Authors
J. Trip, M.D.
G. Drost, M.D., Ph.D.
H.B. Ginjaar, Ph.D.
B.G.M. van Engelen, M.D., Ph.D.
C.G. Faber, M.D., Ph.D.

Clinical features

The core symptoms of hereditary skeletal muscle channelopathies are muscle stiffness (myotonia) and muscle weakness (transient paresis and periodic paralyses). Myotonia is defined as an abnormal delay in muscle relaxation after voluntary or evoked muscle contractions. Transient paresis, on the other hand, is a short and momentary decline in focal muscle force. Periodic paralyses are spontaneous or provoked attacks of generalised muscle weakness. Thus, in myotonia the skeletal muscle membrane is overexcited and in transient paresis and periodic paralyses it is inactive.

Despite having only two core symptoms, hereditary skeletal muscle channelopathies do have several phenotypes. Initially, until the arrival of DNA analysis in the 1990s, these various diseases could only be distinguished on the basis of clinical characteristics. A clinical description of skeletal muscle channelopathies was published earlier in this journal.² In the present paper we provide an overview of the clinical features, pathophysiology, differential diagnosis, therapy and risks of anaesthesia in this group of diseases.

The hereditary skeletal muscle channelopathies can be categorised as chloride, sodium and calcium channelopathies.³ As a rule of thumb, chloride channnelopathies are characterised by myotonia and eventually transient paresis but never by periodic paralysis,whereas sodium channelopathies may feature both myotonia and periodic paralysis and calcium channelopathies only periodic paralysis.⁴

Chloride channelopathies are distinguished in autosomal dominant (Thomsen’s disease) and autosomal recessive (Becker’s disease) myotonia congenita.^5-6 Both diseases are characterised by myotonia, especially during the first muscle contraction after a period of rest. Becker’s disease also demonstrates transient paresis. While clinically, myotonia is best tested in the hand muscles, transient paresis is best tested in the biceps muscle.⁷ Both symptoms improve with continuing exercise, known as the ‘warm-up’ phenomenon.

But what distinguishes the two syndromes? In Thomsen’s disease the first symptoms tend to  manifest themselves in early childhood, whereas in Becker’s disease they first become apparent  at school-age (early teens). In adolescence symptoms may aggravate in Thomsen’s disease, after which a plateau phase is reached or even a decrease of symptoms may occur after the age of 40 years. Patients with Becker’s disease usually have more serious symptoms and often show transient paresis.⁶ In addition, with a prevalence of 1:400,000 in the general population, Thomsen’s disease is less common than Becker’s disease, which occus in 1 in 50,000 individuals.^4,6

Sodium channelopathies comprise different conditions. Besides myotonia, this group of diseases may also be characterised by periodic paralysis and/or chronic muscle weakness. Periodic paralysis are generally provoked by potassium- or carbohydrate-rich meals, rest after exercise or cold temperatures, while chronic muscle weakness results from a developing myopathy.

Paramyotonia congenita was first described by Von Eulenburg.⁸ The disease differs in some points from myotonia congenita in that myotonia worsens after continuing exercise (paradoxical myotonia) and tends to be provoked and exacerbated by cold temperatures.⁸ In addition, myotonia especially manifests itself in face and hand muscles. Moreover, paramyotonia congenita may also show muscle weakness that especially tends to be provoked by exercise or cold temperatures. Contrary to transient paresis, the muscle weakness in paramyotonia congenital may persist for hours. Although some patients may experience chronic muscle weakness, the extent of paramyotonia and paroxysmal muscle weakness remains largely unchanged during life. Hyperkalemic periodic paralysis is a condition characterised by episode of severe, generalised muscle weakness during which often, but not always, an increase in serum potassium, can be established. Tyler and Gamstorp first described the disease in the 1950s.^{9, 10} Onset usually occurs in the first decade of life and attacks can occur with or without (para)myotonia.¹¹ Potassium-rich meals, a period of rest after exercise, emotions/stress, pregnancy and a cold environment tend to trigger or worsen the attacks.¹¹ Usually, attacks first occur in the morning and may last minutes to hours. They increase in frequency during life and in severe cases attacks recur daily. Initially, the weakness is reversible, but some patients develop chronic muscle weakness later in life.¹² The condition has a prevalence of approximately 1 in 200,000.⁴

