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AANEM Monograph

Differential Diagnosis of Myotonic Disorders

Georgios Manousakis, MD Muhammad Al-Lozi, MD Timothy M. Miller, MD, PhD

December 2012 # 27

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Go to www.aanem.org and explore the benefits of membership, Muscle & Nerve, CME opportunities, Nerve & Muscle Junction podcasts and other valuable resources. Differential Diagnosis of Myotonic Disorders Georgios Manousakis, MD University of Minnesota 420 Delaware St. SE Minneapolis, MN

Muhammad Al-Lozi, MD and Timothy M. Miller, MD, PhD Washington University 660 S. Euclid Ave St. Louis, MO

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Copyright© December 2012

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AANEM Monograph# 27 CME STUDY GUIDE AANEM Monograph #27 Differential Diagnosis of Myotonic Disorders Georgios Manousakis, MD University of Minnesota 420 Delaware St. SE Minneapolis, MN

Muhammad Al-Lozi, MD and Timothy M. Miller, MD, PhD Washington University 660 S. Euclid Ave St. Louis, MO

EDUCATIONAL OBJECTIVES Upon completion of this monograph, the reader will acquire skills to: (1 Explain the differential diagnosis of myotonic disorders, and (2) determine electrodiagnostic studies that may aid the differential diagnosis.

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DIFFERENTIAL DIAGNOSIS OF MYOTONIC DISORDERS GEORGIOS MANOUSAKIS1, MD, MUHAMMAD AL-LOZI2, MD, TIMOTHY M. MILLER3, MD, PhD Department of , University of Minnesota, Minneapolis, MN (1) and Department of Neurology, Washington University, St.N Louis, MO (2) ,(3) ABSTRACT: is primarily a muscle disorder RECOGNIZING MYOTONIA CLINICALLY characterized clinically by muscle stiffness with or Patients with myotonia often complain of muscle stiffness without weakness, and electrophysiologically by muscle that improves with repeated use of the muscle, the so- membrane hyperexcitability manifested by myotonic called “warm-up phenomenon.” Clinical demonstration of discharges (electrical myotonia). Myotonic disorders myotonia as delayed relaxation of muscle after voluntary are broadly divided into (type 1 and contraction (handgrip myotonia8, 53), or percussion (e.g., 2) and non-dystrophic myotonias (, at the thenar eminence, see Figs.1 and 2), is the hallmark , and finding on physical examination. Patients with Isaac’s myotonias). In addition to stiffness, myotonic dystrophy syndrome occasionally may have pseudomyotonia of is distinguished by the presence of fixed weakness and their handgrip, but percussion myotonia does not occur.26 systemic features like cataracts and cardiac . In hypothyroidism, myoedema can cause confusion with Non-dystrophic myotonia is mainly manifested by percussion myotonia, but the skin mounding induced by stiffness; however, periodic weakness may occur in percussion is electrically silent.25 Eyelid myotonia can paramyotonia congenita and hyperkalemic periodic be shown by asking the patient to repeatedly close the . Although electrical myotonia is a distinctive eyes tightly. After the first closure, there may be a lag in feature of myotonic disorders, it is not a pathognomonic eye opening, which will improve with repeated efforts feature of them. Myotonic discharges are seen in non- (Fig. 3A). Patients with paramyotonia also complain of myotonic muscle such as Pompe’s disease, muscle stiffness, but the stiffness often worsens rather than myofibrillar , myotubular and improves with repeated exercise (Fig. 3B). Myotonia and some toxic myopathies. However, when myotonic paramyotonia are usually not difficult to distinguish from discharges are abundant and widespread they are muscle cramps that present with a sudden and painful suggestive of a myotonic disorder. focal muscle contracture. Myotonia and paramyotonia are typically painless. INTRODUCTION Myotonia can be viewed as a clinical or electrical phenomenon, but from a physiological standpoint, both result from the same process: muscle membrane hyperexcitability leading to repetitive action potentials after a single nerve stimulus. This can result from primary or secondary dysfunction of chloride or sodium channels; the mechanisms will be analyzed in subsequent sections. Patients with myotonic disorders commonly present with one of three Figure 1: Percussion myotonia of the thenar muscles. symptoms: a) stiffness (the subjective perception of clinical A) The examiner is preparing to strike the thenar muscles with a myotonia), b) fixed weakness or c) episodic weakness reflex hammer. B) Note the dimpling of muscles in the thenar muscle (attacks of paralysis). Stiffness is the dominant clinical group. This dimpling is due to sustained contraction (myotonia) of feature of the non-dystrophic myotonias. Fixed weakness is thenar muscles evoked by direct muscle percussion. a prominent characteristic of the myotonic dystrophies and it can be proximal in myotonic dystrophy type 2 (DM2), mimicking other limb-girdle muscle dystrophies or acquired inflammatory, endocrine or toxic myopathies, or distal in myotonic dystrophy type 1 (DM1), occasionally causing diagnostic confusion with other inherited distal myopathies or even polyneuropathies. The ptosis and facial weakness in DM1 has to be differentiated from ; the presence of ophthalmoplegia, diurnal fluctuations and Figure 2: Percussion myotonia of the wrist extensor muscles. fatiguable ptosis favor the latter. Mild fixed weakness A) The examiner is preparing to strike the wrist extensor muscle can also occur in recessive myotonia congenita and long- group with a reflex hammer. B) Note that the wrist is hung up. This standing periodic paralyses. Lastly, episodic weakness hang up is due to sustained contraction (myotonia) of wrist extensor with myotonia occurs in hyperkalemic muscles evoked by direct muscle percussion. and occasionally paramyotonia congenita. The distinctive clinical and electrodiagnostic characteristics of myotonia will be described in the following paragraphs. As expected, all of the 16 patients with DM1 in their study had classic myotonic discharges. Myokymic potentials (Fig. 5)

