Classification of the Muscle Channelopathies

In contrast to muscular dystrophies, the muscle channelopathies, a group of diseases characterised by impaired muscle excitation or excitation-contraction coupling, can fairly well be treated with a whole series of pharmacological drugs.

However, for a proper treatment proper diagnostics are essential. This article lists state-of-the-art diagnostics and therapies for the two types of myotonic dystrophies, for recessive and dominant myotonia congenita, for the sodium channel myotonias, for the primary dyskalemic periodic paralyses, for central core disease and for malignant hyperthermia susceptibility in detail.

The full article Diagnostics and Therapy of Muscle Channelopathies


4 Replies to “Clinical Trials of Muscle Channelopathies”

  1. Skeletal muscle channelopathies

    Motoneuron activity is transferred to skeletal muscle in the neuromuscular junction generating an action po- tential in the muscle that propagates along the surface membrane including the transverse tubular system (TTS), a membrane region projecting deep into the cell to ensure even distribution of the impulse. The upstroke of the action potential is mediated by opening of the voltage gated Na+ channels (encoded by the SCN4A gene and its accessory beta-subunit encoded by SCN1B) that elicit a Na+ inward current with rapid activation kinet- ics. Repolarization of the membrane by rapid Na+ chan- nel inactivation is additionally supported by opening of K+ channels (encoded by KCNC4 and its accessory sub- unit encoded by KCNE3) that mediate an outward K+ current. Buffering of after potentials is achieved by a high Cl– conductance near the resting potential resulting from the homodimeric Cl– channel encoded by CLCN1.
    At specialized junctions in the TTS, the signal is transmitted from the outer membrane to the inside causing the release of Ca2+-ions from the sarcoplasmic reticulum (SR) which in turn activates the contractile apparatus, a process called excitation-contraction cou- pling. Mainly two Ca2+ channel complexes are involved in this process, the voltage gated pentameric dihydropy- ridine receptor located in the TTS (encoded by the CACNA1S gene and accessory subunits encoded by CACNA2D1, CACNG1, CACNB1) and the homote- trameric ryanodine receptor of the SR (encoded by the RYR1 gene). The voltage gated Ca2+ channel is activated by membrane depolarization and by this, activates the ryanodine receptor by direct protein/protein interac- tion which in turn releases Ca2+ into the cytosol .

  2. Muscle channelopathies and critical points in functional and genetic studies

    Muscle channelopathies are caused by mutations in ion channel genes, by antibodies directed against ion channel proteins, or by changes of cell homeostasis leading to aberrant splicing of ion channel RNA or to disturbances of modification and localization of channel proteins. As ion channels constitute one of the only protein families that allow functional examination on the molecular level, expression studies of putative mutations have become standard in confirming that the mutations cause disease. Functional changes may not necessarily prove disease causality of a putative mutation but could be brought about by a polymorphism instead. These problems are addressed, and a more critical evaluation of the underlying genetic data is proposed.

    Ulm University

  3. Muskuläre Kanalopathien

    Myotonien sind Erkrankungen, bei denen als Hauptsymptom eine generalisierte Muskelsteifigkeit besteht, die besonders nach plötzlichen und heftigen Muskelkontraktionen, etwa beim Erschrecken auftritt und durch unwillkürliche Aktionspotenzialserien ausgelöst wird.

    Im Gegensatz zu den meisten anderen Muskelerkrankungen sind vielfach die Muskeln hypertrophiert. Mutationen in unterschiedlichen Ionenkanälen , die die elektrische Erregbarkeit der Muskelfasermem bran erhöhen, sind ursächlich für die verlängerte Muskelanspannung. Entsprechend der genetischen Ursache unterscheidet man Chlorid- und Natriumkanalmyotonien .

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  4. Skeletal muscle channelopathy: a new risk for sudden infant death syndrome

    Sudden infant death syndrome (SIDS) remains a leading cause of infant mortality, despite a steadily decreasing incidence since the 1990s.1 The reasons for this decline are debated, but it could be due to methodological reasons (eg, changes in reporting or advances in diagnosis of specific diseases) or a reduction of risks, such as an increase in supine sleeping position for infants, as advocated by the Back to Sleep campaign.

    Mutations of SCN4A can cause non-dystrophic myotonia and can, in rare instances, present at infancy with laryngospasm, severe stridor, and respiratory compromise requiring intubation or tracheostomy.

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