Andersen-Tawil syndrome pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Charmaine Patel, M.D. [2]; Raviteja Guddeti, M.B.B.S. [3]
Pathophysiology
Andersen-Tawil syndrome affects the heart, symptoms are a disruption in the rhythm of the heart's lower chambers (ventricular arrhythmia) in addition to the symptoms of long QT syndrome. There are also physical abnormalities associated with Andersen-Tawil syndrome, these typically affect the head, face, and limbs. These features often include an unusually small lower jaw (micrognathia), low-set ears, and an abnormal curvature of the fingers called clinodactyly.
Genetics
The protein made by the KCNJ2 gene forms a channel that transports potassium ions into muscle cells. The movement of potassium ions through these channels is critical for maintaining the normal functions of skeletal muscles which are used for movement and cardiac muscle. Mutations in the KCNJ2 gene alter the usual structure and function of potassium channels or prevent the channels from being inserted correctly into the cell membrane. Many mutations prevent a molecule called PIP2 from binding to the channels and effectively regulating their activity. These changes disrupt the flow of potassium ions in skeletal and cardiac muscle, leading to the periodic paralysis and irregular heart rhythm characteristic of Andersen-Tawil syndrome.[1]
Researchers have not yet determined the role of the KCNJ2 gene in bone development, and it is not known how mutations in the gene lead to the developmental abnormalities often found in Andersen-Tawil syndrome.
Overview
Pathophysiology
Physiology
The normal physiology of [name of process] can be understood as follows:
Pathogenesis
- It is understood that Andersen-Tawil syndrome is the result of mutation in KCNJ2 gene.[2][3]
- KCNJ2 gene encodes for Kir2.1 inward rectifier potassium channel which is a component of the inward rectifier IK1 and involves in repolarizing current during the late phase of repolarization and plays an important role in controlling the diastolic membrane potential of the cardiac membrane.[4]
- The protein encoded by the KCNJ2 gene which is Kir2.1 inward rectifier potassium channel transports potassium ions into muscle cells.
- The movement of Kir2.1 inward rectifier potassium channel ions is very crucial in maintaining the normal functions of skeletal muscles which are used for movement and cardiac muscle.
- Any change in the Kir2.1 inward rectifier potassium channel ions transport especially in the heart leads to abnormal heart rhythm which will result in arrhythmia and long QT or QU syndrome.[5]
- Any change in the Kir2.1 inward rectifier potassium channel ions transport in skeletal muscles leads to periodic paralysis and and developmental abnormalities.[6]
- [Pathogen name] is usually transmitted via the [transmission route] route to the human host.
- Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.
- [Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].
- The progression to [disease name] usually involves the [molecular pathway].
- The pathophysiology of [disease/malignancy] depends on the histological subtype
Genetics
- Andersen-Tawil syndrome is transmitted in autosomal dominant pattern.
- Genes involved in the pathogenesis of Andersen-Tawil syndrome include:[7][8][9][10]
- KCNJ2 gene in 60% of the cases Andersen-Tawil syndrome (ATS) 1 type
- Unknown gene defect in 40% of the cases of Andersen-Tawil syndrome (ATS) 2 type
- KCNJ5 gene is also implicated but no cases reported in Andersen-Tawil syndrome
References
- ↑ Tan SV, Z'graggen WJ, Boërio D; et al. (2012). "Membrane dysfunction in Andersen-Tawil syndrome assessed by velocity recovery cycles". Muscle Nerve. 46 (2): 193–203. doi:10.1002/mus.23293. PMID 22806368. Unknown parameter
|month=ignored (help) - ↑ Limberg MM, Zumhagen S, Netter MF, Coffey AJ, Grace A, Rogers J; et al. (2013). "Non dominant-negative KCNJ2 gene mutations leading to Andersen-Tawil syndrome with an isolated cardiac phenotype". Basic Res Cardiol. 108 (3): 353. doi:10.1007/s00395-013-0353-1. PMID 23644778.
- ↑ Doi T, Makiyama T, Morimoto T, Haruna Y, Tsuji K, Ohno S; et al. (2011). "A novel KCNJ2 nonsense mutation, S369X, impedes trafficking and causes a limited form of Andersen-Tawil syndrome". Circ Cardiovasc Genet. 4 (3): 253–60. doi:10.1161/CIRCGENETICS.110.958157. PMID 21493816.
- ↑ Tristani-Firouzi M, Etheridge SP (2010). "Kir 2.1 channelopathies: the Andersen-Tawil syndrome". Pflugers Arch. 460 (2): 289–94. doi:10.1007/s00424-010-0820-6. PMID 20306271.
- ↑ Haruna Y, Kobori A, Makiyama T, Yoshida H, Akao M, Doi T; et al. (2007). "Genotype-phenotype correlations of KCNJ2 mutations in Japanese patients with Andersen-Tawil syndrome". Hum Mutat. 28 (2): 208. doi:10.1002/humu.9483. PMID 17221872.
- ↑ Ballester LY, Benson DW, Wong B, Law IH, Mathews KD, Vanoye CG; et al. (2006). "Trafficking-competent and trafficking-defective KCNJ2 mutations in Andersen syndrome". Hum Mutat. 27 (4): 388. doi:10.1002/humu.9418. PMID 16541386.
- ↑ Tristani-Firouzi M, Jensen JL, Donaldson MR; et al. (2002). "Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome)". J. Clin. Invest. 110 (3): 381–8. PMID 12163457.
- ↑ Pegan S, Arrabit C, Slesinger PA, Choe S (2006). "Andersen's syndrome mutation effects on the structure and assembly of the cytoplasmic domains of Kir2.1". Biochemistry. 45 (28): 8599–606. doi:10.1021/bi060653d. PMID 16834334.
- ↑ Sansone V, Tawil R (2007). "Management and treatment of Andersen-Tawil syndrome (ATS)". Neurotherapeutics. 4 (2): 233–7. doi:10.1016/j.nurt.2007.01.005. PMID 17395133.
- ↑ Nguyen HL, Pieper GH, Wilders R (2013). "Andersen-Tawil syndrome: clinical and molecular aspects". Int J Cardiol. 170 (1): 1–16. doi:10.1016/j.ijcard.2013.10.010. PMID 24383070.