Last updated
Ion channel image - Kim 2014 PMCID 3935107.png
Sodium channel, implicated in channelopathies including Brugada syndrome, Long QT syndrome, Dravet syndrome, Paramyotonia congenita
Specialty Medical genetics, Neuromuscular medicine, Cardiology
Symptoms Dependent on type. Include: Syncope, muscle weakness, seizures, breathlessness
Complications Dependent on type. Include: Sudden death
CausesGenetic variants

Channelopathies are a group of diseases caused by the dysfunction of ion channel subunits or their interacting proteins. These diseases can be inherited or acquired by other disorders, drugs, or toxins. Mutations in genes encoding ion channels, which impair channel function, are the most common cause of channelopathies. [1] There are more than 400 genes that encode ion channels, found in all human cell types and are involved in almost all physiological processes. [2] Each type of channel is a multimeric complex of subunits encoded by a number of genes. Depending where the mutation occurs it may affect the gating, conductance, ion selectivity, or signal transduction of the channel.


Channelopathies can be categorized based on the organ system which they are associated with. In the cardiovascular system, the electrical impulse needed for each heartbeat is made possible by the electrochemical gradient of each heart cell. Because the heartbeat is dependent on the proper movement of ions across the surface membrane, cardiac channelopathies make up a key group of heart diseases. [3] Long QT syndrome, the most common form of cardiac channelopathy, is characterized by prolonged ventricular repolarization, predisposing to a high risk of ventricular tachyarrhythmias (e.g., torsade de pointes), syncope, and sudden cardiac death. [4]

The channelopathies of human skeletal muscle include hyper- and hypokalemic (high and low potassium blood concentrations) periodic paralysis, myotonia congenita and paramyotonia congenita.

Channelopathies affecting synaptic function are a type of synaptopathy.


Genetic type

Mutations in genes encoding ion channels, which cause defects in channel function, are the most common cause of channelopathies. [5]

Acquired type

Acquired channelopathies are caused by acquired disorders, drug use, toxins, etc. [5]


The types in the following table are commonly accepted.[ by whom? ][ citation needed ] Channelopathies currently under research, like Kir4.1 potassium channel in multiple sclerosis, are not included.

ConditionChannel type
Alternating hemiplegia of childhood Na⁺/K⁺-ATPase
Bartter syndrome various by type
Brugada syndrome various, by type
Catecholaminergic polymorphic ventricular tachycardia (CPVT) Ryanodine receptor
Congenital hyperinsulinism Inward-rectifier potassium ion channel
Cystic fibrosis Chloride channel
Dravet Syndrome Voltage-gated sodium channel
Episodic ataxia Voltage-gated potassium channel
Erythromelalgia Voltage-gated sodium channel
Generalized epilepsy with febrile seizures plus Voltage-gated sodium channel
Familial hemiplegic migraine various
Associated with one particular disabling form of Fibromyalgia [6] Voltage-gated sodium channel
Hyperkalemic periodic paralysis Voltage-gated sodium channel
Hypokalemic periodic paralysis Voltage-gated sodium channel

voltage-dependent calcium channel (calciumopathy)

Lambert–Eaton myasthenic syndrome Voltage-gated calcium channel
Long QT syndrome

main type Romano-Ward syndrome

various, by type
Malignant hyperthermia Ligand-gated calcium channel
Mucolipidosis type IV Non-selective cation channel
Myotonia congenita Voltage-dependent chloride channel
Neuromyelitis optica Aquaporin-4 water channel
Neuromyotonia Voltage-gated potassium channel
Nonsyndromic deafness various
Paramyotonia congenita
(a periodic paralysis)
Voltage-gated sodium channel
Polymicrogyria (brain malformation) Voltage-gated sodium channel, SCN3A [7] ATP1A3 [8]
Retinitis pigmentosa
(some forms)
Ligand-gated non-specific ion channels
Short QT syndrome various potassium channels suspected
Temple–Baraitser syndrome Voltage-gated potassium channel, KCNH1 [9]
Timothy syndrome Voltage-dependent calcium channel
Tinnitus Voltage-gated potassium channel of the KCNQ family
Seizure Voltage-dependent potassium channel [10] [11]
Zimmermann–Laband syndrome, type1 Voltage-gated potassium channel, KCNH1

Related Research Articles

<span class="mw-page-title-main">Brugada syndrome</span> Heart conduction disease

Brugada syndrome (BrS) is a genetic disorder in which the electrical activity of the heart is abnormal due to channelopathy. It increases the risk of abnormal heart rhythms and sudden cardiac death. Those affected may have episodes of syncope. The abnormal heart rhythms seen in those with Brugada syndrome often occur at rest. They may be triggered by a fever.

