Clinical Neurophysiology ofDisorders ofMuscle and Neuromuscular Junction, Including Fatigue Handbook ofClinical Neurophysiology, Vol. 2 Erik Stalberg (Ed.) © 2003 Elsevier B.V.All rights reserved 457

CHAPTER 23

Skeletal muscle : myotonias, periodic paralyses and malignant Frank Lehmann-Horn'i", Holger Lerche'" and Karin Jurkat-Rott"

u Department ofApplied Physiology, Vim Vniversity, D-8908I Vim, Germany b Department ofNeurology, Vim Vniversity, D-8908I Vim, Gennany

23.1. Introduction channel complexes are involved in this process, the voltage-gated pentameric dihydropyridine receptor 23.1.1. Membrane excitability and coupling of located in the TIS (encoded by the CACNA1S gene excitation to contraction on chromosome Iq31-32 and genes for accessory subunits) and the homotetrameric Motoneuron activity is transferred to skeletal of the SR (encoded by the RYR1 gene on chromo- muscle at the neuromuscular junction generating a some 19q13.1). sarcolemmal action potential that propagates from the endplate to the tendon and along the transverse 23.1.2. Channelopathies: episodic stiffness and tubular system (TIS). This membrane region pro- weakness jects deeply into the cell to ensure even distribution of the impulse. The upstroke of the action potential Membrane excitability is regulated by voltage- is mediated by opening of the voltage gated sodium gated ion channels which are essential for the channels (encoded by the SCN4A gene located on stabilization of the resting membrane potential and chromosome 17q13.1-3 and its accessory beta- the generation of the action potential. It is therefore subunit encoded by SCN1B on chromosome not surprising, that ion channels are involved in the 19q13.1) that elicit a sodium inward current with pathogenesis of diseases of . Chan- rapid activation kinetics. Repolarization of the nelopathies are defined as episodically recurring membrane by fast inactivation is disorders caused by a pathology of ion channel supported by opening of delayed rectifier function (Hoffman et aI., 1995). Clinically, skeletal channels that mediate an outward potassium current. muscle ion channelopathies appear as episodes of Buffering of after-potentials is achieved by a high muscle stiffness or weakness triggered by typical chloride conductance near the resting potential circumstances such as cold, exercise, oral potassium resulting from the homodimeric , load, or drugs. According to the mode of transmis- ClC-I, encoded by the gene CLCN1 on chromo- sion and potassium sensitivity, four forms of some. and paramyotonia are distinguished: domi- At specialized junctions in the TIS, the signal is nant (potassium-insensitive) , transmitted from the tubular membrane to the recessive myotonia congenita, dominant potassium- (SR) causing the release of aggravated myotonia, and dominant paramyotonia ions into the myoplasm which activate the congenita. Myotonic dystrophies type I and 2 are contractile apparatus. This process is called excita- chronic progressive multisystemic diseases of domi- tion-contraction coupling. Mainly two calcium nant inheritance and not true channelopathies. They are discussed in this chapter because of the common * Correspondence to: Prof. Dr. Frank Lehmann-Hom, feature of myotonia which is thought to be caused by Abteilung Angewandte Physiologie, Universitat VIm, a pathology of ion channel expression. D-8908l VIm, Germany. While myotonia is brought about by uncontrolled E-mailaddress: repetitive firing of action potentials leading to [email protected] involuntary muscle contraction, lack ofaction poten- 458 F. LEHMAN-HORN ET AL. tials or muscle inexcitability results in weakness. movement is repeated several times (warm-up phe- Three dominant types of episodic weakness with or nomenon), but it recurs after a few minutes of rest. without myotonia are either distinguished by the The patient may experience much difficulty while serum potassium level during the attacks of weak- getting up from a chair or stepping into a bus in a ness, hyper- and hypokalemic periodic paralysis or hurry. On rare occasions, a sudden, frightening noise by concomitant clinical features such as cardiac may cause instantaneous generalized stiffness; the and facial dysmorphia, Andersen's syn- patient may then fall to the ground and remain rigid drome. and helpless for some seconds or even minutes. An electrically silent muscle stiffness triggered by Myotonic signs persist throughout life. The myoto- volatile agents and depolarizing muscle nia may increase with pregnancy, but this usually relaxants as found in malignant hyperthermia is not doesn't create a major problem. Hypothyroidism associated with myotonic runs. It is based on may worsen the myotonia. Contrary to the opinion of uncontrolled intracellular calcium release via the many patients, cold does not substantially worsen ryanodine receptor that is not preceded by action the myotonic stiffness and slowed relaxation (Ricker potentials. An acute, potentially lethal crisis is et al., 1977). characterized by muscle hypermetabolism, rhabdo- Upon examination, OMC patients may have myolysis, body temperature elevation, muscle hypertrophied muscles and an athletic appearance. rigidity, and cardiac arrhythmia. Their muscle strength is normal or even greater than normal and they can be quite successful in those 23.2. Classical myotonia congenita: chloride sports where strength is more important than speed. channel myotonias Tapping of the muscle produces an indentation that persists for several seconds (percussion myotonia). 23.2.1. Dominant Thomsen and recessive Becker Lid lag is usually present, and in some patients, myotonia myotonia of the lid muscles causes blepharospasm Myotonia congenita appears in two forms: Thom- after forceful eye closure. The muscle stretch sen's disease (MIM 160800), or dominant myotonia reflexes are normal and muscle pain is usually not congenita (OMC), the first myotonic disease present. described (Thomsen, 1876), and Becker myotonia Members of a given OMC family can be affected (MIM 255700), or recessive generalized myotonia to different degrees. In a few kinships, the myotonia (Becker, 1977), here termed recessive myotonia is consistently very mild and almost undetectable; congenita (RMC). Both disorders are slowly or non- this was considered a special form and termed progressive, usually non-dystrophic, and caused by myotonia levior. As the inheritance and the molec- allelic of the gene coding for the chloride ular pathogenesis is the same as in Thomsen's channel of the skeletal muscle fiber membrane disease, the term should be abandoned (Lehmann- (Koch et aI., 1992). They are referred to as chloride Horn et al., 1995). channel myotonias. The clinical picture of RMC resembles that of In OMC, the myotonia is usually recognized in OMC. A few special points are worth mentioning. In early childhood, but the milder cases may go many patients, the myotonia is not manifest until the unrecognized until late childhood. The myotonia is age of 10 to 14 years or even later, but in a few it is generalized; the legs are often most affected, causing obvious already at the age of 2 to 3 years. The the children to fall frequently. The cranial as well as severity of the myotonia may slowly increase for a arm and hand muscles can be severely affected, and number of years, but usually not after the age of 25 it may be difficult for the patients to grasp objects. to 30. In general, the myotonia is more severe than in Chewing is sometimes impaired. The myotonic OMC. Thus, RMC patients are more handicapped in stiffness is most pronounced when a forceful daily life, especially by severe myotonic stiffness movement is abruptly initiated after the patient has affecting the leg muscles. They frequently fall down rested for 5 to 10 min. For instance, after making a and have gait problems. Muscle shortening due to strong fist, the patient may not be able to extend the continuous contractions may limit bilateral dorsi- fingers fully for several seconds. The myotonia flexion of the wrist or foot. Severely affected patients decreases or vanishes completely when the same walk on tiptoes and develop a compensatory lordo- SKELETAL MUSCLE CHANNELOPATHIES 459 sis. The leg and gluteal muscles are often markedly from these typical and diagnostically relevant myo- hypertrophied, whereas the neck, shoulder and arm tonic runs, other forms of spontaneous activity do muscles appear poorly developed - especially in old occur, such as positive sharp waves at lower age - resulting in a characteristic disproportionate frequency or more complex discharges like rhythmic figure. Also very disabling is a peculiar transient doublets and triplets. weakness affecting especially the hand and arm In RMC families, the heterozygous parents of muscles (see below). Patients with severe RMC are affected offspring can sometimes be identified by limited in their choice of occupation and they are having short (rarely longer than I s) myotonic unsuited for military service. Life expectancy is discharges of low amplitude on EMG without normal. Alcohol can improve the condition, hunger, clinical manifestation. In addition to myotonic runs, emotion or fatigue usually do not aggravate the heterozygous carriers showed very brief complex myotonia. repetitive discharges, increased insertional activity, and prolonged trains of rhythmic, low-frequency 23.2.2. Clinical neurophysiology ofthe chloride «60 Hz) positive waves lasting several seconds. In channel myotonias two thirds of RMC families, at least one of the parents exhibited this spontaneous activity (Deymeer 23.2.2.1. Electromyographic (EMG)./indings in et aI., 1999). chloride channel myotonias Standard EMG - other parameters. Motor unit The electrophysiological correlate of myotonia is potentials in both forms of myotonia congenita are - independent of the channel type affected - usually normal. In RMC, however, myopathic hyperexcitability of the sarcolemma which causes changes like multiphasic or low amplitude potentials uncontrolled repetitive firing of action potentials can be observed (Streib, 1987). Rarely, specific following an initial voluntary activation. This myo- CIC-l mutations may even induce dystrophic vari- tonic reaction prevents the muscle from immediate ants of the disease with myopathic motor unit relaxation which the patients experience as muscle potentials seen in all extremities (Nagamitsu et ai., stiffness. 2000). CMAP amplitudes and nerve conduction Standard EMG - Spontaneous activity. In Thom- velocities are normal, unless in the period of sen and Becker patients, the myotonic activity can be transient weakness (see below). observed in all routinely examined skeletal muscles. In the EMG, repetitive firing is typically observed as 23.2.2.2. Warm-up phenomenon myotonic bursts which are elicited easily by needle The stiffness is initiated by a forceful muscle insertions or slight mechanical manipulations like contraction, particularly after a period of rest of at tapping. The slowed relaxation which patients least 10 min. This may not necessarily pertain to the experience as muscle stiffness is strongly correlated first contraction which may be relatively unimpeded, to electrical activity as could be shown in biopsied but becomes increasingly obvious following the muscle specimens in vitro (Iaizzo and Lehmann- second and third short but forceful contractions. The Hom, 1990). Interestingly, this is in contrast to the disturbance of muscle relaxation after further con- cold-induced stiffness in . tractions gradually disappears, a phenomenon which Typical are short bursts of action potentials appear- is called warm-up phenomenon, the pathophysio- ing as triphasic spikes or as positive sharp waves logic mechanism of which is still unknown. with amplitude and frequency modulation lasting < 1 s and sometimes up to lOs (Ricker and Meinck, 23.2.2.3. EMG studies during transient weakness 1972a). The most often mentioned but rare pattern, In the more severe Becker type, the stiffness is best recognizable in the acoustic EMG, is that of a usually associated with the symptom of transient myotonic "dive-bomber". This is a short discharge weakness that depends on the patient's past activity characterized by first an increase in frequency and in a similar way as the stiffness. This is best decrease in amplitude and then a decrease in demonstrated when the patient makes a tight fist frequency and increase in amplitude. Much more after a period of rest: the force exerted by the finger frequent though, are short bursts characterized by a flexors vanishes almost completely within a few rising frequency and a falling spike amplitude. Apart seconds. When the patient lifts a heavy object, it may 460 F. LEHMAN-HORN ET AL. slide out of the hand because of loss of muscle disease, the transient weakness occurs much more strength (Ricker et aI., 1978; Deymeer et al., 1998). frequently than in the former one. Consistent with In a similar situation, a patient with dominant MC this clinical observation, however, in some of the would be unable to release the handle for a while. studies in which patients with both diseases were With repeated muscle contractions, the force returns compared, a more heavy stimulus like a higher within 20 to 60 s (Fig. I). stimulating frequency was necessary to induce the Electrophysiologically, the weakness occurring same effect in DMC compared to RMC (Lagueny et experimentally upon repetitive stimulation is accom- al., 1994; Deymeer et aI., 1998). panied by a decrease of the CMAP amplitude, as was shown in a large number of studies (e.g. Ricker and 23.2.3. Molecular diagnosis and pathogenesis of Meinck, 1972b; Brown, 1974; Aminov et al., 1977; the chloride channel myotonias Ricker et aI., 1978; Deymeer et al., 1998). In a more detailed investigation using surface EMG, Zwarts The causative gene for dominant Thomsen and and Van Weerden (1989) also showed, that the recessive Becker myotonia is CLCN1 encoding the muscle fiber conduction velocity (MFCV), the voltage-gated chloride channel of the skeletal muscle median frequency of the power spectrum and the fiber membrane. The chloride channel protein, integrated EMG decline during transient paresis in CIC-l, forms homodimeric double-barrel complexes Becker myotonia. Multi-channel surface EMG, (Mindell et aI., 2001; Dutzler et al., 2002) with two yielding a high spatial-temporal resolution, revealed independent ion-conducting pores each with a fast a gradually developing decrease in peak-to-peak opening mechanism of its own, but also with a gate amplitude of the motor unit action potentials from structure common to both pores (for review Fahlke endplate towards tendon in parallel with the force et al., 2001). Over 50 CIC-l mutations have been decline. This deteriorating membrane function tem- identified (Fig. 2) which, according to our data, porally leads to a complete intramuscular conduction account for approximately 30% of the cases, making block within s in RMC (Drost et al., 2001). Using genetic studies quite arduous. While non-sense and single fiber EMG, qualitatively similar results could splicing mutations always lead to the recessive be obtained. Upon repetitive stimulation, the muscle phenotype, missense mutations are found in Thom- fiber action potential showed a progressive decrease sen and Becker myotonia. A few intermediate in amplitude, marked deformation, and a varying mutations are even able to generate both modes of latency occurring only after a few stimulations transmission probably depending on supplemental (Lagueny et aI., 1994; Trontelj and Stalberg, 1995). genetic or environmental factors. If genetic screen- All of these changes were observed in both DMC ing does not yield a result, linkage analysis including (Thomsen) and RMC (Becker), although in the latter additional family members of defined clinical status Myotonic runs and transient weakness

