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  • Updated 07.16.2023
  • Released 05.19.1994
  • Expires For CME 07.16.2026

Periodic paralysis and the nondystrophic myotonias (skeletal muscle channelopathies)



A diagnosis of skeletal muscle channelopathy can be encouraging for both patients and clinicians as most symptoms respond well to pharmacological treatment. This article on periodic paralysis and the nondystrophic myotonias (skeletal muscle channelopathies) introduces readers to the clinical presentations and current understanding of the pathophysiology of these rare diseases and provides a practical guide on how to investigate and treat them. Updates include significant new developments in our understanding of the clinical presentations of muscle channelopathies and randomized controlled trial data for pharmacological treatments.

Key points

• Episodes of periodic paralysis typically involve generalized muscle weakness with hypotonia and areflexia, but in adults, bulbar and respiratory muscles and cognition are generally spared.

• Bulbar and respiratory muscles are commonly involved in children, especially those with SCN4A gene-related disorders.

• Severe neonatal episodic laryngospasm is a severe phenotype of sodium channel myotonia presenting in infancy.

• Genetic testing is now the mainstay of diagnosing these syndromes in most patients.

• Measuring serum potassium levels, recognizing precipitating factors, and identifying the clinical features of myotonia, cardiac arrhythmia, or distinctive craniofacial and skeletal features help distinguish the different forms of inherited periodic paralysis.

• Serum potassium levels can remain within the normal range during the attacks of both hypokalemic periodic paralysis and hyperkalemic periodic paralysis.

• The cardiac complications of Andersen-Tawil syndrome are greater than previously appreciated, and patients require yearly cardiac review, including Holter monitoring.

• Acetazolamide is most commonly used as prophylactic therapy for periodic paralysis, although clinical trial data on efficacy are still lacking, and some genotypes may be exacerbated by using it.

• In randomized, double-blind, placebo-controlled trials, dichlorphenamide appears promising in ameliorating symptoms in patients with hypokalemic and hyperkalemic periodic paralysis but can be difficult to obtain and is a high-cost drug.

• Sodium channel blockers remain the mainstay of treating myotonia, but mexiletine and lamotrigine benefit from trial evidence of efficacy.

• Mexiletine is now licensed for treating nondystrophic myotonia but at a high cost.

Historical note and terminology

Periodic paralysis (90) and the related myotonic disorders paramyotonia congenita (21) and myotonia congenita (83) were first described over 100 years ago. During the early part of the twentieth century, an association was recognized between episodic weakness and low serum potassium levels (10), and later, with elevated serum potassium levels (adynamia episodica hereditaria) (26). The association between cardiac arrhythmias and periodic paralysis has been noted by several investigators (45). Andersen and colleagues described a triad of periodic paralysis, ventricular ectopy, and characteristic physical features (04), a phenotype later refined by Tawil and colleagues (71). This syndrome is variously referred to as Andersen syndrome, Andersen-Tawil syndrome, or long QT syndrome type 7 (LQT7).

With molecular technology, mutations have been identified in multiple sarcolemmal voltage-gated ion channel genes: sodium, SCN4A gene (hyperkalemic periodic paralysis, paramyotonia congenita, sodium channel myotonia, and, less commonly, hypokalemic periodic paralysis); potassium, KCNJ2 gene (Andersen-Tawil syndrome); calcium, CACNA1S gene (hypokalemic periodic paralysis); and chloride channels, CLCN1 gene (myotonia congenita) (14).

Significant advances in understanding the pathophysiology of these disorders have directly informed pharmacological treatment. Next-generation sequencing and other methodologies (eg, MLPA) show that these clinical phenotypes are due to mutations in the described genes in most patients. The outlier is that in a notable proportion of patients with Andersen-Tawil syndrome, no genetic mutation is identified in KCNJ2.

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