Abstract
We report a young wheelchair-dependent patient with an unclear proximal myopathy and a heterozygous, de-novo Cav1.1-R1239G mutation suggesting hypokalemic periodic paralysis (HypoPP). Sonography showed a loss of the pennate pattern indicative of an edema, whereas fatty degeneration was excluded. Within 7 days of therapy with spironolactone, potassium and physical therapy, muscle strength almost completely normalized, a normal pennate pattern appeared and the edema was markedly reduced. She learned to walk without aid and to do sports and has continued to do so for 11 years until now. Over the years, we tested serum potassium values, muscle strength, muscle edema and muscular sodium content by 1.5 T, 3 T and 7 T 1H and 23Na magnetic resonance imaging. No fatty muscle degeneration developed. Muscular edema-like changes only occurred when she was pregnant and was set to reduced therapy. Because of the ability to do sports again, her mobility was further increased. Our observational study on this single patient may suggest that: (1) muscle imaging and molecular genetics are important diagnostic tools, (2) weakness in periodic paralysis may be reversible, and (3) continued adequate therapy may preserve muscle structure and strength on a longterm, whereas weakness due to fatty degeneration could be considered progressive and irreversible. Although HypoPP is a rare disease, it should be included in differential diagnosis not only if there is paroxysmal weakness, but also in cases of myopathy of unknown origin.
Similar content being viewed by others
References
Resnick JS, Engel WK, Griggs RC, Stam AC (1968) Acetazolamide prophylaxis in hypokalemic periodic paralysis. N Engl J Med 278:582–586
Links TP, Zwarts MJ, Wilmink JT, Molenaar WM, Oosterhuis HJ (1990) Permanent muscle weakness in familial hypokalaemic periodic paralysis. Clinical, radiological and pathological aspects. Brain 113:1873–1889
Jurkat-Rott K, Lehmann-Horn F, Elbaz A, Heine R, Gregg RG, Hogan K, Powers PA, Lapie P, Vale-Santos JE, Weissenbach J et al (1994) A calcium channel mutation causing hypokalemic periodic paralysis. Hum Mol Genet 3:1415–1419
Jurkat-Rott K, Weber MA, Fauler M, Guo XH, Holzherr BD, Paczulla A, Nordsborg N, Joechle W, Lehmann-Horn F (2009) K+-dependent paradoxical membrane depolarization and Na+ overload, major and reversible contributors to weakness by ion channel leaks. Proc Natl Acad Sci USA 106:4036–4041
Ptácek LJ, Tawil R, Griggs RC, Engel AG, Layzer RB, Kwieciński H, McManis PG, Santiago L, Moore M, Fouad G et al (1994) Dihydropyridine receptor mutations cause hypokalemic periodic paralysis. Cell 77:863–868
Jurkat-Rott K, Mitrovic N, Hang C, Kouzmekine A, Iaizzo P, Herzog J, Lerche H, Nicole S, 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
Bulman DE, Scoggan KA, van Oene MD, Nicolle MW, Hahn AF, Tollar LL, Ebers C (1999) A novel sodium channel mutation in a family with hypokalemic periodic paralysis. Neurology 53:1932–1936
Starace DM, Stefani E, Bezanilla F (1997) Voltage-dependent proton transport by the voltage sensor of the Shaker K+ channel. Neuron 19:1319–1327
Starace DM, Bezanilla F (2001) Histidine scanning mutagenesis of basic residues of the S4 segment of the shaker K+ channel. J Gen Physiol 117:469–490
Sokolov S, Scheuer T, Catterall WA (2007) Gating pore current in an inherited ion channelopathy. Nature 446:76–78
Struyk AF, Cannon SC (2007) A Na+ channel mutation linked to hypokalemic periodic paralysis exposes a proton-selective gating pore. J Gen Physiol 130:11–20
Wu F, Mi W, Hernández-Ochoa EO, Burns DK, Fu Y, Gray HF, Struyk AF, Schneider MF, Cannon SC (2012) A calcium channel mutant mouse model of hypokalemic periodic paralysis. J Clin Investig 122:4580–4591
Fan C, Lehmann-Horn F, Weber MA, Bednarz M, Groome JR, Jonsson MK, Jurkat-Rott K (2013) Transient compartment-like syndrome and normokalaemic periodic paralysis due to a Ca(v)1.1 mutation. Brain 136:3775–3786
Groome JR, Lehmann-Horn F, Fan C, Wolf M, Winston V, Merlini L, Jurkat-Rott K (2014) NaV1.4 mutations cause hypokalaemic periodic paralysis by disrupting IIIS4 movement during recovery. Brain 137:998–1008
Matthews E, Portaro S, Ke Q, Sud R, Haworth A, Davis MB, Griggs RC, Hanna MG (2011) Acetazolamide efficacy in hypokalemic periodic paralysis and the predictive role of genotype. Neurology 77:1960–1964
Dias da Silva MR, Cerutti JM, Tengan CH, Furuzawa GK, Vieira TC, Gabbai AA, Maciel RM (2002) Mutations linked to familial hypokalaemic periodic paralysis in the calcium channel alpha1 subunit gene (Cav1.1) are not associated with thyrotoxic hypokalaemic periodic paralysis. Clin Endocrinol (Oxf) 56:367–375
Kim JB, Lee KY, Hur JK (2005) A Korean family of hypokalemic periodic paralysis with mutation in a voltage-gated calcium channel (R1239G). J Korean Med Sci 20:162–165
