Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder: evidence from patients and models of the disease

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. In this study, we report on six additional patients. We shed light on the functional aspects of DCM in PPCS DD and evaluate therapeutic approaches to boost CoA levels both in vitro and in vivo. Methods and Results Whole-exome sequencing identified causative variants in PPCS in six additional individuals presenting with DCM and a spectrum of phenotypes, including neuromuscular signs and neurologic deterioration. Western blotting analyses demonstrated destabilizing effects of identified variants on the PPCS protein. Microplate-based assessment of CoA showed reduced levels of the coenzyme in patient-derived fibroblasts, cardiac progenitor cells, and cardiomyocytes. Functional investigation of DCM in cardiac cells and heart patches revealed defects in contractile function and arrhythmic events, which were partially rescued by pantethine. Long-term clinical assessment showed encouraging benefits in pantethine-treated patients. Conclusion 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.