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Home , Central core disease, Centronuclear myopathy, Channelopathy, Myopathy, Myotonia congenita, Neuromyotonia

Management Topic Section

Muscle

he inherited muscle ion channel diseases (muscle nelopathies and is a hallmark feature of the periodic Tchannelopathies) are a group of disorders of skeletal paralyses. Individuals may experience not only gener- muscle membrane excitability characterised by variable alised limb but also single limb, hemibody or muscle stiffness and/or intermittent weakness. very focal . Bulbar and respiratory mus- is a common but not universal feature of these disorders culature are either spared or insufficiently affected to be which are nevertheless distinct from the myotonic dystro- clinically significant. phies (Table 1). External and environmental factors can Attacks of weakness most commonly occur in the be important triggers to attacks or lead to worsening of morning after waking from sleep but can be triggered by symptoms and may include alterations in serum potassi- stress, fasting (sodium ) or a carbohy- Dr Wojtek Rakowicz is a Specialist Registrar in um levels, reduction in ambient temperature and muscle drate meal (hypokalaemic periodic ). Exercise . After activity, particularly when followed abruptly by rest. followed by rest is a potent trigger for attacks of weakness training in Norwich and Common muscle channelopathies are the result of chlo- in all forms of . Cold exposure can trig- Cambridge he worked in the Neuromuscular ride, sodium and dysfunction and are ger an episode of weakness in the periodic paralyses and, Division at Washington therefore amenable to therapeutic interventions. particularly dramatically, in . University in St Louis. Depressed tendon reflexes during an attack are an He is currently at the ABBREVIATIONS USED IN THIS ARTICLE National Hospital for important clinical pointer to the organicity of 'gener- Neurology MC alised limb weakness' caused by periodic paralysis. Some and Neurosurgery. PMC paramyotonia congenita patients with periodic paralysis develop a fixed PAM potassium-aggravated myotonia which can be significantly disabling. A mild fixed weak- HyperPP hyperkalaemic periodic paralysis ness can develop in patients with myotonia congenita and HypoPP hypokalaemic periodic paralysis paramyotonia congenita.

Presentations MUSCLE HYPERTROPHY MYOTONIA AND PARAMYOTONIA Muscle hypertrophy is a characteristic feature of myoton- Myotonia is the phenomenon of delayed relaxation of ic disorders and is a direct result of muscle overactivity. following voluntary contraction (see Box This is very different from the muscle pseudohypertrophy Dr Michael Hanna is below). Affected individuals may report muscle stiffness seen in some of the dystrophinopathies: the ‘true’ hyper- Consultant and Reader or an inability to relax their muscles after contraction. trophy of myotonic disorders results in increased muscle in Clinical Neurology in Stiffness may be mildly worse in the cold or after pro- strength. Some individuals are able to participate in the Centre for Neuromuscular longed periods of rest but diminishes with repeated mus- sports requiring strength rather than speed or endurance at the National Hospital cle contractions, the so -called warm-up phenomenon. (eg Thomsen-type myotonia). for Neurology and Neurosurgery, Queen The classic clinical findings are an inability to relax Square, London. With after prolonged contraction (eg handgrip) and percus- Chloride channelopathies funding from the DoH sion myotonia, spontaneous after The primary membrane defect in myotonia congenita he has established a national diagnostic direct percussion (eg abductor pollicis brevis). Lid-lag (MC) is reduced chloride conductance. in the service for patients may be seen on suddenly looking downwards after pro- CLCN-1 gene encoding the ClC-1 muscle voltage-gated with muscle longed upwards gaze. These findings become less marked can give rise to allelic disorders with channelopathies." with repetition but reappear after rest. autosomal dominant or recessive modes of inheritance. It In contrast to myotonia, muscle stiffness in paramy- is interesting to note that recent evidence suggests the otonia is precipitated rather than ameliorated by exercise. myotonia in is caused by altered This is the opposite of the warm-up phenomenon in expression of the same chloride channel secondary to myotonia (hence paradoxical myotonia or paramyoto- abnormal RNA aggregation. nia). Paramyotonia is also particularly temperature-sensi- tive. Marked exacerbation by cold and exercise is useful MYOTONIA CONGENITA clinically in distinguishing paramyotonia from myotonia. Becker-type myotonia (recessive MC) is more common and is usually more severe. Muscle stiffness may be worse WEAKNESS in the cold, although never to the extent seen in paramy- Episodic weakness is seen in many of the muscle chan- otonia, and improves with exercise. Onset is usually in the

