A 20-year-old student collapses suddenly in class and dies, despite resuscitation efforts. Review of the medical chart is conducted-including symptoms, review of systems, medical history, and substance use-and is unremarkable except for a family history of sudden cardiac death. Autopsy is performed and myocardial histology is shown in the image. Complete genotyping is most likely to reveal a pathologic mutation that affects a protein belonging to which of the following structures?

Question

A 20-year-old student collapses suddenly in class and dies, despite resuscitation efforts.  Review of the medical chart is conducted-including symptoms, review of systems, medical history, and substance use-and is unremarkable except for a family history of sudden cardiac death.  Autopsy is performed and myocardial histology is shown in the image.  Complete genotyping is most likely to reveal a pathologic mutation that affects a protein belonging to which of the following structures?

Quizplus · Accepted Answer

Histologic examination of this patient's myocardium is consistent with hypertrophic cardiomyopathy (HCM), which is characterized by cardiomyocyte hypertrophy with haphazard cellular arrangement and prominent interstitial spacing with fibrosis. HCM is caused by genetic mutations affecting structural proteins of the cardiac sarcomere, most commonly beta-myosin heavy chain and myosin-binding protein C. Approximately 50% of cases result from recognized familial mutations with autosomal dominant inheritance and variable expression. HCM is one of the most common causes of sudden cardiac death (SCD) in young adults. Although SCD due to HCM often occurs with exertion, it can occur at rest. It is believed that cardiomyocyte disarray and fibrosis alters the spatial relationship of intercalated discs (the primary mediators of organized cardiac conduction), increasing susceptibility to ventricular arrhythmia (eg, ventricular tachycardia, ventricular fibrillation). Chronic myocardial ischemia, which can occur due to insufficient blood supply to hypertrophied myocardium, also contributes to interstitial fibrosis and the risk of arrhythmia. (Choice A) Arrhythmogenic right ventricular cardiomyopathy results from mutations affecting proteins that make up desmosomes (eg, plakoglobin, desmoplakin). There is fibrosis and scarring of the right ventricle that predisposes to ventricular arrhythmias and SCD; however, histology does not demonstrate the cardiomyocyte hypertrophy or marked cellular disarray seen in HCM. (Choice B) Long QT syndrome and Brugada syndrome result from mutations affecting cardiac ion channels. Both disorders can lead to ventricular arrhythmias and SCD; however, they do not involve structural derangement of the myocardium. (Choices C and D) Mutations affecting mitochondria typically interfere with energy production via aerobic metabolism and a number of such diseases (eg, myoclonic epilepsy with ragged red fibers, Barth syndrome) can lead to dilated cardiomyopathy and SCD. Mutations affecting components of the nuclear envelope (eg, lamin A) are also a potential cause of dilated cardiomyopathy complicated by conduction defects and SCD. However, these cardiomyopathies are far less prevalent and do not involve the same structural derangement seen in HCM. Educational objective: Hypertrophic cardiomyopathy is caused by genetic mutations affecting structural proteins of the cardiac sarcomere (eg, beta-myosin heavy chain, myosin-binding protein C) and is one of the most common causes of sudden cardiac death (SCD) in young adults. Histologically, it is characterized by cardiomyocyte hypertrophy with haphazard cellular arrangement and interstitial fibrosis. __________ References: Sudden cardiac death in hypertrophic cardiomyopathy. (http://www.ncbi.nlm.nih.gov/pubmed/23022709)

A 20-Year-Old Student Collapses Suddenly in Class and Dies, Despite