Ion Channel Myopathy

Ion channel myopathies are a heterogeneous group of disorders that are caused by genetic defects in sodium, chloride, and calcium ion channels in the myocyte membranes resulting in myotonia. These myopathies present clinically with symptoms of muscle pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, weakness, stiffness, cramps, and spasm. Diagnosis is made on the basis of clinical presentation, lab testing, electromyography, and genetic testing. Management involves both prevention with diet and exercise modifications and treatment with diuretics in some cases.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definition

Ion channel myopathies are a heterogeneous group of disorders that are caused by genetic defects in sodium, chloride, and calcium ion channels in the myocyte membranes resulting in myotonia.

Classification, epidemiology, and pathophysiology

  • Myotonia congenita: 2 forms based on patterns of transmission
    • Both forms are due to mutations in the CLCN1 gene.
    • Becker form: autosomal recessive (not the same as Becker muscular dystrophy Becker muscular dystrophy Becker muscular dystrophy (BMD) is an X-linked recessive genetic disorder that is caused by a mutation in the DMD gene. Abnormal, partially functional muscle dystrophin protein is produced, which leads to progressive muscle weakness and the eventual loss of ambulation. Becker Muscular Dystrophy)
      • Onset: ages 4–12 as general muscle stiffness
      • More common and severe, generalized form
    • Thomsen form: autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance
      • Onset: infancy to age 3
      • Rare and milder form
    • Prevalence is unknown.
    • Pathophysiology: defect in chloride channels → decreased conductance of chloride into the muscle cell → slowed repolarization of the cell membrane Cell Membrane A cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules. The Cell: Cell Membrane
  • Hypokalemic periodic paralysis: most common type of periodic paralysis (PP)
    • Onset: late childhood to teenage years
    • Autosomal dominant disease 
    • Gene mutations:
      • Most commonly (70%) CALCL1A gene: codes for the alpha-1 subunit of the dihydropyridine-sensitive calcium channel in skeletal muscle
      • Less commonly SCN4A: affects sodium ion channels
    • Prevalence: 1 in 100,000
    • Clinical expression: men > women
    • Pathophysiology: triggering events → increased release of epinephrine or insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin → intracellular potassium shift → hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia
  • Hyperkalemic PP:
    • Onset: 1st decade of life
    • Rare autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance disease 
    • Gene mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in SCN4A that regulates the production of a protein in the sodium channel in skeletal muscle
    • Prevalence: 1 in 200,000
    • Clinical expression: equal in the 2 sexes
    • Pathophysiology:  
      • Normally, the sodium channel is closed in the resting phase after normal muscle contraction.
      • With hyperkalemic PP, the Na channel closes too slowly →  sodium ions continue to leak into the muscle cell →  myotonia (muscle stiffness)
      • If the channel remains open → muscle becomes desensitized → paralysis → potassium ions are released from the muscle → hyperkalemia Hyperkalemia Hyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs. Hyperkalemia

Clinical Presentation and Diagnosis

Symptoms and presentations can appear similar in different ion channel myopathies, making lab testing essential for diagnosis before treatment.

Clinical presentation

Table: Comparison of clinical presentations of ion channel myopathy
Myotonia congenita Hypokalemic periodic paralysis Hyperkalemic periodic paralysis
  • Symptoms vary between individuals.
  • Myotonia in 80%–99%
  • Myalgia in 5%–29%
  • < 5% will have muscle stiffness, weakness, percussion myotonia, or skeletal muscle hypertrophy.
  • Warm-up effect: Stiffness is usually painless and can be relieved by exercise.
  • No cardiac involvement, as seen with myotonic dystrophy
  • Myotonia with relapsing episodes of hypotonic paralysis
  • Lid lag: earliest finding
  • Proximal muscle groups more affected than distal muscle groups
  • Severe attacks can result in complete paralysis.
  • Occurs a few times per year; typically lasts for hours to days
  • No or minimal bulbar/respiratory involvement
  • Progressive proximal myopathy eventually develops after age 50.
  • Weakness or paralysis of muscles in the hips, shoulders, and back
  • > 50% present before age 10
  • Normal sensation
  • May develop fixed proximal weakness
  • Attacks are rarely severe.
  • Occasional pseudohypertrophy of muscles
  • Can occur several times per day
  • Symptoms last for minutes to hours.
Triggers:
  • Vigorous exercise
  • Fasting or other stress
  • High-carbohydrate meals
Triggers:
  • Rest after exercise
  • Fasting or other stress
  • Ingesting potassium-rich food
  • Low-carbohydrate diet
  • Cold exposure
  • Anesthesia Anesthesia Anesthesiology is the field of medicine that focuses on interventions that bring a state of anesthesia upon an individual. General anesthesia is characterized by a reversible loss of consciousness along with analgesia, amnesia, and muscle relaxation. Anesthesiology: History and Basic Concepts

