LQT3
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Long QT Syndrome Microchapters |
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Diagnosis |
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Treatment |
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Case Studies |
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LQT3 On the Web |
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American Roentgen Ray Society Images of LQT3 |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]
Overview
LQT3 is the third most common subtype of long QT syndrome, occurring in 5-10% of LQTS cases. It is most commonly associated with cardiac events that occur during sleep. This subtype is highly likely to show shortening of the QT interval in response to administration of mexilitine. This subtype is caused by a mutation in chromosome 3, which affects the sodium channels. The slow leakage of sodium into the cells causes cell membrane instability, and a prolonged QT interval on EKG.
LQT3 Subtype
| Type | OMIM | Mutation | Notes |
| LQT3 | 603830 | alpha subunit of the sodium channel (SCN5A) | Current through this channel is commonly referred to as INa. Depolarizing current through the channel late in the action potential is thought to prolong APD. The late current is due to failure of the channel to remain inactivated and hence enter a bursting mode in which significant current can enter when it should not. These mutations are more lethal but less common. |
=Genetics and Pathophysiology
The LQT3 type of long QT syndrome accounts for 5-10% of cases, and cardiac events can occur during sleep. This variant involves a mutation of the gene that encodes the alpha subunit of the Na+ ion channel. This gene is located on chromosome 3p21-24, and is known as SCN5A (also hH1 and NaV1.5). The mutations involved in LQT3 slow the inactivation of the Na+ channel, resulting in prolongation of the Na+ influx during depolarization. As the sodium channel is not adequately inactivated, the membrane remains slightly depolarized by the slow leaking of sodium into the cell. This leads to instability of the membrane, and early after-depolarizations. Paradoxically, the mutant sodium channels inactivate more quickly, and may open repetitively during the action potential.
There have been sporadic mutations in SCN5A that have been reported where neither parent of the affected individual had a mutation or a prolonged QT interval. Individuals affected with this sporadic mutation had the added factors of prolonged opening and early re-opening of the sodium channel, resulting in an even greater prolongation of the sodium channel decay time. These sporadic mutations have also bee associated with sudden infant death syndrome [1].
There have been certain polymorphisms of SCN5A that have been noted in about 13 percent of the African American population. These polymorphisms, named Y1102 and S1103Y are associated with a faster sodium channel activation, however are only shown to create a minimal increase in the risk of arrhythmia. Most of the affected subjects never develop an arrhythmia, however they may be at greater risk of long QT syndrome than the general population if they take certain medications or develop hypokalemia [2].
A large number of mutations have been characterized as leading to or predisposing LQT3. Calcium has been suggested as a regulator of SCN5A, and the effects of calcium on SCN5A may begin to explain the mechanism by which some these mutations cause LQT3. Furthermore mutations in SCN5A can cause Brugada syndrome, Cardiac Conduction disease and dilated cardiomyopathy. Rarely some affected individuals can have combinations of these diseases.
References
- ↑ Kambouris NG, Nuss HB, Johns DC, Tomaselli GF, Marban E, Balser JR (1998). "Phenotypic characterization of a novel long-QT syndrome mutation (R1623Q) in the cardiac sodium channel". Circulation. 97 (7): 640–4. PMID 9495298.
- ↑ Clancy CE, Rudy Y (2002). "Na(+) channel mutation that causes both Brugada and long-QT syndrome phenotypes: a simulation study of mechanism". Circulation. 105 (10): 1208–13. PMC 1997279. PMID 11889015.