Figure 3A are essentially rhythmic firing of grouped motor unit action potentials in groups of 2-10 and with a frequency of 2-60 Hz, sounding like “marching soldiers”. Neuromyotonic discharges Figure 3B (Fig. 6) are very high frequency discharges at 100-300 Hz that originate at the peripheral nerve terminal/axons, based on their termination by a local peripheral nerve blockade but not by sleep or general anesthesia. These discharges cannot Figure 3C sustain themselves, so they abruptly decrease in amplitude, producing a “pinging” sound on the oscilloscope. Complex Figure 3-A: Myotonia of the orbicularis oculi. In this series of photographs, the patient is initially looking straight ahead (left). Next repetitive discharges (CRDs, Fig. 7) are repetitive complex the patient is forcibly closing her eyes (center). Then the patient has potentials with a sudden onset and cessation, resembling the been told to open her eyes as wide open as possible (right). Note sound of a motorcycle. These potentials do not wax and wane that the patient is unable to open her eyes because of myotonia like myotonia, although the waveform shape, amplitude, and of the orbicularis oculi muscle. This figure demonstrates classical frequency may change during discharge. Cramps are rarely myotonia, in which the myotonia is most severe after the first captured on EMG, except when the gastrocnemius muscle contraction. If the patient had repeated the forcible eye closures, is tested; they originate at the motor neurons and not the the myotonia would have “warmed up” or lessened with repeated muscle fibers like myotonia, and they are characterized by a closures. sudden painful contraction and on EMG by high frequency Figure 3-B: Paradoxical orbicularis oculi myotonia. In this series of discharges, which can be up to 150 Hz. The discharge photographs, the patient has been asked to forcibly close her eye frequency and the number of motor unit discharges increase and then to open them fully as quickly as possible. Each photograph was taken immediately after the patient was told to open her eyes. gradually during the development of the cramp, and subside After the first forcible eye closure (photograph on left), the patient gradually as the cramp fades (Fig. 8). has no difficulty in opening her eyes. Note the progressive difficulty in fully opening her eyes. After the fourth forcible eye closure (photograph on the right), the patient is unable to open her eyes. Figure 3-C: Paradoxical grip myotonia. In this series of photographs, the patient has been asked to forcibly squeeze the examiner’s fingers and then to open the hand as quickly as possible. Each photograph was taken immediately after the patient was told to open the hand. After the first tight squeeze (photograph on the left), the patient has no difficulty letting go. Note the progressive difficulty in letting go of the examiner’s fingers. After the fourth tight squeeze (photograph Figure 4. Myotonic Discharge. on the right), the patient is unable to let go of the examiner’s fingers. Repetitive discharge at rates of 20-80 Hz are of two types: (1) biphasic (positive-negative) spike potentials less than 5 ms in RECOGNIZING MYOTONIA WITH duration resembling fibrillation potentials, (2) positive waves of ELECTRODIAGNOSTIC TESTING 5 to 20 ms in duration resembling positive sharp waves. Both potential forms are recorded after needle insertion, after voluntary Myotonia on (EMG) is distinct (Fig. 4), muscle contraction or after muscle percussion, and are due to manifesting as spontaneous discharges with a waxing independent, repetitive discharges of single muscle fibers. The and waning of both amplitude and frequency, producing amplitude and frequency of the potentials must both wax and a characteristic sound often compared to a dive-bomber or wane to be identified as myotonic discharges. This change produces a characteristic musical sound in the audio display of the reving-engine.1, 28 These potentials are repetitive discharges electromyography due to the corresponding change in pitch, which with a rate of 20-80 Hz and are of two types: (1) biphasic has bee likened to the sound of a “dive bomber.” spikes less than 5 ms in duration that resemble fibrillation potentials, and (2) positive waves, 5-20 ms in duration, that resemble positive sharp waves. A single myotonic potential may look and sound exactly like a fibrillation potential or positive sharp wave, but it is the multiple runs with the characteristic waxing and waning that distinguish the discharges as myotonic potentials. Needle insertion and movement, muscle contraction, or tapping will often provoke the myotonia. Waning discharges are easily distinguished from myotonic discharges because they lack the characteristic waxing that is part of the classic definition. However, these potentials may represent a subset of myotonia. Logigian and colleagues34 found that 4 of 17 patients with genetically confirmed myotonic dystrophy type 2 (DM2) had only waning discharges without evidence of classic myotonic discharges. Figure 5: Myokymic Discharge Tracings of three different myokymic discharges displayed with a time scale (left) to illustrate the firing pattern and with a different Figure 7: Complex Repetitive Discharge A complex repetitive discharge is a polyphasic or serrated action time scale (right) to illustrate that the individual potentials have the potential that may begin spontaneously or after a needle movement. configuration of a motor unit . A myokymic discharge They have a uniform frequency, shape, and amplitude, with abrupt is a group of motor unit action potentials that fire repetitively and may onset, cessation, or change in configuration. Amplitude ranges be associated with clinical myokymia. Tow firing patterns have been from 100 μV to 1mV and frequency of discharge from 5 to 100 described. Commonly, the discharge is a brief, repetitive firing of Hz. Complex repetitive discharge is the most widely accepted single units for a short period (up to a few seconds) at a uniform rate term, though these potentials have also been referred to as bizarre (2-60 Hz) followed by a short period (up to a few seconds) of silence, high-frequency discharge, bizarre repetitive discharge, bizarre with repetition of the same sequence for a particular potential. Less repetitive potential, near constant frequency trains, pseudomyotonic commonly, the potential recurs continuously at a fairly uniform firing discharge, and synchronized fibrillation. rate (1-5 Hz). Myokymic discharges are a subclass of grouped discharges and repetitive discharges.

Figure 8: Cramp Discharge A cramp discharge arises from the involuntary repetitive firing of motor unit action potentials at a high frequency (up to 150 Hz) in a large area of muscle, usually associated with painful muscle contraction. Both the discharge frequency and the number of motor action potentials firing increase gradually during development, and both subside gradually with cessation.

