chapter 23 skeletal muscle channelopathies: … levior. as the inheritance and the molec-ular...

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

CHAPTER 23

Skeletal muscle channelopathies: myotonias, periodicparalyses and malignant hyperthermia

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

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23.1. Introduction

23.1.1. Membrane excitability and coupling ofexcitation to contraction

Motoneuron activity is transferred to skeletalmuscle at the neuromuscular junction generating asarcolemmal action potential that propagates fromthe endplate to the tendon and along the transversetubular system (TIS). This membrane region pro-jects deeply into the cell to ensure even distributionof the impulse. The upstroke of the action potentialis mediated by opening of the voltage gated sodiumchannels (encoded by the SCN4A gene located onchromosome 17q13.1-3 and its accessory beta-subunit encoded by SCN1B on chromosome19q13.1) that elicit a sodium inward current withrapid activation kinetics. Repolarization of themembrane by fast sodium channel inactivation issupported by opening of delayed rectifier potassiumchannels that mediate an outward potassium current.Buffering of after-potentials is achieved by a highchloride conductance near the resting potentialresulting from the homodimeric chloride channel,ClC-I, encoded by the gene CLCN1 on chromo-some.

At specialized junctions in the TIS, the signal istransmitted from the tubular membrane to thesarcoplasmic reticulum (SR) causing the release ofcalcium ions into the myoplasm which activate thecontractile apparatus. This process is called excita-tion-contraction coupling. Mainly two calcium

* Correspondence to: Prof. Dr. Frank Lehmann-Hom,Abteilung Angewandte Physiologie, Universitat VIm,D-8908l VIm, Germany.

E-mailaddress:[email protected]

channel complexes are involved in this process, thevoltage-gated pentameric dihydropyridine receptorlocated in the TIS (encoded by the CACNA1S geneon chromosome Iq31-32 and genes for accessorysubunits) and the homotetrameric ryanodine receptorof the SR (encoded by the RYR1 gene on chromo-some 19q13.1).

23.1.2. Channelopathies: episodic stiffness andweakness

Membrane excitability is regulated by voltage-gated ion channels which are essential for thestabilization of the resting membrane potential andthe generation of the action potential. It is thereforenot surprising, that ion channels are involved in thepathogenesis of diseases of skeletal muscle. Chan-nelopathies are defined as episodically recurringdisorders caused by a pathology of ion channelfunction (Hoffman et aI., 1995). Clinically, skeletalmuscle ion channelopathies appear as episodes ofmuscle stiffness or weakness triggered by typicalcircumstances such as cold, exercise, oral potassiumload, or drugs. According to the mode of transmis-sion and potassium sensitivity, four forms ofmyotonia and paramyotonia are distinguished: domi-nant (potassium-insensitive) myotonia congenita,recessive myotonia congenita, dominant potassium-aggravated myotonia, and dominant paramyotoniacongenita. Myotonic dystrophies type I and 2 arechronic progressive multisystemic diseases of domi-nant inheritance and not true channelopathies. Theyare discussed in this chapter because of the commonfeature of myotonia which is thought to be caused bya pathology of ion channel expression.

While myotonia is brought about by uncontrolledrepetitive firing of action potentials leading toinvoluntary muscle contraction, lack of action poten-

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tials or muscle inexcitability results in weakness.Three dominant types of episodic weakness with orwithout myotonia are either distinguished by theserum potassium level during the attacks of weak-ness, hyper- and hypokalemic periodic paralysis orby concomitant clinical features such as cardiacarrhythmia and facial dysmorphia, Andersen's syn-drome.

An electrically silent muscle stiffness triggered byvolatile anesthetic agents and depolarizing musclerelaxants as found in malignant hyperthermia is notassociated with myotonic runs. It is based onuncontrolled intracellular calcium release via theryanodine receptor that is not preceded by actionpotentials. An acute, potentially lethal crisis ischaracterized by muscle hypermetabolism, rhabdo-myolysis, body temperature elevation, musclerigidity, and cardiac arrhythmia.

23.2. Classical myotonia congenita: chloridechannel myotonias

23.2.1. Dominant Thomsen and recessive Beckermyotonia

Myotonia congenita appears in two forms: Thom-sen's disease (MIM 160800), or dominant myotoniacongenita (OMC), the first myotonic diseasedescribed (Thomsen, 1876), and Becker myotonia(MIM 255700), or recessive generalized myotonia(Becker, 1977), here termed recessive myotoniacongenita (RMC). Both disorders are slowly or non-progressive, usually non-dystrophic, and caused byallelic mutations of the gene coding for the chloridechannel of the skeletal muscle fiber membrane(Koch et aI., 1992). They are referred to as chloridechannel myotonias.

In OMC, the myotonia is usually recognized inearly childhood, but the milder cases may gounrecognized until late childhood. The myotonia isgeneralized; the legs are often most affected, causingthe children to fall frequently. The cranial as well asarm and hand muscles can be severely affected, andit may be difficult for the patients to grasp objects.Chewing is sometimes impaired. The myotonicstiffness is most pronounced when a forcefulmovement is abruptly initiated after the patient hasrested for 5 to 10 min. For instance, after making astrong fist, the patient may not be able to extend thefingers fully for several seconds. The myotoniadecreases or vanishes completely when the same

F. LEHMAN-HORN ET AL.

movement is repeated several times (warm-up phe-nomenon), but it recurs after a few minutes of rest.The patient may experience much difficulty whilegetting up from a chair or stepping into a bus in ahurry. On rare occasions, a sudden, frightening noisemay cause instantaneous generalized stiffness; thepatient may then fall to the ground and remain rigidand helpless for some seconds or even minutes.Myotonic signs persist throughout life. The myoto-nia may increase with pregnancy, but this usuallydoesn't create a major problem. Hypothyroidismmay worsen the myotonia. Contrary to the opinion ofmany patients, cold does not substantially worsenthe myotonic stiffness and slowed relaxation (Rickeret al., 1977).

Upon examination, OMC patients may havehypertrophied muscles and an athletic appearance.Their muscle strength is normal or even greater thannormal and they can be quite successful in thosesports where strength is more important than speed.Tapping of the muscle produces an indentation thatpersists for several seconds (percussion myotonia).Lid lag is usually present, and in some patients,myotonia of the lid muscles causes blepharospasmafter forceful eye closure. The muscle stretchreflexes are normal and muscle pain is usually notpresent.

Members of a given OMC family can be affectedto different degrees. In a few kinships, the myotoniais consistently very mild and almost undetectable;this was considered a special form and termedmyotonia levior. As the inheritance and the molec-ular pathogenesis is the same as in Thomsen'sdisease, the term should be abandoned (Lehmann-Horn et al., 1995).

The clinical picture of RMC resembles that ofOMC. A few special points are worth mentioning. Inmany patients, the myotonia is not manifest until theage of 10 to 14 years or even later, but in a few it isobvious already at the age of 2 to 3 years. Theseverity of the myotonia may slowly increase for anumber of years, but usually not after the age of 25to 30. In general, the myotonia is more severe than inOMC. Thus, RMC patients are more handicapped indaily life, especially by severe myotonic stiffnessaffecting the leg muscles. They frequently fall downand have gait problems. Muscle shortening due tocontinuous contractions may limit bilateral dorsi-flexion of the wrist or foot. Severely affected patientswalk on tiptoes and develop a compensatory lordo-

SKELETAL MUSCLE CHANNELOPATHIES

sis. The leg and gluteal muscles are often markedlyhypertrophied, whereas the neck, shoulder and armmuscles appear poorly developed - especially in oldage - resulting in a characteristic disproportionatefigure. Also very disabling is a peculiar transientweakness affecting especially the hand and armmuscles (see below). Patients with severe RMC arelimited in their choice of occupation and they areunsuited for military service. Life expectancy isnormal. Alcohol can improve the condition, hunger,emotion or fatigue usually do not aggravate themyotonia.

23.2.2. Clinical neurophysiology of the chloridechannel myotonias

23.2.2.1. Electromyographic (EMG)./indings inchloride channel myotonias

The electrophysiological correlate of myotonia is- independent of the channel type affected -hyperexcitability of the sarcolemma which causesuncontrolled repetitive firing of action potentialsfollowing an initial voluntary activation. This myo-tonic reaction prevents the muscle from immediaterelaxation which the patients experience as musclestiffness.