120jJ.V 100 ms

Fig. 1. Myotonic runs and transient weakness in a patient with recessive myotonia congenita (RMC). Left panels: the two EMG traces show typical myotonic runs of short duration, waxing frequency and waning amplitude. The final high- frequency phase of some runs causes a tetanic contraction of the spiking muscle fiber which induces another discharge in a surrounding fiber. Right panels: Surface EMG of biceps brachii muscle (upper trace) and voluntary isometric force (in Newton) of the forearm flexors (lower trace) show a pattern characteristic for transient weakness. Modified after Ricker et aI., 1978. SKELETAL MUSCLECHANNELOPATHIES 461

Fig. 2. Membrane topology model of the skeletal muscle chloride channel monomer, CIC-I, modified after (Dutzler et aI., 2002). The functional channel is a homodimer. The different symbols used for the known mutations leading to dominant Thomsen-type myotonia and recessive Becker-type myotonia are explained on the left-hand bottom. Conventional I-letter abbreviations were used for replaced amino acids. is a very useful tool to confirm clinical diagnosis. An conductance is drastically reduced in the crucial important issue genetically and prognostically (and vicinity of the resting membrane potential (Fig. 3). in some cases diagnostically) is to exclude the repeat This is not the case for the recessive mutants which expansions causing myotonic dystrophy types 1 do not functionally hinder the co-associated subunit and 2. supplying the explanation why then two mutant Functionally, the fast opening mechanism of each alleles are required to reduce chloride conductance pore of the double barrel dimer channel complex is so much that myotonia develops (at least down to affected by the recessive mutations, whereas a 30%; Palade & Barchi, 1977). Functional alteration common slow additional gate structure shared with of the chloride channels leads to a reduced mem- the co-associated subunit is affected by the dominant brane conductance for chloride decreasing the mutations (Saviane et aI., 1999). The dominant stability of the membrane potential. Regarding the mutants exert a so-called dominant negative effect clinical picture of affected patients, the instability is on the dimeric channel complex as shown by co- obviously highest during voluntary muscle activa- expression studies meaning that mutant/mutant and tion following rest. Repetitive activity then ensues, mutant/wildtype complexes are malfunctional. The giving rise to myotonia. Upon warming-up, the most common feature of the resulting chloride muscle fiber membrane then seems to adapt to the currents is a shift of the activation threshold towards lower chloride conductance. The excessive activity more positive membrane potentials almost out of the may also lead to slowly progressive depolarization physiological range (Pusch et al., 1995; Wagner et between action potentials causing the transient (or aI., 1998). As a consequence of this, the chloride sometimes permanent) weakness. It usually lasts 462 F. LEHMAN-HORN ET AL.

WT only for some seconds, but may nevertheless hamper 0 movement more than the stiffness.

