Long QT Syndrome pathophysiology: Difference between revisions
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The two most common types of LQTS are genetic and drug-induced. Genetic LQTS can arise from mutation to one of several genes. These mutations tend to prolong the duration of the [[ventricular action potential]] (APD), thus lengthening the QT interval. LQTS can be inherited in an [[autosomal dominant]] or an [[autosomal recessive]] fashion. The autosomal recessive forms of LQTS tend to have a more severe[[phenotype]], with some variants having associated [[syndactyly]] (LQT8) or congenital neural deafness (LQT1). A number of specific genes loci have been identified that are associated with LQTS. | The two most common types of LQTS are genetic and drug-induced. Genetic LQTS can arise from mutation to one of several genes. These mutations tend to prolong the duration of the [[ventricular action potential]] (APD), thus lengthening the QT interval. LQTS can be inherited in an [[autosomal dominant]] or an [[autosomal recessive]] fashion. The autosomal recessive forms of LQTS tend to have a more severe[[phenotype]], with some variants having associated [[syndactyly]] (LQT8) or congenital neural deafness (LQT1). A number of specific genes loci have been identified that are associated with LQTS. | ||
===LQT5=== | ===LQT5=== | ||
Revision as of 05:08, 24 August 2012
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Long QT Syndrome Microchapters |
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Long QT Syndrome pathophysiology On the Web |
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]
Overview
Pathophysiology
Genetics
The two most common types of LQTS are genetic and drug-induced. Genetic LQTS can arise from mutation to one of several genes. These mutations tend to prolong the duration of the ventricular action potential (APD), thus lengthening the QT interval. LQTS can be inherited in an autosomal dominant or an autosomal recessive fashion. The autosomal recessive forms of LQTS tend to have a more severephenotype, with some variants having associated syndactyly (LQT8) or congenital neural deafness (LQT1). A number of specific genes loci have been identified that are associated with LQTS.
LQT5
is an autosomal dominant relatively uncommon form of LQTS. It involves mutations in the gene KCNE1 which encodes for the potassium channel beta subunit MinK. In its rare homozygous forms it can lead to Jervell and Lange-Nielsen syndrome
LQT6
is an autosomal dominant relatively uncommon form of LQTS. It involves mutations in the gene KCNE2 which encodes for the potassium channel beta subunit MiRP1, constituting part of the IKr repolarizing K+ current.
LQT7
Andersen-Tawil syndrome is an autosomal dominant form of LQTS associated with skeletal deformities. It involves mutation in the gene KCNJ2 which encodes for the potassium channel protein Kir 2.1. The syndrome is characterized by Long QT syndrome with ventricular arrhythmias, periodic paralysis and skeletal developmental abnormalities as clinodactyly, low-set ears and micrognathia. The manifestations are highly variable.[1]
LQT8
Timothy's syndrome is due to mutations in the calcium channel Cav1.2 encoded by the gene CACNA1c. Since the Calcium channel Cav1.2 is abundant in many tissues, patients with Timothy's syndrome have many clinical manifestations including congenital heart disease, autism, syndactyly and immune deficiency.
LQT9
This newly discovered variant is caused by mutations in the membrane structural protein, caveolin-3. Caveolins form specific membrane domains called caveolae in which among others the NaV1.5 voltage-gated sodium channel sits. Similar to LQT3, these particular mutations increase so-called 'late' sodium current which impairs cellular repolarization.
LQT10
This novel susceptibility gene for LQT is SCN4B encoding the protein NaVβ4, an auxiliary subunit to the pore-forming NaV1.5 (gene: SCN5A) subunit of the voltage-gated sodium channel of the heart. The mutation leads to a positive shift in inactivation of the sodium current, thus increasing sodium current. Only one mutation in one patient has so far been found.
Associated syndromes
A number of syndromes are associated with LQTS.
Jervell and Lange-Nielsen syndrome
The Jervell and Lange-Nielsen syndrome (JLNS) is an autosomal recessive form of LQTS with associated congenital deafness. It is caused specifically by mutation of the KCNE1 and KCNQ1 genes
In untreated individuals with JLNS, about 50 percent die by the age of 15 years due to ventricular arrhythmias.
Romano-Ward syndrome
Romano-Ward syndrome is an autosomal dominant form of LQTS that is notassociated with deafness.
References
- ↑ Tristani-Firouzi M, Jensen JL, Donaldson MR, Sansone V, Meola G, Hahn A, Bendahhou S, Kwiecinski H, Fidzianska A, Plaster N, Fu YH, Ptacek LJ, Tawil R. Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome). Journal of Clinical Investigation. 2002 Aug;110(3):381-8. PMID 12163457.