Cardiomyopathy, Dilated, 2c

A number sign (#) is used with this entry because of evidence that dilated cardiomyopathy-2C (CMD2C) is caused by homozygous or compound heterozygous mutation in the PPCS gene (609853) on chromosome 1p34.

Description

CMD2C is characterized by dilated cardiomyopathy of variable severity, with age of onset ranging from 2 to 20 years. Affected individuals exhibit reduction in coenzyme A (CoA) levels. Some severely affected children die in the first few years of life (Iuso et al., 2018).

For a general phenotypic description and a discussion of genetic heterogeneity of dilated cardiomyopathy (CMD), see 115200.

Clinical Features

Iuso et al. (2018) studied a consanguineous Arab Muslim family (family B) in which 4 sibs had dilated cardiomyopathy of variable severity. The oldest sib presented at age 2 years with asthma-like symptoms, but was diagnosed with CMD only at age 20 years, at which time he had an ejection fraction (EF) of 44%. Cardiac MRI/MRA showed a mildly dilated left ventricle (LV), with moderate to severe decrease in function of both ventricles. His 10-year-old brother presented at 4 months of age with hypovolemic shock and seizures after 2 days of vomiting. Echocardiogram showed LV contractility in the low-normal range and a small patent ductus arteriosus. Cardiac MRI/MRA at age 10 years showed dilated LV with moderately decreased function (EF, 37%). Two younger sibs had normal echocardiograms in the first year of life, but presented with severe dilated cardiomyopathy at ages 2 years and 3 years, respectively, and died despite intensive treatment.

Clinical Variability

Iuso et al. (2018) reported a German girl, born to healthy nonconsanguineous parents (family A), who presented in the first few hours after birth with oxygen desaturation and bradycardia and required ventilatory support. She had severe muscular hypotonia as well as minor dysmorphic features, including cutis laxa, abnormally placed thumbs, abnormal dermatoglyphics, hypoplastic labia minora, and hypoplastic toenails. Over the course of several hospitalizations, evaluation revealed severe dilated cardiomyopathy and pulmonary artery hypertension. She died of multiorgan failure at 3 months of age.

Clinical Management

Iuso et al. (2018) provided oral pantethine supplementation to 2 affected brothers from a consanguineous Arab Muslim family (family B) with dilated cardiomyopathy due to a homozygous missense mutation in the PPCS gene (see MOLECULAR GENETICS). The 20-year-old brother showed mild improvement in exertional dyspnea, with increase in EF from 36 to 48%. His 10-year-old brother remained stable on treatment, with symptoms of heart failure upon exertion and an EF of 45%. The authors suggested that treatment earlier in the clinical course might result in more significant improvement.

Molecular Genetics

By whole-exome sequencing (WES) in a consanguineous Arab-Muslim family (family B) in which 4 sibs had CMD, Iuso et al. (2018) identified homozygosity for a missense mutation in the PPCS gene (E233V; 609853.0001) that segregated fully with disease and was not found in the gnomAD database. WES in a German girl (family A) who died at age 3 months with severe cardiomyopathy, muscular hypotonia, and dysmorphic features, revealed compound heterozygosity for a missense mutation (A180P; 609853.0002) and a 15-bp deletion (609853.0003) in the PPCS gene. Biochemical analysis showed a significant reduction in CoA levels in fibroblasts from all affected individuals, which was rescued by reintroducing wildtype PPCS. The lowest level of CoA was observed in the German girl, who also exhibited extracardiac features; the authors suggested that the presence of the completely inactive A180P PPCS allele, as shown in yeast viability studies, determined the more severe phenotype in that patient.