23.2.4. Differentiation from dystrophic myotonias -5 ~ c: Some RMC patients show progressive generalized ::: -10 muscle weakness, severe distal muscle atrophy, and unusually high serum kinase levels (Naga- mitsu et aI., 2000), making the differentiation from 0 200 400 myotonic dystrophies difficult. Time (ms)

G200R Myotonic dystrophy type 1 (DM 1) 5 Myotonic dystrophy (DM I; MIM 160900) is an autosomal dominant multi-organ disease and the 0 most common inherited muscle disorder in adults. Myotonia is only one of the many symptoms of this ~ -5 ~ progressive disease, the most severe symptom being c: ~ muscle wasting that begins in the distal limb and -10 cranial muscles. Cataract, intraocular hypotension, gonadal atrophy, conduction abnormalities in the heart, hearing deficiencies, and neurocognitive defi- 0 400 BOO Time (ms) cits appear quite often in the course of the disease. The ofDMI is an expansion of an unstable CTG trinucleotide repeat in the 3' untranslated region of the myotonic dystrophy protein kinase (DMPK) gene on chromosome 19q13.3 (for review see Conne et aI., 2000). Its pathogenesis, though not yet clearly understood, is different from that of the non-dystrophic myotonias even though ion channels may be involved, e.g. by alternative splicing. •a wrG200R In the congenital form of DMI, general muscle weakness (particularly pronounced in the face) is the leading finding, combined with retarded locomotor ·100 0 100 and mental development. Myotonia is absent, at least VOltage (mv) in infancy. A decisive criterion for the diagnosis is the occurrence of myotonic dystrophy in the Fig. 3. Behaviour of human skeletal muscle C1C-l chan- patient's mother. Electromyographic investigation is nels expressed in a mammalian cell line. Compared are indicated when a suspicion of myotonic dystrophy currents of normal (WT) and mutant (Gly-2oo-Arg) cannot be ascertained on the basis of clinical and channels, the latter causing dominant myotonia in man genetic findings. Myotonic activity in the EMG of (Thomsen-type). Upper and middle panels: macroscopic currents, recorded in the patch-clamp whole-cell mode, the mother will then corroborate the suspicion. were activated from a holding potential of 0 mV by voltage steps to potentials of -145 to +95 mY, and Electrophysiologic findings in myotonic dystrophy deactivated after 400 ms by polarization to -105 mY. Lower panel: shows the voltage dependence of the relative type 1 (DM1) open probability that is much reduced for the mutant In the adult form of myotonic dystrophy, myotonic channel in the physiological potential range. All mutations EMG activity is less common than in the non- that cause such a voltage shift have dominant effects. dystrophic myotonias and unevenly distributed over Adapted from Wagner et aI., 1998. the muscles of the body. The distal muscles of the SKELETAL MUSCLECHANNELOPATHIES 463 upper extremities, the facial muscles and tibialis In most patients, DM2 is a very slowly pro- anterior show the highest incidence of involvement. gressive disorder with muscle weakness developing Electrical myotonia may be only observed in a few typically after 40 years of age. The symptoms can be muscles or even absent in obligate gene carriers. In aggravated by hypothyroidism and pregnancy. Some children up to ten years, electrical myotonia is rarely patients have an annoying, sometimes disabling, seen, but its incidence increases with age later on. In pain in their muscles, especially in their thighs. The contrast to the chloride channel myotonias, long- pain is not related to myotonic stiffness and is most lasting discharges of 2-30 s duration with falling or apparent at rest. In other patients the discovery of a unchanging frequency and amplitude occur more cataract at age of about 35 years is the first often than the typical short myotonic runs. The manifestation of the disorder. The cataract is poste- maximal frequency is typically 40--60 Hz and thus rior capsular and, for a certain period of time. lower than in chloride channel myotonia (60-100 iridescent like in myotonic dystrophy. Many patients Hz). Positive sharp waves and complex repetitive first complain of intermittent stiffness. When it is discharges are also very common in DMI. Finally, present, it is typically focal, involving one thigh or myopathic changes consisting of short, polyphasic one hand. The movements are jerky and stepwise, potentials with early recruitment are commonly especially in the thumb and index finger and show a found, best in forearm extensor and tibialis anterior "warm up" phenomenon. Because of the variation in muscles (Ricker and Meinck, 1972a; Streib, 1987; the severity of the myotonia and because it is usually Pfeilsticker et aI., 2001). mild in the initial stages of the disorder, it is not Motor and sensory nerve conduction studies unusual for the signs of myotonia to elude clinical frequently show mild signs of peripheral neuropathy. detection. CMAP amplitudes are reduced depending on the degree of dystrophic changes. The exercise test shows a mild to moderate decrement in CMAP Electrophysiologic findings in DM2/PROMM amplitude with a quick recovery, which is not seen in Electromyographic investigation reveals a broad DM2/PROMM (see below) (Streib, 1987; Sander et spectrum of spontaneous activity including myo- al., 1997, 2000; Kuntzer et al., 2000). Muscle fiber tonic discharges, also in most of those patients conduction velocity (MFCV) and power spectra as without obvious clinical myotonia. The myotonic determined by surface EMG are normal in contrast discharges are often scarce, difficult to detect to RMC (Zwarts and Van Weerden, 1989). (multiple muscles have to be investigated) and may be fluctuating (Ricker et al., 1995; Day et al., 1999). Myotonic dystrophy type 2 (DM2)/proximal myo- They can be provoked by heat and diminished by tonic myopathy (PROMM) cold (Sander et aI., 1996) but this is not observed in A second dominant multisystemic myotonic dis- all families (Day et aI., 1999; Moxley et al., 2002). order, similar to classical myotonic dystrophy but In addition to myotonic discharges, fibrillation with no DMPK gene affection, was originally potentials, positive sharp waves, runs of complex described as proximal myotonic myopathy or repetitive discharges, brief runs of high-frequency PROMM (Ricker et aI., 1994). Since some patients (180-240 Hz), '-like' discharges and exhibited distal muscle weakness and dystrophy, the fasciculation potentials do occur (Ricker et aI., 1995; disease was later enlarged to myotonic dystrophy Ricker, 1999). In the original DM2 family, the type 2 (DM2; OMIM 602668) (Ranum et aI., 1998). myotonic discharges were typically brief (0.5-2 s), The disease locus mutation for the two and addi- rarely longer (up to 20-30 s) (Day et al., 1999). A tional clinical variants of DM2 is on chromosome 3q myopathic EMG pattern may be detectable, in (Ranum et aI., 1998; Ricker et al., 1999). The particular in the most affected muscles. Nerve mutation is an expansion of an unstable CCTG conduction studies are usually normal but may be tetranucleotide repeat in intron 1 of the zinc finger abnormal in single cases (Ricker et aI., 1995; Day et protein 9 ZNF9 gene. Parallels between these aI., 1999). Sander et al. (1997, 2000) found a normal mutations indicate that microsatellite expansions in exercise test in PROMMJDM2, which was in RNA can be pathogenic and cause the multisystemic contrast to DMI (see above) and might be useful in features of DMI and DM2 (Liquori et aI., 2001). . 464 F. LEHMAN-HORN ET AL.