MYOTONIA The morphology of myotonic discharges can be of potentials (spikes) or positive sharp waves (see waveform). This allows the source generator to be identified as muscle as distinct from spontaneous activity arising in the motor nerve which has the morphology of a . , caused by abnormal firing of the motor nerve, bears some clinical resemblance to myotonia (stiffness, delayed muscle relaxation, ‘true’ muscle hypertrophy). However, the shape and frequency of discharges in neuromyotonia are easily differentiated from myotonic potentials in the EMG laboratory.

Normal muscle at rest is electrically silent outside the end-plate zone. Electrophysiological myotonia is caused by spontaneous repetitive discharges of a single muscle fibre. Myotonic discharges have a waxing and waning quality that gives rise to the characteristic “dive-bomber” or “chain-saw” sound heard in the EMG laboratory. They are a defining feature of both the dystrophic and non-dystrophic A characteristically waxing and waning myotonic waveform. myotonic (Table 1) but they may also be found in acid maltase deficiency, This particular discharge is made up of positive sharp waves. and .

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periodic potassium progressive distinctive DYSTROPHIC MYOTONIC MYOPATHIES myotonia weakness sensitivity weakness features

non-primary channelopathies* MYOTONIC DYSTROPHY +--+extramuscular features PROXIMAL MYOTONIC MYOPATHY +--+extramuscular features

MYOTONIC CHANNELOPATHIES (non-dystrophic)

chloride channelopathies* RECESSIVE MYOTONIA CONGENITA (BECKER'S-TYPE) + (+ ) - (+ ) lower limb onset DOMINANT MYOTONIA CONGENITA (THOMSEN'S-TYPE) +---generalised onset

sodium channelopathies PARAMYOTONIA CONGENITA ++ - -extreme cold sensitivity HYPERKALAEMIC PERIODIC PARALYSIS +++(+ ) triggered by fasting POTASSIUM-AGGRAVATED MYOTONIA +-+-triggered by potassium ingestion

NON-MYOTONICCHANNELOPATHIES

potassium ANDERSEN'S SYNDROME -++-cardiac/dysmorphic features

calcium channelopathies HYPOKALAEMIC PERIODIC PARALYSIS -++(+ ) triggered by carbohydrate ingestion ----triggered by anaesthetic agents

Table 1: Inherited muscle ion channel diseases and related disorders *NOTE: The myotonia in the myotonic dystrophies appears to result from altered expression of the muscle voltage-gated chloride channel. Chloride channelopathies can occasionally be associated with a dystrophic .

second decade and the condition progresses slowly over tivity is typically much more extreme than in myotonia. years. The lower extremities are affected first, giving rise Characteristic presentations include blepharospasm after to a disproportionate figure with calf and gluteal muscle prolonged crying and tongue stiffness after eating an ice hypertrophy but relatively poorly developed neck and cream. Symptoms of paramyotonia are usually static shoulder girdle muscles. Grip and percussion myotonia through life but attacks of weakness and hyperkalaemia and the lid-lag phenomenon are easily elicited. Thomsen- may appear during . type myotonia (dominant MC) develops in infancy or early childhood with a generalised onset in the limb gir- HYPERKALAEMIC PERIODIC PARALYSIS dles, calves and facial muscles. Patients with HyperPP have episodes of generalised weak- MC is distinguished from myotonic dystrophies by the ness lasting minutes up to 1 hour beginning in the first absence of extramuscular features and the lack of promi- decade of life. Attacks can occur on waking and can be nent weakness (Table 1). Distinguishing dominant and precipitated by the cold, fasting, rest after exercise, emo- recessive forms of MC depends on both the distribution tional stress and potassium ingestion (eg fruit juices). of symptoms and the examination of all family members Symptoms improve with an oral carbohydrate load, mild but may be difficult. While later in onset, the recessive exercise and inhaled }-agonists. Bulbar and respiratory form is usually more disabling and may exhibit the fol- musculature is characteristically spared. Depressed deep lowing features: (1) more severe myotonic stiffness; (2) tendon reflexes during an attack are a key clinical finding episodes of focal short-lived weakness precipitated by and the serum potassium is usually raised (4.5-8.0 mM) if sudden movements after a period of prolonged rest; (3) it is measured early in an attack. Coexisting paramyotonia minor distal wasting and weakness. may be present.

