A 21-year-old Caucasian male presents to the emergency department following an episode of syncope. The syncopal episode was not provoked by any activity or circumstance, nor was it preceded by lightheadedness. The patient has no significant past medical history and he is not taking any medications. An ECG obtained in the ER reveals QT-interval prolongation but is otherwise unremarkable. Assuming this is an inherited condition, the relevant mutation most likely affects which of the following structures?

Question

A 21-year-old Caucasian male presents to the emergency department following an episode of syncope.  The syncopal episode was not provoked by any activity or circumstance, nor was it preceded by lightheadedness.  The patient has no significant past medical history and he is not taking any medications.  An ECG obtained in the ER reveals QT-interval prolongation but is otherwise unremarkable.  Assuming this is an inherited condition, the relevant mutation most likely affects which of the following structures?

Quizplus · Accepted Answer

This patient's sudden-onset syncopal episode suggests a sudden cardiac arrhythmia. QT prolongation in an otherwise healthy young individual is usually congenital. The mutation most likely to cause QT-interval prolongation can be determined based on an understanding of cardiac electrophysiology. On an ECG tracing, the QT interval begins at the start of the QRS complex and ends at the end of the T wave. Thus, the QT-interval reflects the cardiac myocyte action potential duration, which is determined in part by K⁺ currents through channel proteins. The mutations listed in the other answer choices would be less likely to directly affect the cardiac cell action potential duration. There are two important congenital syndromes that cause QT prolongation: Jervell and Lange-Nielsen syndrome (autosomal recessive, with neurosensory deafness) and the more common Romano-Ward syndrome (autosomal dominant, no deafness). Both may predispose to torsades de pointes (a ventricular tachyarrhythmia) at a young age, causing syncopal episodes and possible sudden cardiac death. (Choices A and C) Mutations affecting cardiac cell cytoskeletal proteins or the mitochondrial enzymes of oxidative phosphorylation are thought to cause the genetic form of dilated cardiomyopathy (DCM). DCM usually presents with gradual onset of left-sided heart failure (with symptoms like dyspnea on exertion initially), as opposed to the sudden syncopal episode in a previously asymptomatic patient described above. (Choice B) Mutations in cardiac cell sarcomere proteins (e.g. beta-myosin heavy chain) underlie hypertrophic cardiomyopathy (HCM). Although HCM may present as syncope in a previously asymptomatic young person, the syncope of HCM is typically provoked by exertion. Additionally, QT prolongation is not generally found in HCM. (Choice D) Mutations of a calcium-binding sarcoplasmic reticulum protein might underlie some cases of arrhythmogenic right ventricular cardiomyopathy (ARVC), a progressive fibrofatty replacement of the right ventricular myocardium of uncertain pathogenesis. QT prolongation is not generally seen with ARVC. Educational Objective: Unprovoked syncope in a previously asymptomatic young person may result from a congenital QT prolongation syndrome. The two most important congenital syndromes with QT prolongation − Romano-Ward syndrome and Jervell and Lange-Nielsen syndrome − are thought to result from mutations in a K⁺ channel protein that contributes to the delayed rectifier current (I_K) of the cardiac action potential.

A 21-Year-Old Caucasian Male Presents to the Emergency Department Following