Hereditäre Muskelkanalopathien

Zusammenfassung

Elektrophysiologische und molekulargenetische Untersuchungen haben zur Erkenntnis geführt, dass bestimmte Muskelkrankheiten durch pathologisch veränderte Ionenkanäle verursacht sind. Diese Krankheiten werden deshalb Muskelkanalopathien genannt. Es sind dies die nicht dystrophischen Myotonien und die dyskaliämischen periodischen Paralysen, denen Störungen der Ionenkanäle des Plasmalemms zugrunde liegen, und CoreMyopathien und maligne Hyperthermie (MH), bei denen Kanäle der elektromechanischen Kopplung mutiert sind. Die Sichtweise, dass Muskelkanalopathien eher harmlose Erkrankungen sind, sollte revidiert werden. Nicht nur der Hypermetabolismus bei MH kann zu lebensbedrohlichen Krisen führen, sondern die periodischen Paralysen können ausgeprägte Dyskaliämien bewirken, welche die kardiale Erregungsausbreitung bedrohen. Die Hypokalämie ist bei der thyreotoxischen periodischen Paralysen am stärksten ausgeprägt. Abhängig von der zugrunde liegenden Mutation kommt es bei den periodischen Paralysen zu einer progressiven permanenten Muskelschwäche. Diese Schwäche kann mit einer Membrandepolarisation und einer konsekutiven intrazellulären Akkumulation von Natrium und Wasser erklärt werden. Substanzen, welche die Membran repolarisieren, können die Muskelkraft wiederherstellen und möglicherweise die Degeneration verhindern.

Summary

A combination of electrophysiological and molecular genetic studies has resulted in the discovery of certain skeletal muscle disorders to be caused by pathologically functioning ion channels.The group of thus defined hereditary “muscle channelopathies” comprises nondystrophic myotonias, dyskalemic periodic paralyses, central-core myopathy and multiminicore myopathy, as well as malignant hyperthermia. They have in common an impaired muscle excitation or excitation-contraction coupling that is caused by ion channel mutations. Most muscle channelopathies are considered benign diseases. However, muscle hypermetabolism resulting in muscle stiffness and hyperthermia as in an event of malignant hyperthermia can be life-threatening. Also, forms of familial periodic paralysis can be severe when they produce serious dyskalemia that disturbs cardiac excitation conduction. The hypokalemia is most pronounced in thyrotoxic periodic paralysis. Some of the periodic paralyses are associated with a progressive permanent weakness. The weakness is explained by strongly depolarized, inexcitable muscle fibers that accumulate sodium and water. Drugs that repolarize the fiber membrane can restore muscle strength and may prevent progression. Expression studies of putative mutations have become standard in supporting the disease-causing nature of mutations.

Schlüsselwörter

Ionenkanäle - Muskelkrankheiten - Muskelsteifigkeit - Muskelschwäche - Muskeldegeneration - Myotonie - periodische Paralyse - maligne Hyperthermie - Core-Myopathie

Keywords

Ion channels - muscle disorders - muscle stiffness - muscle weakness - muscle degeneration - myotonia - periodic paralysis - malignant hyperthermia - core myopathy

