A multi-center retrospective chart analysis identifying clinical, biochemical, and radiographic signatures of short-chain enoyl-CoA hydratase (ECHS1) deficiency

Short-chain enoyl-CoA hydratase (ECHS1) catalyzes the hydration of C4-C6 acyl-CoA molecules to produce ATP in fatty acid {beta}-oxidation. Deficiency of the ECHS1 enzyme, ECHS1D, is a rare autosomal recessive disorder that presents with a large and pleomorphic clinical spectrum. We present the largest comprehensive study of known diagnosed ECHS1D patients to date, reporting 26 new patients and 8 novel variants in conjunction with a literature review of 87 previously reported patients. All patients were categorized into neonatal, infantile, and late-onset groups based on age of onset and clinical course. Neonatal-onset cases were characterized by early and severe multisystem disease, often with lactic acidosis, hypotonia, cardiomyopathy, and high early mortality (62.5%). The infantile-onset group was heterogeneous, but many exhibited hallmark features such as dystonia, developmental delay, and basal ganglia involvement on neuroimaging. Mortality was significantly lower than the neonatal cohort (24.4%). Late-onset patients had more localized neurologic symptoms, particularly dystonia, and significantly lower mortality overall (0%). Moreover, we report a 37.5% survival rate in newly reported neonatal onset patients compared with 18.2% in prior reports, possibly reflective of earlier recognition of ECHS1D and greater utilization of therapies including N-acetylcysteine, sodium dichloroacetate, and valine-restricted diet.