Long QT Syndrome pathophysiology
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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.
LQT1
LQT1 is the most common type of long QT syndrome, making up about 40 to 55 percent of all cases. The LQT1 gene is KCNQ1 which has been isolated tochromosome 11p15.5. KCNQ1 codes for the voltage-gated potassium channel KvLQT1that is highly expressed in the heart. It is believed that the product of the KCNQ1 gene produces an alpha subunit that interacts with other proteins (particularly the minK beta subunit) to create the IKs ion channel, which is responsible for the delayed potassium rectifier current of the cardiac action potential.
Mutations to the KCNQ1 gene can be inherited in an autosomal dominant or anautosomal recessive pattern in the same family. In the autosomal recessive mutation of this gene, homozygous mutations in KVLQT1 leads to severe prolongation of the QT interval (due to near-complete loss of the IKs ion channel), and is associated with increased risk of ventricular arrhythmias and congenital deafness. This variant of LQT1 is known as the Jervell and Lange-Nielsen syndrome.
Most individuals with LQT1 show paradoxical prolongation of the QT interval with infusion of epinephrine. This can also unmark latent carriers of the LQT1 gene.
Many missense mutations of the LQT1 gene have been identified. These are often associated with a high risk percentage of symptomatic carriers and sudden death.
LQT2
The LQT2 type is the second most common gene location that is affected in long QT syndrome, making up about 35 to 45 percent of all cases. This form of long QT syndrome most likely involves mutations of the human ether-a-go-go related gene(HERG) on chromosome 7. The HERG gene (also known as KCNH2) is part of the rapid component of the potassium rectifying current (IKr). (The IKr current is mainly responsible for the termination of the cardiac action potential, and therefore the length of the QT interval.) The normally functioning HERG gene allows protection against early after depolarizations (EADs).
Most drugs that cause long QT syndrome do so by blocking the IKr current via the HERG gene. These include erythromycin, terfenadine, andketoconazole. The HERG channel is very sensitive to unintended drug binding due to two aromatic amino acids, the tyrosine at position 652 and thephenylalanine at position 656. These amino acid residues are poised so drug binding to them will block the channel from conducting current. Other potassium channels do not have these residues in these positions and are therefore not as prone to blockage.
LQT3
The LQT3 type of long QT syndrome involves 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. Paradoxically, the mutant sodium channels inactivate more quickly, and may open repetitively during the action potential.
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.
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.