Figure 6: Neuromyotonic Discharge ELECTRODIAGNOSTIC STUDIES THAT MAY The timescale was chosen to illustrate the characteristic firing AID DIFFERENTIAL DIAGNOSIS pattern. A neuromyotonic discharge is a burst of motor unit action Myotonia is the most useful finding on standard EMG potentials that originate in the motor axons firing at high rates (150- and nerve conduction examinations. However, several 300 Hz) for a few seconds, and often start and stop abruptly. The specialized tests may also aid in making or confirming the amplitude of the response typically wanes. Discharge may occur diagnosis of a disorder associated with myotonia: repetitive spontaneously or be initiated by needle movement, voluntary effort, stimulation, the “short” and “long” exercise tests, and the and ischemia or percussion of a nerve provocative cold test.

Repetitive stimulation: It has long been recognized that in myotonic syndromes, repetitive stimulation at 10 Hz leads to a decrement in the compound motor action potential (CMAP).7, 65 This decrement has been attributed to transient inexcitability of the muscle membrane and is more Interpretation of Long Exercise Test: For the periodic commonly seen in recessive myotonia congenita (rMC).40 paralyses, the long exercise test (LET) is often required to Recently, similar decremental responses specific for rMC support the diagnosis39. The typical finding is a delayed were reported with stimulation at 3 Hz44. decline of the CMAP amplitude occurring 20-40 minutes over the course of the test (HypoKPP and HyperKPP). Description of exercise testing and provocative cold test: Immediately after exercise, an increase of CMAP There are two variations of the exercise test: “short” and (HyperKPP) or no change (HypoKPP) is observed. If the “long”. In the “short” exercise test (SET),18, 65 the patient is LET is performed in patients with PMC, similar findings to asked to exercise briefly at maximal isometric contraction the SET are seen (rapid decline of CMAP followed by very (10 seconds). A CMAP is recorded immediately after slow return to baseline). In the other myotonic disorders, the exercise and every 10 seconds thereafter until no change in results of LET are inconsistent or normal. amplitude is observed. Two repetitions of the SET with 60 seconds of rest between trials may increase the diagnostic Interpretation of Provocative Cold Test: In patients with yield. For the long exercise test (LET), the CMAP is tested PMC, cooling of limb will usually produce a large decrement over a 30-45 minute period following 5 minutes of exercise. of CMAP amplitude or loss of CMAP; those abnormalities For the provocative cold test, the limb is immersed in cold may sometimes be absent at room temperature and cooling water (15° C) for 15-30 minutes; the CMAP for an individual is required to unmask them. Occasionally, patients with muscle is recorded before and after the cooling.48 certain rare sodium channel (such as Q270K) During the SET, normal individuals may show an initial will show a pattern resembling MC at room temperature increase or decrease of CMAP amplitude, which will return and convert to a more typical paramyotonic pattern after to baseline values within 10-20 seconds. If a decrement cooling.19 If EMG is performed after cooling, most patients occurs, it generally should not exceed 10% of baseline with PMC will initially show increased myotonic discharges CMAP amplitude. During the LET, a more prominent and fibrillations; with prolonged cooling, a gradual reduction decrement can occur; the cutoff value for an abnormal test of motor unit potential amplitude and recruitment until has been debated, but a >40% decrement of CMAP amplitude complete electrical silence is observed. from pre-exercise baseline is considered abnormal by most experts.18, 68 Classification Scheme for the Myotonic Syndromes After cooling of a limb and repetition of short exercise testing, most normal controls will show a decrease in CMAP To conceptualize the differential diagnosis of myotonic amplitude (in the range of 25%) as well as an increase in syndromes, two distinctions have to be made: first, between CMAP duration (up to 40%)19- the latter reflecting the those diseases with clinical and electrical myotonia, and physiologic effect of delayed sodium channel inactivation those with only electrical myotonia (such as acid maltase and repolarization of membranes in cold. The cumulative deficiency, myofibrillar and centronuclear myopathies, effect of those two opposite-direction changes in CMAP and drug-induced myotonia). In the first group, a further parameters is a minimal change in the CMAP area. Normal distinction can be made between those disorders with values for CMAP changes after cooling have not been well progressive weakness and systemic features (the myotonic established so far. dystrophies type 1 and 2) and those with minimal fixed weakness and no systemic features (the chloride and Interpretation of Short Exercise Test: sodium ). A proposed algorithm to aid in Patients with paramyotonia congenita (PMC) show a >20% the differential diagnosis is outlined in Figure 9. Attention decrement in CMAP amplitude and area, that returns very to specific clinical features, exercise testing and focused slowly to baseline; the abnormality becomes more obvious can lead to correct diagnosis in the majority upon the second or third trial. This is the electrophysiological of cases. Muscle is rarely required; it is particularly equivalent of the worsening of myotonia and weakness with helpful for the diagnosis of myopathies with myotonia exercise that defines this disorder. In patients with myotonia limited to EMG, as long as DM2 is excluded. attributed to chloride channel dysfunction, like myotonia congenita (MC) or myotonic dystrophies, an immediate Disorders with both Clinical and Electrical Myotonia: decrement in CMAP amplitude after exercise, which returns Dystrophies to baseline after 30-60 seconds, is appreciated18. This correlates with the clinical occurrence of transient paresis in Myotonic Dystrophy 1: This is the best known myotonic MC36. Post-exercise myotonic potentials (PEMPs) can be disease and the prototypical due to ribonucleic seen in MC18. In the sodium-channel myotonias, the test acid (RNA)-mediated toxicity. The CTG-repeat expansion at is either normal or shows non-specific abnormalities68. In the dystrophia myotonica-protein kinase (DMPK) gene on hyperkalemic periodic paralysis (HyperKPP), an increase in produces an abnormal RNA that sequesters CMAP amplitude is occasionally noted, and may become proteins like muscleblind-1 (MBNL1) and CUG triplet- more prominent upon repeated trials; however, this finding repeat RNA-binding protein 1 (CUGBP-1) and negatively is not consistently observed68. In hypokalemic periodic affects the splicing of several pre-mRNAs including those paralysis (HypoKPP), which lacks myotonia, the SET is of chloride channel (causing myotonia), insulin receptor typically normal. and tau, explaining the multisystem manifestations of this disease.21 Based on this knowledge, animal models have Myotonia on EMG If dysnorphic facies, short stature–think SJS

Clinical Myotonia (percussion, grip, eyelid)

yes

Prominent weakness +/- systematic Rule out medication exposure, features (cataracts, abnormal ECG, hypothyroidism frontal alopecia, etc).

