Keywords
Muscle channelopathies, chloride and sodium channel myotonias, hyperkalemic, normokalemic and hypokalemic periodic paralysis, Schwartz-Jampel syndrome, epilepsy, episodic ataxia
Introduction
Defective ion channels may play a causal role in disease pathogenesis. This implication was first concluded from the observation of an abnormal ion conductance in muscle fibers biopsied from myotonic goats. In humans, a similar conclusion was reached for patients with paramyotonia congenita (PC) and with periodic paralyses. The term “ion channelopathies” was then coined in the 1990s, and defined for disorders that are caused by malfunction or altered regulation of ion channel proteins. Channelopathies, therefore, can be either hereditary or acquired (the latter usually caused by auto-antibodies).
Hereditary channelopathies can be categorized in those affecting the motor endplate (congenital myasthenic syndromes), the sarcolemma (myotonias and periodic paralyses), and excitation-contraction coupling (malignant hyperthermia, central core myopathy, and multiminicore myopathy). The channel defects result in changes of excitability that one would expect to be constantly present. Fortunately, this is not the case. Clinical symptoms mainly appear episodically, provoked by an out-of-the-normal situation, a so-called trigger. Compensatory mechanisms such as the normalization of the serum potassium level often allow an episode to cross over to complete remission. In addition to the episodes, progressive manifestations with muscular degeneration are present in a substantial percentage of patients.
As many disease mechanisms have been elucidated by functional characterization on the molecular level, the channelopathies are regarded as model disorders. Molecular genetics identify the underlying mutations and thus often enable one to predict the course of the diseases and to assign an individual therapy for the patient. They also allow one to calculate the patient’s risk of having affected offspring.
Electrophysiology of Clinical Weakness and Paralysis
The excitability of a muscle fiber, and thus its ability to generate force and contraction, depends on a high resting potential across its sarcolemma (−80 mV inside with respect to outside). Such fibers are assuming the P1 state in the nomenclature of Jurkat-Rott et al., and they make up the majority of the fibers in a healthy muscle. Owing to the complicated voltage dependence of the membrane conductance on the membrane potential, muscle fibers can also assume a low stable resting potential of about −60 mV. Such “depolarized” fibers are said to be in the P2 state. Their major functional difference is that they cannot be excited and, therefore, are “paralyzed.” In a healthy muscle, fibers in the P2 state make up only a small minority. Mutations in the genes encoding the various ion channels responsible for the membrane potential may influence the electrical stability so that fibers can shift from the P1 state to the P2 state, for short time intervals but also for very long durations. The number of excitable fibers is then very much reduced.
Myotonias
Clinical Presentation of Cl − Channel Myotonias Becker and Thomsen
The major symptom of the myotonias is a generalized muscle stiffness that appears particularly following strong and/or sudden muscle contractions (e.g. when a patient gets scared). The stiffness is caused by a series of involuntary action potentials that can occur in practically all skeletal muscle fibers. The muscles are often hypertrophic, in contrast to what is seen in most other muscle diseases. The involuntary action potentials are caused by one (or two in the case of recessive Becker myotonia) of a great number of mutations in genes encoding muscular ion channels, which all result in increased excitability of the sarcolemma. Depending on the type of channels affected, chloride and sodium channel myotonias are distinguished.
There are two forms of chloride channel myotonia , the rare dominant Thomsen myotonia and the more common recessive Becker myotonia . Both forms are characterized by generalized myotonia and the so-called warm-up phenomenon, a reduction of myotonia in the course of repeated contractions. A typical feature of myotonia would be the inability of let-go after a hearty handshake ( Figure 38.1 ). Such myotonia during closure of the fist is most pronounced when the muscles have remained relaxed for at least 10 minutes. Another typical sign is the “lid-lag” phenomenon, where after a brief look upward, upon a brisk look downward the eyelids do not immediately follow the eyeballs due to muscle stiffness. Gentle tapping on a relaxed muscle may elicit a “myotonic reaction,” a local muscle contraction called “percussion myotonia.” A distinct myotonia may be followed by a “transient weakness” of the same muscle. This weakness hampers the patient more than the stiffness. Hypertrophy is more pronounced with the Becker form than with the Thomsen, whereby the glutei, thighs, and calves are most affected ( Figure 38.2 ). Paradoxically, the power produced by these muscles is less than expected. In severe cases, the hyperactivity will result in shortened muscles leading to pes equinus with consequent lordosis and in reduced extension of the elbow and wrist joints. Males are usually more affected than females. Females often develop myotonic symptoms only when hypothyroid or pregnant. In Becker myotonia, myotonic stiffness is usually first detected within the rather long time span between first school enrollment and the third decade of life. During adulthood, the severity of myotonia remains constant; life expectancy is normal. Becker patients have reduced manual skills, which should be given consideration when occupational choices are made.
