Thompson & Thompson Genetics in Medicine, 8th Edition

Case 28. Long QT Syndrome (Cardiac Ion Channel Gene Mutations; MIM 192500)

Autosomal Dominant or Recessive

Principles

• Locus heterogeneity

• Incomplete penetrance

• Genetic susceptibility to medications

Major Phenotypic Findings

• QTc prolongation (>470 msec in males, >480 msec in females)

• Tachyarrhythmias (torsades de pointes)

• Syncopal episodes

• Sudden death

History and Physical Findings

A.B. is a 30-year-old woman with long QT (LQT) syndrome who presents to the genetics clinic with her husband because they are contemplating a pregnancy. The couple wants to know the recurrence risk for this condition in their children and the genetic testing and prenatal diagnosis options that might be available to them. She is also concerned about potential risks to her own health in carrying a pregnancy. The patient was diagnosed with the LQT syndrome in her early 20s when she was evaluated after the sudden death of her 15-year-old brother. Overall, she is a healthy individual with normal hearing, no dysmorphic features, and an otherwise negative review of systems. She has never had any fainting episodes. Subsequently, electrocardiographic findings confirmed the diagnosis of the syndrome in A.B., and a paternal aunt but not in her father, who had a normal QTc interval. Molecular testing revealed a missense mutation in KCNH2, one that had been previously seen in other families with Romano-Ward syndrome, type LQT2. A.B. was initially prescribed β-blockade medication, which she is continuing, but her cardiologists decided that the less than total efficacy of β-blockers in LQT2 and the previous lethal event in her brother justified the use of an implantable cardioverter-defibrillators in A.B. and her affected relatives. A.B. is the first person in her family to pursue genetic counseling for the LQT syndrome.

Background

Disease Etiology and Incidence

The LQT syndromes are a heterogeneous, panethnic group of disorders referred to as channelopathies because they are caused by defects in cardiac ion channels. The overall prevalence of LQT disorders is approximately 1 in 5000 to 7000 individuals.

The genetics underlying LQT syndromes is complex. First, there is locus heterogeneity. Mutations in at least five known cardiac ion channel genes (KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2) are responsible for most cases of LQT; mutations in additional genes are known, but much rarer. Second, different mutant alleles in the same locus can result in two distinct LQT syndromes with two different inheritance patterns, the Romano-Ward syndrome and the autosomal recessive Jervell and Lange-Nielsen syndrome (MIM 220400).

Pathogenesis

LQT syndrome is caused by repolarization defects in cardiac cells. Repolarization is a controlled process that requires a balance between inward currents of sodium and calcium and outward currents of potassium. Imbalances cause the action potential of cells to increase or decrease in duration, causing elongation or shortening, respectively, of the QT interval on electrocardiography. Most cases of LQT syndrome are caused by loss-of-function mutations in genes that encode subunits or regulatory proteins for potassium channels (genes whose names begin with KCN). These mutations decrease the outward, repolarization current, thereby prolonging the action potential of the cell and lowering the threshold for another depolarization. In other LQT syndrome patients, gain-of-function mutations in a sodium channel gene, SCN5A,lead to an increased influx of sodium, resulting in similar shifting of action potential and repolarization effects.

Phenotype and Natural History

The LQT syndromes are characterized by elongated QT interval and T-wave abnormalities on electrocardiography (Fig. C-28), including tachyarrhythmia and torsades de pointes, a ventricular tachycardia characterized by a change in amplitude and twisting of the QRS complex. Torsades de pointes is associated with a prolonged QT interval and typically stops spontaneously but may persist and worsen to ventricular fibrillation.

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FIGURE C-28 A, Measurement of the QT interval from the electrocardiogram. The diagram depicts the normal electrocardiogram with the P wave representing atrial activation, the QRS complex representing ventricular activation and the start of ventricular contraction, and the T wave representing ventricular repolarization. Owing to heart rate sensitivity of the QT interval, this parameter is corrected (normalized) to heart rate (as reflected by the beat-to-beat RR interval), yielding the QTc. QT and QTc can both be expressed in milliseconds or seconds. B, Arrhythmia onset in long QT syndrome. Three simultaneous (and distinct) electrocardiographic channel recordings in a patient with QT prolongation and runs of continuously varying polymorphic ventricular tachycardia (torsades de pointes). Torsades de pointes may resolve spontaneously or progress to ventricular fibrillation and cardiac arrest. See Sources & Acknowledgments.