Standard EMG - Spontaneous activity. In Thom-sen and Becker patients, the myotonic activity can beobserved in all routinely examined skeletal muscles.In the EMG, repetitive firing is typically observed asmyotonic bursts which are elicited easily by needleinsertions or slight mechanical manipulations liketapping. The slowed relaxation which patientsexperience as muscle stiffness is strongly correlatedto electrical activity as could be shown in biopsiedmuscle specimens in vitro (Iaizzo and Lehmann-Hom, 1990). Interestingly, this is in contrast to thecold-induced stiffness in paramyotonia congenita.Typical are short bursts of action potentials appear-ing as triphasic spikes or as positive sharp waveswith amplitude and frequency modulation lasting < 1s and sometimes up to lOs (Ricker and Meinck,1972a). The most often mentioned but rare pattern,best recognizable in the acoustic EMG, is that of amyotonic "dive-bomber". This is a short dischargecharacterized by first an increase in frequency anddecrease in amplitude and then a decrease infrequency and increase in amplitude. Much morefrequent though, are short bursts characterized by arising frequency and a falling spike amplitude. Apart

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from these typical and diagnostically relevant myo-tonic runs, other forms of spontaneous activity dooccur, such as positive sharp waves at lowerfrequency or more complex discharges like rhythmicdoublets and triplets.

In RMC families, the heterozygous parents ofaffected offspring can sometimes be identified byhaving short (rarely longer than I s) myotonicdischarges of low amplitude on EMG withoutclinical manifestation. In addition to myotonic runs,heterozygous carriers showed very brief complexrepetitive discharges, increased insertional activity,and prolonged trains of rhythmic, low-frequency«60 Hz) positive waves lasting several seconds. Intwo thirds of RMC families, at least one of theparents exhibited this spontaneous activity (Deymeeret aI., 1999).

Standard EMG - other parameters. Motor unitpotentials in both forms of myotonia congenita areusually normal. In RMC, however, myopathicchanges like multiphasic or low amplitude potentialscan be observed (Streib, 1987). Rarely, specificCIC-l mutations may even induce dystrophic vari-ants of the disease with myopathic motor unitpotentials seen in all extremities (Nagamitsu et ai.,2000). CMAP amplitudes and nerve conductionvelocities are normal, unless in the period oftransient weakness (see below).

23.2.2.2. Warm-up phenomenonThe stiffness is initiated by a forceful muscle

contraction, particularly after a period of rest of atleast 10 min. This may not necessarily pertain to thefirst contraction which may be relatively unimpeded,but becomes increasingly obvious following thesecond and third short but forceful contractions. Thedisturbance of muscle relaxation after further con-tractions gradually disappears, a phenomenon whichis called warm-up phenomenon, the pathophysio-logic mechanism of which is still unknown.

23.2.2.3. EMG studies during transient weaknessIn the more severe Becker type, the stiffness is

usually associated with the symptom of transientweakness that depends on the patient's past activityin a similar way as the stiffness. This is bestdemonstrated when the patient makes a tight fistafter a period of rest: the force exerted by the fingerflexors vanishes almost completely within a fewseconds. When the patient lifts a heavy object, it may

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slide out of the hand because of loss of musclestrength (Ricker et aI., 1978; Deymeer et al., 1998).In a similar situation, a patient with dominant MCwould be unable to release the handle for a while.With repeated muscle contractions, the force returnswithin 20 to 60 s (Fig. I).

Electrophysiologically, the weakness occurringexperimentally upon repetitive stimulation is accom-panied by a decrease of the CMAP amplitude, as wasshown in a large number of studies (e.g. Ricker andMeinck, 1972b; Brown, 1974; Aminov et al., 1977;Ricker et aI., 1978; Deymeer et al., 1998). In a moredetailed investigation using surface EMG, Zwartsand Van Weerden (1989) also showed, that themuscle fiber conduction velocity (MFCV), themedian frequency of the power spectrum and theintegrated EMG decline during transient paresis inBecker myotonia. Multi-channel surface EMG,yielding a high spatial-temporal resolution, revealeda gradually developing decrease in peak-to-peakamplitude of the motor unit action potentials fromendplate towards tendon in parallel with the forcedecline. This deteriorating membrane function tem-porally leads to a complete intramuscular conductionblock within s in RMC (Drost et al., 2001). Usingsingle fiber EMG, qualitatively similar results couldbe obtained. Upon repetitive stimulation, the musclefiber action potential showed a progressive decreasein amplitude, marked deformation, and a varyinglatency occurring only after a few stimulations(Lagueny et aI., 1994; Trontelj and Stalberg, 1995).

All of these changes were observed in both DMC(Thomsen) and RMC (Becker), although in the latter


disease, the transient weakness occurs much morefrequently than in the former one. Consistent withthis clinical observation, however, in some of thestudies in which patients with both diseases werecompared, a more heavy stimulus like a higherstimulating frequency was necessary to induce thesame effect in DMC compared to RMC (Lagueny etal., 1994; Deymeer et aI., 1998).

23.2.3. Molecular diagnosis and pathogenesis ofthe chloride channel myotonias

The causative gene for dominant Thomsen andrecessive Becker myotonia is CLCN1 encoding thevoltage-gated chloride channel of the skeletal musclefiber membrane. The chloride channel protein,CIC-l, forms homodimeric double-barrel complexes(Mindell et aI., 2001; Dutzler et al., 2002) with twoindependent ion-conducting pores each with a fastopening mechanism of its own, but also with a gatestructure common to both pores (for review Fahlkeet al., 2001). Over 50 CIC-l mutations have beenidentified (Fig. 2) which, according to our data,account for approximately 30% of the cases, makinggenetic studies quite arduous. While non-sense andsplicing mutations always lead to the recessivephenotype, missense mutations are found in Thom-sen and Becker myotonia. A few intermediatemutations are even able to generate both modes oftransmission probably depending on supplementalgenetic or environmental factors. If genetic screen-ing does not yield a result, linkage analysis includingadditional 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 twoEMG 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 ina surrounding fiber. Right panels: Surface EMG of biceps brachii muscle (upper trace) and voluntary isometric force (inNewton) of the forearm flexors (lower trace) show a pattern characteristic for transient weakness. Modified after Ricker etaI., 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 dominantThomsen-type myotonia and recessive Becker-type myotonia are explained on the left-hand bottom. Conventional I-letterabbreviations were used for replaced amino acids.

is a very useful tool to confirm clinical diagnosis. Animportant issue genetically and prognostically (andin some cases diagnostically) is to exclude the repeatexpansions causing myotonic dystrophy types 1and 2.

Functionally, the fast opening mechanism of eachpore of the double barrel dimer channel complex isaffected by the recessive mutations, whereas acommon slow additional gate structure shared withthe co-associated subunit is affected by the dominantmutations (Saviane et aI., 1999). The dominantmutants exert a so-called dominant negative effecton the dimeric channel complex as shown by co-expression studies meaning that mutant/mutant andmutant/wildtype complexes are malfunctional. Themost common feature of the resulting chloridecurrents is a shift of the activation threshold towardsmore positive membrane potentials almost out of thephysiological range (Pusch et al., 1995; Wagner etaI., 1998). As a consequence of this, the chloride

conductance is drastically reduced in the crucialvicinity of the resting membrane potential (Fig. 3).This is not the case for the recessive mutants whichdo not functionally hinder the co-associated subunitsupplying the explanation why then two mutantalleles are required to reduce chloride conductanceso much that myotonia develops (at least down to30%; Palade & Barchi, 1977). Functional alterationof the chloride channels leads to a reduced mem-brane conductance for chloride decreasing thestability of the membrane potential. Regarding theclinical picture of affected patients, the instability isobviously highest during voluntary muscle activa-tion following rest. Repetitive activity then ensues,giving rise to myotonia. Upon warming-up, themuscle fiber membrane then seems to adapt to thelower chloride conductance. The excessive activitymay also lead to slowly progressive depolarizationbetween action potentials causing the transient (orsometimes permanent) weakness. It usually lasts

• wra G200R

·100 0 100VOltage (mv)

23.2.4. Differentiation from dystrophic myotonias

Myotonic dystrophy type 1 (DM 1)Myotonic dystrophy (DM I; MIM 160900) is anautosomal dominant multi-organ disease and themost common inherited muscle disorder in adults.Myotonia is only one of the many symptoms of thisprogressive disease, the most severe symptom beingmuscle wasting that begins in the distal limb andcranial muscles. Cataract, intraocular hypotension,gonadal atrophy, conduction abnormalities in theheart, hearing deficiencies, and neurocognitive defi-cits appear quite often in the course of the disease.The mutation ofDMI is an expansion of an unstableCTG trinucleotide repeat in the 3' untranslatedregion of the myotonic dystrophy protein kinase(DMPK) gene on chromosome 19q13.3 (for reviewsee Conne et aI., 2000). Its pathogenesis, though notyet clearly understood, is different from that of thenon-dystrophic myotonias even though ion channelsmay be involved, e.g. by alternative splicing.

In the congenital form of DMI, general muscleweakness (particularly pronounced in the face) is theleading finding, combined with retarded locomotorand mental development. Myotonia is absent, at leastin infancy. A decisive criterion for the diagnosis isthe occurrence of myotonic dystrophy in thepatient's mother. Electromyographic investigation isindicated when a suspicion of myotonic dystrophycannot be ascertained on the basis of clinical andgenetic findings. Myotonic activity in the EMG ofthe mother will then corroborate the suspicion.