Clinical Presentation of Na + Channel Myotonias Fluctuans and Permanens
Sodium channel myotonia is also called potassium-sensitive myotonia because the myotonic stiffness is increased after oral intake of potassium (e.g. 1 h after 1–2 potassium tablets). Depending on the mutation, the symptoms may occur in a wide range of severity. The most benign form is called myotonia fluctuans , and the most severe form myotonia permanens . With myotonia fluctuans, work-induced stiffness does occur, but usually with a delay of about an hour. It then lasts for about 1 to 2 hours. The typical warm-up phenomenon is often masked by this delay but may be observed with repeated contractions and relaxations of the extremities. Patients with myotonia permanens may be rendered more or less immobile by the continual activity in many of their muscles. Diagnostic tests administering oral potassium should not be performed in these patients because of the danger that stiff respiratory muscles may lead to respiratory insufficiency. Patients with sodium channel myotonia tend to suffer from cramping when their muscles are being stressed.
For a clinical discrimination between chloride and sodium channel myotonia, one may use the fact that chloride channel myotonia shows warm-up of the eyelid muscles, whereas sodium channel mutations cause paradoxical eyelid myotonia. Further specification is possible by investigating the reactions to cold and potassium. For instance, after cooling of an eye with an ice bag for 10 minutes, a forceful closure of the eye may lead to the inability to open for many seconds. Creatine kinase (CK) values of five times normal may be observed in sodium channel myotonia, whereas in chloride channel myotonia they are at the most a little increased. Some patients, in particular those with sodium-channel myotonia, suffer from muscle pain that increases with the amount of muscle work. Myotonia patients deserve special attention before and during narcosis. In particular, if the myotonia is not readily recognizable as in hyperkalemic periodic paralysis and myotonia fluctuans, the use of potassium and other depolarizing agents such as suxamethonium and cholinesterase inhibitors can provoke the myotonic reaction and thus compromise intubation and respiration. This can induce life-threatening incidents.
Myotonias: Diagnostic Approach
Typical signs of all types of myotonia are bursts of discharges in the EMG that are elicited by the movement of the needle or by tapping on the muscle ( Figure 38.3 ). In addition, sodium channel myotonias show long-lasting series of fibrillation potentials. As with myasthenia gravis at 3 Hz, repetitive nerve stimulation at 10 Hz yields a decrement in chloride channel myotonia. In contrast to myasthenia, however, the decrement begins later, is more pronounced, is not antagonized by Tensilon, and runs parallel with the described transient weakness, i.e. the amplitude recovers with continuing stimulation. No decrement is found in sodium channel myotonia.
The most severe type of sodium channel myotonia is characterized by persistent and severe myotonia, and is therefore called myotonia permanens. Molecular biology has revealed that this condition is caused by specific mutations ( Figure 38.4 ) in the SCN4A gene product, Na v 1.4. The continuous electrical myotonia leads to a generalized muscle hypertrophy that also involves muscles of the face, neck, and shoulders. If the myotonia is aggravated by intake of potassium-rich food or by exercise, ventilation can be impaired by laryngospasm and stiffness of the thoracic muscles. Children are particularly at risk of suffering acute hypoventilation leading to cyanosis and unconsciousness ( Figure 38.5 ). This has led to confusion with epileptic seizures and resulted in treatment with anticonvulsants. As most anticonvulsants block sodium channels, such therapy is effective although the diagnosis is wrong. Severely affected patients would probably not survive without continuous treatment. One patient was misdiagnosed as having the “myogenic type” of Schwartz-Jampel syndrome. Electrophysiological studies revealed impaired sodium channel inactivation. Finally, molecular genetics showed an SCN4A mutation. A further indication of the severity of myotonia permanens is that all patients except one have been sporadic. Due to the severity of the disease, ingestion of potassium or exposure to cold may cause further worsening and should be avoided.