Myotonia is a symptom of a small handful of certain neuromuscular disorders characterized by delayed relaxation of the skeletal muscles after voluntary contraction or electrical stimulation.

Hyperkalemic periodic paralysis is an inherited autosomal dominant disorder that affects sodium channels in muscle cells and the ability to regulate potassium levels in the blood. It is characterized by muscle hyperexcitability or weakness which, exacerbated by potassium, heat or cold, can lead to uncontrolled shaking followed by paralysis. Onset usually occurs in early childhood, but it still occurs with adults.

<span class="mw-page-title-main">Romano–Ward syndrome</span> Medical condition

Romano–Ward syndrome is the most common form of congenital Long QT syndrome (LQTS), a genetic heart condition that affects the electrical properties of heart muscle cells. Those affected are at risk of abnormal heart rhythms which can lead to fainting, seizures, or sudden death. Romano–Ward syndrome can be distinguished clinically from other forms of inherited LQTS as it affects only the electrical properties of the heart, while other forms of LQTS can also affect other parts of the body.

<span class="mw-page-title-main">Andersen–Tawil syndrome</span> Rare autosomal dominant genetic disorder

Andersen–Tawil syndrome, also called Andersen syndrome and long QT syndrome 7, is a rare genetic disorder affecting several parts of the body. The three predominant features of Andersen–Tawil syndrome include disturbances of the electrical function of the heart characterised by an abnormality seen on an electrocardiogram and a tendency to abnormal heart rhythms, physical characteristics including low-set ears and a small lower jaw, and intermittent periods of muscle weakness known as hypokalaemic periodic paralysis.

hERG Mammalian protein found in humans

hERG is a gene that codes for a protein known as Kv11.1, the alpha subunit of a potassium ion channel. This ion channel is best known for its contribution to the electrical activity of the heart: the hERG channel mediates the repolarizing IKr current in the cardiac action potential, which helps coordinate the heart's beating.

Myotonia congenita is a congenital neuromuscular channelopathy that affects skeletal muscles. It is a genetic disorder. The hallmark of the disease is the failure of initiated contraction to terminate, often referred to as delayed relaxation of the muscles (myotonia) and rigidity. Symptoms include delayed relaxation of the muscles after voluntary contraction (myotonia), and may also include stiffness, hypertrophy (enlargement), transient weakness in some forms of the disorder, severe masseter spasm, and cramping. The condition is sometimes referred to as fainting goat syndrome, as it is responsible for the eponymous 'fainting' seen in fainting goats when presented with a sudden stimulus. Of note, myotonia congenita has no association with malignant hyperthermia (MH).

<span class="mw-page-title-main">Inward-rectifier potassium channel</span> Group of transmembrane proteins that passively transport potassium ions

Inward-rectifier potassium channels (Kir, IRK) are a specific lipid-gated subset of potassium channels. To date, seven subfamilies have been identified in various mammalian cell types, plants, and bacteria. They are activated by phosphatidylinositol 4,5-bisphosphate (PIP2). The malfunction of the channels has been implicated in several diseases. IRK channels possess a pore domain, homologous to that of voltage-gated ion channels, and flanking transmembrane segments (TMSs). They may exist in the membrane as homo- or heterooligomers and each monomer possesses between 2 and 4 TMSs. In terms of function, these proteins transport potassium (K+), with a greater tendency for K+ uptake than K+ export. The process of inward-rectification was discovered by Denis Noble in cardiac muscle cells in 1960s and by Richard Adrian and Alan Hodgkin in 1970 in skeletal muscle cells.

Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's membrane. They belong to the superfamily of cation channels and can be classified according to the trigger that opens the channel for such ions, i.e. either a voltage-change ("voltage-gated", "voltage-sensitive", or "voltage-dependent" sodium channel; also called "VGSCs" or "Nav channel") or a binding of a substance (a ligand) to the channel (ligand-gated sodium channels).

Periodic paralysis is a group of rare genetic diseases that lead to weakness or paralysis from common triggers such as cold, heat, high carbohydrate meals, not eating, stress or excitement and physical activity of any kind. The underlying mechanism of these diseases are malfunctions in the ion channels in skeletal muscle cell membranes that allow electrically charged ions to leak in or out of the muscle cell, causing the cell to depolarize and become unable to move.