Diagnosis

  • For hypokalemic PP: Lab results show ↓ serum K+ level during an attack.
  • For hyperkalemic PP: Lab results show ↑ serum K+ levels.
  • For both forms of PP:
    • Myotonia on exam and/or electromyography (EMG) during attacks
    • Family history is important
    • Genetic testing
    • Thyroid function tests should be done.
    • Provocative tests and muscle biopsies are not recommended.
  • For myotonia congenita: clinical suspicion confirmed with genetic studies
    • Muscle biopsy: no signs of dystrophy
    • Labs: CK levels may be elevated.
    • EMG: shows myotonic discharge

Management

Brief flare-ups of symptoms may not need treatment and can resolve with exercise or rest, depending on the disorder and the etiology of the attack.

  • Myotonia congenita:
    • Exercise may temporarily help the myotonia.
    • Medications to treat muscle stiffness:
      • Mexiletine
      • Carbamazepine
      • Phenytoin
    • Caution with increased risk of harmful side effects of anesthesia
    • Relatives should be tested during childhood.
  • Hypokalemic PP: 
    • Treatment of attacks:
      • Confirm potassium level before starting treatment.
      • Normalize serum K+ with oral K+ supplement.
      • IV potassium if arrhythmias present; should not be administered in solutions containing dextrose because of exaggerated insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin response to carbohydrate loads → hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia
    • Prevention:
      • Low-carbohydrate diet
      • Refrain from vigorous exercise.
    • Medications:
      • Oral K+ supplementation
      • K+-sparing diuretics (e.g., spironolactone)
      • Carbonic anhydrase inhibitors Carbonic anhydrase inhibitors Carbonic anhydrase inhibitors (CAIs) block the carbonic anhydrase enzymes in the proximal convoluted tubule, inhibiting the reabsorption of sodium bicarbonate (NaHCO3), which results in diuresis and metabolic acidosis. Carbonic Anhydrase Inhibitors (e.g., acetazolamide)
  • Hyperkalemic PP:
    • Treatment of attacks:
      • Mild physical exercise
      • High-carbohydrate snack/sugar
      • IV calcium gluconate
    • Prevention:
      • Avoid triggers.
      • Avoid ↑ K+ foods and medications.
    • Medications:
      • Thiazide diuretics Thiazide diuretics Thiazide and thiazide-like diuretics make up a group of highly important antihypertensive agents, with some drugs being 1st-line agents. The class includes hydrochlorothiazide, chlorothiazide, chlorthalidone, indapamide, and metolazone. Thiazide Diuretics
      • Carbonic anhydrase inhibitors Carbonic anhydrase inhibitors Carbonic anhydrase inhibitors (CAIs) block the carbonic anhydrase enzymes in the proximal convoluted tubule, inhibiting the reabsorption of sodium bicarbonate (NaHCO3), which results in diuresis and metabolic acidosis. Carbonic Anhydrase Inhibitors
      • Inhaled beta-agonists as needed