Myotonias: Differential Diagnoses
In childhood, recessive or sporadic myotonia may resemble Schwartz-Jampel syndrome (SJS), a rare autosomal recessive disorder characterized by permanent myotonia, myopia, and osteochondrodysplasia including reduced stature, kyphoscoliosis, bending of the diaphyses, and irregular epiphyses. SJS has also been referred to as chondrodystrophic myotonia due to the presence of myotonia, particularly in the face and thighs. Facial characteristics include blepharospasm, myokymic twitching at the chin, and puckered lips ( Figure 38.6 ). Warm-up, the typical phenomenon of chloride channel myotonia, is minimal or lacking. The thigh muscles are often hypertrophic, but the shoulder girdle muscles may be atrophic. Joint contractures, thoracic deformities, and other skeletal abnormalities such as platyspondylosis can be present. Most patients are small in stature due to slow postnatal growth. Frequent additional symptoms are myopia, cataract, strabismus, and nystagmus. Other findings can consist of low-set ears, receding chin, laryngeal stridor, high-pitched and forced voice, and high-arched palate. Most reports describe patients under 10 years of age. Little information is available about the prognosis, but few reports of older children suggest a nonprogressive or stationary course. The EMG shows persistent spontaneous activity, particularly in the face and thigh muscles, described as pseudomyotonic or as complex repetitive discharges. This activity is diminished by curare.
SJS is caused by missense and splice-site mutations in HSPG2 at 1p34–p36, the gene encoding perlecan. Perlecan co-assembles with dystroglycan, and this complex serves as a cell surface receptor for acetylcholine esterase at the neuromuscular junction. The structural importance of perlecan for cartilage and bone development can be attributed in part to the binding partners of perlecan: (1) structural proteins (i.e. collagen type IV, laminins, etc.) protecting the cartilage extracellular matrix, and (2) growth factors such as FGF-7 or FGF-BP influencing chondrocyte activity. EMG on a genetic mouse model confirmed the peripheral nerve as the origin of the spontaneous activity. Perlecan deficiency can be confirmed in skin and muscle samples immunocytochemically.
In adults, when diagnosing myotonia patients one should always think of the myotonic dystrophies (DM), in particular if they have cataracts as in DM1 or atypical breast pain as in DM2.
Myotonias: Therapeutic Interventions
Systematic studies for the therapy of the myotonias do not exist and, therefore, recommendations are not supported by evidence-based data. In cases of benign myotonia no medication is required because patients learn to handle their disorder. Patients with sodium channel myotonia should avoid strenuous ventures such as hiking in the mountains. In cases of severe myotonia where medication seems appropriate, as in myotonia permanens or in cases of Becker myotonia, antiarrhythmic drugs have the best effect. By virtue of their “use-dependent” action, they block in essence the pathologic after-activity without affecting the excitability per se . Their therapeutic window is narrow, however. They do not affect the chloride channels but do improve chloride channel myotonia, although not as effectively as with sodium channel myotonia. For a long time the Ib-antiarrhythmic drug mexiletine was the drug of choice, but recently it has been taken off the market (with the exception of Japan and the United States) because of low cost-effectiveness. As alternatives, the Ic-antiarrhythmic drugs flecainide and propafenone are available. Electro- and echocardiogram should be recorded before administration to avoid a heart bundle block. During use of one of the above antiarrhythmics, patients with heart insufficiency or arrhythmias should have no prolongation of the QRS-complex by more than 20% and the QT time should be no longer than 500 ms. The absolute QTc time should remain stable. Regular cardiologic controls are recommended with all patients. The control of serum potassium values and the monitoring of potential cardiac or central nervous side effects, as well as the avoidance of dehydration, will permit a lifelong treatment, even with beginning in childhood. In the case of cardiac disturbances, one may sidestep to the well-compatible antiepileptic drug lamotrigine. Its most frequent adverse effects are of neurosensory type (diplopia, dizziness) and sometimes exacerbation of epilepsy attacks. Severe cutaneous symptoms were exceptionally observed. Carbamazepine and phenytoin should not be used because of their low antimyotonic action.