Potassium-aggravated myotonia (PAM) was first recognised as a separate clinical entity after the introduction of DNA diagnostics. Formerly, the disorder was probably diagnosed as myotonia congenita. PAM is a collective term for myotonia fluctuans and myotonia permanens, with the distinction being based on the seriousness of the symptoms.¹³ Typical features of myotonia fluctuans are its changing and fluctuating muscle stiffness.¹³ Another hallmark of the condition is the so called “exercise-induced delayed onset myotonia”, in which the myotonia only appears after prolonged exercise, which phenomenon should not be confused with paramyotonia in which the stiffness is directly detectable after a first contraction and worsens after continuing exercise. Myotonia permanens is characterised by a serious and continuous myotonia, which condition is sometimes difficult to clinically differentiate from myotonia congenita. A third type of PAM, known as acetazolamide-responsive myotonia congenital, is painful myotonia that respons well to acetazolamide.¹⁴ None of these various PAMs are associated with cold sensitivity or muscle weakness.

Calciumchannelopathies: Type I hypokalemic periodic paralysis (type 1 HOPP) is the only condition that belongs to this subgroup of channelopathies. In a minority of cases HOPP may also be caused by a sodium channelopathy (type 2 HOPP).¹⁵ The symptoms of the two types are identical and involve attacks of generalised muscle weakness in association with decreased serum potassium. Myotonia does not occur and secondary causes, like hyperthyroidism, need to be ruled out.¹⁶

Onset usually occurs in the second decade of life and always before the age of thirty.¹¹ Carbohydrate-rich meals, rest after exercise and insulin can provoke an attack which can last hours to even days. The frequency of attacks is variable and often decreases after age 40. With a prevalence of about 1:100,000 in the general population HOPP often leads to chronic muscle and may be associated with severe disability.weakness. ^{4, 16}

Differential diagnosis

The most important differential diagnosis of myotonia is myotonic dystrophy type 1, which is more frequent (prevalence of 2.5-12:100,000 persons in population) than the hereditary skeletal muscle channelopathies.³³ The disease has an autosomal dominant inheritance in which the pathology is not only limited to the muscle fibre membrane (sarcolemma) itself. It is a multi system disorder with myotonia, a characteristic distribution of progressive muscle weakness (initially in muscles of the face, throat, neck and distal limb muscles and eventually in proximal limb muscles) and involvement of different organs (heart: conduction defects and arrhythmias; eyes: cataract; smooth muscles: gastro intestinal complaints; lungs: aspiration pneumonia; brain: mental retardation and hypersomnolence).³³ 

Proximal myotonic myopathy, also called myotonic dystrophy type 2, is a disease mimicking myotonic dystrophy type 1 with the distinction that there is pronounced proximal muscle weakness.³⁴ It is possible to distinguish between the two disorders via DNA analysis.

Thyrotoxic periodic paralysis is the most important disease to differentiate from hypokalemic and hyperkalemic periodic paralysis. Like the other two, the disorder is characterised by identical attacks of generalised muscle weakness and also the possibility of hypokalemia. At the time of the first attack the clinical thyrotoxic symptoms may be undetected and go undetected.⁴ Thus, in cases of the periodic paralyses it is always recommended to check the patient’s  thyroid function.

Ancillary investigations

In the so-called non-dystrophic myotonias, a subgroup of the hereditary skeletal muscle channelopathies, needle electromyography (EMG) shows myotonic discharges. These discharges are especially triggered by insertion or manipulation of the needle and typically wax and wane in frequency and amplitude, with the changes in frequency causing the characteristic sound of an accelerating motorcycle.¹⁷ Myotonic discharges are detectable in almost all muscles of patients with a non-dystrophic myotonia (i.e. myotonia congenita, paramyotonia congenita and PAM). In hyperkalemic periodic paralysis (hyperPP) such discharges may be absent and in HOPP no myotonic discharges are present.

Like myotonia, transient paresis is detectable with neurophysiological tests. There is, for example, a strong correlation between transient paresis and the overall decrement of the compound muscle action potential (CMAP) after repetitive nerve stimulation (RNS).^18,19 However, a certain decrement could be found in all forms of myotonia.²⁰ On the other hand, different diseases of the hereditary skeletal muscle channelopathies may be distinguished by the differences in CMAP output after short or long exercise tests.^21,22 Fournier described five EMG patterns, each correlating with a subgroup of mutations.²³  High-density surface EMG is another method to measure transient paresis.⁷

For the further diagnosis of periodic paralysis, i.e. the differentiation between hyperPP and HOPP,  the oral potassium and the glucose loading test, respectively, are recommended. ^{24, 25}

Note that on the basis of the above-mentioned tests a definitive diagnosis of the various hereditary skeletal muscle channelopathies is not always possible, which requires DNA analysis, a technique that did not become available until the 1990s. In the Netherlands DNA-based diagnoses are currently being conducted by the third author (Ieke B. Ginjaar) at the department of Human and Clinical Genetics of the University Medical Centre in Leiden.

