Importantly, the observed ETFDH deficiency-induced lipid accumulation and abnormal energy metabolism suggesting that antioxidant intervention or modulation of ZNF267 signaling pathways may constitute viable treatment strategies for MADD.This study not only expands the pathogenic variant spectrum in ETFDH gene but also redefine it’s role as a potential therapeutic node in polycystic kidney and hepatorenal neoplasms. Here, ETFDH is linked to multiple acyl-CoA dehydrogenase deficiency.