In the most common LQT syndrome, Romano-Ward, syncope due to cardiac arrhythmia is the most frequent symptom; if undiagnosed or left untreated, it recurs and can be fatal in 10% to 15% of cases. However, between 30% and 50% of individuals with the syndrome never show syncopal symptoms. Cardiac episodes are most frequent from the preteen years through the 20s, with the risk decreasing over time. Episodes may occur at any age when triggered by QT-prolonging medications (see list at http://www.qtdrugs.org). Nonpharmacological triggers for cardiac events in the Romano-Ward syndrome differ on the basis of the gene responsible. LQT1 triggers are typically adrenergic stimuli, including exercise and sudden emotion. Individuals with LTQ2 are at risk with exercise and at rest and with auditory stimuli, such as alarm clocks and phones. LQT3 individuals have episodes with slower heart rates during rest periods and sleep. In addition, 40% of LQT1 cases are symptomatic before 10 years of age; in 10% of LTQ2 and rarely in LQT3 do symptoms occur before 10 years of age. There are at least 10 genes associated with LQT syndromes, of which two—KCNQ1 and KCNH2—account for over 80% of cases.

The LQT syndrome exhibits reduced penetrance in terms of both electrocardiographic abnormalities and syncopal episodes. As many as 30% of affected individuals can have QT intervals that overlap with the normal range. Variable expression of the disorder can occur within and between families. Due to reduced penetrance, exercise electrocardiography is often used for diagnosis of at-risk family members but is not 100% sensitive.

LQT syndromes may be accompanied by other findings on physical examination. For example, Jervell and Lange-Nielsen syndrome (MIM 220400) is characterized by congenital, profound sensorineural hearing loss together with LQT syndrome. It is an autosomal recessive disorder caused by particular mutations within the same two genes (KCNQ1 and KCNE1) implicated in the autosomal dominant Romano-Ward syndrome. Heterozygous relatives of Jervell and Lange-Nielsen syndrome patients are not deaf but have a 25% risk for LQT syndrome.

Management

Treatment of the LQT syndrome is aimed at prevention of syncopal episodes and cardiac arrest. Optimal treatment is influenced by identification of the gene responsible in a given case. For instance, β-blocker therapy before the onset of symptoms is most effective in LQT1 and, to a somewhat lesser extent, in LQT2, but its efficacy in LQT3 is reduced. β-Blockade therapy must be monitored closely for age-related dose adjustment, and it is imperative that doses are not missed. Pacemakers may be necessary for individuals with bradycardia; access to external defibrillators may be appropriate. Implantable cardioverter-defibrillators may be needed in individuals with LQT3 or in other individuals with the LQT syndrome in whom β-blocker therapy is problematic, such as in patients with asthma, depression, or diabetes and those with a history or family history of cardiac arrest. Medications such as the antidepressant amitriptyline, over-the-counter cold medications such as phenylephrine and diphenhydramine, or antifungal drugs, including fluconazole and ketoconazole, should be avoided because of their effect on prolonging the QT interval or causing increased sympathetic tone. Activities and sports likely to be associated with intense physical activity, emotion, or stress should also be avoided.

Inheritance Risk

Individuals with the Romano-Ward syndrome have a 50% chance of having a child with the inherited gene mutations. Most individuals have an affected (although perhaps asymptomatic) parent, because the rate of de novo mutations is low. A detailed family history and careful cardiac evaluation of family members are extremely important and could be lifesaving. The recurrence risk in siblings of patients with Jervell and Lange-Nielsen syndrome is 25%, as expected with an autosomal recessive condition. The penetrance of LQT alone, without deafness, is 25% in heterozygous carriers in Jervell and Lange-Nielsen syndrome families.

Questions for Small Group Discussion

1. Some genetic syndromes rely on clinical evaluation, even with the availability of molecular testing, for diagnosis. In the case of LQT, how would you proceed with a patient thought to have LQT on family history? Why?

2. Discuss the ethics of testing minors in this condition.

3. You have just diagnosed a child with Jervell and Lange-Nielsen syndrome. What do you counsel the family in regard to recurrence risk and management for other family members?

References

Alders M, Mannens MMAM. Romano-Ward syndrome. [Available from] http://www.ncbi.nlm.nih.gov/books/NBK1129/.

Guidicessi JR, Ackerman MJ. Genotype- and phenotype-guided management of congenital long QT syndrome. Curr Probl Cardiol. 2013;38:417–455.

Martin CA, Huang CL, Matthews GD. The role of ion channelopathies in sudden cardiac death: implications for clinical practice. Ann Med. 2013;45:364–374.

Tranebjaerg L, Samson RA, Green GE. Jervell and Lange-Nielsen syndrome. [Available from] http://www.ncbi.nlm.nih.gov/books/NBK1405/.