Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics The Nondystrophic Myotonias Chad R. Heatwole* and Richard T. Moxley III*† *Department of Neurology and †Department of Pediatrics, University of Rochester, Rochester, New York Summary: The nondystrophic myotonias are a heterogeneous (paramyotonia congenita, potassium-aggravated myotonia, set of rare diseases that demonstrate clinical myotonia, electri- and hyperkalemic periodic paralysis with myotonia). The cal myotonia, or both. These disorders are distinguished from variants that occur in each of these conditions are com- myotonic dystrophy type 1 (DM-1), the more recently de- mented on. The differentiating features of the nondystrophic scribed proximal myotonic myopathy/myotonic dystrophy type myotonias are summarized, and their predominant clinical, 2 (PROMM/DM-2), and proximal myotonic dystrophy (a vari- electrodiagnostic, and genetic characteristics are tabulated. ant of DM-2) by characteristic clinical features, lack of abnor- For a comprehensive review of pertinent research and stud- mal nucleotide repeat expansions in the DM-1 and DM-2 ies with application to diagnosis and treatment of individuals genes, lack of cataracts and endocrine disturbances, and ab- with nondystrophic myotonic disorders, the present article is sence of significant histopathology in the muscle biopsy. The best read in the context of other articles in this issue, espe- present article reviews each of the nondystrophic myotonias cially those on ion channel physiology (Cannon) and phar- by exploring the unique clinical features, electrodiagnostic macology (Conte-Camerino), and on hyperkalemic periodic findings, diagnostic criteria, gene mutations, and response to paralysis (Lehmann-Horn). Key Words: Nondystrophic myo- pharmacologic therapy. These diseases are divided into tonia, Becker’s disease, Thomsen’s disease, myotonia levior, those with chloride channel dysfunction (the myotonia con- paramyotonia congenita, hyperkalemic periodic paralysis with genita disorders) and those with sodium channel dysfunction myotonia. INTRODUCTION prolonged muscle contraction after an abrupt external mechanical compression of a specific muscle. This is Myotonia is an intrinsic disorder of muscle caused by demonstrated by percussing a myotonic muscle with a defects in either ion channel or muscle membrane func- tion. Clinically, myotonia in the individual muscle fibers reflex hammer. Any muscle can be tested this way; how- summates to produce a prolonged time for relaxation ever, the thenar eminence and wrist extensor muscles are after voluntary muscle contraction and external mechan- the ones most often evaluated. ical stimulation.1 Patients with nondystrophic myotonia Electrical hyperexcitability of individual muscle fibers often describe their main symptom as a “painless stiff- is the fundamental alteration that underlies myotonia and ness” that occurs immediately after initiating a muscle causes the delay in muscle relaxation after contraction or contraction after a period of inactivity or rest. For exam- percussion. Myotonic discharges appear in affected mus- ple, suddenly climbing a flight of stairs after several cle fibers after stimulation or puncture with a needle minutes of sitting often serves as a clinical trigger. electrode and leads to prolonged, spontaneous trains of Muscle action and percussion are effective methods of muscle fiber action potentials that wax and wane in am- eliciting myotonia on physical examination. In action plitude and frequency.2 Frequencies may range from 20 myotonia, a muscle continues to contract after use. Clas- to 150 Hz, with amplitudes of the potentials in the 10 to sically, the muscle action of myotonia produces an iso- 1000 mV range. Myotonic discharges by definition last tonic contraction. A patient is unable to release the grip 500 ms or longer and should be identified in at least three after making a fist or after a strong handshake. Percus- areas of an individual muscle outside of an endplate sion myotonia, unlike action myotonia, is an abnormally region.3 The sound produced by myotonic discharges during electrophysiological study is one of the most dis- tinct in electromyography and has been likened to the Address correspondence and reprint requests to: Chad R. Heatwole, 601 Elmwood Ave., Box 673, Rochester, NY 14642. E-mail: Chad_ sound of such things as a World War II dive bomber, a [email protected]. motorcycle motor, and a chain saw.4 A myotonic potential 238 Vol. 4, 238–251, April 2007 © The American Society for Experimental NeuroTherapeutics, Inc. NONDYSTROPHIC MYOTONIAS 239 appears on an EMG study as a positive wave or brief spike their variants, comprise the nondystrophic chloride chan- potential, typically occurring in