ALPK3 Biallelic Mutations Implicated in Pediatric Cardiomyopathy

Patients with biallelic mutations in ALPK3 presented with severe hypertrophic and/or dilated cardiomyopathy.

The newly identified gene, ALPK3, has been implicated in early onset cardiomyopathy, according to research published in the Journal of American College of Cardiology. Patients with biallelic mutations presented with severe hypertrophic or dilated cardiomyopathy (HCM/DCM) in utero, at birth, or during early childhood. ALPK3 encodes a nuclear kinase that is essential for early differentiation of cardiomyocytes.

In the study, investigators evaluated 5 patients from 3 families of various ethnicities (Dutch, Moroccan, and Turkish) who had pediatric cardiomyopathy caused by homozygous truncating mutations. Two of the 10 family members presented with HCM with an unusual distribution of hypertrophy.

“Despite recent advances in understanding the genetic etiologies of pediatric cardiomyopathy, a substantial number of cases remain unsolved, suggesting that other genes await discovery,” researchers wrote. “Establishing an underlying genetic cause for cardiomyopathy allows pre-symptomatic identification of family members at risk and facilitates reproductive decision making.”

This clinical investigation included high-resolution ultrasound, 12-lead electrocardiography, transthoracic echocardiography, and physical and postmortem examinations.

Family A’s child was born at 35 weeks after an uneventful pregnancy and presented with respiratory insufficiency and cyanosis. He had severe left ventricular (LV) dilation, markedly reduced contractility of both ventricles, and mitral and tricuspid regurgitation. At 5 days, he died due to progressive heart failure. There was no family history of sudden death or cardiomyopathies, nor were there any abnormalities in the parents or siblings.

Family B’s child was examined via ultrasound at 33 weeks of gestation and revealed generalized hydrops fetalis and cardiomegaly with reduced contractility. At 35 weeks, the pregnancy ended in intrauterine fetal death. The only abnormality revealed in physical examination (parents declined an autopsy) was massive skin edema. The same family had a second pregnancy that ended in a spontaneous abortion.

In their third pregnancy, ultrasound examinations at 20 and 26 weeks of gestation revealed an enlarged heart and severely reduced contractility, a thickened myocardium with spongy appearance, and severe tricuspid regurgitation. Severe fetal hydrops developed at 30 weeks, and at 36 weeks, the patient was born with severe respiratory distress, resulting in death 2 hours postpartum. Echocardiography revealed severe hypertrophy and dilation of both ventricles.

Later, the parents had twin girls born at 37 weeks. At day 4, echocardiography revealed severe concentric HCM in 1 of the twins. This remained stable during subsequent years. This family also had no history of sudden cardiac death or cardiomyopathies, or abnormalities in either parent or the twin sister.

Family C’s second child was diagnosed with severe HCM at 4 years of age. He had an out-of-hospital cardiac arrest at 7 years of age, caused by ventricular arrhythmias. Afterward, he received an implantable cardiac-defibrillator (ICD) and he has since experienced several ICD-appropriate shocks. At 11 years of age, cardiac examination revealed severe concentric LV hypertrophy. In this family’s case, the father was diagnosed with HCM at age 27 years, and at 37 years, cardiac magnetic imaging showed concentric LV and RV hypertrophy. A paternal uncle was also diagnosed with HCM at age 29 years, and at age 45 years, asymmetric septal hypertrophy and RV hypertrophy.

ALPK3-related cardiomyopathy has morphological features of both HCM and DCM, and is characterized by biventricular involvement and atypical distribution of hypertrophy. Our findings emphasize the essential role of cardiac transcription factor pathways in normal myocardial development,” researchers concluded.

More studies are necessary to identify the molecular and cellular mechanisms that are a part of cardiomyopathy development, particularly in patients with these genetic mutations.


Almomani R, Verhagen JMA, Herkert JC, et al. Biallelic truncating mutations in ALPK3 cause severe pediatric cardiomyopathy. J Am Coll Cardiol. 2016;67(5):515-525. doi: 10.1016/j.jacc.2015.10.093.