A 6-year-old boy is evaluated in the office for difficulty hearing. The patient has no ear pain, discharge, or upper respiratory symptoms. Initial testing suggests that he has bilateral sensorineural hearing loss. He has no motor deficits or cerebellar signs. His paternal uncle died suddenly at age 12. Examination of the ears, nose, and throat is normal. ECG shows normal sinus rhythm with a prolonged QT interval (520 msec). Echocardiogram shows normal left and right ventricular function with no significant valvular disease. A genetic defect affecting which of the following is most likely present in this patient?
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This patient's clinical presentation is suggestive of Jervell and Lange-Nielsen syndrome, an autosomal recessive disorder characterized by profound bilateral sensorineural hearing loss and congenital long QT syndrome, which predisposes individuals to syncope and sudden cardiac death.
This syndrome occurs secondary to mutations in genes (eg, KCNQ1, KCNE1) that encode the alpha and beta subunits of voltage-gated potassium channels. These subunits contribute to the slow-acting component of the outward-rectifying potassium current, which is responsible for ventricular repolarization during phase 3 of the cardiac action potential. Mutations in the potassium channel lead to a decrease in potassium current with prolongation of action potential duration and the QT interval. QT interval prolongation predisposes to the development of life-threatening ventricular arrhythmias, such as torsades de pointes and ventricular fibrillation.
(Choices A and D) Brugada syndrome is an autosomal dominant condition that can be associated with mutations in cardiac sodium or L-type calcium channels, leading to characteristic ECG changes (eg, pseudo right bundle branch block, ST-segment elevation in leads V1-V3) and an increased risk of ventricular tachyarrhythmias and sudden cardiac death.
(Choice B) Duchenne muscular dystrophy is an X-linked disorder caused by mutations in dystrophin, a structural membrane protein that stabilizes the plasma membrane of myocytes. Patients typically present with progressive proximal muscle degeneration and weakness. Additional features may include cardiomyopathy and conduction abnormalities.
(Choice E) Genetic defects in the sodium-potassium ATPase pump typically are not associated with long QT syndrome. Cardiac glycosides (eg, digoxin) inhibit the sodium-potassium ATPase in myocardial cells, resulting in a mild increase in intracellular sodium and subsequent inhibition of the sodium-calcium exchanger. This leads to increased intracellular calcium and cardiac contractility, which can help reduce symptoms in patients with advanced systolic heart failure.
Educational objective:
Jervell and Lange-Nielsen syndrome is an autosomal recessive disorder characterized by profound bilateral sensorineural hearing loss and congenital long QT syndrome, which predisposes to ventricular arrhythmias and sudden cardiac death. This condition occurs secondary to mutations in genes that encode voltage-gated potassium channels.