Myotonias: Pathophysiology
The mutations responsible for the myotonias are located in the genes CLCN1 and SCN4A , encoding the muscular chloride and sodium channels, respectively. In both forms of chloride channel myotonia, Becker and Thomsen, the mutations lead to decreased activity of the chloride channels in the sarcolemma, which reduces the chloride conductance of the latter. Physiologically the chloride conductance of a muscle fiber comes up to 80% of the total membrane conductance at rest. This resting conductance is passive (“ohmic”), and its rather high value is very important for a stabilization of the muscle fiber’s resting potential of the P1 state close to −80 mV. When the chloride conductance is lower than 30% of the total membrane conductance, the muscle fibers still stay favorably in the P1 state at rest, but they become hyperexcitable. Clinically, this results in myotonia. During the state of transient weakness, an increased number of muscle fibers are believed to stay in the P2 state at the end of a myotonic series of action potentials.
Mutations of the muscle chloride channel gene with dominant and recessive mode of inheritance are responsible for Becker and Thomsen type myotonia, respectively ( Figure 38.7 ). Functionally, the approximately 10 dominant mutations exert a dominant-negative effect on the homodimeric channel complex as shown by co-expression studies, meaning that mutant/mutant and mutant/wild-type complexes are malfunctional. The most common feature of the resulting chloride currents is a shift of the activation threshold towards less negative membrane potentials almost out of the physiological range. As a consequence of this, the chloride conductance is drastically reduced in the vicinity of the resting membrane potential ( Figure 38.8 ). Interestingly, both testosterone and progesterone rapidly and reversibly exert a similar effect on chloride conductance. The approximately 100 recessive mutations do not functionally hinder the associated subunit. This explains why two mutant alleles are required to reduce chloride conductance sufficiently for myotonia to develop clinically in Becker myotonia. Heterozygous carriers of a recessive mutation are healthy but may exhibit some myotonic runs in the EMG.
Dominant mutations in the gene encoding the muscular voltage-dependent sodium channel Na v 1.4 are responsible for sodium-channel myotonia ( Figure 38.4 ). The electrophysiologic findings consist of a small persistent current and a mildly slowed current decay ( Figure 38.9 ). The fast inactivation is always accompanied by accelerated recovery from the inactivated state, which reduces the refractory time of the channels and contributes to the generation of repetitive action potentials. This pattern may be explained by a destabilization of the inactivated channel state. That is, the channel does not “like” to enter this state and tries to “escape” (e.g. due to a reduced binding affinity between the “latch bar and the catch”). In agreement with the phenotypic severity of three mutations at the same site, the electrophysiological alterations are minor for G1306A (myotonia fluctuans), moderate for G1306V (intermediate myotonia), and most pronounced for G1306E (myotonia permanens). As the persistent sodium current and the associated membrane depolarization are small, the main clinical feature is myotonia while weakness does not occur. In addition to dominant missense mutations, aberrant splicing has been reported to cause sodium-channel myotonia.
Myotonias: Molecular Genetics
The prevalence of Thomsen myotonia is now estimated at approximately 1:400,000, i.e. much lower than the 1:23,000 of the premolecular era. This is owing to the fact that about 20% of families with “Thomsen” myotonia are now identified as having sodium-channel mutations that result in a different disease with very similar symptomatology. Other “Thomsen” families were found to have Becker myotonia with pseudodominant inheritance. In contrast to the decreased prevalence of Thomsen myotonia, the prevalence of Becker myotonia is now thought to be 1:24,000, much higher than Becker’s original estimate of 1:50,000, suggesting a prevalence of 1:78 for the occurrence of a single recessive CLCN1 mutation. This high prevalence explains the high probability of pseudodominant chloride channel myotonia. Another surprise was the observation that most myotonia permanens patients harbor a de novo Na v 1.4 mutation. The fact that the parents are not affected can lead to the clinical diagnosis of Becker myotonia.
Paramyotonia
Clinical Presentation
Paramyotonia is a sodium channel myotonia that, depending on the specific mutation, may or may not also show characteristics of hyperkalemic periodic paralysis. Typically, the myotonic stiffness is negligible in warm muscles, but may assume very cumbersome degrees during exposure of the muscles to cold. A slight cold draft may suffice to “freeze” the musculature ( Figure 38.10 ). The warm-up phenomenon might be present in some muscles; however, repeated contractions usually rather increase the muscle stiffness (“paradoxical myotonia”). With extended duration of cooling, the stiffness tends to give way to weakness, which can then last for hours, even after warming the muscles. The mentioned periods of generalized paralysis experienced by patients with certain mutations may occur at rest and in a warm environment.