Some RMC patients show progressive generalizedmuscle weakness, severe distal muscle atrophy, andunusually high serum creatine kinase levels (Naga-mitsu et aI., 2000), making the differentiation frommyotonic dystrophies difficult.

only for some seconds, but may nevertheless hampermovement more than the stiffness.

Electrophysiologic findings in myotonic dystrophytype 1 (DM1)In the adult form of myotonic dystrophy, myotonicEMG activity is less common than in the non-dystrophic myotonias and unevenly distributed overthe muscles of the body. The distal muscles of the

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WT

0

-5

~c:::: -10

0 200 400Time (ms)

G200R5

0

~ -5~c:~

-10

0 400 BOOTime (ms)

Fig. 3. Behaviour of human skeletal muscle C1C-l chan-nels expressed in a mammalian cell line. Compared arecurrents of normal (WT) and mutant (Gly-2oo-Arg)channels, the latter causing dominant myotonia in man(Thomsen-type). Upper and middle panels: macroscopiccurrents, recorded in the patch-clamp whole-cell mode,were activated from a holding potential of 0 mV byvoltage steps to potentials of -145 to +95 mY, anddeactivated after 400 ms by polarization to -105 mY.Lower panel: shows the voltage dependence of the relativeopen probability that is much reduced for the mutantchannel in the physiological potential range. All mutationsthat cause such a voltage shift have dominant effects.Adapted from Wagner et aI., 1998.

SKELETAL MUSCLECHANNELOPATHIES

upper extremities, the facial muscles and tibialisanterior show the highest incidence of involvement.Electrical myotonia may be only observed in a fewmuscles or even absent in obligate gene carriers. Inchildren up to ten years, electrical myotonia is rarelyseen, but its incidence increases with age later on. Incontrast to the chloride channel myotonias, long-lasting discharges of 2-30 s duration with falling orunchanging frequency and amplitude occur moreoften than the typical short myotonic runs. Themaximal frequency is typically 40--60 Hz and thuslower than in chloride channel myotonia (60-100Hz). Positive sharp waves and complex repetitivedischarges are also very common in DMI. Finally,myopathic changes consisting of short, polyphasicpotentials with early recruitment are commonlyfound, best in forearm extensor and tibialis anteriormuscles (Ricker and Meinck, 1972a; Streib, 1987;Pfeilsticker et aI., 2001).

Motor and sensory nerve conduction studiesfrequently show mild signs of peripheral neuropathy.CMAP amplitudes are reduced depending on thedegree of dystrophic changes. The exercise testshows a mild to moderate decrement in CMAPamplitude with a quick recovery, which is not seen inDM2/PROMM (see below) (Streib, 1987; Sander etal., 1997, 2000; Kuntzer et al., 2000). Muscle fiberconduction velocity (MFCV) and power spectra asdetermined by surface EMG are normal in contrastto RMC (Zwarts and Van Weerden, 1989).

Myotonic dystrophy type 2 (DM2)/proximal myo-tonic myopathy (PROMM)A second dominant multisystemic myotonic dis-order, similar to classical myotonic dystrophy butwith no DMPK gene affection, was originallydescribed as proximal myotonic myopathy orPROMM (Ricker et aI., 1994). Since some patientsexhibited distal muscle weakness and dystrophy, thedisease was later enlarged to myotonic dystrophytype 2 (DM2; OMIM 602668) (Ranum et aI., 1998).The disease locus mutation for the two and addi-tional clinical variants of DM2 is on chromosome 3q(Ranum et aI., 1998; Ricker et al., 1999). Themutation is an expansion of an unstable CCTGtetranucleotide repeat in intron 1 of the zinc fingerprotein 9 ZNF9 gene. Parallels between thesemutations indicate that microsatellite expansions inRNA can be pathogenic and cause the multisystemicfeatures of DMI and DM2 (Liquori et aI., 2001).

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In most patients, DM2 is a very slowly pro-gressive disorder with muscle weakness developingtypically after 40 years of age. The symptoms can beaggravated by hypothyroidism and pregnancy. Somepatients have an annoying, sometimes disabling,pain in their muscles, especially in their thighs. Thepain is not related to myotonic stiffness and is mostapparent at rest. In other patients the discovery of acataract at age of about 35 years is the firstmanifestation of the disorder. The cataract is poste-rior capsular and, for a certain period of time.iridescent like in myotonic dystrophy. Many patientsfirst complain of intermittent stiffness. When it ispresent, it is typically focal, involving one thigh orone hand. The movements are jerky and stepwise,especially in the thumb and index finger and show a"warm up" phenomenon. Because of the variation inthe severity of the myotonia and because it is usuallymild in the initial stages of the disorder, it is notunusual for the signs of myotonia to elude clinicaldetection.

Electrophysiologic findings in DM2/PROMMElectromyographic investigation reveals a broadspectrum of spontaneous activity including myo-tonic discharges, also in most of those patientswithout obvious clinical myotonia. The myotonicdischarges are often scarce, difficult to detect(multiple muscles have to be investigated) and maybe fluctuating (Ricker et al., 1995; Day et al., 1999).They can be provoked by heat and diminished bycold (Sander et aI., 1996) but this is not observed inall families (Day et aI., 1999; Moxley et al., 2002).In addition to myotonic discharges, fibrillationpotentials, positive sharp waves, runs of complexrepetitive discharges, brief runs of high-frequency(180-240 Hz), 'neuromyotonia-like' discharges andfasciculation potentials do occur (Ricker et aI., 1995;Ricker, 1999). In the original DM2 family, themyotonic discharges were typically brief (0.5-2 s),rarely longer (up to 20-30 s) (Day et al., 1999). Amyopathic EMG pattern may be detectable, inparticular in the most affected muscles. Nerveconduction studies are usually normal but may beabnormal in single cases (Ricker et aI., 1995; Day etaI., 1999). Sander et al. (1997, 2000) found a normalexercise test in PROMMJDM2, which was incontrast to DMI (see above) and might be useful indifferential diagnosis.

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23.3. Myotonias with and without paralyses:sodium channel myotonias

23.3. J. Potassium-aggravated myotonias (delayedmyotonias)

For many families with dominant myotoniathought to have a subtype of Thomsen's disease, amuscle chloride channel disease, molecular geneticsrevealed mutations in SCN4A, the gene encoding thea-subunit of the adult skeletal muscle voltage-gatedNa' channel. In contrast to Thomsen's disease, thesepatients develop severe stiffness which occurs after adelay following strong exercise or oral ingestion ofpotassium (potassium-aggravated myotonias, PAM).The spectrum of the degree of myotonia is large,ranging from the mild myotonia jluctuans to the verysevere myotonia permanens.

In the mildest form, the affected individuals arenot aware of a muscle stiffness or experiencestiffness that tends to fluctuate from day to day,hence the name myotonia jluctuans (Ricker et al.,1990, 1994). Most patients do not experience muscleweakness and their muscle stiffness is not sub-stantially sensitive to cold. Although the musclestiffness is provoked by exercise this type ofmyotonia should not be confused with paradoxicalmyotonia. Within a period of exercise, the relaxationtime of the contractions is normal or - if increased -shows rather a warm-up than paradoxical myotonia.Paradoxical myotonia, if present, is restricted to theeyelid muscles. However, after rest of severalminutes, a single contraction might then producesuch a severe stiffness (delayed myotonia) that thepatient is unable to move for several hours. Thissometimes painful exercise-induced muscle cramp-ing may be induced by or associated withhyperkalemia or other depolarizing agents (Heine etal., 1993; Orrell et al., 1998). Another atypical butrelated disorder is acetazolamide-responsive myoto-nia, also known as atypical myotonia congenita(Ptacek et al., 1994). In this form, muscle pain maybe induced by exercise and the symptoms arealleviated by acetazolamide.

A further disease is characterized by severe andpersisting myotonia and is therefore called myotoniapermanens (Lerche et al., 1993). Continuous myo-tonic activity is noticeable on EMG and molecularbiology has revealed that this condition is caused bya specific mutation (GI306E) in the SCN4A geneproduct. The continuous electrical myotonia leads to


a generalized muscle hypertrophy including facemuscles. Particularly the muscles of the neck and theshoulders are markedly hypertrophied. When themyotonia is aggravated, e.g. by intake of potassium-rich food or by exercise, ventilation might beimpaired due to stiffness of the thoracic muscles.Children are particularly at risk from suffering acutehypoventilation leading to cyanosis and uncon-sciousness. This led to confusion with epilepticseizures and resulted in treatment with anticon-vulsants such as carbamazepine which proved bene-ficial because of their antimyotonic properties. Suchpatients would probably not survive without con-tinuous treatment. One of the patients wasmisdiagnosed as having the "myogenic type" ofSchwartz-Jampel syndrome (Spaans et al., 1990),until electrophysiological studies indicated thatsodium channel inactivation was impaired (Leh-mann-Hom et al., 1990) and molecular geneticsenabled the identification of SCN4A mutations(Lerche et al., 1993). A further indication of theseverity of this disease is that all patients reported todate are sporadic cases harbouring a de novomutation and have no children.

