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Familial hypertrophic cardiomyopathy (HCM) is usually caused by autosomal dominant pathogenic mutations in genes encoding sarcomeric or sarcomere-associated cardiac muscle proteins. The disease mainly affects adults, although young children with severe HCM have also been reported. We describe four unrelated neonates with lethal cardiomyopathy, and performed molecular studies to identify the genetic defect. We also present a literature overview of reported patients with compound heterozygous or homozygous pathogenic MYBPC3 mutations and describe their clinical characteristics. All four children presented with feeding difficulties, failure to thrive, and dyspnea. They died from cardiac failure before age 13 weeks. Features of left ventricular noncompaction were diagnosed in three patients. In the fourth, hypertrabeculation was not a clear feature, but could not be excluded. All of them had septal defects. Two patients were compound heterozygotes for the pathogenic c.2373dup p.(Trp792fs) and c.2827C > T p.(Arg943*) mutations, and two were homozygous for the c.2373dup and c.2827C > T mutations. All patients with biallelic truncating pathogenic mutations in MYBPC3 reported so far (n=21) were diagnosed with severe cardiomyopathy and/or died within the first few months of life. In 62% (13/21), septal defects or a patent ductus arteriosus accompanied cardiomyopathy. In contrast to heterozygous pathogenic mutations, homozygous or compound heterozygous truncating pathogenic MYBPC3 mutations cause severe neonatal cardiomyopathy with features of left ventricular noncompaction and septal defects in approximately 60% of patients.

Background Although gender may be one of the important factors modifying phenotypic expression in hypertrophic cardiomyopathy (HCM), there has been little information on it. Methods and results We investigated gender differences in the clinical features of HCM caused by cardiac myosin-binding protein C gene (MYBPC3) mutations. Sixty-one subjects (28 families) carrying MYBPC3 mutations were studied. Of the 61 subjects with MYBPC3 mutations, 50 patients including 23 female patients were phenotype-positive by echocardiography. Disease penetrance in subjects aged ≤40 years old was 92% in males and 67% in females. Females showed delayed onset of left ventricular hypertrophy compared with males in subjects who were genotype-positive. Female patients were more symptomatic at diagnosis than were males (mean New York Heart Association class: 1.7 ± 0.8 versus 1.2 ± 0.4, p = 0.012). From a longitudinal point of view by age, no significant gender difference in cardiovascular deaths or cardiovascular events was found. During the follow-up period after diagnosis of HCM (13 ± 8 years), female patients who were phenotype-positive had significantly more frequent heart failure events than did phenotypically affected male patients (p = 0.028). Conclusions Although females with MYBPC3 mutations showed later onset of the disease, female patients were more symptomatic at diagnosis and had more frequent heart failure events once they had developed hypertrophy.

Introduction Hypertrophic cardiomyopathy (HCM) is an autosomal dominant heart disease mostly due to mutations in genes encoding sarcomeric proteins. HCM is characterised by asymmetric hypertrophy of the left ventricle (LV) in the absence of another cardiac or systemic disease. At present it lacks specific treatment to prevent or reverse cardiac dysfunction and hypertrophy in mutation carriers and HCM patients. Previous studies have indicated that sarcomere mutations increase energetic costs of cardiac contraction and cause myocardial dysfunction and hypertrophy. By using a translational approach, we aim to determine to what extent disturbances of myocardial energy metabolism underlie disease progression in HCM. Methods Hypertrophic obstructive cardiomyopathy (HOCM) patients and aortic valve stenosis (AVS) patients will undergo a positron emission tomography (PET) with acetate and cardiovascular magnetic resonance imaging (CMR) with tissue tagging before and 4 months after myectomy surgery or aortic valve replacement + septal biopsy. Myectomy tissue or septal biopsy will be used to determine efficiency of sarcomere contraction in-vitro, and results will be compared with in-vivo cardiac performance. Healthy subjects and non-hypertrophic HCM mutation carriers will serve as a control group. Endpoints Our study will reveal whether perturbations in cardiac energetics deteriorate during disease progression in HCM and whether these changes are attributed to cardiac remodelling or the presence of a sarcomere mutation per se. In-vitro studies in hypertrophied cardiac muscle from HOCM and AVS patients will establish whether sarcomere mutations increase ATP consumption of sarcomeres in human myocardium. Our follow-up imaging study in HOCM and AVS patients will reveal whether impaired cardiac energetics are restored by cardiac surgery.