23.3. Myotonias with and without paralyses: a generalized muscle hypertrophy including face sodium channel myotonias muscles. Particularly the muscles of the neck and the shoulders are markedly hypertrophied. When the 23.3. J. Potassium-aggravated myotonias (delayed myotonia is aggravated, e.g. by intake of potassium- myotonias) rich food or by exercise, ventilation might be For many families with dominant myotonia impaired due to stiffness of the thoracic muscles. thought to have a subtype of Thomsen's disease, a Children are particularly at risk from suffering acute muscle chloride channel disease, molecular genetics hypoventilation leading to and uncon- revealed mutations in SCN4A, the gene encoding the sciousness. This led to confusion with epileptic a-subunit of the adult skeletal muscle voltage-gated seizures and resulted in treatment with anticon- Na' channel. In contrast to Thomsen's disease, these vulsants such as carbamazepine which proved bene- patients develop severe stiffness which occurs after a ficial because of their antimyotonic properties. Such delay following strong exercise or oral ingestion of patients would probably not survive without con- potassium (potassium-aggravated myotonias, PAM). tinuous treatment. One of the patients was The spectrum of the degree of myotonia is large, misdiagnosed as having the "myogenic type" of ranging from the mild myotonia jluctuans to the very Schwartz-Jampel syndrome (Spaans et al., 1990), severe myotonia permanens. until electrophysiological studies indicated that In the mildest form, the affected individuals are sodium channel inactivation was impaired (Leh- not aware of a muscle stiffness or experience mann-Hom et al., 1990) and molecular genetics stiffness that tends to fluctuate from day to day, enabled the identification of SCN4A mutations hence the name myotonia jluctuans (Ricker et al., (Lerche et al., 1993). A further indication of the 1990, 1994). Most patients do not experience muscle severity of this disease is that all patients reported to weakness and their muscle stiffness is not sub- date are sporadic cases harbouring a de novo stantially sensitive to cold. Although the muscle mutation and have no children. stiffness is provoked by exercise this type of In both myotonia jluctuans and myotonia perma- myotonia should not be confused with paradoxical nens, depolarising agents such as potassium or myotonia. Within a period of exercise, the relaxation suxamethonium may aggravate the myotonia but do time of the contractions is normal or - if increased - not induce weakness. It is well recognized that there shows rather a warm-up than paradoxical myotonia. is an increased incidence of adverse - Paradoxical myotonia, if present, is restricted to the related events with the use of depolarising relaxants eyelid muscles. However, after rest of several in myotonic disorders. The incidence of such events minutes, a single contraction might then produce seems to be highest in myotonia jluctuans families such a severe stiffness (delayed myotonia) that the (Ricker et al., 1994; Vita et al., 1995). There seems patient is unable to move for several hours. This to be no biological reason for this and it most likely sometimes painful exercise-induced muscle cramp- relates to the frequent absence of clinical myotonia ing may be induced by or associated with in these patients making the anesthesiologists una- or other depolarizing agents (Heine et ware of the condition. al., 1993; Orrell et al., 1998). Another atypical but related disorder is acetazolamide-responsive myoto- Electrophysiologic findings in PAM nia, also known as atypical myotonia congenita In routine EMG examination, typical myotonic runs (Ptacek et al., 1994). In this form, muscle pain may are observed in all muscles examined, even during be induced by exercise and the symptoms are the spells of absence of clinical myotonia. In alleviated by acetazolamide. addition to these short-lasting myotonic bursts which A further disease is characterized by severe and are typical for the chloride channel myotonias, long- persisting myotonia and is therefore called myotonia lasting runs of fibrillation-like activity with slow or permanens (Lerche et al., 1993). Continuous myo- no changes of frequency and amplitude may occur tonic activity is noticeable on EMG and molecular (Fig. 6). These may appear constantly in some biology has revealed that this condition is caused by patients. When delayed onset myotonia is recorded, a specific mutation (GI306E) in the SCN4A gene the relaxation disturbance can be fully explained by product. The continuous electrical myotonia leads to electrical activity which is in contrast to para- SKELETAL MUSCLECHANNELOPATHIES 465 myotonia congenita (see below). There is no altera- tions many patients have no complaints but some tion of the activity in cold environment, but experience myotonia in a warm environment which myotonic runs and fibrillation-like activity are then mostly presents rather with a warm-up phe- enhanced by potassium intake in parallel with the nomenon. clinical myotonia. Motor unit potentials appeared In most families the stiffness gives way to flaccid normal (Ricker et al., 1990, 1994). weakness or even to paralysis on intensive exercise and cooling. Some, but not all, families with PC also 23.3.2. Paramyotonia congenita: paradoxical have attacks of generalized hyperkalemic periodic myotonia and cold-induced weakness paralysis provoked by rest or ingestion of potassium Paramyotonic symptoms are present at birth and lasting for an hour or less. In contrast, the cold- remain often unchanged for the entire lifetime. The induced weakness usually lasts several hours even cardinal symptom of paramyotonia congenita (PC, when the muscles are immediately rewarmed. Mus- MIM 168300) is cold-induced muscle stiffness that cle relaxation, slightly slowed in some patients at increases with continued activity ("paradoxical myo- normal temperature, becomes normal when the tonia", Fig. 4). Particularly in the course of repeated muscles are warmed. strong contractions of the orbicularis oculi muscles, the opening of the eyelids is more and more impeded Electrophysiologic findings in PC until the eyes cannot be opened to more than a slit. Electrical discharges in the EMG may be absent at In the cold (or even in a cool wind), the face may normal or increased temperature, but occasional appear mask-like, and the eyes cannot be opened for myotonic runs do occur. Upon cooling, a fibrillation- several seconds. Working in the cold makes the like spontaneous EMG activity develops consistently fingers so stiff that the patient becomes unable to which is maximal at a muscle temperature of about move them within minutes. Many patients exhibit 29°C. With a further drop in temperature, this the lid lag phenomenon and some of them percus- spontaneous activity decreases and almost dis- sion myotonia. Muscle pain, atrophy or hypertrophy appears at 24°C when the muscle gets paralysed are not typical for the disease. Under warm condi- (Haas et aI., 1981). In another single patient, long-lasting repetitive (complex) discharges were reported at room temperature, when the patient had no muscle stiffness, and upon cooling myotonic j\J~V~~uULt~~lWLI50 discharges developed whereas the other activity N ~1s ceased (Weiss et 1997). In patients with myoto- :I • • \ aI., nia in a warm environment, there was rather a 11 mV warm-up phenomenon, and clinical myotonia could be related to electrical activity at room temperature. , " However, the muscle stiffness which developed in all patients upon cooling of the forearm in a water bath of 15°C, was not related to electrical myotonia and interpreted as depolarization-induced contracture of the muscle fibers. With further cooling, most patients develop a flaccid weakness accompanied by elec- trical silence. Consequently, CMAP amplitudes decrease upon cooling corresponding to the develop- ing weakness. Motor unit potentials as well as motor and sensory nerve conduction studies are normal Fig. 4. Courses of voluntary isometric muscle contrac- (Haass et aI., 1981; Lehmann-Hom et aI., 1984; tions (in Newton) and the corresponding surface EMG Ricker et al., 1986; Streib, 1987). activity underneath (modified from Haass et al., 1981). 23.3.3. Hyperkalemic periodic paralysis: rest- and The patients had to maximally contract their muscles for about 3 to 5 s and then to relax the muscles. The upper two potassium-induced paralysis traces show the warm-up phenomenon, the lower two The disease was first described by Tyler et al., in traces paradoxical myotonia. 1951, and Helweg-Larsen et al., in 1955, and was 466 F. LEHMAN-HORN ET AL.

force 125W :~ IJ,-----.....,-:~::r-..-- I1_·.....

force ~ (N) dlglt~rum 300 ." lJ---~m. flexor -41_~' 100 ---' _ .;...__ ""\i

K+ (mM) 7 __I ...... _ ..... 6 .,. . 5 ... ~ • •••• 4 ~ ...... ,., ... • 3

00 00 10 14 time

Fig. 5. Serum potassium and force (in Newton) of the quadriceps muscle of a hyperkalemic periodic paralysis patient during an attack induced by 20 min exercise of 125 W followed by rest in bed. Note the physiologic increase in serum potassium during exercise and the pathologic second rise associated with weakness at rest. Minimal exercise of the leg muscles abolished the weakness. Adapted from Ricker et al., 1986). extensively investigated by Gamstorp in 1956 who spontaneous attack commonly starts in the morning named it "adynamia episodica hereditaria." The before breakfast and lasts 15 minutes to an hour, and disease differs from hypokalemic periodic paralysis then disappears. During the day, rest often provokes in that it is usually associated with myotonia, at least an attack. Sustained mild exercise after a period of in the EMG, and that potassium can provoke an strenuous exercise may postpone or prevent the attack of weakness and that also a spontaneous weakness in the exercising muscle groups and attack is associated with an increase in serum improve the recovery of muscle force (working off) potassium. Intake of potassium and glucose have while the resting muscles become weak (Fig. 5). opposite effects in the two disorders, while potas- In the interictal state, the clinical myotonia is sium triggers a hyperkalemic attack and glucose is a usually very mild and never impedes voluntary remedy, glucose provokes hypokalemic attacks movements. It is most readily observed in the facial, which are ameliorated by potassium intake. The term lingual, thenar, and finger extensor muscles. The hyperkalemic periodic paralysis (HyperPP), which generalized weakness is usually accompanied by a stresses the potassium-related distinctions, is pre- significant increase of serum potassium (up to 5 to 6 ferred (MIM 170500). In general, HyperPP has an mM). Sometimes the serum potassium level remains earlier onset and more frequent attacks, but these are within the upper normal range and only seldom much shorter and milder than in the hypokalemic reaches cardiotoxic levels, although it may become form (Gamstorp, 1956). life-threatening in very rare cases. As the serum The attacks usually begin in the first decade of potassium increases, the precordial T waves in the life. Initially, they are infrequent but then increase in ECG increase in amplitude. When the serum potas- frequency and severity. Potassium-rich food or a sium level begins to rise, the serum sodium level potassium load as during a provocative test, usually falls 3 to 9 mM. This fall is caused by sodium entry precipitates an attack. Cold environment, emotional into muscle; this, in tum, causes a shift of water into stress, glucocorticoids, and pregnancy provoke or the muscles (observed by some patients as swelling) worsen the attacks. After strenuous exercise, weak- that causes hemoconcentration and increases the ness can follow within a few minutes of rest. A serum potassium level. SKELETAL MUSCLECHANNELOPATHIES 467