• Literatur

• 1 Alfonsi E. et al. Efficacy of propafenone in paramyotonia congenita. Neurology 2007; 68: 1080-1.
• 2 Brandt A. et al. Screening of the ryanodine receptor gene in 105 malignant hyperthermia families: novel mutations and concordance with the in-vitro contracture test. Hum Mol Genet 1999; 08: 2055-62.
• 3 Chun TU. et al. Polymorphic ventricular tachycardia and KCNJ2 mutations. Heart Rhythm 2004; 01: 242-3.
• 4 Deymeer F. et al. Transient weakness and compound muscle action potential decrement in myotonia congenita. Muscle Nerve 1998; 21: 1334-7.
• 5 Dupré N. et al. Clinical, electrophysiologic, and genetic study of non-dystrophic myotonia in FrenchCanadians. Neuromuscul Disord 2009; 19: 330-4.
• 6 Fontaine B. et al. Hyperkalemic periodic paralysis and the adult muscle sodium channel alphasubunit gene. Science 1990; 250: 1000-2.
• 7 Fontaine B. et al. Mapping of the hypokalaemic periodic paralysis (HypoPP) locus to chromosome 1q31-32 in three European families. Nature Genet 1994; 06: 267-72.
• 8 Heatwole CR, Moxley RT. The nondystrophic myotonias. Neurotherapeutics 2007; 04: 238-51.
• 9 Ikeda K. et al. Acetazolamide-induced weakness in hypokalemic periodic paralysis. Intern Med 2002; 41: 743-5.
• 10 Jungbluth H. Multi-minicore Disease. Orphanet J Rare Dis 2007; 02: 31.
• 11 Jungbluth H. et al. Minicore myopathy with ophthalmoplegia caused by mutations in the ryanodine receptor type 1 gene. Neurology 2005; 65: 1930-5.
• 12 Junker J. et al. Amiodarone and acetazolamide for the treatment of genetically confirmed severe Andersen syndrome. Neurology 2002; 59: 466.
• 13 Jurkat-Rott K, Lehmann-Horn F. Genotype-phenotype correlation and therapeutic rationale in hyperkalemic periodic paralysis. Neurotherapeutics 2007; 04: 216-24.
• 14 Jurkat-Rott K, Lehmann-Horn F. Muscle channelopathies and critical points in functional and genetic studies. J Clin Invest 2005; 115: 2000-9.
• 15 Jurkat-Rott K, Lehmann-Horn F. Hyperkalemic periodic paralysis type 1 in: GeneR eviews at GeneTests: Medical Genetics Information Resource 2009. www.genetests.org
• 16 Jurkat-Rott K, Lehmann-Horn F. Paroxysmal muscle weakness – the familial periodic paralyses. J Neurol 2006; 253: 1391-8.
• 17 Jurkat-Rott K, McCarthy T, Lehmann-Horn F. Genetics and pathogenesis of malignant hyperthermia. Muscle Nerve 2000; 23: 4-17.
• 18 Jurkat-Rott K. et al. Voltage-sensor sodium channel mutations cause hypokalemic periodic paralysis type 2 by enhanced inactivation and reduced current. Proc Natl Acad Sci USA 2000; 97: 9549-54.
• 19 Jurkat-Rott K. et al. A calcium channel mutation causing hypokalemic periodic paralysis. Hum Mol Genet 1994; 03: 1415-9.
• 20 Jurkat-Rott K. et al. K+-dependent paradoxical membrane depolarization and Na+ overload, major and reversible contributors to weakness by ion channel leaks. Proc Natl Acad Sci USA 2009; 106: 4036-41.
• 21 Klingler W, Lehmann-Horn F, Jurkat-Rott K. Complications of anesthesia in neuromuscular disorders. Neuromusc Disord 2005; 15: 195-206.
• 22 Klingler W. et al. 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) activates skeletal muscle nicotinic acetylcholine receptors. J Pharmacol Exp Ther 2005; 314: 1267-73.
• 23 Klingler W. et al. Core Myopathies and Risk of Malignant Hyperthermia. Anesth & Analg 2009; 109: 1167-73.
• 24 Koch MC. et al. The skeletal muscle chloride channel in dominant and recessive human myotonia. Science 1992; 257: 797-800.
• 25 Kubota T. et al. New mutation of the Na channel in the severe form of potassium-aggravated myotonia. Muscle Nerve 2009; 39: 666-73.
• 26 Kubota T. et al. A mutation in a rare type of intron in a sodium-channel gene results in aberrant splicing and causes myotonia. Hum Mutat. 2011 Mar 15; E-pub ahead of print.
