Inherited

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.

Epidemiology

 * 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

Clinical Presentation

 * 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
 * Bradycardia
 * 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

LQT1

 * 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

LQT2

 * 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

LQT3

 * 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

LQT4

 * 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

LQT5

 * 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 [51].

LQT6

 * 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.

LQT7

 * 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.

= Phenotypes/Clinical Features: =

Romano-Ward syndrome

 * 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

= Other: =

Rett syndrome

 * 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

Timothy syndrome

 * Multisystem disorder including
 * Syndactyly
 * Dysmorphic features
 * Cognitive deficits
 * Autism
 * Arrhythmias, severe QT prolongation (QTc >650 msec)
 * Associated with de novo mutation in the cardiac L-type calcium channel.