Electrophysiologic findings in HyperPP

Even though myotonic stiffness is often not clini- o M cally present, the EMG reveals myotonic activity in most families. In addition to short-lasting myotonic mV bursts, long-lasting runs of fibrillation-like action potentials with slow changes of frequency and -40 amplitude occur (Fig. 6) which can be provoked by -' II'" exercise. The myotonia strongly supports the diag- J - nosis of HyperPP and usually excludes HypoPP. At -80 the beginning of an attack, the bursts of fibrillation potentials may increase and explain the sensation of 2 sec muscle tension. In some patients paresthesia heralds the attack, probably induced by the hyperkalemia. During a severe attack, insertional EMG activity disappears, voluntary effort elicits few if any motor unit potentials, and the evoked CMAP amplitude is diminished. Interictally, motor unit potentials, motor and sensory nerve conduction studies are usually normal. Only in patients with a specific, frequent mutation (T704M), a chronic progressive myopathy with a myopathic pattern in the EMG may develop. In about 50% of the T704M carriers, neither clinical nor electrical myotonia is detectable (Subramony and Wee, 1986; Streib, 1987; Ptacek et aI., 1991; Lehmann-Horn et al., 1993). In contrast to PC, cooling does not decrease CMAP amplitudes in HyperPP (Subramony et aI., 1986) but may induce muscle weakness in vitro, with a different pathophysiological mechanism than in PC, i.e. without a membrane depolarization (Lehmann-Horn et al., 1987a; Ricker et al., 1989). The exercise test is abnormal in HyperPP as in HypoPP and Andersen's syndrome (see section on HypoPP for a description of the test), as CMAP amplitudes and areas first increase during the short period of exercise and then gradually decrease over a period of 20-40 min. within the post-exercise period. Such a pattern is also seen in secondary periodic paralysis. Thus, the test is helpful to establish the diagnosis ofperiodic paralysis, but does not distinguish between any of the different forms (McManis et aI., 1986; Subramony and Wee, 1986; Kuntzer et aI., 2000). However, also rest without exercise may produce weakness in HyperPP (Ricker K, Camacho L, Grafe P, Lehmann-Horn F, Rudel R: Adynamia episodica hereditaria: what causes the weakness? Muscle Nerve, 10: 883-891, 1989). If this is the case also in HypoPP has not been reported up to now. In PC, the test yields a decrease immediately after exercise with a subsequent return 468 F. LEHMAN-HORN ET AL. to baseline (McManis et aI., 1986; Subramony and test reduces the force of contraction by more than Wee, 1986; Kuntzer et al., 2000). 50% and prolongs the relaxation time from 0.5 s up to 50 s. In other patients, the abnormalities appear 23.3.4. Specific provocative testing ofsodium after an additional maximal voluntary contraction channel disorders lasting I to 2 min. The test is positive if the relaxation is markedly slowed whereby the isometric According to the description above, a provocative force exerted by the finger flexors often falls to 10% test for PAM is an exercise test that measures the or less of the pre-test value. muscle stiffness after a forceful and long-lasting A provocative test for HyperPP to be best voluntary contraction and following short contrac- performed in the morning prior to carbohydrate tions generated by the patient in intervals of several ingestion can confirm the clinical diagnosis. This minutes (Ricker et aI., 1990). For the differential consists of the administration of 2 to 109 potassium diagnosis to DMC, the increase in muscle stiffness chloride in an unsweetened solution in the fasting induced by oral ingestion of potassium can be state. Serum potassium levels should be determined observed clinically and by relaxation measurements. approximately in intervals of 20 minutes prior to and Potassium must not be administered to patients with after ingestion, the ECG monitored and an anesthe- myotonia permanens because of the potential stiff- tist available in case of a wide-spread paralysis ness of ventilatory muscles. involving respiratory muscles. After the ingestion, The diagnosis of PC can be verified by the the patient should avoid all muscle activity. The test following cooling tests: First, the amplitude of the is contraindicated in subjects who are already evoked compound muscle action potential is reduced hyperkalemic and in those who do not have adequate by cooling (Gutmann et aI., 1986; Jackson et aI., renal or adrenal reserve. An abnormally high serum 1994). This test can be easily performed and is potassium level between attacks suggests secondary supposed to differentiate between PC and HyperPP rather than primary hyperkalemic periodic paralysis. (Subramony et al., 1986). For the exercise test in PC The provocative test usually induces an attack within see section above on electrophysiology of HyperPP. the next hour which lasts about 30 to 60 minutes, The second test is highly specific but demands similarly to spontaneously occurring attacks of facilities which may not be available everywhere: weakness. An alternative test without potassium cooled paramyotonia muscles are slow to relax and ingestion consists of exercise on a bicycle ergometer generate decreased force on maximal voluntary for 30 minutes so that the pulse rate increases to contraction (Ricker et aI., 1986). The test is per- 120-160 beats/min followed by absolute rest in bed formed by determining the isometric force and (Ricker et al., 1989). Serum potassium rises during relaxation time of the long finger flexor muscles exercise and then declines to almost the pre-exercise before and after immersing hand and forearm in a level, as in healthy individuals. At 10-20 minutes water bath of 15°C for 30 min. In some patients, the after the onset of rest, a second hyperkalemic period occurs in patients but not in normal subjects; during this period, the patients become paralysed. Record- Fig. 6. Intracellular recordings of excised muscle fibers ings of the evoked compound muscle action from patients with sodium channel myotonias. Upper potential during rest and exercise are also helpful in panel: part of a run of a PAM muscle fiber which showed confirming the diagnosis of periodic paralysis (exer- stable amplitude and frequency for minutes before a cise test, see above). potential step induced bigeminal or trigeminal activity which may be estimated as complex repetitive activity in 23.3.5. Molecular genetics and pathogenesis of an extracellular recording. Middle panel: single fiber activityreveals doublepotentials in the biceps brachiiof a sodium channel myotonia and paralysis patient with myotonia permanens (de novo G1306E carrier) earlier described as Schwartz-Jampel syndrome In PAM, there are 8 mutations known in 5 of the (Spaans et al., 1990). Lowerpanel: a long-lasting run of a 24 exons of the a-subunit of the voltage-gated HyperPP muscle fiber is characterized by slowly pro- sodium channel clarifying approximately 30% of the gressive membrane depolarization associated with cases (Fig. 7). The mutations are situated either ar decreasingamplitude and increasing frequency. intracellularly faced positions (e.g. II 160V. Placek er SKELETAL MUSCLECHANNELOPATHIES 469 aI., 1994; V1589M, Heine et al., 1993) potentially tion. The slowing is most likely caused by an involved in the formation of the docking site for the impaired movement of the inactivation gate itself inactivation gate or its hinge (G1306AN/E, Lerche (i.e. the intracellular loop connecting domains III et aI., 1993; Mitrovic et aI., 1995) which is situated and IV) or by a disturbed formation of the docking in the vicinity of the IFM particle (Fig. 8). This may site of the IFM inactivation particle (Fig. 8), since explain the electrophysiological finding of a com- the mutations are predominantly situated either in bined pattern showing a small persistent current and the inactivation gate (T1313M, McClatchey et al., a mildly to moderately slowed current decay (Fig. 1992) or in the voltage sensor of repeat IV (R1448HJ 9A). C/SIP, Ptacek et aI., 1992; Chahine et al., 1994; In PC, there are 12 known mutations in 4 of the 24 Lerche et al., 1996; Bendahhou et al., 1999) which is exons of SCN4A accounting for approximately 50% moving outward (Yang et al., 1996) thereby pre- of the patients (Fig. 7). The mutations cause a sumably initiating the formation of the docking site. slowed current decay, a small persistent current (Fig. For one of the mutations (R1448P), slowing of the 9B), and an acceleration of recovery from inactiva- formation of a receptor site could be demonstrated

Fig. 7. Membrane topology model ofthe voltage-gated sodium channel of skeletal muscle. The a subunit functions as ion- conducting channel and consists of four highly homologous domains (repeats I-IV) containing six transmembrane segments each (S I-S6). The S6 transmembrane segments and the S5-S6 loops form the ion selective pore, and the 54 segments contain positively charged residues conferring voltage dependence to the protein. The repeats are connected by intracellular loops; one of them, the ill-IV linker, contains the supposed inactivation particle of the channel. When inserted in the membrane, the four repeats of the protein fold to generate a central pore as schematically indicated on the right-hand bottom of the figure. The different symbols used for the known mutations leading to potassium-aggravated myotonia. paramyotonia congenita or two types of periodic paralysis are explained on the left-hand bottom. Conventional l-letter abbreviations were used for replaced amino acids. 470 F. LEHMAN-HORN ET AL. using an inactivation gate peptide (Peter et al., inactivation apparatus, especially the docking site 1999). Strong slowing of the current decay, which is for the inactivation particle. Any malformation may particularly observed for PC-causing mutations, may reduce the affinity between the "latch bar and the explain the paradoxical myotonia, since in this case, catch" (Fig. 8). The mutations disturb fast and slow the abnormal, depolarising sodium inward current channel inactivation and produce a long-lasting flows during the action potential, i.e. with increasing persistent sodium current (Lehmann-Hom et a\., exercise (Lerche et al., 1996; Mitrovic et al., 1999). 1987a, 1991; Cannon et al., 1991; Cannon and In HyperPP, there are 7 mutations known in 4 of Strittmatter, 1993; Cummins et al., 1993; Cummins the 24 exons of SCN4A causative in half of the cases and Sigworth, 1996; Hayward et aI., 1997; Rojas et (Fig. 7). The mutations are situated at several al., 1999). Whereas fast inactivation occurs within disseminated intracellularly faced positions (e.g. millis and terminates the action potential, slow T704M, Ptacek et al., 1991; M1592V, Rojas et al., inactivation acts on a time scale of seconds. When 1991) potentially involved in generating parts of the both processes are disturbed, which is only found for

