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The long Qt syndrome causes sudden cardiac death in the youth.

Long QT syndrome is a major cause of sudden death among young people. It can be congenital or acquired. Its appearance is usually associated with drugs and electrolyte imbalance (hypokalemia, hypocalcemia, and hypomagnesemia). The clinical presentation varies and ranges from asymptomatic patients (diagnosed by family screening) to patients with syncope, seizures, ventricular arrhythmias, ventricular fibrillation and typically torsades de pointes.

Congenital form is associated with mutations in genes encoding ion channels and related proteins. Prolongation of the QT interval may arise for a decrease in potassium current repolarization or inadequate delay sodium entry in myocyte. To date more than 500 have described mutations and polymorphisms in the 130 long QT syndrome generating 10 different types. Although almost all disorders inducing long QT intervals are associated with alterations in the potassium channel, certain types are associated with alterations in sodium channel.
All mutations in the potassium channels (IKs, IKr, Iki) cause functional loss, which reduces the release of potassium from the cells. This means that the channels are kept open longer, so that the QT interval is prolonged due to longer ventricular repolarization. The many mutations which have been described, 300 are located in six potassium channel genes different and represent a 50% -60% of clinical cases of long QT syndrome. One is the KCNQ1 (KvLQT1), which binds to the protein encoded by the gene KCNE1 (minK) to form a functional complex Iks. KCNQ1 mutations result in a 40% -50% of cases of long QT, including long QT syndrome type 1, the most common of all types of long QT syndrome, characterized by delayed and repolarization after prolonged QT interval.
When their heritage stems from an autosomal dominant pattern, called Romano-Ward syndrome and, when original autosomal recessive, it is the Jervell and Lange-Nielsen, which is often associated with deafness. Recently described six new mutations two intron exon four. For the KCNE1 gene have been described to date five mutations that lead to 2% -5% of cases of long QT syndrome is believed to be altered complexes and IKr IKs. Other affected gene is KCNH2 (HERG, human-Ethera-go-go-related), which encodes the alpha subunit of complex Ikr. The alpha subunit is determined by the KCNE2 (MiRP1). Ikr This complex is the main inducing rapid repolarization of phase 3. Mutations in KCNH2 (they have identified more than 80) cause functional loss Ikr channel and provide a 35% -45% of cases of long QT syndrome type 2 autosomal dominant inheritance. In the case of the KCNE2 gene, the mutation also creates a channel functional loss, causing the long QT syndrome type 6, very rare (<1%). Another gene involved in long QT syndrome is KCNJ2, found on chromosome 17. This gene encodes Ik1 (Kir2.1) and contributes to phase 3 repolarization maintaining membrane potential. Mutations in this gene are associated with loss of function leading to long QT syndrome 7 or Anderson-Tawil syndrome. The incidence of this syndrome is very low and rarely linked to syncope or sudden death, although there may be episodes of tachycardia polymorphic or bidirectional.
Long QT syndrome type 3 is associated with mutations in the SCN5A gene. The mutation causes a defect functional derivative of incomplete inactivation of the channel, which allows the entry of sodium ions continuously in the cell during repolarization, which favors its function. Patients with long QT syndrome type 3 presents arrhythmias and symptoms related to bradycardia at rest (especially at night). Long QT syndrome type 10 is caused by a mutation in the gene encoding subunit SCN4B beta (NaVß4) sodium channel. Beta subunit plays an important role in regulating the kinetics of the channel, signal transduction and expression of the sodium channel subunit. NaVß4 subunit causes a negative shift in the voltage-dependent sodium channel activation. SCN4B This mutation induces a positive change in the inactivation of sodium channels, which increases sodium current and delayed repolarization similar to what happens in the long QT syndrome type 3. Long QT syndrome type 9 is caused by a mutation in caveolin-3. It is believed that this type QT interval increases, affecting the functionality of sodium channels. Mutations in this gene improves the function of the sodium channels, as long QT type 3.
Long QT syndrome 8-also called Timothy syndrome has been described recently. Its defects are due to a mutation that encodes the pore CACNA1C (Cav1.2) cardiac calcium channel type L. This is a rare type, but causes the highest mortality rate. The mutation causes an increase with impaired function and loss ICa channel dependent voltage, which causes a prolongation of the action potential and ECG QT interval extremely long.
Clinically, up to 30% of long QT syndrome have an average QT interval, or at the limit of normal, and therefore require more detailed phenotypic detection and / or genetic screening to establish a diagnosis. Since there is a wide variety of mechanisms that cause this syndrome, it is essential to identify the causative mutations to determine treatment. However, genetic screening is negative in a third of patients.

Cardiovascular Genetics Center
IDIBGI C/ Dr Castany s/n
Parc Hospitalari Martí i Julià (M-2)
17290 Salt, Girona
Tel: 872 987087