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1
Question:

A 17-year-old boy collapses while jogging and dies despite resuscitation efforts.  He has no medical history; however, his family history is significant for an uncle who died suddenly at age 20.  The boy is 185.4 cm (6 ft 1 in) tall and weighs 80 kg (176.4 lb).  Autopsy reveals significant left ventricular hypertrophy predominantly affecting the interventricular septum.  There are no valvular abnormalities.  Assuming the boy died of an inherited condition, which of the following proteins was most likely affected by the relevant mutation?

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Explanation:

Hypertrophic cardiomyopathy

Inheritance

  • Autosomal dominant with incomplete penetrance
  • Mutations affecting proteins of the cardiac sarcomere
  • Most common: myosin-binding protein C & β-myosin heavy chain

Phenotypic
manifestations

  • Myocardial disarray & coronary microvascular dysfunction
  • Asymmetric septal hypertrophy with dynamic LVOT obstruction
  • LV stiffening with diastolic dysfunction
  • Increased risk of ventricular arrhythmias & SCD

Clinical
presentation

  • Often asymptomatic
  • Exertional dyspnea, angina, palpitations, light-headedness, syncope
  • Systolic murmur that increases in intensity with ↓ LV blood volume
  • Audible S4

LV = left ventricular; LVOT = left ventricular outflow tract; SCD = sudden cardiac death.

Sudden cardiac death (SCD) in a young patient with a family history of SCD and autopsy findings of asymmetric septal hypertrophy is highly suggestive of hypertrophic cardiomyopathy (HCM).  HCM is an autosomal dominant genetic disorder caused by mutations in genes encoding myocardial contractile proteins of the sarcomere.  The most common mutations are single-point missense mutations affecting myosin-binding protein C and beta-myosin heavy chain.

SCD in HCM typically results from ventricular arrhythmia, which is encouraged by the following:

  • Conduction disturbances caused by cardiomyocyte disarray altering the spatial relationship of intercalated discs (the primary mediators of organized cardiac conduction)

  • Myocardial ischemia resulting from increased oxygen demand of the hypertrophied myocardium and decreased oxygen supply due to both microvascular dysfunction and dynamic left ventricular outflow tract obstruction

(Choices B, C, D, and E)  X-linked recessive mutations affecting the dystrophin protein are responsible for both Duchenne and Becker muscular dystrophy and can lead to dilated cardiomyopathy.  Autosomal dominant mutations affecting glycoprotein fibrillin-1 cause Marfan syndrome, which is characterized by abnormalities of the skeleton (eg, disproportionately long extremities, pectus deformity, scoliosis), eyes (lens dislocation), and cardiovascular system (eg, aortic root dilation, aortic regurgitation).  Autosomal dominant or recessive mutations affecting inward rectifier potassium channels cause long QT syndrome.  Acquired mutations affecting the transthyretin protein cause cardiac amyloidosis and resulting restrictive or dilated cardiomyopathy in older patients (eg, age >60).  All these conditions can cause SCD, but none involve asymmetric septal hypertrophy.

Educational objective:
Hypertrophic cardiomyopathy (HCM) is an autosomal dominant inherited condition resulting from mutations affecting genes that encode for myocardial contractile proteins of the sarcomere; myosin-binding protein C and beta-myosin heavy chain are the most commonly affected proteins.  HCM is characterized by asymmetric septal hypertrophy and increased risk of sudden cardiac death.