[Medline]
  7. Plaster NM, Tawil R, Tristani-Firouze M, Canun S, Bendahhou S, Tsunoda A, Donaldson MR, Iannaccone ST, Brunt E, Barohn R, Clark J, Deymeer F, George AL, Fish FA, Hahn A, Nitu A, Ozdemir C, Serdaroglu P, Subramony S, Wolfe G, Fu Y-H, Ptácek LJ 2001 Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen’s syndrome. Cell 105:511–519[CrossRef][Medline]
  8. Jen J, Ptácek LJ 2001 Channelopathies. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. Metabolic and molecular bases of inherited disease, ed 8. New York: McGraw-Hill; 5223–5238
  9. 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, Ptácek LJ 1997 Genotype-phenotype correlations of DHP Receptor {alpha}1-subunit gene mutations causing hypokalemic periodic paralysis. Neuromuscul Disord 7:33–38[CrossRef][Medline]
  10. Dias Da Silva M, Cerutti JM, Tengan C, Furuzawa GK, Vieira TC, Gabbai AA, Maciel RM 2002 Mutations linked to familial hypokalaemic periodic paralysis in the calcium channel {alpha}1 subunit gene are not associated with thyrotoxic hypokalaemic periodic paralysis. Clin Endocrinol 56:367–375[CrossRef][Medline]




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