Proximal weakness of no DM2 DNA testing adductors, respiratory failure, yes yes no if negative tongue weakness

- yes

Dry blood spot for a-glucosidase/ GAA gentic testing Proximal and neck Distal and facial flexor weakness, + weakness, ptosis myalgias, Northern Adult Pompe European origin

DM1 – DNA testing DM2 – DNA testing Short Exercise Testing + Cooling

Normal CMAP decrement > 20%

abnormal Return to baseline in Slow return to baseline < 2 minutes HyperkPP SCN4A Larger with Long-exercise testing Smaller decrement on sequencing repeat trials repeat trials

normal PMC MC

Leg myotonia, warm-up Eyelid myotonia, cold phenomenon, transient or exercise-induced SCN4A gene CLCN1 gene paresis, no cold-worsening worsening, prominent sequencing sequencing or paramyotonia pain

Consider DM2 DNA testing CLCN1 sequencing SCN4A sequencing if negative

Figure 9. Algorithm for the differential diagnosis of electrical myotonia. CLCN1= chloride channel protein 1, CMAP= compound muscle action potential, DM1, DM2= myotonic dystrophy 1, 2, EMG= electromyography, PMC=paramyotonia congenita, MC=myotonia congenita, HyperKPP= hyperkalemic periodic paralysis, GAA= glucosidase alpha, SCN4A= sodium channel type 4, subunit alpha, SJS= Schwartz-Jampel syndrome. been recently developed that reproduce some of the features Disorders with both Clinical and Electrical Myotonia: of the disease.49,74 The exact cause of weakness is uncertain; Non-Dystrophic Myotonias alternate splicing of several proteins associated with muscle has been hypothesized.20,46 Incidence is 12-14 per 100,000. The disorders included in this subgroup are caused by Patients with DM1 have a recognizable facial appearance genetic mutations in chloride or sodium channels. They are with small temporalis muscles, ptosis, and a long, lean face. classified as non-dystrophic diseases based on the assumption Cranial muscle abnormalities may also include dysphagia, that they do not cause progressive muscle damage over dysarthria, and sometimes eye-movement abnormalities. time; this concept however, has been challenged by recent Weakness is predominantly distal, with prominent finger- ultrasound71 and magnetic resonance imaging (MRI) studies. flexor and foot dorsiflexion weakness. Other characteristic The tremendous advances in over the last decade features include frontal baldness and cataracts in nearly all have revealed the considerable clinical overlap between patients, as well as cardiac, gastrointestinal, endocrinologic chloride and sodium channelopathies, to the point they and neurobehavioral abnormalities.73 Impaired glucose can become clinically indistinguishable;30 they have also tolerance is more frequent than in the general population, as allowed recognition of several unusual, very severe or very are low testosterone levels in males. Cardiac abnormalities mild phenotypes across the myotonic spectrum. Some of are apparent on EKG with evidence of heart-blocks and those complexities, and clues for the differential diagnosis atrial arrhythmias. Extreme sensitivity to sedatives and between them, will be presented below. Genetic testing may prolonged respiratory failure after surgical procedures is be performed in specialized centers, which are best located not uncommon. Dysphagia, intestinal pseudoobstruction, by a National Institution of Health internet-based resource irritable-bowel like symptoms and gallbladder sludging are (www.genetests.org). quite frequent. The rate of disease progression is slow and overall life expectancy is reduced due to sudden deaths from Chloride Channelopathies: Myotonia Congenita: Myotonia cardiac arrhythmias, and less commonly respiratory diseases congenita is secondary to a in the CLCN1 (chloride and neoplasms.35 On examination, handgrip or percussion channel protein of ), and may be transmitted myotonia is evident, but eyelid myotonia is unusual. Of either dominantly (Thomsen’s) or recessively (Becker’s).56 particular interest is congenital myotonic dystrophy, which R894X is the most well-known mutation, and, for unclear is attributed to the phenomenon of anticipation whereby reasons, it may be recessive in some families and dominant triplet repeat instability in the gametes leads to an increased in others.15 A dose effect has been recently demonstrated expansion of the triplet repeat. In DM1 this may be for dominantly inherited mutant alleles.3 The effect of the pronounced, with a nearly asymptomatic mother giving birth mutations is usually a loss-of-function of the chloride channel, to a child with a greatly expanded CTG repeat, manifested leading to an elevation of the resting membrane potential and by developmental delay and severe neonatal , thus a tendency toward repeated muscle depolarizations.10 generalized weakness and ventilator-dependence. Clinical At the mildest end of the spectrum, some patients may manifest and electrical myotonia is often absent at birth and may not only increased insertional activity on EMG.43 Myotonia is the appear before 3-5 years.29 The diagnosis is confirmed by prominent clinical symptom,36 and typically presents in early genetic analysis, which is performed widely. childhood, causing stiffness when initiating an activity. Once these patients have “warmed up”, they may perform activities Myotonic Dystrophy 2 (Proximal Myotonic Myopathy- at a normal or advanced level, including competitive sports. PROMM): DM2 or PROMM is another triplet repeat Parents may describe this as weakness and clumsiness in disorder that shares many of the