Ion Channel Myopathy

Overview

Definition

Ion channel myopathies are a heterogeneous group of disorders that are caused by genetic defects in sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia, chloride Chloride Inorganic compounds derived from hydrochloric acid that contain the Cl- ion. Electrolytes, and calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes ion channels Channels The Cell: Cell Membrane 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 Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics.
  • Becker form: autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritance (not the same as Becker muscular dystrophy Muscular Dystrophy 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 Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency is unknown.
  • Pathophysiology: defect in chloride Chloride Inorganic compounds derived from hydrochloric acid that contain the Cl- ion. Electrolytes channels Channels The Cell: Cell Membrane → decreased conductance of chloride Chloride Inorganic compounds derived from hydrochloric acid that contain the Cl- ion. Electrolytes into the muscle cell → slowed repolarization Repolarization Membrane Potential 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 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 Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics mutations:
    • Most commonly (70%) CALCL1A gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics: codes for the alpha-1 subunit of the dihydropyridine-sensitive calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes channel in skeletal muscle
    • Less commonly SCN4A: affects sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia ion channels Channels The Cell: Cell Membrane
  • Prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency: 1 in 100,000
  • Clinical expression: men > women
  • Pathophysiology: triggering events → increased release of epinephrine Epinephrine The active sympathomimetic hormone from the adrenal medulla. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. Sympathomimetic Drugs 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 Potassium An element in the alkali group of metals with an atomic symbol k, atomic number 19, and atomic weight 39. 10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte that plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. Hyperkalemia 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 Gene Mutation Myotonic Dystrophies in SCN4A that regulates the production of a protein in the sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia channel in skeletal muscle
  • Prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency: 1 in 200,000
  • Clinical expression: equal in the 2 sexes
  • Pathophysiology:
    • Normally, the sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia channel is closed in the resting phase Resting phase Skin: Structure and Functions after normal muscle contraction.
    • With hyperkalemic PP, the Na channel closes too slowly →  sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia ions continue to leak into the muscle cell →  myotonia (muscle stiffness)
    • If the channel remains open → muscle becomes desensitized → paralysis → potassium Potassium An element in the alkali group of metals with an atomic symbol k, atomic number 19, and atomic weight 39. 10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte that plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. Hyperkalemia 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

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 Electromyography Recording of the changes in electric potential of muscle by means of surface or needle electrodes. Becker Muscular Dystrophy (EMG) during attacks
  • Family history Family History Adult Health Maintenance is important
  • Genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies
  • Thyroid Thyroid The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland: Anatomy function tests should be done.
  • Provocative tests and muscle biopsies are not recommended.
• For myotonia congenita: clinical suspicion confirmed with genetic studies
  • Muscle biopsy Muscle Biopsy Trichinella/Trichinellosis: 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 Mexiletine Antiarrhythmic agent pharmacologically similar to lidocaine. It may have some anticonvulsant properties. Class 1 Antiarrhythmic Drugs (Sodium Channel Blockers)
    • Carbamazepine Carbamazepine A dibenzazepine that acts as a sodium channel blocker. It is used as an anticonvulsant for the treatment of grand mal and psychomotor or focal seizures. It may also be used in the management of bipolar disorder, and has analgesic properties. First-Generation Anticonvulsant Drugs
    • Phenytoin Phenytoin An anticonvulsant that is used to treat a wide variety of seizures. The mechanism of therapeutic action is not clear, although several cellular actions have been described including effects on ion channels, active transport, and general membrane stabilization. Phenytoin has been proposed for several other therapeutic uses, but its use has been limited by its many adverse effects and interactions with other drugs. First-Generation Anticonvulsant Drugs
  • Caution with increased risk of harmful side effects of anesthesia Anesthesia A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. Anesthesiology: History and Basic Concepts
  • Relatives should be tested during childhood.
• Hypokalemic PP:
  • Treatment of attacks:
    • Confirm potassium Potassium An element in the alkali group of metals with an atomic symbol k, atomic number 19, and atomic weight 39. 10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte that plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. Hyperkalemia level before starting treatment.
    • Normalize serum K⁺ with oral K⁺ supplement.
    • IV potassium Potassium An element in the alkali group of metals with an atomic symbol k, atomic number 19, and atomic weight 39. 10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte that plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. Hyperkalemia if arrhythmias present; should not be administered in solutions containing dextrose Dextrose Intravenous Fluids 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 Diuretics Agents that promote the excretion of urine through their effects on kidney function. Heart Failure and Angina Medication (e.g., spironolactone Spironolactone A potassium sparing diuretic that acts by antagonism of aldosterone in the distal renal tubules. It is used mainly in the treatment of refractory edema in patients with congestive heart failure, nephrotic syndrome, or hepatic cirrhosis. Its effects on the endocrine system are utilized in the treatments of hirsutism and acne but they can lead to adverse effects. Potassium-sparing Diuretics)
    • Carbonic anhydrase Carbonic anhydrase A family of zinc-containing enzymes that catalyze the reversible hydration of carbon dioxide. They play an important role in the transport of carbon dioxide from the tissues to the lung. Carbonic Anhydrase Inhibitors inhibitors (e.g., acetazolamide Acetazolamide One of the carbonic anhydrase inhibitors that is sometimes effective against absence seizures. It is sometimes useful also as an adjunct in the treatment of tonic-clonic, myoclonic, and atonic seizures, particularly in women whose seizures occur or are exacerbated at specific times in the menstrual cycle. However, its usefulness is transient often because of rapid development of tolerance. Its antiepileptic effect may be due to its inhibitory effect on brain carbonic anhydrase, which leads to an increased transneuronal chloride gradient, increased chloride current, and increased inhibition. Carbonic Anhydrase Inhibitors)
• Hyperkalemic PP:
  • Treatment of attacks:
    • Mild physical exercise
    • High-carbohydrate snack/sugar
    • IV calcium gluconate Calcium gluconate The calcium salt of gluconic acid. The compound has a variety of uses, including its use as a calcium replenisher in hypocalcemic states. Hypocalcemia
  • Prevention:
    • Avoid triggers.
    • Avoid ↑ K⁺ foods and medications.
  • Medications:
    • Thiazide Thiazide Heterocyclic compounds with sulfur and nitrogen in the ring. This term commonly refers to the benzothiadiazines that inhibit sodium-potassium-chloride symporters and are used as diuretics. Hyponatremia diuretics Diuretics Agents that promote the excretion of urine through their effects on kidney function. Heart Failure and Angina Medication
    • Carbonic anhydrase Carbonic anhydrase A family of zinc-containing enzymes that catalyze the reversible hydration of carbon dioxide. They play an important role in the transport of carbon dioxide from the tissues to the lung. Carbonic Anhydrase Inhibitors inhibitors
    • Inhaled beta-agonists as needed