Winczewska-Wiktor A, Steinborn B, Lehman-Horn F, Biczysko W, Wiktor M, Gurda B, Jurkat-Rott K (2007) Myopathy as the first symptom of hypokalemic periodic paralysis—case report of a girl from a Polish family with CACNA1S (R1239G) mutation. Adv Med Sci 52(Suppl 1):155–157
Sansone VA, Burge J, McDermott MP, Smith PC, Herr B, Tawil R, Pandya S, Kissel J, Ciafaloni E, Shieh P, Ralph JW, Amato A, Cannon SC, Trivedi J, Barohn R, Crum B, Mitsumoto H, Pestronk A, Meola G, Conwit R, Hanna MG, Griggs RC (2016) Muscle Study Group. Randomized, placebo-controlled trials of dichlorphenamide in periodic paralysis. Neurology 86:1408–1416
Glemser PA, Jaeger H, Nagel AM, Ziegler AE, Simons D, Schlemmer HP, Lehmann-Horn F, Jurkat-Rott K, Weber MA (2017) (23)Na MRI and myometry to compare eplerenone vs. glucocorticoid treatment in Duchenne dystrophy. Acta Myol 36:2–13
Weber MA, Nagel AM, Jurkat-Rott K, Lehmann-Horn F (2011) Sodium (23Na) MRI detects elevated muscular sodium concentration in Duchenne muscular dystrophy. Neurology 77:2017–2024
Nagel AM, Amarteifio E, Lehmann-Horn F, Jurkat-Rott K, Semmler W, Schad LR, Weber MA (2011) 3 Tesla sodium inversion recovery magnetic resonance imaging allows for improved visualization of intracellular sodium content changes in muscular channelopathies. Investig Radiol 46:759–766
Amarteifio E, Nagel AM, Weber MA, Jurkat-Rott K, Lehmann-Horn F (2012) Hyperkalemic periodic paralysis and permanent weakness: 3-T MR imaging depicts intracellular 23Na overload—initial results. Radiology 264:154–163
Weber MA, Nagel AM, Marschar AM, Glemser P, Jurkat-Rott K, Wolf MB, Ladd ME, Schlemmer HP, Kauczor HU, Lehmann-Horn F (2016) 7-T (35)Cl and (23)Na MR imaging for detection of mutation-dependent alterations in muscular edema and fat fraction with sodium and chloride concentrations in muscular periodic paralyses. Radiology 280:848–859
Nagel AM, Lehmann-Horn F, Weber MA, Jurkat-Rott K, Wolf MB, Radbruch A, Umathum R, Semmler W (2014) In vivo 35Cl MR imaging in humans: a feasibility study. Radiology 271:585–595
Marden FA, Connolly AM, Siegel MJ, Rubin DA (2005) Compositional analysis of muscle in boys with Duchenne muscular dystrophy using MR imaging. Skelet Radiol 34:140–148
Wattjes MP, Kley RA, Fischer D (2010) Neuromuscular imaging in inherited muscle diseases. Eur Radiol 20:2447–2460
Weber MA, Nagel AM, Wolf MB, Jurkat-Rott K, Kauczor HU, Semmler W, Lehmann-Horn F (2012) Permanent muscular sodium overload and persistent muscle edema in Duchenne muscular dystrophy: a possible contributor of progressive muscle degeneration. J Neurol 259:2385–2392
Weber MA, Krakowski-Roosen H, Hildebrandt W, Schröder L, Ionescu I, Krix M, Kinscherf R, Bachert P, Kauczor HU, Essig M (2007) Assessment of metabolism and microcirculation of healthy skeletal muscles by magnetic resonance and ultrasound techniques. J Neuroimaging 17:323–331
Nielles-Vallespin S, Weber MA, Bock M, Bongers A, Speier P, Combs SE, Wöhrle J, Lehmann-Horn F, Essig M, Schad LR (2007) 3D radial projection technique with ultrashort echo times for sodium MRI: clinical applications in human brain and skeletal muscle. Magn Reson Med 57:74–81
Weber MA, Nielles-Vallespin S, Essig M, Jurkat-Rott K, Kauczor HU, Lehmann-Horn F (2006) Muscle Na+ channelopathies—MRI detects intracellular 23Na accumulation during episodic weakness. Neurology 67:1151–1158
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
Acknowledgements
We thank the patient for the perfect compliance. K. J. R. and M. A. W. were supported by the Eva Luise Köhler Research Award for Rare Diseases. F. L. H. was endowed Senior Research Professor of the non-profit Hertie-Foundation. K. J. R., H. L. and F. L. H. were supported by research grants from the German Federal Research Ministry (BMBF, IonNeurONet, 01GM1105A), and K. J. R., M. A. W. and F. L. H. by the German Society for Patients with Muscle Disorders (DGM).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflicts of interest
The authors report no conflicts of interest.
Ethical approval
All human studies have been approved by the appropriate local ethics committee and have been performed in accordance with the ethical standards laid down in the Declaration of Helsinki. Informed consent was obtained prior to inclusion in the study.
Additional information
Dedicated to Eva Luise Köhler, former First Lady of Germany and patron of the ACHSE (Chronic Rare Disease Alliance) and our mentor, colleague and friend, Frank Lehmann-Horn, who initiated the study and sadly passed away in May 2018.
Rights and permissions
About this article
Cite this article
Weber, MA., Jurkat-Rott, K., Lerche, H. et al. Strength and muscle structure preserved during long-term therapy in a patient with hypokalemic periodic paralysis (Cav1.1-R1239G). J Neurol 266, 1623–1632 (2019). https://doi.org/10.1007/s00415-019-09302-3
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00415-019-09302-3