features of DM1. The addition to or instead of stiffness. Affected children appear disease-causing mutation is a CCTG expansion in intron “athletic” with increased muscle bulk, presumably because of 1 of the zinc finger protein 9 gene. DM2 is an adult-onset the sustained muscle activity. The symptoms often improve which is more prevalent in Northern with age but do not completely disappear. In the recessive Europe and is typically associated with myotonia, proximal form, Becker’s, myotonia tends to be more severe than the weakness including neck flexors, cataracts, cardiac dominant Thomsen’s, and transient weakness upon initiation arrhythmias, insulin resistance, and other multisystem of exercise often occurs. Myotonia is appreciated in the limbs features of adult-onset DM1.13,33,58,73 Later onset, proximal more than the eyelids, and cold-sensitivity is not common. weakness and lack of congenital form allow differentiation from DM173 Autoimmune disorders also tend to occur Sodium channelopathies: Hyperkalemic periodic paralysis, more frequently than DM1 patients and the general paramyotonia congenita, sodium-channel myotonias, and population.69 However, DM2 is often a difficult diagnosis: other unusual phenotypes myalgias mimicking fibromyalgia or other pain disorders,2 Mutations in the sodium channel type 4 subunit alpha protein strikingly focal weakness without clinical myotonia,42 calf (SCN4A) can cause a very broad spectrum of disorders: hypertrophy, prominent myotonia without weakness,17 and from life-threatening infantile myotonia presenting as rhabdomyolysis episodes are some atypical presentations. laryngospasm,22,32 or congenital hypotonia with dysmorphic Laboratory tests reveal multiple non-specific abnormalities, features,37 to the more common phenotypes of PMC and including low IgG levels.24 Genetic testing establishes the HyperkPP, to non-myotonic disorders such as HypoPP diagnosis. or congenital myasthenic syndrome. The mutations are dominantly inherited, or may occur de novo, particularly with the more severe infantile phenotypes. They are usually gain-of-function, leading to enhanced activation or loss of chronic potassium wasting (e.g., renal tubular acidosis) slow or fast inactivation11 of the sodium channel, which may also cause episodic muscle weakness. Andersen-Tawil makes the muscle fibers persistently depolarized. Loss of syndrome, which is associated with mutations in potassium function mutations are less common and are associated with channel, inwardly rectifying, subfamily J, member 2 some cases of periodic paralysis.10,27 The most common (KCNJ2) gene,51 consists of the triad of cardiac arrhythmias, residues affected are T704M and M1592V in HyperKPP, dysmorphic features, and periodic paralysis. There is no and R1448C and T1313M in PMC41. Genotypic-phenotypic myotonia. correlations are far from perfect, however: for example, Schwartz-Jampel Syndrome: Schwartz-Jampel syndrome, the same mutation causing PMC can manifest as stridor in also known as chondrodystrophic myotonia, is associated infancy.38 Other mutations, such as Q270K produce a clinical with severe myotonia, muscular hypertrophy, and many picture hard to distinguish from chloride-channel MC. dysmorphic features, such as short stature, diffuse HyperKPP is characterized by attacks of weakness, provoked disease, contractures and oculofacial abnormalities by resting after exercise, fasting, or eating potassium-rich (blepharophimosis, micrognathia, etc.).47, 66 Muscle stiffness foods.9,41,56 The attacks occur relatively frequently (one per is one of the first symptoms that presents in childhood. There day to one per week), are short-lived (minutes to hours), and is no warm-up phenomenon. The EMG findings more closely usually are not completely disabling. EMG studies show resemble or CRDs. Unlike typical myotonia, myotonia in approximately 75% of HyperKPP patients.41 the repetitive, high-frequency discharges in this disorder do Some of them complain of stiffness and show clinical not wax and wane. Schwartz-Jampel syndrome is caused myotonia as well. During the attack, the serum potassium by loss-of-function mutation in the HSPG2 (heparan sulfate level is often elevated. Muscle biopsy shows a vacuolar proteoglycan 2 or basement membrane-specific heparan myopathy. sulfate proteoglycan core protein) gene that encodes perlecan, Patients with PMC mainly complain of stiffness worsened a proteoglycan secreted into basement membranes.47 by repeated exercise, but can also have attacks similar to those of HyperKPP. The major factor provoking stiffness Electrical without Clinical Myotonia in these patients is cold temperature. EMG consistently demonstrates myotonia, but unusual high-amplitude As mentioned previously, several patients with DM2 may bursting, “tornado-shaped”, as well as low amplitude high have proximal weakness with myotonia appreciated only frequency “music” discharges were recently reported.68 In on EMG. In addition, adult-onset acid maltase deficiency both HyperKPP and PMC, the paramyotonia and attacks of (AMD, Pompe disease or glycogenosis type II) is the weakness decrease in middle age. In cases where periodic classic example of this pattern.56 AMD presents with slowly paralysis or PMC are being questioned, the exercise test progressive truncal, tongue and proximal limb weakness, and cooling test may be particularly helpful (see previous particularly affecting the hip adductors and pectoralis sections for details). Nearly all cases of PP are associated