long QT syndrome
- related: cardiac arrythmia
- tags: #literature #cardiology
The ECG shows a long QT interval, and this, along with the syncopal episode, allows for the diagnosis of long QT syndrome (LQTS).
Urinary incontinence during loss of consciousness is notoriously unreliable as a diagnostic indication of seizures, and channelopathies are sometimes misdiagnosed for this reason. A history of sudden cardiac death should be sought, with a high index of suspicion; automobile accidents are sometimes caused by sudden syncope in a driver. LQTSs may be congenital or acquired. The most common causes of acquired LQTS are hypokalemia, hypomagnesemia, and QT-prolonging medications (for the definitive list, see crediblemeds.org). Congenital LQTSs are caused by mutations in genes coding for cardiac ion channels. Two clinical phenotypes have been identified: an autosomal dominant form with a purely cardiac phenotype, originally named the Romano-Ward syndrome, and an autosomal recessive type with sensorineural deafness and arrhythmias, originally called the Jervell and Lange-Nielsen syndrome.
Currently, LQTSs have been divided into three main types, characterized by the gene mutation, but each with a characteristic (although variable) phenotype. Type 1 LQTS accounts for about 45% of LQTS and is often triggered by exercise, particularly swimming. It is usually associated with a mutation in the KCNQ1 gene, which causes loss of function of outward-rectifying potassium channels. Type 2 LQTS accounts for about 25% to 40% of cases and is often triggered by exercise. Type 2 LQTS is associated with different potassium channel mutations in the KCNQ2 gene (formerly called hERG, for human ether-a-go-go-related gene, a gene analogous to a mutation in fruit flies that caused shaking legs when they were anesthetized with ether), which cause loss of function as well. Most medications that prolong QT act on this gene. Type 3 LQTS is less common, 5% to 10%, and often leads to arrhythmias at rest or during sleep (see Figure 3). Type 3 LQTS is associated with a gain-of-function mutation in the sodium channel gene SNC5A. As such, although the genetics are somewhat variable, LQTSs are most likely to be caused by loss-of-function mutations in outward potassium genes (choice B is correct).
These mutations cause delayed repolarization and lengthening of the QT interval, rendering the cells more susceptible to early afterdepolarizations that can trigger torsades de pointes, a syndrome defined by polymorphic ventricular tachycardia in the presence of a long QT interval (polymorphic ventricular tachycardia without a long QT interval is an ischemic arrhythmia). Congenital LQTSs can be unmasked by precipitating factors, such as liquid diets, as in this case. Liquid diets can produce electrolyte abnormalities, worsening the effects of genetic abnormalities in cardiac ion channels.
Characterizing the genetics of LQTSs is important for therapeutic and prognostic reasons. Patients with LQTS, especially those with type 1 LQTS, often respond well to β-blockers, which decrease cardiac events. Patients with type 2 LQTS who do not respond to β-blockers may respond to medications that increase potassium levels, such as spironolactone, and patients with type 3 LQTS who do not respond may be tried on the sodium channel blocker mexiletine. Screening first-degree relatives for LQTS mutations is important, although incomplete penetrance makes the therapeutic implications somewhat challenging. Whether to put an implantable defibrillator in an individual patient with LQTS is also a clinical challenge. Gain-of-function mutations in sodium channel genes form a small minority of patients with LQTS (choice C is incorrect). Loss-of-function mutations in sodium channel genes have also been associated with Brugada syndrome. Gain-of-function mutations in potassium channels have not been associated with an identified syndrome, although there is some suggestion they may predispose to atrial fibrillation (choice A is incorrect). Loss-of-function mutations in sodium channels have been associated with some forms of epilepsy (choice D is incorrect).123