Sodium channelopathies POTASSUM-AGGRAVATED MYOTONIA Mutations in SCN4A gene encoding the Skm-1 skeletal Some individuals with mutations present muscle voltage-gated sodium channel can cause four dif- with symptoms of myotonia which, unlike MC, are potas- ferent skeletal muscle channelopathies paramyotonia sium-sensitive. Several variants of PAM (also known as congenita (PMC), hyperkalaemic periodic paralysis sodium channel myotonia) have been described. The (HyperPP), hypokalaemic periodic paralysis (HypoPP) myotonia can be painful, can fluctuate and may be and occasionally potassium-aggravated myotonia (PAM), induced by exercise but the variants share the characteris- although HypoPP is more commonly the result of muta- tic of being worse after potassium ingestion (eg fruit tions in the skeletal muscle calcium channel (see below). juices). Unlike other sodium channelopathies, however, PMC and HyperPP may occur in the same kindred. The there is no true weakness and symptoms are not usually diseases are inherited in an autosomal dominant fashion, worse in the cold. usually with complete penetrance. Calcium channelopathies PARAMYOTONIA CONGENITA Pathological mutations are recognised in two different Symptoms of PMC start in infancy and primarily affect muscle calcium channels. Mutations in the non-voltage- bulbar, facial, neck and hand muscles. In contrast to sensitive gene (RYR1) encoding a sar- myotonia, stiffness can be precipitated by exercise and is coplasmic reticulum calcium channel involved in excita- often followed by a period of true weakness. Cold sensi- tion-contraction coupling cause malignant hyperthermia