muscles. Unlike other glycogen storage diseases, the heart with mild to moderate weakness in later adult life.6,31,41 and liver are not enlarged, although EKG is often abnormal The term “Sodium-channel myotonia” refers to a spectrum showing a pre-excitation syndrome. Serum creatine kinase of disorders characterized by pure, often episodic myotonia, levels are increased and EMG shows evidence of multiple without attacks of weakness. Some of these disorders are spontaneous discharges including myotonic discharges, aggravated by potassium administration, but not by cold fibrillation potentials, positive sharp waves, CRDs, and exposure; examples are myotonia fluctuans, in which small motor unit action potentials, with predominance in myotonia appears after exercise in a delayed fashion;59 proximal muscles, particularly paraspinal. Muscle biopsy myotonia permanens, which is severe, persistent, and shows periodic acid Schiff positive vacuoles, and acid painful and can lead to respiratory compromise12 and phosphatase positive granules. Diagnosis is confirmed -responsive myotonia.54, 72 Others appear as by one of the following52: a) direct measurement of alpha late adult-onset, painful, cold-aggravated myotonias.4,61,63 glucosidase (GAA) activity on fresh muscle, fibroblasts Exercise testing is often normal or non-specific.16, 68 or blood or b) genetic testing for GAA mutations. A more Differential diagnosis of the latter group of disorders includes malignant form of the disease may present in infancy with the chloride channelopathies. The following characteristics, heart muscle and neuronal involvement. It is important to although imperfect, favor an SCN4A mutation36: myotonia recognize AMD, because enzyme replacement therapy is limited to eyelids,67 marked cold sensitivity or paramyotonia, now available. prominent pain, lack of warm-up phenomenon and transient Electrical myotonia almost never occurs in congenital paresis.70 Electrodiagnostic studies and genetic testing can myopathies, with the exceptions of centronuclear (CNM)23 sort out difficult cases. and myofibrillar myopathies (MFM). The phenotype of When considering HyperKPP or PMC, the main differential CNM varies from severe neonatal hypotonia and respiratory consideration is HypoKPP,9,56 which does not show any failure, to adult-onset distal weakness. Opthalmoplegia is clinical or electrical myotonia.41 Attacks of weakness are typical feature. MFMs64 are characterized by highly variable more prolonged in HypoKPP (lasting hours to days) and ages of onset, patterns of weakness, and degrees of cardiac, more severe, often leaving the patient unable to walk. respiratory and peripheral nerve involvement. For both Inherited forms of HypoKPP are secondary to calcium-, or conditions, the diagnosis is established by muscle biopsy less commonly sodium-channel mutations. Metabolic causes and genetic testing. are most often secondary to , although Other Disorders: 12. Colding-Jorgensen, E., Duno, M., Vissing, J. Autosomal There are other disorders in which myotonia is occasionally dominant monosymptomatic myotonia permanens. recognized, although usually not as a predominant or Neurology 67: 153-155, 2006. essential part of the presentation. Muscle diseases such as 13. Day JW, Ricker K, Jacobsen JF, Rasmussen LJ, Dick KA, polymyositis and inclusion-body myositis, or severe active Kress W, et al. Myotonic dystrophy type 2: molecular, denervation are rarely associated with myotonic potentials. diagnostic and clinical spectrum. Neurology 2003;60:657- In some of these cases, CRDs may be mistaken for myotonic 664. potentials. Fibrillation potentials, positive sharp waves, 14. Dromgoole SH, Campion DS, Peter JB. Myotonia-induced by and myotonic discharges have been reported previously clofibrate and sodium chlorophenoxy isobutyrate. Biochem in hypothyroid patients,45 but myotonic discharges are Med 1975;14:238-240. not common. Electrical myotonia may also be caused 15. Dunø M, Colding-Jørgensen E, Grunnet M, Jespersen T, or unmasked by some drugs: 20,25-diazacholesterol,55 Vissing J, Schwartz M Difference in allelic expression of clofibrate,14 2,4-dichlorophenoxyacetate, chloroquine,5 the CLCN1 gene and the possible influence on the myotonia colchicine,62 cyclosporine, propranolol, and congenita phenotype. Eur J Hum Genet. 2004 Sep;12(9):738- hydroxymethylgutaryl coenzyme A reductase inhibitors.50, 60 43. 16. Dupre N, Chrestian N, Bouchard JP, Rossignol E, Brunet D, Conclusions: Sternberg D et al. Clinical, electrophysiologic,and genetic study of non-dystrophic myotonia in French-Canadians. Recognizing the associated clinical and EMG characteristics Neuromuscul Disord 2009;19:330-334. of myotonia and paramyotonia greatly aids neuromuscular 17. Fialho D, Schorge S, Pucovska U, Davies NP, Labrum R, diagnosis. During routine electrodiagnostic testing, a few Haworth A et al. Chloride channel myotonia: exon 8 hot-spot additional historical details and a brief physical examination for dominant-negative interactions. Brain. 2007 Dec;130(Pt are likely to provide the correct diagnosis or suggest further 12):3265-74 investigations. 18. Fournier E, Arzel M, Sternberg D, et al. Electromyography guides toward subgroups of mutations in muscle References: channelopathies. Ann Neurol 2004;45:650-661. 19. Fournier E, Viala K, Gervais H, Sternberg D, Arzel-Hézode 1. Aminoff MJ. Electrodiagnosis in clinical neurology. New M, Laforêt P et al. Cold extends electromyography distinction York: Churchill-Livingstone; 1999. between mutations causing myotonia. Ann 2. Auvinen S, Suominen T, Hannonen P, Bachinski LL, Krahe Neurol. 