Journal Article

Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models

Zhang, Fangfang, Lampert, Brent C., Truxal, Kristen, Finazzi, Dario, Messias, Ana C., Laugwitz, Karl-Ludwig, Ahrens-Nicklas, Rebecca, Kuebler, Sarah, Güra, Miriam A., Yeo, Mildrid, Nandi, Deipanjan, Poch, Christine M., Rahman, Shamima, Iuso, Arcangela, Gosselin, Rachel, Rippert, Alyssa, Sibon, Ody C., Horowitz Cederboim, Smadar, Anikster, Yair, Zanuttigh, Enrica, Nissan, Batel, Durst, Ronen, Gnutti, Barbara, Li, Dong, Gardham, Alice, Schüller, Hans-Joachim, Meier, Anna B., Moretti, Alessandra, Dorn, Tatjana

2025

Overview

Background PPCS deficiency disorder (PPCS DD) is an ultra-rare, autosomal recessive form of dilated cardiomyopathy (DCM) caused by pathogenic variants in PPCS, which encodes the enzyme catalyzing the second step in the coenzyme A (CoA) biosynthesis pathway. To date, only six patients worldwide have been identified. Methods Whole-exome sequencing was performed to identify pathogenic PPCS variants in affected individuals. Protein stability was assessed by Western blotting. CoA levels were quantified using a microplate-based assay in patient-derived fibroblasts, cardiac progenitor cells, and cardiomyocytes. Functional evaluation of cardiac cells and engineered heart patches was conducted to investigate contractile performance and arrhythmogenicity. Pantethine was tested as a potential therapeutic agent both in vitro and through long-term clinical follow-up in patients. Results Causative PPCS variants are identified in six individuals with DCM and variable associated features, including neuromuscular and neurological symptoms. Identified variants lead to reduced PPCS protein stability and decreased cellular CoA levels. Cardiac cells exhibit impaired contractility and arrhythmias, which are partially rescued by pantethine treatment. Clinically, patients receiving pantethine show sustained improvement over time. Conclusions Our study expands the genetic and clinical spectrum of PPCS deficiency disorder, identifying six new cases with diverse phenotypes. Functional investigations reveal reduced CoA levels and dysfunction in patient-derived cardiac cells. Pantethine treatment shows promise in partially rescuing DCM phenotypes, both in vitro and in patients. However, complete reversal may require early intervention. These findings underscore the importance of timely diagnosis and treatment in PPCS DD. Future research should focus on optimizing pantethine supplementation and exploring additional therapies to enhance CoA levels and cardiac function in affected individuals. Zhang, Dorn, Gnutti et al. identify pathogenic PPCS variants in people with PPCS deficiency disorder. Cardiac cells exhibit impaired contractility and arrhythmias, which is partially rescued by pantethine treatment. Plain language summary PPCS deficiency disorder is an extremely rare inherited disease that causes heart muscle weakness (dilated cardiomyopathy) and other symptoms. It results from changes in a gene involved in making coenzyme A (CoA), a vital molecule for cell energy. This study identified six new patients with the condition and investigated how these gene changes affect heart function. Researchers used patient cells and lab-grown heart tissues to study the disease and tested pantethine, a compound that helps increase CoA levels. They found that pantethine improved heart cell function and showed positive effects in treated patients. These results highlight the importance of early diagnosis and treatment. In the future, therapies such as pantethine could offer hope for improving heart health in affected individuals.

• Publisher: Nature Publishing Group UK,Springer Nature B.V,Nature Portfolio
• Subject: 13/100 / 14 / 14/63 / 45 / 692/4019/592 / 692/699/317 / 82/29 / Antibodies / Cardiomyocytes / Cardiomyopathy / Consent / Ethics / Fibroblasts / Inclusion / Kinases / Medicine / Medicine & Public Health / Metabolism / Metabolites / Mutation / Neurodegeneration / Patients / Penicillin / Proteins