Genetics

The skeletal muscle membrane contains voltage-gated sodium, chloride and calcium channels. Fast moving ions that run through these channels regulate the de- and repolarisation of the muscle membrane. Skeletal muscle sodium channels are important in generating an action potential but also have a role in the repolarisation phase of the membrane (fast inactivation). Skeletal muscle chloride channels play an important role in regulating muscle excitability, as the chloride conductance is essential for the repolarisation phase. After an action potential, the calcium initiate the excitation-contraction coupling that results in a contraction of the muscle. In hereditary skeletal muscle channelopathies one of the above-mentioned processes is disturbed, leading to myotonia, periodic paralysis or a combination of both.

Chloride channelopathies are caused by mutations in the skeletal muscle chloride-channel gene (CLCN1; voltage-gated chloride channel, type 1) on chromosome 7q, encoding the chloride channel of the skeletal muscle membrane. To date, about 80 different mutations in this gene have been associated with myotonia congenita.^{26, 27} Mutations strongly reduce chloride conductance resulting in a lack of functional chloride channels, which, in turn results in a higher resting membrane potential making the skeletal muscle membrane vulnerable for depolarisations. A reduced chloride conductance of 30% may cause the overexcited muscle membrane to produce repetitive depolarisations (myotonia).²⁸

When the resting membrane potential is much higher, the muscle membrane may become temporarily inexcitable or inactive, which forms the basis for transient paresis.

Sodium channelopathies are caused by mutations in the skeletal muscle sodium-channel gene (SCN4A; voltage-gated sodium channel, type 4A) on chromosome 17q encoding for SkM1, the alpha subunit of the sodium channel. At least 30 different missense mutations underlying these sodium-channel disorders have been identified.^{29, 30} All sodium channelopathies have an autosomal dominant inheritance and most mutations lead to an impaired repolarisation, particularly by hampering the fast inactivation of the sodium channels. When the preceding depolarisation is limited, the already recovered sodium channels can be reactivated immediately after their repolarisatio, which leads to an overexcited muscle membrane with repetitive depolarisations (myotonia). However, when the preceding depolarisation is strong, the inactivated state of sodium channels is prolonged, leading to an inexcitable or inactive muscle membrane resulting in periodic paralysis.

Calcium channelopathies are caused by mutations in the dihydropyridine (DHP) receptor gene, CACNA1S (voltage-gated calcium channel, alpha-1S subunit), on chromosome 1.³¹ A crucial part of the calcium-channel, the DHP receptor fulfils an important function in the excitation-contraction coupling mechanism. During an attack there is a permanent muscle-membrane depolarisation (overexcitation) in combination with a conduction block (inactivation).³² The pathophysiological relationship between the permanent muscle-membrane depolarisation, conduction block and calcium-channel defect is, as yet, unknown.¹¹

Therapy
Myotonia responds well to drugs reducing or blocking sodium channels of the muscle fibre membrane.^35-37 The agents alleviate myotonia by reducting of the hyperexcitability of the cell membrane. Expert opinion suggests mexiletine as the drug of choice although data supporting the effectiveness of the drug are as yet not available.³⁸ The three double-blind randomised studies that have been conducted were small-scale and restricted to myotonic dystrophy and no such myotonia studies have been performed for hereditary skeletal-muscle channelopathies.³⁹

Depolarising drugs such as suxamethonium and anticholinesterases exacerbate the myotonia or provoke a clinical situation resembling malignant hyperthermia. Especially aggravated myotonia in the jaw muscles may impede intubation or ventilation, which may result in life-threatening situations. Thus, depolarising muscle relaxants and anticholinesterases are contraindicated in patients with myotonia.⁴

Periodic paralyses: Prevention of provocative factors is the therapy of choice for periodic paralyses although acute and prophylactic drug treatments are also available.^40-41

Suxamethonium in combination with hypokalemia may provoke rhabdomyolysis or respiratory insufficiency during anaesthesia. It is hence essential that the use of depolarising relaxants is avoided and that body temperature and serum potassium are kept constant throughout anaesthesia.⁴

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