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which can be associated with (cf. channelopathies but is not diagnostically useful. Serum A case study on Andersen's Rakowicz (2003): ACNR 2(6):11-13). Pathogenic muta- potassium levels during an episode of weakness may be syndrome will soon be tions in the dihydropyridine receptor gene (CACNA1S) depressed, normal or raised in potassium-sensitive disor- available on our web site. encoding the muscle voltage-gated calcium channel give ders but should be normal in between attacks unless a See www.acnr.com for more rise to HypoPP. The disease is inherited with autosomal secondary disturbance of potassium handling is present. information. dominant inheritance but with reduced penetrance in Important secondary causes to consider include potassi- women. Recently HypoPP has also been reported in asso- um-wasting , primary hyperaldosteronism, inad- ciation with mutations in exon 12 of the SCN4A gene equate dietary intake, excessive sweating, diarrhoea, kid- encoding the muscle voltage-gated sodium channel. ney dysfunction and chronic liquorice ingestion. A 12- lead ECG should be performed in every individual with HYPOKALAEMIC PERIODIC PARALYSIS periodic paralysis to exclude cardiac conduction defects. HypoPP is the commonest inherited periodic paralysis. is generally not required although a lack of As in HyperPP, episodes of weakness can be triggered by Type2B fibres is recognised in MC and slowly progressive the cold, prolonged rest, rest after exercise and emotional proximal muscle weakness in HypoPP is accompanied by stress but are usually of longer duration (hours to days). a vacuolar myopathy. Unlike HyperPP heavy meals rather than fasting predis- pose the individual with HypoPP to an attack and there DNA-BASED DIAGNOSIS may be a characteristic history of weakness occurring on DNA-based diagnosis is now the most rapid, accurate and waking on the day after a large meal. Depressed deep ten- safe method to achieve a diagnosis. An accurate genetic don reflexes during an attack are a key clinical finding and diagnosis is important not only to confirm a clinical diag- the serum potassium is usually depressed (2-3 mM). nosis but also because it allows correct genetic counselling Although attacks may be very mild and kindreds fre- and guides therapeutic options. In the UK genetic diag- quently include asymptomatic individuals, compromised nosis is now available for all the channelopathies respiratory function has occasionally been reported. The described in this article (see Footnote). presence of even asymptomatic myotonia excludes the diagnosis of HypoPP. NEUROPHYSIOLOGY An important of HypoPP is Nerve conduction studies are normal except for com- symptomatic hypokalaemia. ‘Secondary’ HypoPP is seen pound motor action potentials (CMAPs) which are most frequently in the context of treatment with potassi- depressed during an attack of periodic paralysis. Muscle um-wasting diuretics but can be the result of primary fibre action potentials are generally normal but mild hyperaldosteronism, inadequate dietary intake, excessive myopathic changes may be seen in Thomsen-type myoto- potassium loss (sweat, gastrointestinal and renal) and nia and late in the course of the periodic paralyses. chronic liquorice ingestion. Usually in symptomatic Myotonic discharges are a cardinal feature of the hypokalaemia the patient is persistently weak rather than myotonic myopathies (see Box), may be present in some experiencing attacks of weakness. In some Far-Eastern cases of HyperPP and exclude a diagnosis of HypoPP. populations can lead to attacks of weak- Initial transient dense followed by electrical ness with a depressed serum potassium concentration silence (prolonged ) on muscle cooling (20oC) which are very similar to HypoPP but the cause is are diagnostic of PMC. Changes in CMAP amplitude unknown. during and after short and prolonged exercise testing can ACKNOWLEDGEMENTS The authors would like to thank be helpful in the diagnosis of MC and the periodic paral- Dr M Al-Lozi for comments on Potassium channelopathies yses. an earlier version of this Two muscle potassium channelopathies are now recog- manuscript and for supplying the nised. A rare form of HyperPP is described in association Treatments example of a myotonic with mutations in the MinK gene. A more common Acute and prophylactic treatments can be used in the waveform. potassium channelopathy is Andersen’s syndrome caused muscle channelopathies. Patients with mild MC may not REFERENCE by mutations in the KCNJ2 gene encoding the muscle require treatment. However, most MC and PMC patients Davies NP, Hanna MG. (2001) voltage-independent Kir2.1. will benefit significantly from antimyotonic treatment The skeletal muscle and in our experience the antiarrhythmic drug channelopathies: basic science, clinical and treatment. ANDERSEN'S SYNDROME is easily the most effective. Pretreatment ECG is impor- Curr Opin Neurol 14:539-51. The diagnosis of Andersen’s syndrome is based on a triad tant. of (1) periodic paralysis; (2) prolonged QT interval or Acute attacks of HyperPP can be treated at onset with FOOTNOTE ventricular arrhythmias; (3) dysmorphic features. The continued slight exercise or ingesting carbohydrates. A national clinical and diagnostic service is available at the Centre attacks of paralysis may be accompanied by a reduced, Lifestyle preventive measures in HyperPP may be helpful. for at the normal or raised serum potassium level. Cardiac involve- Prevention of attacks can usually be achieved with car- National Hospital for Neurology ment varies from the asymptomatic to in bonic anhydrase inhibitors, either or & Neurosurgery. This service is childhood and requires close cardiological supervision. dichlorphenamide. diuretics may also be useful funded by the Department of Health through national Dysmorphic features include short stature, low-set ears, preventive agents. }-agonists such as salbutamol have a specialist commissioning and any hypertelorism, micrognathia, a short index finger and useful role to play in preventing HyperPP attacks in cer- patient in the UK can be referred of the toes. It is important to note that dys- tain patients. for this service. Further details morphic features may be subtle and that cardiac compli- Mild attacks of HypoPP need no treatment but potas- are available from Dr MG Hanna cations can present at any age. Therefore in any patient sium chloride may be given orally (but not in a carbohy- [email protected] with periodic paralysis a careful search for dysmorphic drate-containing drink) in more severe attacks. Correspondence to: features should be undertaken as well as a 12-lead ECG. Intravenous potassium replacement is not usually Dr Wojtek Rakowicz, required and may be hazardous. Attacks of HypoPP are National Hospital for Neurology Investigations best prevented by avoiding carbohydrate-rich meals and and Neurosurgery, Queen Square, LABORATORY TESTING heavy exercise but carbonic anhydrase inhibitors are often London WC1N 3BG. Serum CK may be mildly raised in many of the muscle effective. E.Mail. [email protected]

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