2006 Sep;60(3):356-65 R, Udd B. Myotonic dystrophy type 2 found in two of sixty- 20. Fugier C, Klein AF, Hammer C, Vassilopoulos S, Ivarsson three persons diagnosed as having fibromyalgia. Arthritis Y, Toussaint A Misregulated alternative splicing of BIN1 is Rheum. 2008 Nov;58(11):3627-31 associated with T tubule alterations and muscle weakness in 3. Bernard G, Poulin C, Puymirat J, Sternberg D, Shevell M. myotonic dystrophy. Nat Med. 2011 Jun;17(6):720-5. Dosage effect of a dominant CLCN1 mutation: a novel 21. Gatchel JR, Zoghbi HY. Diseases of Unstable Repeat syndrome. J Child Neurol. 2008 Feb;23(2):163-6. Expansion: Mechanisms and Common Principles Nature 4. Bissay V, Keymolen K, Lissens W, Laureys G, Schmedding Reviews Genetics 2005; 6: 743-755 E, Keyser JD Late onset painful cold-aggravated myotonia: 22. Gay S, Dupuis D, Faivre L, Masurel-Paulet A, Labenne three families with SCN4A L1436P mutation. Neuromuscul M, Colombani M et al. Severe neonatal non-dystrophic Disord. 2011 Aug;21(8):590-3. myotonia secondary to a novel mutation of the voltage-gated 5. Blomberg LH. Dystrophia myotonica probably caused by sodium channel (SCN4A) gene. Am J Med Genet A. 2008 chloroquine. Acta Neurol Scand Suppl 1965;13 Pt 2:647-651. Feb 1;146(3):380-3. 6. Bradley WG, Taylor R, Rice DR, Hausmanowa-Petruzewicz 23. Gil-Peralta A, Rafel E, Bautista J, Alberca R. Myotonia in I, Adelman LS, Jenkison M, et al. Progressive myopathy in J Neurol Neurosurg Psychiatry. hyperkalemic periodic paralysis. Arch Neurol 1990;47:1013- 1978;41(12):1102-8. 1017. 24. Heatwole C, Johnson N, Goldberg B, Martens W, Moxley 7. Brown JC. Muscle weakness after rest in myotonic disorders; R 3rd. Laboratory abnormalities in patients with myotonic an electrophysiological study. J Neurol Neurosurg Psychiatry dystrophy type 2. Arch Neurol. 2011 Sep;68(9):1180-4. 1974;37:1336-1342. 25. Hornung K, Nix WA. Myoedema. A clinical and 8. Brown WF, Bolton CF, Aminoff MJ. Neuromuscular function electrophysiological evaluation. Eur Neurol. 1992;32(3):130- and disease: basic, clinical, and electrodiagnostic aspects. 3. Philadelphia: WB Saunders; 2002. 26. Isaacs H. A syndrome of continuous muscle fibre activity. J 9. Cannon SC. An expanding view for the molecular basis Neurol Neurosurg Psychiatry. 1961 Nov;24(4):319-25. of familial periodic paralysis. Neuromuscul Disord 27. Jurkat-Rott K, Holzherr B, Fauler M, Lehmann-Horn F. 2002;12:533-543. Sodium channelopathies of skeletal muscle result from gain 10. Cannon SC. Pathomechanisms in channelopathies of skeletal or loss of function. Pflugers Arch. 2010 Jul;460(2):239-48. muscle and brain. Annu Rev Neurosci. 2006;29:387-415. 28. Kimura J. Electrodiagnosis in diseases of nerve and muscle: 11. Cannon SC, Brown RH Jr, Corey DP. A sodium channel principles and practice. New York: Oxford University Press; defect in hyperkalemic periodic paralysis: potassium-induced 2001. failure of inactivation. Neuron 1991;6:619-626. 29. Kuntz NL. Clinical and electrophysiological profile of 46. Nakamori M, Kimura T, Fujimura H, Takahashi MP, Sakoda congenital myotonic dystrophy. Ann Neurol 1984; 19: 931-4. S. Altered mRNA splicing of in type 1 myotonic 30. Lee SC, Kim HS, Park YE, Choi YC, Park KH, Kim DS dystrophy Muscle Nerve. 2007 Aug;36(2):251-7. Clinical Diversity of SCN4A-Mutation-Associated Skeletal 47. Nicole S, Davoine CS, Topaloglu H, Cattolico L, Barral Muscle Sodium J Clin Neurol. 2009 D, Beighton P, et al. Perlecan, the major proteoglycan of Dec;5(4):186-91. basement membranes, is altered in patients with Schwartz- 31. Links T, Zwarts MJ, Wilmink JT, Molenaar WM, Oosterhuis Jampel syndrome (chondrodystrophic myotonia). Nat Genet HJ. Permanent muscle weakness in familial hypokalaemic 2000;26:480-483. periodic paralysis. Clinical, radiological and pathological 48. Nielsen VK, Friis ML, Johnsen T. Electromyographic aspects. Brain 1990;113:1873-1889. distinction between paramyotonia congenita and myotonia 32. Lion-Francois L, Mignot C, Vicart S, Manel V, Sternberg D, congenita: effect of cold. Neurology 1982;32:827-832. Landrieu P. Severe neonatal episodic laryngospasm due to de 49. Orengo JP, Chambon P, Metzger D, Mosier DR, Snipes GJ, novo SCN4A mutations: a new treatable disorder. Neurology. Cooper TA Expanded CTG repeats within the DMPK 3’ UTR 2010 Aug 17;75(7):641-5. causes severe skeletal muscle wasting in an inducible mouse 33. Liquori CL, Ricker K, Moseley ML, Jacobsen JF, Kress W, model for myotonic dystrophy. Proc Natl Acad Sci U S A. Naylor SL, et al. Myotonic dystrophy type 2 caused by a 2008 Feb 19;105(7):2646-51. CCTG expansion in intron 1 of ZNF9. Science 2001;293:864- 50. Pierno S, De Luca A, Tricarico D, Roselli A, Natuzzi F, 867. Ferrannini E, et al. Potential risk of myopathy by HMG- 34. Logigian EL, Ciafoloni E, Quinn C, Dilek N, Pandya S, CoA reductase inhibitors: a comparison of pravastatin and Moxley, et al. Muscle Nerve 2007 ;35 :479-485 simvastatin effects on membrane electrical properties of rat 35. Mathieu J, Allard P, Potvin L, Prevost C, Begin P. A 10-year skeletal muscle fibers. J Pharmacol Exp Ther 1995;275:1490- study of mortality in a cohort of patients with myotonic 1496. dystrophy. Neurology 1999;52:1658-1662. 51. Plaster NM, Tawil R, Tristani-Firouzi M, Canun S, 36. Matthews E, Fialho D, Tan SV, Venance SL, Cannon SC, Bendahhou S, Tsunoda A, et al. Mutations in Kir2.1 cause Sternberg D et al. The non- dystrophic myotonias: molecular the developmental and episodic electrical phenotypes of pathogenesis, diagnosis and treatment. Brain. 