Differential Diagnosis

• Andersen-Tawil syndrome Andersen-Tawil syndrome A form of inherited long QT syndrome (or LQT7) that is characterized by a triad of potassium-sensitive periodic paralysis, ventricular ectopic beats, and abnormal features such as short stature, low-set ears, and scoliosis. It results from mutations of KCNJ2 gene which encodes a channel protein that regulates resting membrane potential. Long QT 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 Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics causing an ion defect in the potassium Potassium An element in the alkali group of metals with an atomic symbol k, atomic number 19, and atomic weight 39. 10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte that plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. Hyperkalemia channel. Andersen-Tawil syndrome Andersen-Tawil syndrome A form of inherited long QT syndrome (or LQT7) that is characterized by a triad of potassium-sensitive periodic paralysis, ventricular ectopic beats, and abnormal features such as short stature, low-set ears, and scoliosis. It results from mutations of KCNJ2 gene which encodes a channel protein that regulates resting membrane potential. Long QT 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 Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies. There is no standard protocol for treatment, but prevention with carbonic anhydrase Carbonic anhydrase A family of zinc-containing enzymes that catalyze the reversible hydration of carbon dioxide. They play an important role in the transport of carbon dioxide from the tissues to the lung. Carbonic Anhydrase Inhibitors 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 Myalgias Painful sensation in the muscles. Tick-borne Encephalitis Virus; however, type 1 Type 1 Spinal Muscular Atrophy is severe and carries a reduced life expectancy Life expectancy Based on known statistical data, the number of years which any person of a given age may reasonably expected to live. Population Pyramids, whereas type 2 Type 2 Spinal Muscular Atrophy is mild, with a normal life expectancy Life expectancy Based on known statistical data, the number of years which any person of a given age may reasonably expected to live. Population Pyramids. Diagnosis is made clinically, with genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies, and by EMG. Management is primarily supportive.
• Paramyotonia congenita: rare congenital Congenital Chorioretinitis 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 Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia channel mutations in the SCN4A gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics. 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 Acetylcholine A neurotransmitter found at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. Receptors and Neurotransmitters of the CNS receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. 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 Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia, ptosis Ptosis Cranial Nerve Palsies, diplopia Diplopia A visual symptom in which a single object is perceived by the visual cortex as two objects rather than one. Disorders associated with this condition include refractive errors; strabismus; oculomotor nerve diseases; trochlear nerve diseases; abducens nerve diseases; and diseases of the brain stem and occipital lobe. Myasthenia Gravis, 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: Types and Functions, and electrophysiologic studies. Management involves increasing the activity of acetylcholine Acetylcholine A neurotransmitter found at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. Receptors and Neurotransmitters of the CNS at the neuromuscular junction Neuromuscular junction The synapse between a neuron and a muscle. Skeletal Muscle Contraction.
• 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 Thyroid The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland: Anatomy function. Management is by maintaining a euthyroid Euthyroid Thyroiditis state, and preventive treatment with beta-blockers Beta-blockers Drugs that bind to but do not activate beta-adrenergic receptors thereby blocking the actions of beta-adrenergic agonists. Adrenergic beta-antagonists are used for treatment of hypertension, cardiac arrhythmias, angina pectoris, glaucoma, migraine headaches, and anxiety. Class 2 Antiarrhythmic Drugs (Beta Blockers) is used.