Paramyotonia: Diagnostic Approach
In patients without myotonia in a warm environment, electrical discharges in the EMG may be absent at normal or increased temperature, but occasional myotonic runs do occur. In patients with myotonia in a warm environment, there are myotonic bursts and myotonic after-activity reveals a warm-up phenomenon. Upon cooling, a fibrillation-like spontaneous EMG activity develops consistently that is maximal at a muscle temperature of about 29°C. This spontaneous activity decreases with a further drop in temperature, and voluntary activity almost disappears at 24°C when the muscle becomes paralyzed. Consequently, CMAP amplitudes in paramyotonia patients decrease upon cooling corresponding to the developing weakness.
Paramyotonia: Differential Diagnoses
Brody disease is a rare inherited myopathy due to reduced SERCA1 Ca-ATPase activity caused by recessive ATP2A1 mutations. The reduced calcium reuptake into the sarcoplasmic reticulum causes delayed muscle relaxation and silent contractures. The disease has mostly been diagnosed by measurement of SERCA1 activity. Since mutation analysis became available in 1996, it has appeared that not all patients with reduced SERCA1 activity indeed have ATP2A1 mutations, and a distinction between Brody disease (with ATP2A1 mutations) and Brody syndrome (without ATP2A1 mutations) was proposed in 2012.
Paramyotonia: Therapeutic Interventions
With paramyotonia patients, a short-term therapy (e.g. for 2 to 3 days before exposure to cold) is preferable to a long-term treatment. The same is true for sodium channel myotonia and extreme bodily stress. Patients with hyperkalemic periodic paralysis should avoid strong bodily stress and should have frequent and smaller meals. They should also avoid potassium-rich food (dried fruit, bananas, apricots, cauliflower, leguminous plants, etc.). For prophylaxis, medication with thiazide diuretics or carbonic anhydrase inhibitors is recommended. While both types of drugs stimulate excretion of potassium, the latter do so only to a small extent and can therefore be used for the hypokalemic form as well (see below). Beta-sympathomimetic drugs like salbutamol, when taken at the onset of an episode, may ease the symptom rather quickly. Also, the simultaneous application of glucose and insulin may lower serum potassium rather quickly.
Paramyotonia: Pathophysiology
Most paramyotonia mutations are situated in protein parts relevant for channel inactivation, in the inactivation gate itself (i.e. the intracellular loop connecting domains III and IV like T1313M), in the outermost arginine of the voltage sensor in domain IV (R1448H/C/S/P), in intracellular S4–S5 loops of domain III or IV (e.g. F1473S), or in the C-terminus (F1705I) ( Figure 38.4 ). During cooling to 27°C in vitro , paramyotonia muscle fibers slowly depolarize from −85 mV to about −40 mV whereas normal muscle fibers depolarize by not more than 5 mV. The depolarization is associated with a long-lasting burst of action potentials, which ends when the membrane potential approximates values of −55 mV. At this voltage, most genetically normal sodium channels are inactivated and therefore the muscle fibers become inexcitable and paralyzed. Functional expression of the mutant channels revealed slowed fast inactivation and accelerated recovery from the inactivated state and an uncoupling of fast inactivation from activation ( Figure 38.9 ). As slow sodium channel inactivation should also be incomplete to maintain depolarization-induced paralysis, several groups examined the effects of temperature on slow inactivation of the mutant channels. The results were not uniform and were difficult to interpret since entry into slow inactivation was already changed by the strikingly slowed fast inactivation. Bouts of long-lasting weakness in paramyotonia can be explained with an ongoing membrane depolarization in the majority of muscle fibers (i.e. a preference of fibers to stay in the P2 state). Further sustained depolarization of paramyotonic fibers to potentials positive to −40 mV induces a calcium release in the absence of an action potential, leading to an electrically silent muscle contraction, a contracture. Highly specific for PC is 23 Na MRI, which can visualize the myoplasmic sodium accumulation that is related to the membrane depolarization and correlates well with the grade of paresis ( Figure 38.11 ).