Fig. 8. Hinged-lid model of fast inactivation of sodium channels. Bird's eye view of the channel consisting of four similar repeats (I to IV). The channel is shown cut and spread open between repeats I and IV to allow a view of the intracellular loop between repeats III and IV.The loop acts as the inactivation gate whose hinge GG (a pair of glycines) allows it to swing between two positions, i.e. the open channel state and the inactivated closed state where the inactivation particle IFM (the amino acids isoleucine, phenylalanine and methionine) binds to its acceptor. Various substitutions of one of the two glycines cause potassium-aggravated myotonia of different clinical severity (G1306A, myotonia fluctuans; G1306V, moderate myotonia; G1306E, myotonia permanens). The model also shows one of the four voltage sensors, IlS4, which moves outwardly at membrane depolarization thereby opening the channel pore. Mutations in IIS4 cause HypoPP type 2. SKELETAL MUSCLE CHANNELOPATHIES 471

A B effect of potassium on channel gating could not be Control Control observed (Wagner et aI., 1997). In paramoyotonia congenita, silent contractures can occur in addition HyperPP to myotonic contractions as shown by extracellular 5ms 10ms recordings on excised muscle bundles by use of 11 electrodes designed to pick up all electrical activity. ~ Part of the slowed relaxation which followed the direct electrical stimulation and cooling were not caused by action potentials (Ricker et al., 1986). The Fig. 9. Two examples of faulty inactivation of mutant most likely explanation is a long-lasting contracture sodium channels of skeletal muscle associated with HyperPP (A) and PC (B). The mutant genes were induced by the sustained membrane depolarization expressed in human embryonic kidney cells and their the latter of which in tum blocks the generation of currents compared to those of normal channels. A: Patch- subsequent action potentials. clamp recordings reveal a persistent inward sodium current. B: Slowed inactivation is more pronounced with 23.4. Periodic paralyses without myotonia: the PC mutant. various cation channelopathies 23.4.1. Familial hypokalemic periodic paralysis- mutations causing HyperPP (Cummins and Sig- types 1 and 2 worth, 1996; Hayward et aI., 1997), a particularly long-lasting, depolarizing sodium inward current can The clinical symptoms of the disease (MIM occur, like observed in HyperPP muscle specimens 170400) were well described in the 19th century. (Lehmann-Horn et aI., 1987a). This finding is most However, it was not until 1934 that hypokalemia was probably responsible for the clinical differences of documented during the paralytic attacks. Although HyperPP compared to the other sodium channel familial hypokalemic periodic paralysis is the most disorders, since the profound and long-lasting depo- common of the primary periodic paralyses, its larizations should increase the tendency to develop prevalence is estimated to only 1:100,000. The paralytic attacks. disease is transmitted as an autosomal dominant trait In vitro electrophysiology and functional expres- with reduced penetrance in women. The severity of sion studies have shown that genetically determined the symptoms can vary greatly within a family. defects of sodium channels underlie the depolariza- Severe cases present in early childhood, mild cases tion. The mutant sodium channels then do not close as late as the third decade of life or may go properly and the resulting inward sodium current is unrecognized. Initially, the attacks are infrequent, associated with a slowly progressive membrane but after a few months or years, they increase in depolarization which initially, i.e, as long as the frequency and eventually may recur daily. An attack depolarization is small, further increases the mem- may range in severity from slight temporary weak- brane excitability (Lehmann-Horn et al., 1987b). A ness of an isolated muscle group to generalized further progressing depolarization of 20-30 mV paralysis. Paralytic attacks usually occur in the leads to complete inactivation at least of the wildtype second half of the night or the early morning hours channel population, and renders the membrane and on awakening the patient is unable to move his inexcitable and the muscle paralysed (Lehmann- arms, legs or trunk. In most cases, the cranial Hom et al., 1987a). This state is also temporary, as muscles are spared. Usually, strength gradually excitability of the muscle fibers returns when, by increases as the day passes. Occasionally, the action of the sodium/potassium pump, the mem- weakness lasts for several days. brane resting potential slowly assumes the The trigger for a nocturnal attack is often physiological value of about -80 mV.The triggering strenuous physical activity or a carbohydrate-rich of the myotonia by e.g. potassium, as in potassium- meal on the preceding day. During the day, attacks aggravated myotonia, is explained by the physio- can be provoked or worsened by high carbohydrate logical depolarization which follows an elevation of and high sodium intake, and by excitement. Injection serum potassium according to Nernst, thus unmask- of a mixture of antiphlogistics and local ing the sodium channel inactivation defect. A direct can trigger a severe attack after a few hours. 472 F. LEHMAN-HORN ET AL.

Exposure to cold can induce local weakness. Slight potentials (De Grandis et aI., 1978; Bertorini et al., physical activity can sometimes prevent or delay 1994). mild attacks. The exercise test is performed with strong volun- During major attacks, the serum potassium tary muscle contractions for 1-5 min. interupted by decreases, though not always below the normal short intervals every 15-20 s to avoid ischemia, best range, and there is urinary retention of sodium, performed in one of the distal hand muscles like the potassium, chloride and water. The serum potassium abductor pollicis brevis or abductor digiti minimi. In decrease is accompanied by a parallel decrease in any type of primary or secondary periodic paralysis, serum phosphorus. Oliguria, obstipation, and dia- usually a greater than normal increase in CMAP phoresis can occur during major attacks. Sinus amplitude or area during exercise is followed by a bradycardia and ECG signs of hypokalemia (U progressive decline of approximately 50% of max- waves) appear when the serum potassium falls below imum force over 20-40 min. after the exercise the normal range. Clinical or histopathologic signs period. When the mean value +2 SD of normal of cardiomyopathy are absent. controls is taken as a cut off (corresponding to Independently of the severity and frequency of the 40-50% decline), the test is positive in about 80% of paralytic attacks, many patients develop a chronic periodic paralysis patients. (McManis et aI., 1986; progressive myopathy which can be very severe and Streib, 1987; Kuntzer et aI., 2000). In chloride disabling (Links et al., 1990). On the other hand, channelopathies, paramyotonia congenita or myo- many patients do not recognize their permanent tonic dystrophy, the test may also be abnormal, but weakness as abnormal. This myopathy mainly usually shows a maximal decline directly after affects the pelvic girdle and proximal and distal exercise with recovery during the exercise period lower limb muscles. The MRI scan shows hypodense which is in clear contrast to the progressive decline areas in the core of the hip extensor muscles and seen in PP (McManis et aI., 1986; Streib, 1987; replacement of muscle by fat. Sander et aI., 1997). Measurement of muscle strength or torque induced by nerve stimulation is Electrophysiologic findings in HypoPP another option to characterize muscle function in EMG evidence of myotonia usually excludes the periodic paralysis patients (Day et aI., 2002). diagnosis of HypoPP. When there is no permanent weakness, the motor unit potentials are normal 23.4.1.1. Specific provocative testing for between the attacks; those with permanent weakness hypokalemic periodic paralysis show myopathic changes and fibrillation potentials When the serum potassium of a patient cannot be or sometimes a peculiar, so far unexplained neuro- investigated during a full-blown spontaneous attack, genic pattern. During a severe attack, insertional tests are required to establish the diagnosis of activity disappears, voluntary effort elicits few if any periodic paralysis and to determine its type. Because motor unit potentials, and the evoked CMAP is systemic provocative tests carry the risk of inducing either abnormally small or absent. Interictally, a severe attack, they must be performed by an muscle fiber conduction velocity measured with experienced physician and a stand-by anesthetist, surface or invasive EMG is abnormally low. This and the serum potassium and glucose levels and the method can also be used to detect asymptomatic ECG closely monitored. Provocative tests with carriers. The invasive method is easier to perform glucose with or without the additional use of insulin and more sensitive, in particular in asymptomatic must never be done in patients who are already carriers. The median frequency of the power spec- hypokalemic and potassium chloride must not be trum is also reduced (Troni et aI., 1983; Zwarts et aI., given to patients unless they have adequate renal and 1988; Van der Hoeven et aI., 1994; Links and Van adrenal function. der Hoeven, 2000). In two studies with single fiber The simplest systemic provocative test exploits EMG, fiber densities were increased interictally for the physiologic potency of glucose, or of glucose older patients but not for those under 40 years of age. plus insulin, to cause hypokalemia. Oral administra- During an attack of one patient, there was a slight tion of glucose, 2 g1kg body weight, in the early increase in jitter with several blocks indicating the morning combined with 10 to 20 units of crystalline failure of the muscle membrane to conduct action insulin, given subcutaneously, may provoke a para- SKELETAL MUSCLECHANNELOPATHlES 473