trains of discharges.2 nel myotonias. Paramyotonia congenita, hyperkalemic The majority of patients with myotonic disorders have periodic paralysis, the three forms of potassium aggra- both clinical and electrical myotonia. Some individuals vated myotonia, and their variants comprise the nondys- have only electrical myotonia early in the course of their trophic sodium channel myotonias.9 disease, with clinical myotonia occurring later in life. Clinically, the nondystrophic myotonias can usually Historically, myotonias have been divided into two be differentiated based on their inheritance pattern, classes, based on the presence of progressive muscle response to stimuli (including cold, potassium ingestion, wasting and weakness and on evidence of dystrophic exercise, and drug therapy), electrodiagnostic features, changes from muscle histology. The dystrophic myo- muscle histology, genetic mutations, and myotonia tonic disorders consist of myotonic dystrophy type 1 characteristics.1 Clinical response to cold exposure or (DM-1) or the classical Steinert’s form of myotonic dys- exercise testing can help in classifying nondystrophic trophy, proximal myotonic myopathy/myotonic dystro- myotonias, and it is useful to inquire about these re- phy type 2 (PROMM/DM-2), and proximal myotonic sponses before undertaking electrodiagnostic testing. dystrophy (a variant of DM-2 with only electrical Cold frequently worsens clinical myotonia, a feature that myotonia and more severe muscle wasting than typical has been verified electrodiagnostically in paramyotonia DM-2). The remaining myotonic disorders without pro- congenita and acetazolamide-responsive myotonia.10 If a gressive weakness, wasting, and dystrophic histopathol- patient has a history of cold-induced symptoms, the arm ogy fall into the diverse group of diseases known as the may be wrapped in a plastic bag and submerged in cold nondystrophic myotonias.5 water prior to EMG to either augment or eliminate myo- The usual classification of nondystrophic myotonias tonic features. Detailed descriptions of protocols used includes myotonia congenita, paramyotonia congenita, previously for cold-water immersion and testing are potassium-aggravated myotonia, and hyperkalemic peri- available in the pioneering studies by Ricker and col- odic paralysis with myotonia. All share a common leagues.11–13 etiology: ion channel dysfunction. These ion channel Long or short exercise testing as a part of the electro- myotonic disorders have distinctive clinical findings that diagnostic evaluation of a patient with myotonia may distinguish them not only from the dominantly inherited also prove useful in differentiating those with nondys- myotonic dystrophies but also from several other disor- trophic myotonia from other myotonic disorders.2 The ders that demonstrate myotonic discharges on EMG long exercise test is implemented by having a patient study. maximally contract an intrinsic hand muscle for 4 to 5 There are other conditions that can produce electrical min, with periods of relaxation every 15 to 20 s.3 This myotonia in the absence of prominent clinical myotonia exercise is followed by a series of recordings at set time and that often cause progressive weakness.4 These in- intervals, to analyze the amplitude and duration of the clude acid maltase deficiency, polymyositis, myotubular evoked compound muscle action potential (CMAP). congenital myopathy, hypothyroidism, and malignant Similarly, short exercise testing requires 5 to 10 s of hyperpyrexia.2,4 Occasionally, even severe denervation maximal isometric contraction of an intrinsic hand mus- may produce non-sustained electrical myotonia.2 Clini- cle followed by a series of recordings of evoked CMAPs cal and EMG myotonia may also be precipitated or un- at set time intervals.3 masked by medication or toxin exposure. Such agents Both cold immersion testing and exercise testing have include clofibrate, propranolol, fenoterol, terbutaline, col- limitations in establishing the diagnosis of a nondystro- chicine, penicillamine, diazocholesterol, monocarboxylic phic myotonia. Limited studies are available to establish acids, 3-hydroxy-3-methylglutaryl coenzyme A (HMG- the reliability and reproducibility of either type of testing CoA) reductase inhibitors, cyclosporine, anthracene-9- in the same individuals over time, and there are no stud- carboxylic acid, and 2,4-dichlorophenoxyacetic acid.2,4,6,7 ies in kindreds with known genetic mutations that have Other conditions, such as Schwartz–Jampel syndrome, established the usefulness of cold immersion and exer- stiff person syndrome, acquired generalized peripheral cise testing in family members with mild or no symp- nerve hyperexcitability and hereditary familial episodic toms. There are