2010 Jan;133(Pt Andersen’s syndrome. Cell 2001;105:511-519. 1):9-22 Review. 52. Pompe Disease Diagnostic Group. Methods for a prompt and 37. Matthews E, Guet A, Mayer M, Vicart S, Pemble S, Sternberg reliable laboratory diagnosis of Pompe disease: report from D. Neonatal hypotonia can be a sodium channelopathy: an international consensus meeting. Mol Genet Metab. 2008 recognition of a new phenotype. Neurology. 2008 Nov Mar;93(3):275-81. 18;71(21):1740-2. 53. Pourmand R. Neuromuscular diseases: expert clinicians’ 38. Matthews, E., Manzur, A. Y., Sud, R., Muntoni, F., Hanna, views. Boston: Butterworth- Heinemann; 2001. M. G. Stridor as a neonatal presentation of skeletal muscle 54. Ptacek LJ, Tawil R, Griggs RC, Storvick D, Leppert M. sodium channelopathy. Arch. Neurol. 68: 127-129, 2011 Linkage of atypical myotonia congenita to a sodium channel 39. McManis PG, Lambert EH, Daube JR. The exercise test in locus. Neurology 1992;42:431-433. periodic paralysis. Muscle Nerve 1986;9:704-710. 55. Ramsey RB, McGarry JD, Fischer VW, Sarnat HB. 40. Michel P, Sternberg D, Jeannet PY, Dunand M, Thonney Alteration of developing and adult rat muscle membranes by F, Kress W et al. Comparative efficacy of repetitive nerve zuclomiphene and other hypocholesterolemic agents. Acta stimulation, exercise, and cold in differentiating myotonic Neuropathol (Berl) 1978;44:15-19. disorders. Muscle Nerve. 2007 Nov;36(5):643-50. 56. Renner DR, Ptacek LJ. Periodic paralyses and nondystrophic 41. Miller TM, Dias da Silva MR, Miller HA, Kwiecinski H, myotonias. Adv Neurol 2002;88:235-252. Mendell JR, Tawil R, et al. Correlating phenotype and 57. Ricker K, Hertel G, Langscheid K, Stodieck G. Myotonia not genotype in the periodic paralyses. Neurology 2004;63:1647- aggravated by cooling. Force and relaxation of the adductor 1655. pollicis in normal subjects and in myotonia as compared to 42. Milone M, Batish SD, Daube JR. Myotonic dystrophy type paramyotonia. J Neurol 1977;216:9-20. 2 with focal asymmetric muscle weakness and no electrical 58. Ricker K, Koch MC, Lehmann-Horn F, Pongratz D, Otto M, myotonia. Muscle Nerve. 2009 Mar;39(3):383-5. Heine R, et al. Proximal myotonic myopathy: a new dominant 43. Mitchell CW, Bertorini TE. Diffusely increased insertional disorder with myotonia, muscle weakness, and cataracts. activity: “EMG disease” or asymptomatic myotonia Neurology 1994;44:1448-1452. congenita? A report of 2 cases. Arch Phys Med Rehabil. 2007 59. Ricker K, Lehmann-Horn F, Moxley RT 3rd. Myotonia Sep;88(9):1212-3. fluctuans Arch Neurol. 1990 Mar;47(3):268-72. 44. Modoni A, Dʼamico A, Dallapiccola B, Mereu ML, 60. Rosenson RS. Current overview of statin-induced myopathy. Merlini L, Pagliarani S, et al. Low-Rate Repetitive Nerve Am J Med 2004;116:408-416. Stimulation Protocol in an Italian Cohort of Patients Affected 61. Rossignol E, Mathieu J, Thiffault I, Tétreault M, Dicaire by Recessive Myotonia Congenita. J Clin Neurophysiol. 2011 MJ, Chrestian N et al. A novel founder SCN4A mutation Feb; 28(1):39-44. causes painful cold-induced myotonia in French-Canadians. 45. Mrabet H, Masmoudi S, Mrabet A. Myotonia and Neurology. 2007 Nov 13;69(20):1937-41. hypothyroidism. Rev Neurol (Paris). 2007 Sep;163(8-9):837-9. 62. Rutkove SB, De Girolami U, Preston DC, Freeman R, Nardin RA, Gouras GK, et al. Myotonia in colchicine myoneuropathy. Muscle Nerve 1996;19:870-875. 63. Schoser BG, Schröder JM, Grimm T, Sternberg D, Kress W A large German kindred with cold-aggravated myotonia and a heterozygous A1481D mutation in the SCN4A gene. Muscle Nerve. 2007 May;35(5):599-606. 64. Selcen D. Myofibrillar myopathies. Neuromuscul Disord. 2011 Mar;21(3):161-71. 65. Streib EW. Evoked response testing in myotonic syndromes. Muscle Nerve 1984;7:590-592. 66. Stum M, Davoine CS, Vicart S, Guillot-Noel L, Topaloglu H, Carod-Artal FJ, et al. Spectrum of HSPG2 (Perlecan) mutations in patients with Schwartz-Jampel syndrome. Hum Mutat 2006;27:1082-1091. 67. Stunnenberg BC, Ginjaar HB, Trip J, Faber CG, van Engelen BG, Drost G. Isolated eyelid closure myotonia in two families with sodium channel myotonia. Neurogenetics. 2010 May;11(2):257-60. 68. Tan SV, Matthews E, Barber M, Burge JA,Rajakulendran S, Fialho D et al. Refined exercise testing can aid DNA- based diagnosis in muscle channelopathies. Ann Neurol 2011;69:328-340. 69. Tieleman AA, den Broeder AA, van de Logt AE, van Engelen BG Strong association between myotonic dystrophy type 2 and autoimmune diseases. J Neurol Neurosurg Psychiatry. 2009 Nov;80(11):1293-5. 70. Trip J, Drost G, Ginjaar HB, Nieman FH, van der Kooi AJ, de Visser M, van Engelen BG, Faber CG. Redefining the clinical phenotypes of non-dystrophic myotonic syndromes. J Neurol Neurosurg Psychiatry. 2009 Jun;80(6):647-52. 71. Trip J, Pillen S, Faber CG, van Engelen BG, Zwarts MJ, Drost G. Muscle ultrasound measurements and functional muscle parameters in non-dystrophic myotonias suggest structural muscle changes Neuromuscul Disord. 2009 Jul;19(7):462-7. 72. Trudell RG, Kaiser KK, Griggs RC. Acetazolamide- responsive myotonia congenita. Neurology. 1987 Mar;37(3):488-91. 73. Turner C, Hilton-Jones D. The myotonic dystrophies: diagnosis and management. J Neurol Neurosurg Psychiatry. 2010 Apr;81(4):358-67. 74. Ward AJ, Rimer M, Killian JM, Dowling JJ, Cooper TA. CUGBP1 overexpression in mouse skeletal muscle reproduces features of myotonic dystrophy type 1 Hum Mol Genet. 2010 Sep 15;19(18):3614-22.