In both myotonia jluctuans and myotonia perma-nens, depolarising agents such as potassium orsuxamethonium may aggravate the myotonia but donot induce weakness. It is well recognized that thereis an increased incidence of adverse anesthesia-related events with the use of depolarising relaxantsin myotonic disorders. The incidence of such eventsseems to be highest in myotonia jluctuans families(Ricker et al., 1994; Vita et al., 1995). There seemsto be no biological reason for this and it most likelyrelates to the frequent absence of clinical myotoniain these patients making the anesthesiologists una-ware of the condition.

Electrophysiologic findings in PAMIn routine EMG examination, typical myotonic runsare observed in all muscles examined, even duringthe spells of absence of clinical myotonia. Inaddition to these short-lasting myotonic bursts whichare typical for the chloride channel myotonias, long-lasting runs of fibrillation-like activity with slow orno changes of frequency and amplitude may occur(Fig. 6). These may appear constantly in somepatients. When delayed onset myotonia is recorded,the relaxation disturbance can be fully explained byelectrical activity which is in contrast to para-

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myotonia congenita (see below). There is no altera-tion of the activity in cold environment, butmyotonic runs and fibrillation-like activity areenhanced by potassium intake in parallel with theclinical myotonia. Motor unit potentials appearednormal (Ricker et al., 1990, 1994).

23.3.2. Paramyotonia congenita: paradoxicalmyotonia and cold-induced weakness

Paramyotonic symptoms are present at birth andremain often unchanged for the entire lifetime. Thecardinal symptom of paramyotonia congenita (PC,MIM 168300) is cold-induced muscle stiffness thatincreases with continued activity ("paradoxical myo-tonia", Fig. 4). Particularly in the course of repeatedstrong contractions of the orbicularis oculi muscles,the opening of the eyelids is more and more impededuntil the eyes cannot be opened to more than a slit.In the cold (or even in a cool wind), the face mayappear mask-like, and the eyes cannot be opened forseveral seconds. Working in the cold makes thefingers so stiff that the patient becomes unable tomove them within minutes. Many patients exhibitthe lid lag phenomenon and some of them percus-sion myotonia. Muscle pain, atrophy or hypertrophyare not typical for the disease. Under warm condi-

j\J~V~~uULt~~lWLI50 N~1s

11 mV

Fig. 4. Courses of voluntary isometric muscle contrac-tions (in Newton) and the corresponding surface EMGactivity underneath (modified from Haass et al., 1981).The patients had to maximally contract their muscles forabout 3 to 5 s and then to relax the muscles. The upper twotraces show the warm-up phenomenon, the lower twotraces paradoxical myotonia.

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tions many patients have no complaints but someexperience myotonia in a warm environment whichthen mostly presents rather with a warm-up phe-nomenon.

In most families the stiffness gives way to flaccidweakness or even to paralysis on intensive exerciseand cooling. Some, but not all, families with PC alsohave attacks of generalized hyperkalemic periodicparalysis provoked by rest or ingestion of potassiumlasting for an hour or less. In contrast, the cold-induced weakness usually lasts several hours evenwhen the muscles are immediately rewarmed. Mus-cle relaxation, slightly slowed in some patients atnormal temperature, becomes normal when themuscles are warmed.

Electrophysiologic findings in PCElectrical discharges in the EMG may be absent atnormal or increased temperature, but occasionalmyotonic runs do occur. Upon cooling, a fibrillation-like spontaneous EMG activity develops consistentlywhich is maximal at a muscle temperature of about29°C. With a further drop in temperature, thisspontaneous activity decreases and almost dis-appears at 24°C when the muscle gets paralysed(Haas et aI., 1981). In another single patient,long-lasting repetitive (complex) discharges werereported at room temperature, when the patient hadno muscle stiffness, and upon cooling myotonicdischarges developed whereas the other activityceased (Weiss et aI., 1997). In patients with myoto-nia in a warm environment, there was rather awarm-up phenomenon, and clinical myotonia couldbe related to electrical activity at room temperature.However, the muscle stiffness which developed in allpatients upon cooling of the forearm in a water bathof 15°C, was not related to electrical myotonia andinterpreted as depolarization-induced contracture ofthe muscle fibers. With further cooling, most patientsdevelop a flaccid weakness accompanied by elec-trical silence. Consequently, CMAP amplitudesdecrease upon cooling corresponding to the develop-ing weakness. Motor unit potentials as well as motorand sensory nerve conduction studies are normal(Haass et aI., 1981; Lehmann-Hom et aI., 1984;Ricker et al., 1986; Streib, 1987).23.3.3. Hyperkalemic periodic paralysis: rest- andpotassium-induced paralysis

The disease was first described by Tyler et al., in1951, and Helweg-Larsen et al., in 1955, and was

466 F. LEHMAN-HORN ET AL.

force 125W

:~ I1_·.....IJ,-----.....,-:~::r-..--

."force

(N) ~300 lJ--- m. flexor dlglt~rum100 ---' _ ~ .;...__-41_~' ""\i

K+(mM)

76543

~ ...... ... ............__I _ ......,. .• ••••

~...,., ... •

1000 1400 time

Fig. 5. Serum potassium and force (in Newton) of the quadriceps muscle of a hyperkalemic periodic paralysis patientduring an attack induced by 20 min exercise of 125 W followed by rest in bed. Note the physiologic increase in serumpotassium during exercise and the pathologic second rise associated with weakness at rest. Minimal exercise of the legmuscles abolished the weakness. Adapted from Ricker et al., 1986).

extensively investigated by Gamstorp in 1956 whonamed it "adynamia episodica hereditaria." Thedisease differs from hypokalemic periodic paralysisin that it is usually associated with myotonia, at leastin the EMG, and that potassium can provoke anattack of weakness and that also a spontaneousattack is associated with an increase in serumpotassium. Intake of potassium and glucose haveopposite effects in the two disorders, while potas-sium triggers a hyperkalemic attack and glucose is aremedy, glucose provokes hypokalemic attackswhich are ameliorated by potassium intake. The termhyperkalemic periodic paralysis (HyperPP), whichstresses the potassium-related distinctions, is pre-ferred (MIM 170500). In general, HyperPP has anearlier onset and more frequent attacks, but these aremuch shorter and milder than in the hypokalemicform (Gamstorp, 1956).

The attacks usually begin in the first decade oflife. Initially, they are infrequent but then increase infrequency and severity. Potassium-rich food or apotassium load as during a provocative test, usuallyprecipitates an attack. Cold environment, emotionalstress, glucocorticoids, and pregnancy provoke orworsen the attacks. After strenuous exercise, weak-ness can follow within a few minutes of rest. A

spontaneous attack commonly starts in the morningbefore breakfast and lasts 15 minutes to an hour, andthen disappears. During the day, rest often provokesan attack. Sustained mild exercise after a period ofstrenuous exercise may postpone or prevent theweakness in the exercising muscle groups andimprove the recovery of muscle force (working off)while the resting muscles become weak (Fig. 5).

In the interictal state, the clinical myotonia isusually very mild and never impedes voluntarymovements. It is most readily observed in the facial,lingual, thenar, and finger extensor muscles. Thegeneralized weakness is usually accompanied by asignificant increase of serum potassium (up to 5 to 6mM). Sometimes the serum potassium level remainswithin the upper normal range and only seldomreaches cardiotoxic levels, although it may becomelife-threatening in very rare cases. As the serumpotassium increases, the precordial T waves in theECG increase in amplitude. When the serum potas-sium level begins to rise, the serum sodium levelfalls 3 to 9 mM. This fall is caused by sodium entryinto muscle; this, in tum, causes a shift of water intothe muscles (observed by some patients as swelling)that causes hemoconcentration and increases theserum potassium level.


Electrophysiologic findings in HyperPPEven though myotonic stiffness is often not clini-cally present, the EMG reveals myotonic activity inmost families. In addition to short-lasting myotonicbursts, long-lasting runs of fibrillation-like actionpotentials with slow changes of frequency andamplitude occur (Fig. 6) which can be provoked byexercise. The myotonia strongly supports the diag-nosis of HyperPP and usually excludes HypoPP. Atthe beginning of an attack, the bursts of fibrillationpotentials may increase and explain the sensation ofmuscle tension. In some patients paresthesia heraldsthe attack, probably induced by the hyperkalemia.During a severe attack, insertional EMG activitydisappears, voluntary effort elicits few if any motorunit potentials, and the evoked CMAP amplitude isdiminished. Interictally, motor unit potentials, motorand sensory nerve conduction studies are usuallynormal. Only in patients with a specific, frequentmutation (T704M), a chronic progressive myopathywith a myopathic pattern in the EMG may develop.In about 50% of the T704M carriers, neither clinicalnor electrical myotonia is detectable (Subramonyand Wee, 1986; Streib, 1987; Ptacek et aI., 1991;Lehmann-Horn et al., 1993).