Differential Diagnosis

  • Andersen-Tawil syndrome: rare genetic disorder associated with a mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations of the KCNJ2 gene causing an ion defect in the potassium channel. Andersen-Tawil syndrome is characterized by a triad of symptoms that include episodes of muscle weakness and paralysis, arrhythmias, and distinctive facial and skeletal features. The diagnosis is made clinically with confirmatory genetic testing. There is no standard protocol for treatment, but prevention with carbonic anhydrase inhibitors is used.
  • Myotonic dystrophy: Myotonic dystrophy types 1 and 2 are autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance heterogeneous diseases that primarily affect the muscles, but unlike other muscular dystrophies, they have multisystem effects. Both types present with myotonia, muscle weakness, and myalgias; however, type 1 is severe and carries a reduced life expectancy, whereas type 2 is mild, with a normal life expectancy. Diagnosis is made clinically, with genetic testing, and by EMG. Management is primarily supportive.
  • Paramyotonia congenita: rare congenital autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance form of myotonia caused by sodium channel mutations in the SCN4A gene. Paramyotonia congenita is described as paradoxical in that the myotonia becomes worse with exercise and is considered by some to be the same disorder as hyperkalemic periodic paralysis. It typically presents before age 10 with muscle stiffness in the face or upper extremities. Diagnosis is clinical, and distinction from other myotonias is by EMG and genomic sequencing.
  • Myasthenia gravis Myasthenia Gravis Myasthenia gravis (MG) is an autoimmune neuromuscular disorder characterized by weakness and fatigability of skeletal muscles caused by dysfunction/destruction of acetylcholine receptors at the neuromuscular junction. MG presents with fatigue, ptosis, diplopia, dysphagia, respiratory difficulties, and progressive weakness in the limbs, leading to difficulty in movement. Myasthenia Gravis (MG): autoimmune neuromuscular disorder caused by dysfunction/destruction of acetylcholine receptors. Myasthenia gravis Myasthenia Gravis Myasthenia gravis (MG) is an autoimmune neuromuscular disorder characterized by weakness and fatigability of skeletal muscles caused by dysfunction/destruction of acetylcholine receptors at the neuromuscular junction. MG presents with fatigue, ptosis, diplopia, dysphagia, respiratory difficulties, and progressive weakness in the limbs, leading to difficulty in movement. Myasthenia Gravis presents with fatigue, ptosis, diplopia, and progressive weakness in the limbs, typically occurring with milder degrees of exertion than PP, and does not occur in “attacks.” Myasthenia gravis Myasthenia Gravis Myasthenia gravis (MG) is an autoimmune neuromuscular disorder characterized by weakness and fatigability of skeletal muscles caused by dysfunction/destruction of acetylcholine receptors at the neuromuscular junction. MG presents with fatigue, ptosis, diplopia, dysphagia, respiratory difficulties, and progressive weakness in the limbs, leading to difficulty in movement. Myasthenia Gravis often involves bulbar and extraocular muscles, which are rarely, if ever, affected in hyperkalemic PP. Diagnosis is based on clinical presentation, detection of antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins, and electrophysiologic studies. Management involves increasing the activity of acetylcholine at the neuromuscular junction.
  • Thyrotoxic periodic paralysis ( TPP TPP Thrombotic thrombocytopenic purpura (TTP) is a life-threatening condition due to either a congenital or an acquired deficiency of ADAMTS-13, a metalloproteinase that cleaves multimers of von Willebrand factor (VWF). The large multimers then aggregate excessive platelets resulting in microvascular thrombosis and an increase in consumption of platelets. Thrombotic Thrombocytopenic Purpura): form of hypokalemic periodic paralysis. Thyrotoxic periodic paralysis most commonly presents as sudden-onset weakness in the proximal muscles after age 20. The diagnosis is made clinically and with lab testing for thyroid function. Management is by maintaining a euthyroid state, and preventive treatment with beta-blockers is used.

References

  1. Statland JM, et al. (2018). Review of the diagnosis and treatment of periodic paralysis. Muscle Nerve 57:522–530. DOI: 10.1002/mus.26009
  2. Neki NS. (2016). Hyperthyroid hypokalemic periodic paralysis. Pakistan Journal of Medical Sciences, vol. 32, no. 4, 2016, pp. 1051–52. PubMed Central. https://pubmed.ncbi.nlm.nih.gov/27648066/
  3. Ceccato F, Scaroni C. (2019). Central adrenal insufficiency: open issues regarding diagnosis and glucocorticoid treatment. Clinical Chemistry and Laboratory Medicine 57:1125–1135. https://doi.org/10.1515/cclm-2018-0824
  4. Lacomis D. (2019). Myopathies of systemic disease. UpToDate. Retrieved August 26, 2021, from https://www.uptodate.com/contents/myopathies-of-systemic-disease
  5. Taminato T, et al. (2020). Paramyotonia congenita with persistent distal and facial muscle weakness: a case report with literature review. Journal of Neuromuscular Diseases 7:193–201. DOI: 10.3233/JND-190440
  6. Gutmann L, Conwit R. (2021). Hyperkalemic periodic paralysis. UpToDate. Retrieved August 26, 2021, from https://www.uptodate.com/contents/hyperkalemic-periodic-paralysis
  7. Genetic and Rare Diseases Information Center (GARD). (2017). Myotonia congenita. Retrieved August 26, 2021, from https://rarediseases.info.nih.gov/diseases/12301/myotonia-congenita

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