Editors-in-Chief: Arnoldas Giedrimas, MD and Alena Goldman, MD
Congenital Long QT Syndrome
Mutations in 7 genes have been identified, designated LQT1 - LQT7, accounting for majority of cases. Two clinical phenotypes are described for patients with the disorder, based on inheritance patterns and presence or absence of sensorineural hearing loss.
- 3000 to 4000 annual sudden deaths in childhood in the US
- Incidence of congenital LQTS estimated at 1 in 2,500 to 10,000 in the general population
- May be asymptomatic, found via baseline EKG or family history
- Symptomatic patients can present with palpitations, presyncope, syncope, seizures, or cardiac arrest.
- Arrhythmias can include:
- Torsade de pointes
- Multiform VPCs
- Uniform VPCs
- Monomorphic VT
- Triggers of arrhythmia vary with the genetic abnormalities
- Excercise most common in patients with LQT1 mutation
- Acute arousal (exercise, emotion, noise) more likely triggers in LQT1 and LQT2 than LQT3.
- Auditory stimuli (alarm clock, telephone) most typically seen in LQT2
- Patients with LQT3 are at highest risk of events when at rest or asleep
- Causes of acquired LQTS can precipitate cardiac events in patients with congenital LQTS
- Accounts for 40-55% cases
- Short arm chromosome 11
- Protein responsible for the slowly acting component of the outward-rectifying potassium current (IKs)
- Also required for inner ear formation (homozygous mutations liked to Jervell-Lange-Nielse syndrome, see below)
- Often have paradoxial QT prolongation with epinephrine administration
- Accounts for 35-45% cases
- Chromosome 7
- HERG protein respondible for rapidly acting component of the outward-rectifying potassium current (IKr)
- Most drugs that cause LQT block the IKr current mediated by HERG
- Accounts for 8-10% cases
- Chromosome 3
- Involves sodium channel leading to impaired inactivation
- Different mutations in this gene also responsible for other disorders:
- Brugada syndrome
- Sudden Unexpected Nocturnal Death Syndrome
- Congenital sick sinus syndrome
- Familial dilated cardiomyopathy
- Chrosome 4q25-27
- Loss of function mutation of Ankyrin-B, a plasma protein (the only type that does not involved ion channel) that links the lipid bilayer to the membrane skeleton
- Patients often have:
- sinus node dysfunction
- sinus bradycardia
- junctional escape rhythm
- atrial fibrillation
- Accounts for 3% cases
- Chromosome 21
- Mutation in minK gene, which together with LQT1 forms the slowly acting component of the outward-rectifying potassium current.
- Homozygous mutations have been reported to cause the Jervell-Lange-Nielsen syndrome .
- Accounts for 2% cases
- Chromosome 21q22.1-22.2
- Mutation in the minK related peptide 1 (MiRP1 or KCNE2) gene, which assembles with HERG, affecting IKr.
- One polymorphism in MiRP1, present in 1.6% of population, is clinically silent, though to predispose to drug-induced LQTS.
- Very rare, described in 17 cases
- Chromosome 17
- KCNJ2 gene which encodes Kir2.1, the inward rectifier potassium channel, in cardiac and skeletal muscle.
- Mutations prolong the terminal phase of the myocardial action potential.
- Autosomal dominant mutations leading to Andersen-Tawil syndrome, patients develop periodic paralysis, skeletal developmental abnormalities, and LQTS.
- Autosomal dominant
- May result from any of the LQTS mutations
- Not associated with deafness
Jervell and Lange-Nielsen syndrome
- Autosomal recessive
- Has been found with LQT1 and LQT5 mutations
- Associated with sensorineural deafness
- Represents a more malignant phenotype with earlier and more frequent rates of cardiac events
- Neurodevelopmental disease, primarily in females, with mutation in MECP2 gene, does not affect ion channel
- Associated with prolonged QT, sudden cardiac death
- Mechanism of QT prolongation unknown
- Multisystem disorder including
- Dysmorphic features
- Cognitive deficits
- Arrhythmias, severe QT prolongation (QTc >650 msec)
- Associated with de novo mutation in the cardiac L-type calcium channel.