ECHS1 mutations cause combined respiratory chain deficiency resulting in Leigh syndrome.

The human ECHS1 gene encodes the short-chain enoyl coenzyme A hydratase, the enzyme that catalyzes the second step of β-oxidation of fatty acids in the mitochondrial matrix. We report on a boy with ECHS1 deficiency who was diagnosed with Leigh syndrome at 21 months of age. The patient presented with hypotonia, metabolic acidosis, and developmental delay. A combined respiratory chain deficiency was also observed. Targeted exome sequencing of 776 mitochondria-associated genes encoded by nuclear DNA identified compound heterozygous mutations in ECHS1. ECHS1 protein expression was severely depleted in the patient's skeletal muscle and patient-derived myoblasts; a marked decrease in enzyme activity was also evident in patient-derived myoblasts. Immortalized patient-derived myoblasts that expressed exogenous wild-type ECHS1 exhibited the recovery of the ECHS1 activity, indicating that the gene defect was pathogenic. Mitochondrial respiratory complex activity was also mostly restored in these cells, suggesting that there was an unidentified link between deficiency of ECHS1 and respiratory chain. Here, we describe the patient with ECHS1 deficiency; these findings will advance our understanding not only the pathology of mitochondrial fatty acid β-oxidation disorders, but also the regulation of mitochondrial metabolism.