Fig. 10. Subunits of the voltage-gated . The a l subunit resembles a of the sodium channel however the function of the various parts, e.g. the ill-IV linker, may not be the same. aiS, 131 to 134, and 'Y are auxilliary subunits. Mutations shown here als subunitof the skeletalmuscleL-typecalciumchannel(=dihydropyridine receptor, DHPR)have been described for man (HypoPP, MHS5) and mice (mdg). Conventional I-letter abbreviations are used for the replaced amino acids.The symbols indicatethe diseases as explained at the bottomof the left-hand side. lytic attack within 2 to 3 hours. Exercise and intake method. A negative test does not exclude the of carbohydrates the evening before, increase the diagnosis of primary HypoPP because at times potency of the test. If the test is equivocal, patients may be refractory. intravenous administration of 1.5 to 3 g glucose per As in HyperPP, the exercise test, which deter- kg body weight over 60 minutes may provoke an mines the amplitude of the compound action attack. In cases that are difficult to diagnose, potential, or torque measurement may be used (see intravenous insulin in doses not exceeding 0.1 U/kg above). A positive test result confirms the diagnosis at 30 and 60 minutes during the glucose infusion of a periodic paralysis and - in combination with a may precipitate an attack. Another form of the test provocative factor - its type. uses prolonged glucose loading, 50 g glucose in 150 ml water administered hourly for up to 15 hours. 23.4.1.2. Molecular pathogenesis ofhypokalemic Paresis normally appears within 7 to 15 hours and periodic paralysis paralysis within 12 to 16 hours. If these tests fail to Differentiating this disorder from HyperPP is of induce an attack, they may be repeated after exercise prognostic and therapeutic relevance. In 60% of the and combined with salt loading (sodium chloride, patients with a positive family history, one of the 2 g orally, every hour, for a total of four doses). In three known missense mutations in the CACNAIS general, a serum potassium level of 3.0 mM or less gene, which encodes the L-type calcium channel of should be achieved. The test is positive when skeletal muscle, can be identified (Fig. 10) (Jurkat- weakness ensues. CMAPs should be measured as Rott et aI., 1994). In about 20% of pedigrees, one of well to confirm the weakness by an objective the four known SCN4A mutations can be detected 474 F. LEHMAN-HORN ET AL.

(Fig. 7) (Jurkat-Rott et aI., 2000b; Sternberg et al., WT HypoPP 2001). In both the calcium and the sodium channel, :> 20 the mutations are located solely in the voltage .s o 2ms Cii sensing S4 segments of either domain 2 or domains ~ -20 2 and 4 respectively (Fig. 8). (An additional base .$! change has been reported for two families in a gene 8. -40 c:: which codes for the accessory a subunit of the ~ -60 kv3.4/MiRP2 channel complex. Because of the .0 E -80 genetic heterogeneity, testing of additional family Q) members for linkage to the known loci is recom- ~ -100 mended in case of negative results.) The mutations causing the more frequent calcium Fig. II. Intracellular recordings of action potentials from channel variant, HypoPP type I, show similar a muscle fiber segment of a hypokalemic periodic functional consequences though their significance is paralysis patient(HypoPP) compared to thoseof a healthy unclear: a reduction of current amplitudes, slight control (WT). The action potentials were elicited from lowering of the voltage threshold for inactivation and various holding potentials by a short depolarizing pulse. Note their slower rise and faIl and their smaller size for slowing of the rate of activation (Lapie et aI., 1996; HypoPP. Jurkat-Rott et aI., 1998; Morrill and Cannon, 1999). Since electrical muscle activity, evoked by nerve stimulation, is reduced or even absent during attacks, agents such as insulin and glucose, but do not a failure of excitation is more likely than a failure of explain the development of the depolarization itself. excitation-contraction coupling. Nevertheless, the 23.4.2. Andersen's syndrome - dyskalemic periodic hypokalemia-induced, large membrane depolariza- paralysis with arrhythmia and dysmorphia tion observed in excised muscle fibers (Rudel et al., 1984; Ruff, 1999) might also reduce calcium release Andersen's syndrome (not to be confused with by inactivating sarcolemmal and t-tubular sodium Andersen disease, type IV glycogen storage disease) channels, and would explain why repolarization of is defined as a clinical triad consisting of dyskalemic the membrane by activation of ATP-sensitive potas- periodic paralysis, ventricular ectopy, and dys- sium channels restores force. morphic features (Tawil et al., 1994; Sansone et aI., Whereas in HyperPP the inactivated state of the 1997). The dysmorphic features may be variable and sodium channel is destabilized, it is stabilized in the include small stature, low-set ears, hypoplastic sodium channel variant of HypoPP type 2. Func- mandible, clinodactyly, and scoliosis. Cardiac distur- tional expression of the mutants revealed reduced bances may also show a variety of phenotypes such current amplitudes, hyperpolarizing shifts of volt- as prolongation of the QT interval, ventricular age-dependent fast and - for some mutations - slow bigeminy, and short runs of bidirectional ventricular inactivation, and a slowed recovery from the fast- . Sudden deaths in this syndrome proba- inactivated state (Jurkat-Rott et aI., 2000b; Struyk et bly due to cardiac arrest have been reported. aI., 2000; Bendahhou et aI., 2001; Kuzmenkin et al., Similarly to HypoPP, myotonia is not a feature of 2002). All changes enhance channel inactivation this syndrome. In contrast to HyperPP and HypoPP (Fig. 8) and lead to a reduced number of sodium patients, the response to oral potassium is unpredict- channels available for the generation and propaga- able: it improves weakness in patients with low tion of action potentials, i.e. the excitability of the serum potassium, in some families however, it myofibers is generally reduced (Fig. II). In agree- improves arrhythmia but exacerbates episodic paral- ment with these findings, smaller and more slowly ysis. During an attack, serum potassium may be conducted action potentials were recorded in myo- high, low, or normal. fibers biopsied from patients carrying a sodium Several mutations in a voltage insensitive a channel mutation (Jurkat-Rott et aI., 2000b). These subunit of a expressed in both abnormal channel properties reduce the availability skeletal and cardiac muscle have been described of sodium channels when HypoPP fibers are already (Plaster et al., 2001) (Fig. 12). These channels are depolarized, i.e. following infusion of triggering protein tetramers each consisting of only two SKELETAL MUSCLECHANNELOPATHIES 475 membrane spanning segments (Ml and M2) and an similar results as seen in HypoPP (Katz et al., interlinker forming the ion conducting pore. They 1999). function as inward going rectifiers, i.e. they are decisive for maintaining the resting potential (rectifi- 23.5. Malignant hyperthermia cation) by conducting potassium ions into the cell 23.5.1. Clinical features and pathogenesis of (inward going) which enlarges the concentration malignant hyperthermia gradient to the extracellular space and hyper- polarizes the cell. The mutations causing Andersen Susceptibility to malignant hyperthermia (MH) syndrome reduce this potassium current and a susceptibility is an autosomal dominantly trans- mutant monomer is capable of exerting a dominant mitted predisposition of clinically inconspicuous negative effect on a whole tetramer corresponding to individuals to respond with uncontrollable skeletal the dominant mode of transmission of the disorder muscle hypermetabolism upon exposure to volatile (Plaster et al., 2001). anesthetics or depolarizing muscle relaxants (Denborough and Lovell, 1960). The triggering Electrophysiological findings in Andersen's syn- substances lead to an increase in the concentration of drome Standard needle electromyography is usu- free myoplasmic calcium which is released from the ally normal and does not show myotonic discharges sarcoplasmic reticulum calcium stores via the mus- (Sansone et al., 1997). The exercise test shows cle ryanodine receptor channel (Iaizzo et al., 1988).

Fig. 12. Membrane topology model of the voltage-independent potassium inward going rectifier channel Kir2.l of skeletal muscle. Mutations in the coding KCNJ2 gene which cause the Andersen's syndrome. 476 F. LEHMAN-HORN ETAL.

