Medicine:Channelopathy

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Short description: Diseases caused by dysfunction of ion channels or related proteins
Channelopathy
Sodium channel, implicated in channelopathies including Brugada syndrome, long QT syndrome, Dravet syndrome, paramyotonia congenita
SpecialtyMedical genetics, neuromuscular medicine, cardiology
SymptomsDependent on type. Include: Syncope, muscle weakness, seizures, breathlessness
ComplicationsDependent 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]

Channels are typically formed as complexes of several individual, often identical or homologous, proteins.[3][4] Depending on the type and location of the mutation, it may lead to (partial) loss of function, affect gating, conductance, ion selectivity, or signal transduction of the channel. Gain of function variants in channels are also associated with several diseases, and a key target for knockdown genetic therapies. [5]

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.[6] 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.[1]

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.

Causes

Genetic

Mutations in genes encoding ion channels, which cause defects in channel function, are the most common cause of channelopathies.[1] Non-coding changes can also result in channelopathy. Changes in the promoter region, binding site of transcription factors and at splice sites are known to be causative for several epilepsies.[7]

Acquired

Channelopathies can develop due to:

Types

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

Condition Channel type
Bartter syndrome various, by type
Brugada syndrome various, by type
CACNA1C-related disorders Voltage-gated calcium channel
Catecholaminergic polymorphic ventricular tachycardia (CPVT) Ryanodine receptor
Congenital hyperinsulinism Inward-rectifier potassium ion channel
Cystic fibrosis Chloride channel, CFTR
Dravet syndrome Voltage-gated sodium channel
Epilepsy various, including: sodium, potassium, calcium, chloride channels, GABAA receptors, ionotropic glutamate receptors, nicotinic acetylcholine receptors and hyperpolarization-activated cyclic nucleotide-gated channels[7]
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[8] Voltage-gated sodium channel
Hyperkalemic periodic paralysis Voltage-gated sodium channel
Hypokalemic periodic paralysis Voltage-gated sodium channel or
Voltage-dependent calcium channel (calciumopathy)
KCNH1-related disorders Voltage-gated potassium channel, KCNH1
KCNT1-related epilepsy Voltage-gated potassium channel, KCNT1
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[9] ATP1A3[10]
Retinitis pigmentosa (some forms) Ligand-gated non-specific ion channels
SCN2A-related disorders Voltage-gated sodium channel, SCN2A
Short QT syndrome various potassium channels suspected
Temple–Baraitser syndrome Voltage-gated potassium channel, KCNH1[11]
Timothy syndrome Voltage-dependent calcium channel
Tinnitus Voltage-gated potassium channel of the KCNQ family
Seizure
Zimmermann–Laband syndrome, type1 Voltage-gated potassium channel, KCNH1

Ion channels versus ion pumps

Both channels and pumps are ion transporters which move ions across membranes. Channels move ions quickly, through passive transport, down electrical and concentration gradients (moving "downhilll"); whereas pumps move ions slowly, through active transport, building-up gradients (moving "uphill").[12] Historically the difference between the two seemed cut and dried; however, recent research has shown that in some ion transporters, it is not always clear whether it functions as a channel or a pump.[12]

Diseases involving ion pumps can produce symptoms similar to channelopathies, as they both involve the movement of ions across membranes. Brody disease (also known as Brody myopathy) includes symptoms similar to myotonia congenita, including muscle stiffness and cramping after initiating exercise (delayed muscle relaxation). However, it is pseudo-myotonia as those with Brody disease have normal EMG.[13]

Due to similar symptoms, different genes for both channels and pumps can be associated with the same disease. For instance, polymicrogyria has been associated with the channel gene SCN3A[14] and the pump gene ATP1A3,[10] among other genes that are not ion transporters.[15]

