Differentiation of neonatal and infantile onset ECHS1 deficiency using SCEH enzyme activity and plasma acylcarnitine...

Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (ECHS1D) is an autosomal recessive disorder that presents in the neonatal or infantile period with encephalopathy and lactic acidosis. Biomarkers are variable, with many ECHS1D patients having elevated plasma C4-carnitine and urine 2-methyl-2,3-dihydroxybutyric acid while others have none. Neonates often succumb prior to molecular sequencing results being returned. ECHS1D diagnosis may be faster if biomarkers are used in plasma and urine along with enzyme activity measurement. Short-chain enoyl-CoA hydratase activity was performed in six ECHS1D fibroblasts with neonatal or infantile onset. DBS cards were obtained from two patients and one carrier. Control fibroblasts (n = 11) activity was 229.62 ± 68.52 nmol/min/mg. Neonatal ECHS1D fibroblasts activity was 3.92 ± 0.62 nmol/min/mg. Infantile onset ECHS1D fibroblasts activity was 17.27 ± 2.14 nmol/min/mg. Control DBS SCEH activity was 141.18 ± 34.00 nmol/min/mg (n = 10) and one neonatal and infantile patient sample showed approximately 2 % and 27 % activity, respectively. One carrier had 45 % activity. We described five new cases of ECHS1D and analyzed seven total cases. We determined SCEH activity reference ranges in neonatal and infantile onset ECHS1D fibroblasts. For the first time, we demonstrated SCEH activity in DBS with separation between ECHS1D and controls. SCEH activity in DBS could allow for newborn screening for ECHS1D as new treatments are developed. SYNOPSIS: Neonatal and infantile onset ECHS1D can be differentiated via fibroblast and dried blood spot short-chain enoyl-CoA hydratase activity and detection of plasma S-(2-carboxypropyl)cysteine carnitine species to allow for faster diagnosis and prompt treatment.