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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.

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