Muscle ion channel disorders, or channelopathies, are a heterogeneous group of disorders that are associated with features of abnormal skeletal muscle excitability. Muscle channelopathies may be classified by clinical phenotype, genotype, or the ion channel involved. The periodic paralyses are a group of disorders associated with prominent features of episodic flaccid weakness. Non-dystrophic myotonia describes a group of myotonic disorders associated with or without episodic weakness. Features of myotonia are present in both non-dystrophic myotonic and dystrophic forms of myotonia such as myotonic dystrophy type 1 and type 2, but myotonic dystrophy type 1 and 2 are nucleotide repeat disorders associated with progressive muscle dysfunction and multisystem involvement.
Autosomal dominant and recessive myotonia congenita (MC) are associated with mutations of the chloride channel gene, CLCN1, in greater than 95% of cases.
Paramyotonia congenita (PC) is an autosomal dominant disorder related to mutations of the sodium channel gene, SCN4A.
Sodium channel myotonias (SCM) are related to SCN4A channel mutations.
Hyperkalemic periodic paralysis (HyperKPP) is related to a mutation of the sodium channel gene, SCN4A.
Hypokalemic periodic paralysis (HypoKPP) is related to a mutation of the voltage gated calcium channel gene, CACNA1S, in 70% of patients; SCN4A channel mutations account for about 10%.
Andersen Tawil syndrome (ATS) is related to a mutation of the potassium channel gene, KCNJ2.
Thyrotoxic periodic paralysis (TPP) is related to untreated thyrotoxicosis, but a mutation in the potassium channel gene, KCNE3, was identified in a series of patients.1
Epidemiology including risk factors and primary prevention
Muscle channelopathies are uncommon, limited to a rare group of disorders. The estimated prevalence of the non-dystrophic myotonia and periodic paralysis is 1-7 per 100,000.2-5
The normal processes of depolarization, repolarization, or maintenance of the resting membrane potential are disrupted in skeletal muscle channelopathies, leading to isolated muscle fiber hypoexcitability or hyperexcitability, or combined features of hypo- and hyperexcitability.
Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)
Muscle channelopathies are not, in general, considered progressive disorders. The non-dystrophic myotonias range in severity, with some forms causing a severe neonatal onset associated with respiratory compromise to mild, late onset myotonia. Periodic paralysis may be associated with progressive features of fixed limb weakness.
Specific secondary or associated conditions and complications
Most forms of non-dystrophic myotonia and periodic paralysis are associated with isolated skeletal muscle symptoms. One particular exception is ATS, which is usually associated with cardiac arrhythmias and dysmorphic features. Thyrotoxic periodic paralysis may be associated with features of thyroid disease and has been associated with mutations in Kir2.6, a skeletal muscle-specific Kir channel, result in increased susceptibility for developing episodic weakness in the setting of hyperthyroidism6,7.
2. ESSENTIALS OF ASSESSMENT
MC is characterized by myotonia that is most pronounced after rest. Myotonia improves with exercise, the so called “warm up phenomenon”. There is no associated weakness. Triggers include cold, stress, and pregnancy.
PC is characterized by muscle stiffness myotonia aggravated by exercise and cold. There is “paradoxical” worsening of myotonia with repeated exercise, i.e., paramyotonia. Triggers may include cold and exercise.
SCM is a diverse group of disorders characterized by clinical and electrical myotonia and occasionally episodic weakness. If episodic weakness is absent, SCM may closely mimic myotonia congenita. Distinguishing features of frequent muscle pain and prominent eyelid myotonia can be clinical clues to help guide genetic testing.8 Some clinical sub-phenotypes of SCM include: myotonia fluctuans-delayed onset of myotonia, aggravated exercise and potassium, myotonia permanens-constant, severe myotonia, which may cause ventilatory impairment, and acetazolamide-responsive myotonia. Triggers include cold and exercise.
HypoKPP is characterized by episodic attacks of muscle weakness, usually sparing the muscles of respiration, deglutition, and ocular motility. Typically patients awaken with paralysis hours after exertion or a meal rich in carbohydrates. Blood potassium at the beginning of an attack is usually below normal. Potassium chloride ingestion may hasten recovery. Age of onset is within the second decade. There are no symptoms of clinical myotonia. Triggers include rest after exercise and high carbohydrate meals.
HyperKPP is characterized by episodic attacks of muscle weakness. Triggers may include exercise, fasting, or cold exposure. Age of onset is earlier than HypoKPP, usually during the first decade, and attacks are usually milder but more frequent. Symptoms of prominent myotonia are typically absent. Blood potassium is inconsistently increased during attacks. Triggers include rest after exercise and potassium-rich foods.
ATS is characterized by periodic paralysis, cardiac manifestations ranging from mild EKG abnormalities to ventricular arrhythmia and associated sudden death, and dysmorphic features. Significant clinical heterogeneity has been described in ATS. Attacks of weakness are often provoked with rest after exercise.
TPP is characterized by periodic paralysis in the setting of hyperthyroidism. The clinical features mimic those of hypokalemic periodic paralysis. Symptoms of myotonia are lacking.
