Phosphopantothenoylcysteine synthetase (PPCS) deficiency disorder (PPCS DD) is an ultra-rare genetic disease causing dilated cardiomyopathy (DCM) and variable neuromuscular symptoms due to impaired CoA biosynthesis. Until recently, only six patients worldwide had been identified. In our latest study, published in [Journal name when accepted], we identified six additional patients with PPCS DD and investigated disease mechanisms and treatment avenues.
Using patient-derived fibroblasts and iPSC-derived cardiomyocytes, we demonstrated that pathogenic PPCS variants reduce protein stability and cellular CoA levels, leading to impaired cardiac contractility and arrhythmias. Importantly, pantethine supplementation partially restored CoA levels and improved cardiac cell function in vitro. Clinical follow-up of patients treated with pantethine showed sustained improvement in cardiac parameters and quality of life, although early intervention may be required for maximal benefit.
Our work expands the genetic and clinical understanding of PPCS DD and highlights pantethine as a potential therapeutic strategy. Future studies will explore optimal dosing, timing, and combination therapies to fully correct metabolic deficits and prevent progressive cardiac dysfunction in this devastating condition.