<span class="mw-page-title-main">Hypokalemic periodic paralysis</span> Medical condition

Hypokalemic periodic paralysis (hypoKPP), also known as familial hypokalemic periodic paralysis (FHPP), is a rare, autosomal dominant channelopathy characterized by muscle weakness or paralysis when there is a fall in potassium levels in the blood. In individuals with this mutation, attacks sometimes begin in adolescence and most commonly occur with individual triggers such as rest after strenuous exercise, high carbohydrate meals, meals with high sodium content, sudden changes in temperature, and even excitement, noise, flashing lights, cold temperatures and stress. Weakness may be mild and limited to certain muscle groups, or more severe full-body paralysis. During an attack, reflexes may be decreased or absent. Attacks may last for a few hours or persist for several days. Recovery is usually sudden when it occurs, due to release of potassium from swollen muscles as they recover. Some patients may fall into an abortive attack or develop chronic muscle weakness later in life.

<span class="mw-page-title-main">Paramyotonia congenita</span> Medical condition

Paramyotonia congenita (PC) is a rare congenital autosomal dominant neuromuscular disorder characterized by "paradoxical" myotonia. This type of myotonia has been termed paradoxical because it becomes worse with exercise whereas classical myotonia, as seen in myotonia congenita, is alleviated by exercise. PC is also distinguished as it can be induced by cold temperatures. Although more typical of the periodic paralytic disorders, patients with PC may also have potassium-provoked paralysis. PC typically presents within the first decade of life and has 100% penetrance. Patients with this disorder commonly present with myotonia in the face or upper extremities. The lower extremities are generally less affected. While some other related disorders result in muscle atrophy, this is not normally the case with PC. This disease can also present as hyperkalemic periodic paralysis and there is debate as to whether the two disorders are actually distinct.

Neuromuscular medicine is a subspecialty of neurology and physiatry that focuses the diagnosis and management of neuromuscular diseases. The field encompasses issues related to both diagnosis and management of these conditions, including rehabilitation interventions to optimize the quality of life of individuals with these conditions. This field encompasses disorders that impact both adults and children. Neuromuscular disease can be caused by autoimmune disorders, genetic or hereditary disorders such as channelopathies, or neurodegenerative diseases. Because they frequently have no cure, the focus is managing the condition to provide improvements in the patients quality. Rehabilitation robotics is a new frontier for neurological rehabilitation treatments.


Sodium channel protein type 5 subunit alpha, also known as NaV1.5 is an integral membrane protein and tetrodotoxin-resistant voltage-gated sodium channel subunit. NaV1.5 is found primarily in cardiac muscle, where it mediates the fast influx of Na+-ions (INa) across the cell membrane, resulting in the fast depolarization phase of the cardiac action potential. As such, it plays a major role in impulse propagation through the heart. A vast number of cardiac diseases is associated with mutations in NaV1.5 (see paragraph genetics). SCN5A is the gene that encodes the cardiac sodium channel NaV1.5.

<span class="mw-page-title-main">CLCN1</span>

The CLCN family of voltage-dependent chloride channel genes comprises nine members which demonstrate quite diverse functional characteristics while sharing significant sequence homology. The protein encoded by this gene regulates the electric excitability of the skeletal muscle membrane. Mutations in this gene cause two forms of inherited human muscle disorders: recessive generalized myotonia congenita (Becker) and dominant myotonia (Thomsen).


Sodium channel protein type 1 subunit alpha (SCN1A), is a protein which in humans is encoded by the SCN1A gene.


Sodium channel protein type 2 subunit alpha , is a protein that in humans is encoded by the SCN2A gene. Functional sodium channels contain an ion conductive alpha subunit and one or more regulatory beta subunits. Sodium channels which contain sodium channel protein type 2 subunit alpha are sometimes called Nav1.2 channels.

<span class="mw-page-title-main">KCND3</span>

Potassium voltage-gated channel subfamily D member 3 also known as Kv4.3 is a protein that in humans is encoded by the KCND3 gene. It contributes to the cardiac transient outward potassium current (Ito1), the main contributing current to the repolarizing phase 1 of the cardiac action potential.