In contrast to PC, cooling does not decreaseCMAP amplitudes in HyperPP (Subramony et aI.,1986) but may induce muscle weakness in vitro,with a different pathophysiological mechanism thanin PC, i.e. without a membrane depolarization(Lehmann-Horn et al., 1987a; Ricker et al., 1989).The exercise test is abnormal in HyperPP as inHypoPP and Andersen's syndrome (see section onHypoPP for a description of the test), as CMAPamplitudes and areas first increase during the shortperiod of exercise and then gradually decrease overa period of 20-40 min. within the post-exerciseperiod. Such a pattern is also seen in secondaryperiodic paralysis. Thus, the test is helpful toestablish the diagnosis of periodic paralysis, but doesnot distinguish between any of the different forms(McManis et aI., 1986; Subramony and Wee, 1986;Kuntzer et aI., 2000). However, also rest withoutexercise may produce weakness in HyperPP (RickerK, Camacho L, Grafe P, Lehmann-Horn F, Rudel R:Adynamia episodica hereditaria: what causes theweakness? Muscle Nerve, 10: 883-891, 1989). Ifthis is the case also in HypoPP has not been reportedup to now. In PC, the test yields a decreaseimmediately after exercise with a subsequent return

omV

-40

-80

467

M

- -'J II'"

2 sec

468

to baseline (McManis et aI., 1986; Subramony andWee, 1986; Kuntzer et al., 2000).

23.3.4. Specific provocative testing of sodiumchannel disorders

According to the description above, a provocativetest for PAM is an exercise test that measures themuscle stiffness after a forceful and long-lastingvoluntary contraction and following short contrac-tions generated by the patient in intervals of severalminutes (Ricker et aI., 1990). For the differentialdiagnosis to DMC, the increase in muscle stiffnessinduced by oral ingestion of potassium can beobserved clinically and by relaxation measurements.Potassium must not be administered to patients withmyotonia permanens because of the potential stiff-ness of ventilatory muscles.

The diagnosis of PC can be verified by thefollowing cooling tests: First, the amplitude of theevoked compound muscle action potential is reducedby cooling (Gutmann et aI., 1986; Jackson et aI.,1994). This test can be easily performed and issupposed to differentiate between PC and HyperPP(Subramony et al., 1986). For the exercise test in PCsee section above on electrophysiology of HyperPP.The second test is highly specific but demandsfacilities which may not be available everywhere:cooled paramyotonia muscles are slow to relax andgenerate decreased force on maximal voluntarycontraction (Ricker et aI., 1986). The test is per-formed by determining the isometric force andrelaxation time of the long finger flexor musclesbefore and after immersing hand and forearm in awater bath of 15°C for 30 min. In some patients, the

Fig. 6. Intracellular recordings of excised muscle fibersfrom patients with sodium channel myotonias. Upperpanel: part of a run of a PAM muscle fiber which showedstable amplitude and frequency for minutes before apotential step induced bigeminal or trigeminal activitywhich may be estimated as complex repetitive activity inan extracellular recording. Middle panel: single fiberactivity reveals doublepotentials in the biceps brachiiof apatient with myotonia permanens (de novo G1306Ecarrier) earlier described as Schwartz-Jampel syndrome(Spaans et al., 1990). Lowerpanel: a long-lasting run of aHyperPP muscle fiber is characterized by slowly pro-gressive membrane depolarization associated withdecreasingamplitude and increasing frequency.


test reduces the force of contraction by more than50% and prolongs the relaxation time from 0.5 s upto 50 s. In other patients, the abnormalities appearafter an additional maximal voluntary contractionlasting I to 2 min. The test is positive if therelaxation is markedly slowed whereby the isometricforce exerted by the finger flexors often falls to 10%or less of the pre-test value.

A provocative test for HyperPP to be bestperformed in the morning prior to carbohydrateingestion can confirm the clinical diagnosis. Thisconsists of the administration of 2 to 109 potassiumchloride in an unsweetened solution in the fastingstate. Serum potassium levels should be determinedapproximately in intervals of 20 minutes prior to andafter ingestion, the ECG monitored and an anesthe-tist available in case of a wide-spread paralysisinvolving respiratory muscles. After the ingestion,the patient should avoid all muscle activity. The testis contraindicated in subjects who are alreadyhyperkalemic and in those who do not have adequaterenal or adrenal reserve. An abnormally high serumpotassium level between attacks suggests secondaryrather than primary hyperkalemic periodic paralysis.The provocative test usually induces an attack withinthe next hour which lasts about 30 to 60 minutes,similarly to spontaneously occurring attacks ofweakness. An alternative test without potassiumingestion consists of exercise on a bicycle ergometerfor 30 minutes so that the pulse rate increases to120-160 beats/min followed by absolute rest in bed(Ricker et al., 1989). Serum potassium rises duringexercise and then declines to almost the pre-exerciselevel, as in healthy individuals. At 10-20 minutesafter the onset of rest, a second hyperkalemic periodoccurs in patients but not in normal subjects; duringthis period, the patients become paralysed. Record-ings of the evoked compound muscle actionpotential during rest and exercise are also helpful inconfirming the diagnosis of periodic paralysis (exer-cise test, see above).

23.3.5. Molecular genetics and pathogenesis ofsodium channel myotonia and paralysis

In PAM, there are 8 mutations known in 5 of the24 exons of the a-subunit of the voltage-gatedsodium channel clarifying approximately 30% of thecases (Fig. 7). The mutations are situated either arintracellularly faced positions (e.g. II 160V. Placek er


aI., 1994; V1589M, Heine et al., 1993) potentiallyinvolved in the formation of the docking site for theinactivation gate or its hinge (G1306AN/E, Lercheet aI., 1993; Mitrovic et aI., 1995) which is situatedin the vicinity of the IFM particle (Fig. 8). This mayexplain the electrophysiological finding of a com-bined pattern showing a small persistent current anda mildly to moderately slowed current decay (Fig.9A).

In PC, there are 12 known mutations in 4 of the 24exons of SCN4A accounting for approximately 50%of the patients (Fig. 7). The mutations cause aslowed current decay, a small persistent current (Fig.9B), and an acceleration of recovery from inactiva-

469

tion. The slowing is most likely caused by animpaired movement of the inactivation gate itself(i.e. the intracellular loop connecting domains IIIand IV) or by a disturbed formation of the dockingsite of the IFM inactivation particle (Fig. 8), sincethe mutations are predominantly situated either inthe inactivation gate (T1313M, McClatchey et al.,1992) or in the voltage sensor of repeat IV (R 1448HJC/SIP, Ptacek et aI., 1992; Chahine et al., 1994;Lerche et al., 1996; Bendahhou et al., 1999) which ismoving outward (Yang et al., 1996) thereby pre-sumably initiating the formation of the docking site.For one of the mutations (R 1448P), slowing of theformation of a receptor site could be demonstrated

Fig. 7. Membrane topology model of the 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 transmembranesegments each (S I-S6). The S6 transmembrane segments and the S5-S6 loops form the ion selective pore, and the 54segments contain positively charged residues conferring voltage dependence to the protein. The repeats are connected byintracellular loops; one of them, the ill-IV linker, contains the supposed inactivation particle of the channel. When insertedin the membrane, the four repeats of the protein fold to generate a central pore as schematically indicated on the right-handbottom 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-letterabbreviations were used for replaced amino acids.

470

using an inactivation gate peptide (Peter et al.,1999). Strong slowing of the current decay, which isparticularly observed for PC-causing mutations, mayexplain the paradoxical myotonia, since in this case,the abnormal, depolarising sodium inward currentflows during the action potential, i.e. with increasingexercise (Lerche et al., 1996; Mitrovic et al., 1999).

In HyperPP, there are 7 mutations known in 4 ofthe 24 exons of SCN4A causative in half of the cases(Fig. 7). The mutations are situated at severaldisseminated intracellularly faced positions (e.g.T704M, Ptacek et al., 1991; M1592V, Rojas et al.,1991) potentially involved in generating parts of the


inactivation apparatus, especially the docking sitefor the inactivation particle. Any malformation mayreduce the affinity between the "latch bar and thecatch" (Fig. 8). The mutations disturb fast and slowchannel inactivation and produce a long-lastingpersistent sodium current (Lehmann-Hom et a\.,1987a, 1991; Cannon et al., 1991; Cannon andStrittmatter, 1993; Cummins et al., 1993; Cumminsand Sigworth, 1996; Hayward et aI., 1997; Rojas etal., 1999). Whereas fast inactivation occurs withinmillis and terminates the action potential, slowinactivation acts on a time scale of seconds. Whenboth 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 similarrepeats (I to IV). The channel is shown cut and spread open between repeats I and IV to allow a view of the intracellularloop between repeats III and IV.The loop acts as the inactivation gate whose hinge GG (a pair of glycines) allows it to swingbetween two positions, i.e. the open channel state and the inactivated closed state where the inactivation particle IFM (theamino acids isoleucine, phenylalanine and methionine) binds to its acceptor. Various substitutions of one of the two glycinescause potassium-aggravated myotonia of different clinical severity (G1306A, myotonia fluctuans; G 1306V, moderatemyotonia; G1306E, myotonia permanens). The model also shows one of the four voltage sensors, IlS4, which movesoutwardly at membrane depolarization thereby opening the channel pore. Mutations in IIS4 cause HypoPP type 2.