Myotonia or delayed muscle relaxation is the cardinal feature of non-dystrophic myotonia. It is related to mild repetitive muscle fiber depolarization, and this may be described clinically or electrophysiologically. Clinical myotonia describes the clinically apparent phenomenon of delayed muscle relaxation. This is usually elicited with a muscle contraction (such as grip or eye closure) or percussion of the muscle. The electrical correlate of myotonia is the needle electromyographic recording of a repetitive muscle fiber action potential after needle insertion, muscle contraction, or muscle percussion (i.e., myotonic discharges). Typical myotonia improves with repeated muscular contraction, known as the warm up phenomenon. In contrast, paradoxical myotonia, typical of PC, worsens with repeated contraction. The main clinical feature of periodic paralysis is flaccid weakness. Between bouts of weakness, patients with a phenotype of periodic paralysis may be asymptomatic and have a completely normal examination. Some patients with periodic paralysis will have myotonia. Some patients with periodic paralysis will have some persistent weakness between bouts or attacks and some patients will develop persistent or fixed weakness over time.9
Routine testing: metabolic profile, creatine kinase, and thyroid profile.
Muscle biopsy is not indicated in periodic paralysis or myotonic disorders.
Autosomal dominant and recessive MC are associated with mutations of the chloride channel gene, CLCN1. Sequencing will detect a mutation in over 95% of patients with the clinical diagnosis of autosomal dominant or recessive myotonia congenita. Duplication/deletion testing methods are also available.
PC and SCM are related to SCN4A channel mutations.
HyperKPP is related to point mutations in the sodium channel gene, SCN4A. Targeted gene analysis can detect a mutation in about 50% of patients.
HypoKPP is related to a mutation of the voltage gated calcium channel gene, CACNA1S, in 70% of patients; SCN4A channel mutations account for about 10%.
ATS is related to a mutation of the potassium channel gene, KCNJ2, in 70%.
Patients with myotonic dystrophy, in particular myotonic dystrophy type 2, may present with features of myotonia lacking overt weakness, mimicking the presentation of a non-dystrophic myotonic disorder. Thus testing for these disorders should be considered in select undefined myotonic disorders.
Supplemental assessment tools
Electrodiagnostic testing: Exercise Tests
The long and short exercise tests are variations of the compound motor action potential (CMAP) recorded from the abductor digiti minimi (ADM) and are used to assess muscle fiber excitability. The exercise test was originally designed on the basis that patients have reduced CMAP amplitudes during acute bouts of periodic paralysis and that exercise is a common trigger of myotonia and paralysis.5 The long exercise test utilizes an ulnar motor nerve recording from ADM. The nerve is supramaximally stimulated to obtain maximal CMAP amplitude at rest. Following a period of 5 minutes maximal contraction of the ADM muscle, the CMAP amplitude is recorded at frequent intervals for up to 60 minutes.3,5 A greater than 40% reduction in the CMAP amplitude is considered abnormal and suggests a problem such as periodic paralysis in the correct clinical context. The short exercise test is similar to the long exercise, but involves recording CMAP amplitude for 1 minute after a 10-second bout of isometric exercise.3,6 This is repeated three times and sometimes after limb cooling to determine CMAP decrement. Reported references values vary, but a decrement of amplitude greater than 20% is considered abnormal. Five patterns of abnormalities on the long and short exercise tests have been described in patients with muscle channelopathies. These patterns (I-V) can help determine the clinical phenotype and guide genetic testing, but some patients will not fit perfectly with these patterns.8,10
Pattern I (PC) : abundant myotonic discharges on the needle electrode examination, an immediate drop in CMAP amplitude on the short exercise test that worsens with each trial, and variable decrement on the long exercise test.
Pattern II (MC) : abundant myotonic discharges on the needle electrode examination, decrement on the short exercise test that improves with repeated trials, and no change on the long exercise test.
Pattern III (SCM) : abundant myotonic discharges on the needle electrode examination, no change on the short exercise test, and no change on the long exercise test.
Pattern IV (HyperKPP and ATS) : myotonic discharges on the needle electrode examination, no change on the short exercise test, and decrement on the long exercise test.
Pattern V (HypoKPP) : no myotonic discharges, no change on the short exercise test, and decrement on the long exercise test.
Early predictions of outcomes
A precise phenotypic and genotypic diagnosis is of critcal importance to provide prognosis, determine the most appropriate therapeutic intervention, and for accurate genetic counseling. Often patients with non-dystrophic myotonia can manage symptoms of myotonia without medications, and myotonia usually responds well to medications to reduce muscle fiber excitability. Similarly prophylactic medications usually reduced severity of episodic attacks of weakness in periodic paralysis.