<span class="mw-page-title-main">Thyrotoxic periodic paralysis</span> Human disease

Thyrotoxic periodic paralysis (TPP) is a condition featuring attacks of muscle weakness in the presence of hyperthyroidism. Hypokalemia is usually present during attacks. The condition may be life-threatening if weakness of the breathing muscles leads to respiratory failure, or if the low potassium levels lead to cardiac arrhythmias. If untreated, it is typically recurrent in nature.

Louis Ptáček is an American neurologist and professor who contributed greatly to the field of genetics and neuroscience. He was also an HHMI investigator from 1997 to 2018. His chief areas of research include the understanding of inherited Mendelian disorders and circadian rhythm genes. Currently, Ptáček is a neurology professor and a director of the Division of Neurogenetics in University of California, San Francisco, School of Medicine. His current investigations primarily focus on extensive clinical studies in families with hereditary disorders, which include identifying and characterizing the genes responsible for neurological variations.


  1. Kim JB (January 2014). "Channelopathies". Korean Journal of Pediatrics. 57 (1): 1–18. doi:10.3345/kjp.2014.57.1.1. PMC   3935107 . PMID   24578711.
  2. Imbrici P, Liantonio A, Camerino GM, De Bellis M, Camerino C, Mele A, et al. (2016-05-10). "Therapeutic Approaches to Genetic Ion Channelopathies and Perspectives in Drug Discovery". Frontiers in Pharmacology. 7: 121. doi: 10.3389/fphar.2016.00121 . PMC   4861771 . PMID   27242528.
  3. Marbán E (January 2002). "Cardiac channelopathies". Nature. 415 (6868): 213–218. Bibcode:2002Natur.415..213M. doi:10.1038/415213a. PMID   11805845. S2CID   4419017.
  4. Kim JB (January 2014). "Channelopathies". Korean Journal of Pediatrics. 57 (1): 1–18. doi:10.3345/kjp.2014.57.1.1. PMC   3935107 . PMID   24578711.
  5. 1 2 Kim JB (January 2014). "Channelopathies". Korean Journal of Pediatrics. 57 (1): 1–18. doi:10.3345/kjp.2014.57.1.1. PMC   3935107 . PMID   24578711.
  6. Vargas-Alarcon G, Alvarez-Leon E, Fragoso JM, Vargas A, Martinez A, Vallejo M, Martinez-Lavin M (February 2012). "A SCN9A gene-encoded dorsal root ganglia sodium channel polymorphism associated with severe fibromyalgia". BMC Musculoskeletal Disorders. 13: 23. doi:10.1186/1471-2474-13-23. PMC   3310736 . PMID   22348792.
  7. Smith RS, Kenny CJ, Ganesh V, Jang A, Borges-Monroy R, Partlow JN, et al. (September 2018). "Sodium Channel SCN3A (NaV1.3) Regulation of Human Cerebral Cortical Folding and Oral Motor Development". Neuron. 99 (5): 905–913.e7. doi:10.1016/j.neuron.2018.07.052. PMC   6226006 . PMID   30146301.
  8. Smith RS, Florio M, Akula SK, Neil JE, Wang Y, Hill RS, et al. (June 2021). "Early role for a Na+,K+-ATPase (ATP1A3) in brain development". Proceedings of the National Academy of Sciences of the United States of America. 118 (25): e2023333118. doi: 10.1073/pnas.2023333118 . PMC   8237684 . PMID   34161264.
  9. Simons C, Rash LD, Crawford J, Ma L, Cristofori-Armstrong B, Miller D, et al. (January 2015). "Mutations in the voltage-gated potassium channel gene KCNH1 cause Temple-Baraitser syndrome and epilepsy". Nature Genetics. 47 (1): 73–77. doi:10.1038/ng.3153. PMID   25420144. S2CID   52799681.
  10. Hunter JV, Moss AJ (January 2009). "Seizures and arrhythmias: Differing phenotypes of a common channelopathy?". Neurology. 72 (3): 208–209. doi:10.1212/01.wnl.0000339490.98283.c5. PMID   19153369. S2CID   207103822.
  11. Mulley JC, Scheffer IE, Petrou S, Berkovic SF (April 2003). "Channelopathies as a genetic cause of epilepsy". Current Opinion in Neurology. 16 (2): 171–176. doi:10.1097/00019052-200304000-00009. PMID   12644745. S2CID   40441842.


VIDEO Channel Surfing in Pediatrics by Carl E. Stafstrom, M.D., at the UW-Madison Health Sciences Learning Center.