Novel Alpk3 Gene Mutation Causes Cardiomyopathy

Introduction:
Incorporation of new generation sequencing in the diagnostic evaluation of patients with cardiomyopathy can help detect new genes involved in disease pathogenesis. This in turn increases diagnostic accuracy and may provide a tool for individualized/personalized treatment.

Methods and results:
A 27-year-old male presented to our intensive care unit with cardiogenic shock. He was diagnosed with heart failure during childhood, but did not have proper medical surveillance since. His parents were first cousins and healthy. One sibling died in his thirties from sudden cardiac death, and three other siblings were healthy. Until the age of 26 he was asymptomatic and did not take any medications. At the age of 26 he developed exercise dyspnea and fatigue and was diagnosed with congestive heart failure (with severe left and right ventricular dysfunction as demonstrated by echocardiogram). Prior to his admission he deteriorated rapidly and eventually developed cardiogenic shock which required treatment with inotropic agents. He was transferred to our hospital for further treatment. Echocardiography demonstrated biventricular concentric thickening and biatrial enlargement. There was markedly reduced systolic biventricular function, and Doppler evidence of elevated left ventricular filling pressures.

Because the parents of the patient were related, exome sequencing analysis was performed. A homozygote stop mutation Chr15:85383423 C>T, p.Gln507X in the ALPK3 gene was identified. Histopathological examination of myocardial biopsy demonstrated cardiomyocyte hypertrophy with areas of necrosis and interstitial fibrosis. Desmin immunostain showed disrupted intercalated discs. Electron microscopy demonstrated myofibrillar disarray.

Conclusions:
This case demonstrates a novel APLK3 gene mutation causing cardiomyopathy, with histopathological features resembling animal models. Findings on histopathology and electron microscopy support the role of ALPK3 gene in intercalated disc formation and myofibril organization, and require additional investigation on the exact gene mechanism. Our case demonstrates the significance of myocardial biopsy and full genetic investigation in cardiomyopathy cases.