• 27 Lehmann-Horn F, Jurkat-Rott K, Rüdel R. Diagnostics and therapy of muscle channelopathies – guidelines of the Ulm Muscle Centre. Acta Myologica 2008; 27: 98-113.
• 28 Lehmann-Horn F, Rüdel R, Jurkat-Rott K. Nondystrophic myotonias and periodic paralyses. In: Myology. AG Engel, C Franzini-Armstrong. (eds.) New York: McGraw-Hill; 2004
• 29 Lerche H. et al. Human sodium channel myotonia: Slowed channel inactivation due to substitutions for a glycine within the III/IV linker. J Physiol (Lond) 1993; 470: 13-22.
• 30 McCarthy TV. et al. Localisation of the malignant hyperthermia susceptibility locus to human chromosome 19q12-13.2. Nature 1990; 343: 562-4.
• 31 Meyer T. et al. Progressive muscle atrophy with hypokalemic periodic paralysis and calcium channel mutation. Muscle Nerve 2008; 37: 120-4.
• 32 Mohammadi B. et al. Preferred mexiletine block of human sodium channels with IVS4 mutations and its pH-dependence. Pharmacogenet Genomics 2005; 15: 235-44.
• 33 Mohammadi B. et al. Mechanisms of cold sensitivity of paramyotonia congenita mutation R1448H and overlap syndrome mutation M1360V. J Physiol 2003; 547: 691-8.
• 34 Monnier N. et al. Malignant-hyperthermia susceptibility is associated with a mutation of the a1-subunit of the human dihydropyridine-sensitive L-type voltage-dependent calcium-channel receptor in skeletal muscle. Am J Hum Genet 1997; 60: 1316-25.
• 35 Monnier N. et al. A homozygous splicing mutation causing a depletion of skeletal muscle RYR1 is associated with multi-minicore disease congenital myopathy with ophthalmoplegia. Hum Mol Genet 2003; 12: 1171-8.
• 36 Ording H. et al. In vitro contracture test for diagnosis of malignant hyperthermia following the protocol of the European MH Group: results of testing patients surviving fulminant MH and unrelated low-risk subjects. The European Malignant Hyperthermia Group. Acta Anaesthesiol Scand 1997; 41: 955-66.
• 37 Orrell RW, Jurkat-Rott K, Lehmann-Horn F, Lane RJM. Familial cramp due to potassium aggravated myotonia. J Neurology, Neurosurgery, and Psychiatry 1998; 65: 569-72.
• 38 Ricker K, Moxley RT, Heine R, Lehmann-Horn F. Myotonia fluctuans. A third type of muscle sodium channel disease. Arch Neurol 1994; 51: 1095-102.
• 39 Robinson R. et al. Mutations in RYR1 in malignant hyperthermia and central core disease. Hum Mutat 2006; 27: 977-89.
• 40 Rüdel R, Ricker K, Lehmann-Horn F. Transient weakness and altered membrane characteristic in recessive generalized myotonia (Becker). Muscle Nerve 1988; 11: 202-11.
• 41 Ryan DP. et al. Mutations in potassium channel Kir2.6 cause susceptibility to thyrotoxic hypokalemic periodic paralysis. Cell 2010; 140: 88-98.
• 42 Sansone V, Meola G, Links TP, Panzeri M, Rose MR. Treatment for periodic paralysis. Cochrane Database Syst Rev. 2008 23. CD005045.
• 43 Stunnenberg BC. et al. Isolated eyelid closure myotonia in two families with sodium channel myotonia. Neurogenetics 2010; 11: 257-60.
• 44 Tawil R. et al. Randomized trials of dichlorphenamide in the periodic paralyses. Working Group on Periodic Paralysis. Ann Neurol 2000; 47: 46-53.
• 45 Trip J, Drost G, Van Engelen BG, Faber CG. Drug treatment for myotonia. Cochrane Database Syst Rev. 2006 01. CD004762.
• 46 Weber MA. et al. Muscle Na+ channelopathies: MRI detects intracellular 23Na accumulation during episodic weakness. Neurology 2006; 67: 1151-8.
• 47 Zhou H. et al. Epigenetic allele silencing unveils recessive RYR1 mutations in core myopathies. Am J Hum Genet 2006; 79: 859-68.
• 48 Zullo A. et al. Functional characterization of ryanodine receptor (RYR1) sequence variants using a metabolic assay in immortalized B-lymphocytes. Hum Mutat 2009; 30: E575-90.