Abstract
Mitochondrial short-chain enoyl-CoA hydratase deficiency (ECHS1D) is caused by mutations in ECHS1 (OMIM 602292) and is a recently identified inborn error of valine and fatty acid metabolism. This defect leads to secondary mitochondrial dysfunction. The majority of previously reported patients had the Leigh syndrome, with a median life expectancy of approximately 2 years. We report two siblings born 3 years apart with prenatal findings including facial dysmorphia, oligohydramnios, intrauterine growth restriction, and premature delivery. They had severe lactic acidosis with onset within the first hours of life, had congenital dilated cardiomyopathy, and died at 16 h of life and 2 days of life, respectively.Biochemical evaluation of these patients showed elevated butyryl-carnitine in the blood and elevated methylmalonyl/succinyl-CoA and decreased hydroxybutyryl-CoA in frozen liver of patient 2, confirming abnormal short-chain fatty acid metabolism. Elevated butyryl-carnitine has been reported only in a single previous case of ECHS1 deficiency, which also had neonatal onset. Pyruvate and lactate levels were both elevated with a normal pyruvate-lactate ratio. This supports the previous hypothesis that lactic acidosis in these patients results from secondary inhibition of the pyruvate dehydrogenase complex. The biomarker 2,3-dihydroxy-2-methylbutyric acid was detected in patient 2, but at lower levels than in previously reported cases.These cases extend our understanding of the severe end of the phenotypic spectrum of ECHS1 deficiency, clarify the range of biochemical abnormalities associated with this new disorder, and highlight the need to suspect this disease in patients presenting with comparable metabolic derangements and dysmorphic features.