Periodic paralysis and related disorders

Mananya Satayaprasert MD (Dr. Satayaprasert of Wheaton Franciscan Health Care has no relevant financial relationships to disclose.)
Jau-Shin Lou MD PhD (Dr. Lou of University of North Dakota School of Medicine and Health Science and Sanford Health has no relevant financial relationships to disclose.)
Michio Hirano MD, editor. (Dr. Hirano of Columbia University has no relevant financial relationships to disclose.)
Originally released May 19, 1994; last updated March 23, 2015; expires March 23, 2018

This article includes discussion of periodic paralysis and related disorders, adynamia episodica hereditaria, Andersen-Tawil syndrome, Becker generalized myotonia, HPP, HYPP, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, myotonia congenita, myotonia congenita (autosomal dominant), myotonia congenita (autosomal recessive), myotonia fluctuans, myotonia permanens, paramyotonia congenital, Thomsen disease, and Von Eulenberg syndrome. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

This article on periodic paralysis and related disorders introduces readers to the clinical presentations, basic concepts, and current understanding of the pathophysiology of these rare disorders or channelopathies. Although the clinical management of these channelopathies remains somewhat unchanged, pathophysiological studies are an active field of ongoing research, with new genes and new insights being discovered with increasing frequency.

Key points

 

• Episodes of periodic paralysis typically involve generalized muscle weakness with hypotonia and areflexia but spare bulbar and respiratory muscles and cognition.

 

• Measurement of serum potassium levels during the attacks, recognition of precipitating factors, clinical or electrical myotonia, findings on electrodiagnostic tests, cardiac arrhythmia, and distinctive craniofacial and skeletal features help in distinguishing variant 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.

 

• Many genes have been identified for these channelopathies, but the exact mechanisms by which ion channel defects lead to each phenotype remain unclear.

 

• Even though acetazolamide is most commonly used as chronic therapy for hypokalemic periodic paralysis, hyperkalemic periodic paralysis, and related syndromes, there is no clear evidence that acetazolamide is effective from a randomized, double blind, placebo-controlled trial.

Historical note and terminology

Periodic paralysis (Westphal 1885) and the related disorders paramyotonia congenita (Eulenberg 1886) and myotonia congenita (Thomsen 1876) 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 (Biemond and Daniels 1934), and later, with elevated serum potassium levels (adynamia episodica hereditaria) (Gamstorp 1956). The association between cardiac arrhythmias and periodic paralysis has been noted by several investigators (Klein et al 1963; Lisak et al 1972). Andersen and colleagues described a triad of periodic paralysis, ventricular ectopy, and characteristic physical features (Andersen et al 1971), a phenotype later refined by Tawil and colleagues (Tawil et al 1994; Sansone et al 1997). This syndrome is variously referred to as Andersen syndrome, Andersen-Tawil syndrome, or long QT syndrome type 7 (LQT7).

With molecular technology, mutations have now been identified in multiple voltage-gated ion channels: sodium (hyperkalemic periodic paralysis, paramyotonia congenita, potassium aggravated myotonia, and uncommonly, hypokalemic periodic paralysis), potassium (Andersen-Tawil syndrome), calcium (hypokalemic periodic paralysis), and chloride channels (myotonia congenita) (Catterall 1988). With the degree of overlap between the traditional, clinically defined syndromes and the degree of genotypic heterogeneity, it is now clear that the traditional classification of the periodic paralyses is too restrictive. Furthermore, although molecular medicine has dramatically enhanced our understanding of these disorders, there remains much work to be done to further characterize the clinical and pathophysiologic features and establish more effective treatments. For example, whereas loci for most of the periodic paralyses have been established and the genes at least partly characterized, a substantial proportion of patients have no mutation in identified genes. Ongoing research is investigating further loci in this unique, complex, and challenging group of disorders.

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