Disrupted valine metabolism and SCPC-mediated neurological toxicity in ECHS1 deficiency

Background

ECHS1 Deficiency (ECHS1D) is a rare neurometabolic disorder caused by loss of function in the mitochondrial enzyme short-chain enoyl-CoA hydratase (ECHS1), leading to developmental delay, dystonia, seizures, and early mortality. Impaired ECHS1 activity disrupts valine catabolism, resulting in accumulation of reactive valine-derived intermediates associated with disease severity, though direct experimental evidence of neuronal toxicity and therapeutic modifiability remains limited. This study aimed to define the consequences of impaired ECHS1 activity, focusing on valine-derived intermediates and their impact on neuronal mitochondrial function.