See also

References

  1. ↑ 1.0 1.1 1.2 "Channelopathies". Korean Journal of Pediatrics 57 (1): 1–18. January 2014. doi:10.3345/kjp.2014.57.1.1. PMID 24578711. 
  2. ↑ "Therapeutic Approaches to Genetic Ion Channelopathies and Perspectives in Drug Discovery". Frontiers in Pharmacology 7: 121. 2016-05-10. doi:10.3389/fphar.2016.00121. PMID 27242528. 
  3. ↑ "Chapter 4: Channels and Transporters". Neuroscience (2nd ed.). Sinauer Associates Inc.. 2001. ISBN 978-0-87893-741-7. https://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.chapter.227. 
  4. ↑ "Chapter 6: Electrical Excitability and Ion Channels". Basic neurochemistry: molecular, cellular, and medical aspects. Philadelphia: Lippincott-Raven. 1999. ISBN 978-0-397-51820-3. https://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=bnchm.chapter.421. 
  5. ↑ Golinski, SR; Soriano, K; Briegel, AC; Burke, MC; Tang, S; Carvill, GL; Sherrill, E; Lentucci, C et al. (29 April 2026). "RNA targeting therapy for a prenatally enriched potassium channel associated with severe childhood epilepsy and premature death.". Nature Communications 17 (1). doi:10.1038/s41467-026-72334-7. PMID 42056090. Bibcode: 2026NatCo..17.5864G. 
  6. ↑ "Cardiac channelopathies". Nature 415 (6868): 213–218. January 2002. doi:10.1038/415213a. PMID 11805845. Bibcode: 2002Natur.415..213M. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 Karen M J van Loo; Becker, A. J. (January 2020). "Transcriptional Regulation of Channelopathies in Genetic and Acquired Epilepsies". Frontiers in Cellular Neuroscience 13. doi:10.3389/fncel.2019.00587. PMID 31992970. 
  8. ↑ "A SCN9A gene-encoded dorsal root ganglia sodium channel polymorphism associated with severe fibromyalgia". BMC Musculoskeletal Disorders 13. February 2012. doi:10.1186/1471-2474-13-23. PMID 22348792. 
  9. ↑ "Sodium Channel SCN3A (NaV1.3) Regulation of Human Cerebral Cortical Folding and Oral Motor Development". Neuron 99 (5): 905–913.e7. September 2018. doi:10.1016/j.neuron.2018.07.052. PMID 30146301. 
  10. ↑ 10.0 10.1 "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). June 2021. doi:10.1073/pnas.2023333118. PMID 34161264. Bibcode: 2021PNAS..11823333S. 
  11. ↑ "Mutations in the voltage-gated potassium channel gene KCNH1 cause Temple-Baraitser syndrome and epilepsy". Nature Genetics 47 (1): 73–77. January 2015. doi:10.1038/ng.3153. PMID 25420144. 
  12. ↑ 12.0 12.1 Gadsby, David C. (May 2009). "Ion channels versus ion pumps: the principal difference, in principle". Nature Reviews. Molecular Cell Biology 10 (5): 344–352. doi:10.1038/nrm2668. ISSN 1471-0080. PMID 19339978. Bibcode: 2009NRMCB..10..344G. 
  13. ↑ Braz, Luís; Soares-Dos-Reis, Ricardo; Seabra, Mafalda; Silveira, Fernando; Guimarães, Joana (October 2019). "Brody disease: when myotonia is not myotonia". Practical Neurology 19 (5): 417–419. doi:10.1136/practneurol-2019-002224. ISSN 1474-7766. PMID 30996034. 
  14. ↑ Smith, Richard S.; Kenny, Connor J.; Ganesh, Vijay; Jang, Ahram; Borges-Monroy, Rebeca; Partlow, Jennifer N.; Hill, R. Sean; Shin, Taehwan et al. (2018-09-05). "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. ISSN 0896-6273. PMID 30146301. 
  15. ↑ Stutterd, Chloe A.; Leventer, Richard J. (June 2014). "Polymicrogyria: a common and heterogeneous malformation of cortical development". American Journal of Medical Genetics. Part C, Seminars in Medical Genetics 166C (2): 227–239. doi:10.1002/ajmg.c.31399. ISSN 1552-4876. PMID 24888723. 

Bibliography

Classification

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

Template:Diseases of myoneural junction and muscle

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