SKELETAL MUSCLE CHANNELOPATHIES 471

Fig. 9. Two examples of faulty inactivation of mutantsodium channels of skeletal muscle associated withHyperPP (A) and PC (B). The mutant genes wereexpressed in human embryonic kidney cells and theircurrents compared to those of normal channels. A: Patch-clamp recordings reveal a persistent inward sodiumcurrent. B: Slowed inactivation is more pronounced withthe PC mutant.

A BControl Control

11HyperPP

5ms

~10ms

effect of potassium on channel gating could not beobserved (Wagner et aI., 1997). In paramoyotoniacongenita, silent contractures can occur in additionto myotonic contractions as shown by extracellularrecordings on excised muscle bundles by use ofelectrodes designed to pick up all electrical activity.Part of the slowed relaxation which followed thedirect electrical stimulation and cooling were notcaused by action potentials (Ricker et al., 1986). Themost likely explanation is a long-lasting contractureinduced by the sustained membrane depolarizationthe latter of which in tum blocks the generation ofsubsequent action potentials.

23.4. Periodic paralyses without myotonia:various cation channelopathies

mutations causing HyperPP (Cummins and Sig-worth, 1996; Hayward et aI., 1997), a particularlylong-lasting, depolarizing sodium inward current canoccur, like observed in HyperPP muscle specimens(Lehmann-Horn et aI., 1987a). This finding is mostprobably responsible for the clinical differences ofHyperPP compared to the other sodium channeldisorders, since the profound and long-lasting depo-larizations should increase the tendency to developparalytic attacks.

In vitro electrophysiology and functional expres-sion studies have shown that genetically determineddefects of sodium channels underlie the depolariza-tion. The mutant sodium channels then do not closeproperly and the resulting inward sodium current isassociated with a slowly progressive membranedepolarization which initially, i.e, as long as thedepolarization is small, further increases the mem-brane excitability (Lehmann-Horn et al., 1987b). Afurther progressing depolarization of 20-30 mVleads to complete inactivation at least of the wildtypechannel population, and renders the membraneinexcitable and the muscle paralysed (Lehmann-Hom et al., 1987a). This state is also temporary, asexcitability of the muscle fibers returns when, byaction of the sodium/potassium pump, the mem-brane resting potential slowly assumes thephysiological value of about -80 mV.The triggeringof the myotonia by e.g. potassium, as in potassium-aggravated myotonia, is explained by the physio-logical depolarization which follows an elevation ofserum potassium according to Nernst, thus unmask-ing the sodium channel inactivation defect. A direct

23.4.1. Familial hypokalemic periodic paralysis-types 1 and 2

The clinical symptoms of the disease (MIM170400) were well described in the 19th century.However, it was not until 1934 that hypokalemia wasdocumented during the paralytic attacks. Althoughfamilial hypokalemic periodic paralysis is the mostcommon of the primary periodic paralyses, itsprevalence is estimated to only 1:100,000. Thedisease is transmitted as an autosomal dominant traitwith reduced penetrance in women. The severity ofthe symptoms can vary greatly within a family.Severe cases present in early childhood, mild casesas late as the third decade of life or may gounrecognized. Initially, the attacks are infrequent,but after a few months or years, they increase infrequency and eventually may recur daily. An attackmay range in severity from slight temporary weak-ness of an isolated muscle group to generalizedparalysis. Paralytic attacks usually occur in thesecond half of the night or the early morning hoursand on awakening the patient is unable to move hisarms, legs or trunk. In most cases, the cranialmuscles are spared. Usually, strength graduallyincreases as the day passes. Occasionally, theweakness lasts for several days.

The trigger for a nocturnal attack is oftenstrenuous physical activity or a carbohydrate-richmeal on the preceding day. During the day, attackscan be provoked or worsened by high carbohydrateand high sodium intake, and by excitement. Injectionof a mixture of antiphlogistics and local anestheticscan trigger a severe attack after a few hours.

472

Exposure to cold can induce local weakness. Slightphysical activity can sometimes prevent or delaymild attacks.

During major attacks, the serum potassiumdecreases, though not always below the normalrange, and there is urinary retention of sodium,potassium, chloride and water. The serum potassiumdecrease is accompanied by a parallel decrease inserum phosphorus. Oliguria, obstipation, and dia-phoresis can occur during major attacks. Sinusbradycardia and ECG signs of hypokalemia (Uwaves) appear when the serum potassium falls belowthe normal range. Clinical or histopathologic signsof cardiomyopathy are absent.

Independently of the severity and frequency of theparalytic attacks, many patients develop a chronicprogressive myopathy which can be very severe anddisabling (Links et al., 1990). On the other hand,many patients do not recognize their permanentweakness as abnormal. This myopathy mainlyaffects the pelvic girdle and proximal and distallower limb muscles. The MRI scan shows hypodenseareas in the core of the hip extensor muscles andreplacement of muscle by fat.

Electrophysiologic findings in HypoPPEMG evidence of myotonia usually excludes thediagnosis of HypoPP. When there is no permanentweakness, the motor unit potentials are normalbetween the attacks; those with permanent weaknessshow myopathic changes and fibrillation potentialsor sometimes a peculiar, so far unexplained neuro-genic pattern. During a severe attack, insertionalactivity disappears, voluntary effort elicits few if anymotor unit potentials, and the evoked CMAP iseither abnormally small or absent. Interictally,muscle fiber conduction velocity measured withsurface or invasive EMG is abnormally low. Thismethod can also be used to detect asymptomaticcarriers. The invasive method is easier to performand more sensitive, in particular in asymptomaticcarriers. The median frequency of the power spec-trum is also reduced (Troni et aI., 1983; Zwarts et aI.,1988; Van der Hoeven et aI., 1994; Links and Vander Hoeven, 2000). In two studies with single fiberEMG, fiber densities were increased interictally forolder patients but not for those under 40 years of age.During an attack of one patient, there was a slightincrease in jitter with several blocks indicating thefailure of the muscle membrane to conduct action


potentials (De Grandis et aI., 1978; Bertorini et al.,1994).

The exercise test is performed with strong volun-tary muscle contractions for 1-5 min. interupted byshort intervals every 15-20 s to avoid ischemia, bestperformed in one of the distal hand muscles like theabductor pollicis brevis or abductor digiti minimi. Inany type of primary or secondary periodic paralysis,usually a greater than normal increase in CMAPamplitude or area during exercise is followed by aprogressive decline of approximately 50% of max-imum force over 20-40 min. after the exerciseperiod. When the mean value +2 SD of normalcontrols is taken as a cut off (corresponding to40-50% decline), the test is positive in about 80% ofperiodic paralysis patients. (McManis et aI., 1986;Streib, 1987; Kuntzer et aI., 2000). In chloridechannelopathies, paramyotonia congenita or myo-tonic dystrophy, the test may also be abnormal, butusually shows a maximal decline directly afterexercise with recovery during the exercise periodwhich is in clear contrast to the progressive declineseen in PP (McManis et aI., 1986; Streib, 1987;Sander et aI., 1997). Measurement of musclestrength or torque induced by nerve stimulation isanother option to characterize muscle function inperiodic paralysis patients (Day et aI., 2002).

23.4.1.1. Specific provocative testing forhypokalemic periodic paralysis

When the serum potassium of a patient cannot beinvestigated during a full-blown spontaneous attack,tests are required to establish the diagnosis ofperiodic paralysis and to determine its type. Becausesystemic provocative tests carry the risk of inducinga severe attack, they must be performed by anexperienced physician and a stand-by anesthetist,and the serum potassium and glucose levels and theECG closely monitored. Provocative tests withglucose with or without the additional use of insulinmust never be done in patients who are alreadyhypokalemic and potassium chloride must not begiven to patients unless they have adequate renal andadrenal function.