During an MH reaction, a massive myoplasmic calcium release is induced, leading to muscle contracture especially of the masseter, generalized rigidity, and heat production. Hypermetabolism associated with the sarcoplasmic calcium elevation upregulates glycogenolysis resulting in excess lac- tate production, metabolic , and hyper- activation of the oxidative cycle with increased ATP depletion, high oxygen consumption and carbon dioxide production with hypoxemia and hyper- capnia. Tachycardia may be observed as an early sign. During the course of the crisis, occurs with subsequent elevation, hyperkalemia potentially leading to ventricular fib- rillation, and with the possibility of renal failure. Hyperthermia may be a late sign in some cases. If an episode is survived, normalization of edematous muscle and creatine kinase levels occur within 10-15 days. As so-called awake episodes following heavy exercise have been reported, carriers of the trait are unsuited for military service. For diagnosis of MH susceptibility, a func- tional test on skeletal muscle , the in vitro o malignant hyperthermia (MH) contracture test (lVCT), can be performed which D malignant hyperthermia/central cores(MHlCC) (CCO) reveals high concordance with the genetic phenotype o central coredl8ealle with nemaline rods (CCDln.rods) (Brandt et al., 1999). In the majority of families, linkage to the gene - dol«lon • ClCR·Tost 'Canlno MH encoding the skeletal muscle ryanodine receptor, Fig. 13. Cartoon of the homotetrameric ryanodine recep- RyRl, a calcium channel which under the control of tor, the calcium release channel situated in the membrane the voltage-dependent dihydropyridine-sensitive L- of the sarcoplasmic reticulum (SR). The cytosolic part of type calcium channel of skeletal muscle, can be the protein complex, the so-called foot, bridges the gap found (MacLennan et al., 1990; McCarthy et al., between the transverse tubular system and the SR. 1990). To date, more than 20 disease-causing point Mutations have been described for the skeletal muscle mutations in RyRI have been identified in man, most ryanodine receptor (RyRl), which cause susceptibility to situated in the cytoplasmic part, the foot, of the malignant hyperthermia (MHS) and central core disease protein (Fig. 13) (for review see Jurkat-Rott et al., (CCD). 2000a). The base of the homotetrameric protein, is located in the membrane of the sarcoplasmic retic- However only for one (MH susceptibility type 5) of ulum, and forms the ion-conducting pore. Func- these loci, a causative gene has been identified, tionally, hypersensitivity of RyRI to anesthetic CACNAIS, so that this very rare type of MH is triggering agents has been shown to be pathogenet- allelic to hypokalemic periodic paralysis type I ically causative in functional tests of both muscle, (HypoPP-l). In contrast to the voltage sensor isolated native proteins, and heterologously mutations specific for HypoPP-l (and HypoPP-2), expressed full-length receptors (Censier et al., 1998). the two mutations so far described for MH are Therapeutically, during an anesthetic crisis, dan- situated in the myoplasmic loop connecting repeats trolene, an RyRI inhibitior, is very effective III and IV the function of which is unknown (Fig. reducing the mortality rate from former 70% to 10). The two mutations underline the functional link currently 10%. between RyRI and the DHPR in excitation-contrac- MH could be very highly heterogeneous with 5 tion coupling (Monnier et al., 1997; Lehmann-Horn additional chromosomal loci mapped until now. and Jurkat-Rott, 1999). SKELETAL MUSCLECHANNELOPATHlES 477

23.5.2. Functional neurophysiology and in vitro no spontaneous activity but an increased duration of testing ofmalignant hyperthermia susceptibility motor unit potentials (Steiss et aI., 1981). Susceptibility to MH itself is not associated with a 23.5.3. Central core disease: myopathy with primary structural myopathy or electromyographic malignant hyperthermia susceptibility or contractile alterations. Due also to lack of clinical symptoms under normal conditions, an MH in vitro Central core disease (CCD) is a congenital contracture test (IVCT) for biopsied muscle bundles myopathy often associated with skeletal anomalies was developed by the European (EMHG) and North (Shy and Magee, 1956). Pathognomonic is the American (NAMHG) malignant hyperthermia abundance of central cores along type 1 muscle groups (European Malignant Hyperprexia Group, fibers. CCD is often associated with MH susceptibil- 1984; Larach, 1989). This test requires a large fresh ity (Shuaib et al., 1987), and allelic to the RyRI gene muscle biopsy and is therefore invasive in nature and locus of MH (Haan et aI., 1990; Kausch et aI., 1991). not easily performed on children. It is based on the The myopathy is characterized by congenital muscle tendency of MH muscle to be abnormally sensitive hypotonia (floppy infant syndrome), proximally to stimuli that induce SR calcium release. The pronounced weakness, delayed motor development, underlying procedure in both EMHG and NAMHG and slight CK elevation. In addition skeletal test protocols is the measurement of contractures anomalies such as congenital hip displacement and upon flooding or gradually increasing concentrations skoliosis are frequent. Later in life, muscle strength of and separately of (Fig. 14). A positive reaction to a triggering agent is dependent on contracture force at concentrations below 50 1hresholdat 2% predefined thresholds for each substance. Three -.r ~, categories result by each test according to the j r European protocol, contracture under or at the I -----~halothane thresholds of both substances is considered to be 4% MH-susceptible (MHS), one pathologic and one 10 I 2% normal result is classified as equivocal (MHE), and ~ two normal reactions to both agents means not i I 0% susceptible (MHN). In general, correlation between 0 20 40 60 80 100 120 140 the results of these two tests is quite good and the time [min] test shows a high sensitivity (true positives, 99% for EMHG and 92-97% for NAMHG) and specificity (true negatives, 93.6% for EMHG and 53-78% for ttreshold NAMHG. -.f at 1.5nft1 In contrast to the IVCT test protocols primarily CIl100 aimed at determining the clinical risk of anesthesia- J caffeine related events, diagnostic testing in Japan is l 32 JrIJI performed by a functional test based on the quantifi- 4J1'tl1 cation of calcium-induced calcium release (CICR) in 2 J1'tl1 saponized muscle fibers (Kawana et al., 1992). The oJ1'tl1 precision of this method and correlation to the other I10 / 0 20 40 60 80 100 protocols is unknown. time [rrin] Clinical electrophysiology Fig. 14. In vitro contracture test in muscle bundles of a Standard electrophysiology in MH is normal. Fol- malignant hyperthermia susceptible patient according to lowing injections of caffeine, succinylcholine or the European protocol. Upper panel: halothane, Lower halothane locally in the muscle revealed a decrease panel: caffeine in increasing concentrations. After initial of the CMAP amplitude which correlated to in vitro prestretching (peak in the curve), note the development of testing in 9 MH patients (Eng et al., 1984). A pathologic contractures C~ 200 mN) at 2 vol.% halothane detailed EMG study in MH suceptible pigs revealed and 1.5 mM caffeine. 478 F. LEHMAN-HORN ET AL.

IMyotonias and periodic paralyses (PP) I Myotonic bursts?

IPP wIthout myotonia I dystrophic or non-dystrophic myotonia or PP wIth myotonia interictal arrhythmia or dysmorphia? multsystemic myotonia or repeat expansion? i \"' non-dystrophic myotonia or multisyslemic pp pure PP myotonic dystrophy I I PP with myotonia

hyperthyroidism? induced by carbohydrates K' or cold sensitivity? or associated wllh hypokalemia? '\es eCTG eTG

sodium channel chloride channel yes myotonia myotonia

K' indUC;!d cJld~'induced weakness induce~ myotonia dominant myotonia 7 I [TPP I IHypoPP I IHyperPP I [E] 1PAM 1 IDMCI / \ _--'--,1 \-'---_ Itype 1 IItype 21 Ifluctuans IIpermanensI

Fig. 15. Flow diagram I. Differential diagnostic scheme of myotonias and periodic paralyses. usually improves except for rare cases showing coupling process has been found in a skeletal muscle progressive muscle weakness. It is one of the rare expression system suggesting a dominant negative known myopathies for which strong physical exer- effect of the CCD mutations on the voltage- cise seems to be beneficial (Hagberg et al., 1980) controlled caIcium release (Avila et al., 2001). This although exercise-induced muscle cramps are often functional disruption may contribute to the muscle reported. Autosomal dominant inheritance is highly weakness and atrophy in the patients. predominant and although several sporadic cases Electromyography in CCD have been reported, a clear recessive trait has not yet Motor and sensory conduction velocities are always been demonstrated. The clinical expression of the normal. A myopathic pattern of spontaneous EMG disease is highly variable. Not all mutation carriers activity and motor unit potentials is typically found in a family may develop this myopathy but instead in CCD (Fardeau M, Tome FMS. Congenital myo- may only have the MH trait (Islander et aI., 1995). pathies. In: Myology, Ed. Engel AG, Franzini- Except for one mutation, all situated in the C- Armstrong C, McGraw Hill 1994, pp 1487-1532). terminus of the RyRI protein thought to form the Single fiber EMG revealed an increase in fiber channel pore region (Fig. 13). Expression of these density and a normal jitter (Cruz Martinez et al., mutations in non-muscle cells led to the finding of a 1979). leaky calcium release channel compatible with the view of a myoplasrnic calcium overload responsible Acknowledgements for the mitochondrial and cell damage (Lynch et aI., 1999; Tilgen et aI., 2001). Recently a selective We thank U. Richter for drawing the cartoons. disruption of the orthograde excitation-contraction This work was supported by the German Research SKELETAL MUSCLECHANNELOPATHIES 479

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