3. REHABILITATION MANAGEMENT AND TREATMENTS
Available or current treatment guidelines
There are no FDA-approved therapeutic options for the treatment of myotonia or periodic paralysis. The most effective treatment strategy relates to the specific symptoms (myotonia vs. paralysis), clinical phenotype, ion channel involved, and specific mutation. Determination of the most appropriate therapy can be challenging due to the interaction of genetic and phenotypic variation on treatment response. Numerous agents have been tried with mixed success. The following list includes the most commonly utilized medications for each phenotype:
HypoKPP: Acetazolamide and dichlorphenamide can be used to reduce the frequency of attacks of intermittent weakness. Approximately 50% of all patients with HypoKPP will respond to acetazolamide but a favorable response is more likely in patients with a CACNA1S mutation.11 Potassium supplementation is occasionally used chronically but usually only to address acute bouts of weakness.
HyperKPP: Medications used to reduce the severity and frequency of intermittent weakness include anhydrase inhibitors and thiazide diuretics.
MC, SCM and PC: Prominent weakness is usually lacking in these groups of disorders. Myotonia is the most troublesome symptom. The most well-studied medication for management of muscle over activity/myotonia is mexiletine.12 Other agents that may work in some cases include lamotrigine, phenytoin, procainamide, ranolazine, and acetazolamide13,14.
TPP: Treatment includes management of thyrotoxicosis and beta antagonist agents.
ATS: Carbonic anhydrase inhibitors and thiazides may be used to reduce the frequency and severity of episodes of weakness. Antiarrhythmic medications and, less frequently, cardiac defibrillators are used to manage the cardiac symptoms.
Patient & family education
Periodic Paralysis Association: http://www.periodicparalysis.org
Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills
The muscle channelopathies are a genetically and phenotypically heterogeneous group of disorders.
Muscle channelopathies may present with isolated or overlapping features of muscle over activity (myotonia) or inexcitability (periodic paralysis).
Patients with isolated periodic paralysis may have completely normal physical examination findings between attacks.
Myotonia may be described clinically or electrically. Some patients with electrical myotonia may not have overt clinical myotonia, but all patients with clinical myotonia should have electrical correlates of myotonic discharges on electromyography.
The short and long exercise tests are variations of the CMAP response that can help guide genetic testing and clinical management.
4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE
5.GAPS IN THE EVIDENCE-BASED KNOWLEDGE
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- Emery AE. Population frequencies of inherited neuromuscular diseases–a world survey. Neuromuscular disorders : NMD 1991;1(1):19-29.
- Deenen JC, Horlings CG, Verschuuren JJ, Verbeek AL, van Engelen BG. The Epidemiology of Neuromuscular Disorders: A Comprehensive Overview of the Literature. Journal of neuromuscular diseases 2015;2(1):73-85.
- Hughes MI, Hicks EM, Nevin NC, Patterson VH. The prevalence of inherited neuromuscular disease in Northern Ireland. Neuromuscular disorders : NMD 1996;6(1):69-73.
- Papponen H, Toppinen T, Baumann P, Myllyla V, Leisti J, Kuivaniemi H, Tromp G, Myllyla R. Founder mutations and the high prevalence of myotonia congenita in northern Finland. Neurology 1999;53(2):297-302.
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- Cheng C-J, Lin S-H, Lo Y-F, Yang S-S, Hsu Y-J, Cannon SC, Huang C-L. Identification and Functional Characterization of Kir2.6 Mutations Associated with Non-familial Hypokalemic Periodic Paralysis. Journal of Biological Chemistry 2011;286(31):27425-27435.
- Tan SV, Matthews E, Barber M, Burge JA, Rajakulendran S, Fialho D, Sud R, Haworth A, Koltzenburg M, Hanna MG. Refined exercise testing can aid dna-based diagnosis in muscle channelopathies. Annals of Neurology 2011;69(2):328-340.
- Links TP, Zwarts MJ, Wilmink JT, Molenaar WM, Oosterhuis HJ. Permanent muscle weakness in familial hypokalaemic periodic paralysis. Clinical, radiological and pathological aspects. Brain : a journal of neurology 1990;113 ( Pt 6):1873-1889.
- Fournier E, Arzel M, Sternberg D, Vicart S, Laforet P, Eymard B, Willer JC, Tabti N, Fontaine B. Electromyography guides toward subgroups of mutations in muscle channelopathies. Ann Neurol 2004;56(5):650-661.
- Matthews E, Portaro S, Ke Q, Sud R, Haworth A, Davis MB, Griggs RC, Hanna MG. Acetazolamide efficacy in hypokalemic periodic paralysis and the predictive role of genotype. Neurology 2011;77(22):1960-1964.
- Statland JM, Bundy BN, Wang Y, et al. Mexiletine for symptoms and signs of myotonia in nondystrophic myotonia: A randomized controlled trial. JAMA 2012;308(13):1357-1365.
- Arnold WD, Kline D, Sanderson A, Hawash AA, Bartlett A, Novak KR, Rich MM, Kissel JT. Open-label trial of ranolazine for the treatment of myotonia congenita. Neurology 2017.
- Andersen G, Hedermann G, Witting N, Duno M, Andersen H, Vissing J. The antimyotonic effect of lamotrigine in non-dystrophic myotonias: a double-blind randomized study. Brain : a journal of neurology 2017;140(9):2295-2305.
Original Version of the Topic
William D. Arnold, MD. Nondystrophic myotonia and periodic paralysis. 08/30/2013.
William D. Arnold, MD
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