The simplest systemic provocative test exploitsthe physiologic potency of glucose, or of glucoseplus insulin, to cause hypokalemia. Oral administra-tion of glucose, 2 g1kg body weight, in the earlymorning combined with 10 to 20 units of crystallineinsulin, given subcutaneously, may provoke a para-

SKELETAL MUSCLECHANNELOPATHlES 473

Fig. 10. Subunits of the voltage-gated calcium channel. The a l subunit resembles a of the sodium channel however thefunction 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)havebeen described for man (HypoPP, MHS5) and mice (mdg). Conventional I-letter abbreviations are used for the replacedamino acids.The symbols indicate the diseases as explained at the bottomof the left-hand side.

lytic attack within 2 to 3 hours. Exercise and intakeof carbohydrates the evening before, increase thepotency of the test. If the test is equivocal,intravenous administration of 1.5 to 3 g glucose perkg body weight over 60 minutes may provoke anattack. In cases that are difficult to diagnose,intravenous insulin in doses not exceeding 0.1 U/kgat 30 and 60 minutes during the glucose infusionmay precipitate an attack. Another form of the testuses prolonged glucose loading, 50 g glucose in 150ml water administered hourly for up to 15 hours.Paresis normally appears within 7 to 15 hours andparalysis within 12 to 16 hours. If these tests fail toinduce an attack, they may be repeated after exerciseand combined with salt loading (sodium chloride,2 g orally, every hour, for a total of four doses). Ingeneral, a serum potassium level of 3.0 mM or lessshould be achieved. The test is positive whenweakness ensues. CMAPs should be measured aswell to confirm the weakness by an objective

method. A negative test does not exclude thediagnosis of primary HypoPP because at timespatients may be refractory.

As in HyperPP, the exercise test, which deter-mines the amplitude of the compound actionpotential, or torque measurement may be used (seeabove). A positive test result confirms the diagnosisof a periodic paralysis and - in combination with aprovocative factor - its type.

23.4.1.2. Molecular pathogenesis ofhypokalemicperiodic paralysis

Differentiating this disorder from HyperPP is ofprognostic and therapeutic relevance. In 60% of thepatients with a positive family history, one of thethree known missense mutations in the CACNAISgene, which encodes the L-type calcium channel ofskeletal muscle, can be identified (Fig. 10) (Jurkat-Rott et aI., 1994). In about 20% of pedigrees, one ofthe four known SCN4A mutations can be detected


agents such as insulin and glucose, but do notexplain the development of the depolarization itself.

Fig. II. Intracellular recordings of action potentials froma muscle fiber segment of a hypokalemic periodicparalysis patient(HypoPP) compared to thoseof a healthycontrol (WT). The action potentials were elicited fromvarious holding potentials by a short depolarizing pulse.Note their slower rise and faIl and their smaller size forHypoPP.

2ms

HypoPPWT

oCii~ -20.$!8. -40c::~ -60.0E -80Q)

~ -100

:> 20

.s

23.4.2. Andersen's syndrome - dyskalemic periodicparalysis with arrhythmia and dysmorphia

Andersen's syndrome (not to be confused withAndersen disease, type IV glycogen storage disease)is defined as a clinical triad consisting of dyskalemicperiodic paralysis, ventricular ectopy, and dys-morphic features (Tawil et al., 1994; Sansone et aI.,1997). The dysmorphic features may be variable andinclude small stature, low-set ears, hypoplasticmandible, clinodactyly, and scoliosis. Cardiac distur-bances may also show a variety of phenotypes suchas prolongation of the QT interval, ventricularbigeminy, and short runs of bidirectional ventriculartachycardia. Sudden deaths in this syndrome proba-bly due to cardiac arrest have been reported.Similarly to HypoPP, myotonia is not a feature ofthis syndrome. In contrast to HyperPP and HypoPPpatients, the response to oral potassium is unpredict-able: it improves weakness in patients with lowserum potassium, in some families however, itimproves arrhythmia but exacerbates episodic paral-ysis. During an attack, serum potassium may behigh, low, or normal.

Several mutations in a voltage insensitive asubunit of a potassium channel expressed in bothskeletal and cardiac muscle have been described(Plaster et al., 2001) (Fig. 12). These channels areprotein tetramers each consisting of only two

(Fig. 7) (Jurkat-Rott et aI., 2000b; Sternberg et al.,2001). In both the calcium and the sodium channel,the mutations are located solely in the voltagesensing S4 segments of either domain 2 or domains2 and 4 respectively (Fig. 8). (An additional basechange has been reported for two families in a genewhich codes for the accessory a subunit of thekv3.4/MiRP2 channel complex. Because of thegenetic heterogeneity, testing of additional familymembers for linkage to the known loci is recom-mended in case of negative results.)

The mutations causing the more frequent calciumchannel variant, HypoPP type I, show similarfunctional consequences though their significance isunclear: a reduction of current amplitudes, slightlowering of the voltage threshold for inactivation andslowing of the rate of activation (Lapie et aI., 1996;Jurkat-Rott et aI., 1998; Morrill and Cannon, 1999).Since electrical muscle activity, evoked by nervestimulation, is reduced or even absent during attacks,a failure of excitation is more likely than a failure ofexcitation-contraction coupling. Nevertheless, thehypokalemia-induced, large membrane depolariza-tion observed in excised muscle fibers (Rudel et al.,1984; Ruff, 1999) might also reduce calcium releaseby inactivating sarcolemmal and t-tubular sodiumchannels, and would explain why repolarization ofthe membrane by activation of ATP-sensitive potas-sium channels restores force.

Whereas in HyperPP the inactivated state of thesodium channel is destabilized, it is stabilized in thesodium channel variant of HypoPP type 2. Func-tional expression of the mutants revealed reducedcurrent amplitudes, hyperpolarizing shifts of volt-age-dependent fast and - for some mutations - slowinactivation, and a slowed recovery from the fast-inactivated state (Jurkat-Rott et aI., 2000b; Struyk etaI., 2000; Bendahhou et aI., 2001; Kuzmenkin et al.,2002). All changes enhance channel inactivation(Fig. 8) and lead to a reduced number of sodiumchannels available for the generation and propaga-tion of action potentials, i.e. the excitability of themyofibers is generally reduced (Fig. II). In agree-ment with these findings, smaller and more slowlyconducted action potentials were recorded in myo-fibers biopsied from patients carrying a sodiumchannel mutation (Jurkat-Rott et aI., 2000b). Theseabnormal channel properties reduce the availabilityof sodium channels when HypoPP fibers are alreadydepolarized, i.e. following infusion of triggering


membrane spanning segments (Ml and M2) and aninterlinker forming the ion conducting pore. Theyfunction as inward going rectifiers, i.e. they aredecisive for maintaining the resting potential (rectifi-cation) by conducting potassium ions into the cell(inward going) which enlarges the concentrationgradient to the extracellular space and hyper-polarizes the cell. The mutations causing Andersensyndrome reduce this potassium current and amutant monomer is capable of exerting a dominantnegative effect on a whole tetramer corresponding tothe dominant mode of transmission of the disorder(Plaster et al., 2001).

Electrophysiological findings in Andersen's syn-drome Standard needle electromyography is usu-ally normal and does not show myotonic discharges(Sansone et al., 1997). The exercise test shows

475

similar results as seen in HypoPP (Katz et al.,1999).

23.5. Malignant hyperthermia

23.5.1. Clinical features and pathogenesis ofmalignant hyperthermia

Susceptibility to malignant hyperthermia (MH)susceptibility is an autosomal dominantly trans-mitted predisposition of clinically inconspicuousindividuals to respond with uncontrollable skeletalmuscle hypermetabolism upon exposure to volatileanesthetics or depolarizing muscle relaxants(Denborough and Lovell, 1960). The triggeringsubstances lead to an increase in the concentration offree myoplasmic calcium which is released from thesarcoplasmic reticulum calcium stores via the mus-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 skeletalmuscle. Mutations in the coding KCNJ2 gene which cause the Andersen's syndrome.

476

During an MH reaction, a massive myoplasmiccalcium release is induced, leading to musclecontracture especially of the masseter, generalizedrigidity, and heat production. Hypermetabolismassociated with the sarcoplasmic calcium elevationupregulates glycogenolysis resulting in excess lac-tate production, metabolic acidosis, and hyper-activation of the oxidative cycle with increased ATPdepletion, high oxygen consumption and carbondioxide production with hypoxemia and hyper-capnia. Tachycardia may be observed as an earlysign. During the course of the crisis, rhabdomyolysisoccurs with subsequent creatine kinase elevation,hyperkalemia potentially leading to ventricular fib-rillation, and myoglobinuria with the possibility ofrenal failure. Hyperthermia may be a late sign insome cases. If an episode is survived, normalizationof edematous muscle and creatine kinase levelsoccur within 10-15 days. As so-called awakeepisodes following heavy exercise have beenreported, carriers of the trait are unsuited for militaryservice. For diagnosis of MH susceptibility, a func-tional test on skeletal muscle biopsy, the in vitrocontracture test (lVCT), can be performed whichreveals high concordance with the genetic phenotype(Brandt et al., 1999).

In the majority of families, linkage to the geneencoding the skeletal muscle ryanodine receptor,RyRl, a calcium channel which under the control ofthe voltage-dependent dihydropyridine-sensitive L-type calcium channel of skeletal muscle, can befound (MacLennan et al., 1990; McCarthy et al.,1990). To date, more than 20 disease-causing pointmutations in RyRI have been identified in man, mostsituated in the cytoplasmic part, the foot, of theprotein (Fig. 13) (for review see Jurkat-Rott et al.,2000a). The base of the homotetrameric protein, islocated in the membrane of the sarcoplasmic retic-ulum, and forms the ion-conducting pore. Func-tionally, hypersensitivity of RyRI to anesthetictriggering agents has been shown to be pathogenet-ically causative in functional tests of both muscle,isolated native proteins, and heterologouslyexpressed full-length receptors (Censier et al., 1998).Therapeutically, during an anesthetic crisis, dan-trolene, an RyRI inhibitior, is very effectivereducing the mortality rate from former 70% tocurrently 10%.

MH could be very highly heterogeneous with 5additional chromosomal loci mapped until now.

F. LEHMAN-HORN ETAL.

o malignant hyperthermia (MH)D malignant hyperthermia/central cores(MHlCC)

central core disease (CCO)o central coredl8ealle with nemaline rods (CCDln.rods)

- dol«lon • ClCR·Tost 'Canlno MH

Fig. 13. Cartoon of the homotetrameric ryanodine recep-tor, the calcium release channel situated in the membraneof the sarcoplasmic reticulum (SR). The cytosolic part ofthe protein complex, the so-called foot, bridges the gapbetween the transverse tubular system and the SR.Mutations have been described for the skeletal muscleryanodine receptor (RyRl), which cause susceptibility tomalignant hyperthermia (MHS) and central core disease(CCD).

However only for one (MH susceptibility type 5) ofthese loci, a causative gene has been identified,CACNAIS, so that this very rare type of MH isallelic to hypokalemic periodic paralysis type I(HypoPP-l). In contrast to the voltage sensormutations specific for HypoPP-l (and HypoPP-2),the two mutations so far described for MH aresituated in the myoplasmic loop connecting repeatsIII and IV the function of which is unknown (Fig.10). The two mutations underline the functional linkbetween RyRI and the DHPR in excitation-contrac-tion coupling (Monnier et al., 1997; Lehmann-Hornand Jurkat-Rott, 1999).

SKELETAL MUSCLECHANNELOPATHlES

23.5.2. Functional neurophysiology and in vitrotesting ofmalignant hyperthermia susceptibility

Susceptibility to MH itself is not associated with aprimary structural myopathy or electromyographicor contractile alterations. Due also to lack of clinicalsymptoms under normal conditions, an MH in vitrocontracture test (IVCT) for biopsied muscle bundleswas developed by the European (EMHG) and NorthAmerican (NAMHG) malignant hyperthermiagroups (European Malignant Hyperprexia Group,1984; Larach, 1989). This test requires a large freshmuscle biopsy and is therefore invasive in nature andnot easily performed on children. It is based on thetendency of MH muscle to be abnormally sensitiveto stimuli that induce SR calcium release. Theunderlying procedure in both EMHG and NAMHGtest protocols is the measurement of contracturesupon flooding or gradually increasing concentrationsof halothane and separately of caffeine (Fig. 14). Apositive reaction to a triggering agent is dependenton contracture force at concentrations belowpredefined thresholds for each substance. Threecategories result by each test according to theEuropean protocol, contracture under or at thethresholds of both substances is considered to beMH-susceptible (MHS), one pathologic and onenormal result is classified as equivocal (MHE), andtwo normal reactions to both agents means notsusceptible (MHN). In general, correlation betweenthe results of these two tests is quite good and thetest shows a high sensitivity (true positives, 99% forEMHG and 92-97% for NAMHG) and specificity(true negatives, 93.6% for EMHG and 53-78% forNAMHG.

In contrast to the IVCT test protocols primarilyaimed at determining the clinical risk of anesthesia-related events, diagnostic testing in Japan isperformed by a functional test based on the quantifi-cation of calcium-induced calcium release (CICR) insaponized muscle fibers (Kawana et al., 1992). Theprecision of this method and correlation to the otherprotocols is unknown.

Clinical electrophysiologyStandard electrophysiology in MH is normal. Fol-lowing injections of caffeine, succinylcholine orhalothane locally in the muscle revealed a decreaseof the CMAP amplitude which correlated to in vitrotesting in 9 MH patients (Eng et al., 1984). Adetailed EMG study in MH suceptible pigs revealed

477

no spontaneous activity but an increased duration ofmotor unit potentials (Steiss et aI., 1981).

23.5.3. Central core disease: myopathy withmalignant hyperthermia susceptibility

Central core disease (CCD) is a congenitalmyopathy often associated with skeletal anomalies(Shy and Magee, 1956). Pathognomonic is theabundance of central cores along type 1 musclefibers. CCD is often associated with MH susceptibil-ity (Shuaib et al., 1987), and allelic to the RyRI genelocus of MH (Haan et aI., 1990; Kausch et aI., 1991).The myopathy is characterized by congenital musclehypotonia (floppy infant syndrome), proximallypronounced weakness, delayed motor development,and slight CK elevation. In addition skeletalanomalies such as congenital hip displacement andskoliosis are frequent. Later in life, muscle strength

r 50 1hresholdat 2%-.

~, rj I -----~halothane

i I

~4%

10

I2%0%

0 20 40 60 80 100 120 140time [min]

f ttresholdat 1.5nft1-.

CIl100 lJ caffeine

I /32 JrIJI4J1'tl12 J1'tl1oJ1'tl110

0 20 40 60 80 100time [rrin]

Fig. 14. In vitro contracture test in muscle bundles of amalignant hyperthermia susceptible patient according tothe European protocol. Upper panel: halothane, Lowerpanel: caffeine in increasing concentrations. After initialprestretching (peak in the curve), note the development ofpathologic contractures C~ 200 mN) at 2 vol.% halothaneand 1.5 mM caffeine.


IMyotonias and periodic paralyses (PP) IMyotonic bursts?

eCTG eTG

myotonic dystrophy

chloride channelmyotonia

'\es

K' or cold sensitivity?

non-dystrophic myotonia orPP with myotonia

dystrophic or non-dystrophic myotonia or PP wIth myotonia

multsystemic myotonia or repeat expansion?

i \"'

sodium channelyes myotonia

K' indUC;!d cJld~'induced 7weakness induce~ myotonia dominant

myotoniaI

IHyperPP I [E] 1PAM 1 IDMCI

_--'--,1 \-'---_Ifluctuans I IpermanensI[TPP I IHypoPP I

/ \Itype 1I Itype 21

IPP wIthout myotonia Iinterictal arrhythmia or dysmorphia?

multisyslemic pp Ipure PP Ihyperthyroidism? induced by carbohydrates

or associated wllh hypokalemia?

Fig. 15. Flow diagram I. Differential diagnostic scheme of myotonias and periodic paralyses.

usually improves except for rare cases showingprogressive muscle weakness. It is one of the rareknown myopathies for which strong physical exer-cise seems to be beneficial (Hagberg et al., 1980)although exercise-induced muscle cramps are oftenreported. Autosomal dominant inheritance is highlypredominant and although several sporadic caseshave been reported, a clear recessive trait has not yetbeen demonstrated. The clinical expression of thedisease is highly variable. Not all mutation carriersin a family may develop this myopathy but insteadmay only have the MH trait (Islander et aI., 1995).

Except for one mutation, all situated in the C-terminus of the RyRI protein thought to form thechannel pore region (Fig. 13). Expression of thesemutations in non-muscle cells led to the finding of aleaky calcium release channel compatible with theview of a myoplasrnic calcium overload responsiblefor the mitochondrial and cell damage (Lynch et aI.,1999; Tilgen et aI., 2001). Recently a selectivedisruption of the orthograde excitation-contraction

coupling process has been found in a skeletal muscleexpression system suggesting a dominant negativeeffect of the CCD mutations on the voltage-controlled caIcium release (Avila et al., 2001). Thisfunctional disruption may contribute to the muscleweakness and atrophy in the patients.

Electromyography in CCDMotor and sensory conduction velocities are alwaysnormal. A myopathic pattern of spontaneous EMGactivity and motor unit potentials is typically foundin CCD (Fardeau M, Tome FMS. Congenital myo-pathies. In: Myology, Ed. Engel AG, Franzini-Armstrong C, McGraw Hill 1994, pp 1487-1532).Single fiber EMG revealed an increase in fiberdensity and a normal jitter (Cruz Martinez et al.,1979).

Acknowledgements

We thank U. Richter for drawing the cartoons.This work was supported by the German Research


Foundation (DFG, JU470/l) and the network onExcitation-contraction coupling and calcium signal-ing in health and disease of the IHP Program fundedby the European Community.

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chapter 23 skeletal muscle channelopathies: … levior. as the inheritance and the molec-ular...

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