Clinical, biochemical and metabolic characterisation of a mild form of human short-chain enoyl-CoA hydratase deficiency: significance of increased N-acetyl-S-(2-carboxypropyl)cysteine excretion
- 6 August 2015
- journal article
- case report
- Published by BMJ in Journal of Medical Genetics
- Vol. 52 (10), 691-698
- https://doi.org/10.1136/jmedgenet-2015-103231
Abstract
Background Short-chain enoyl-CoA hydratase—ECHS1—catalyses many metabolic pathways, including mitochondrial short-chain fatty acid β-oxidation and branched-chain amino acid catabolic pathways; however, the metabolic products essential for the diagnosis of ECHS1 deficiency have not yet been determined. The objective of this report is to characterise ECHS1 and a mild form of its deficiency biochemically, and to determine the candidate metabolic product that can be efficiently used for neonatal diagnosis. Methods We conducted a detailed clinical, molecular genetics, biochemical and metabolic analysis of sibling patients with ECHS1 deficiency. Moreover, we purified human ECHS1, and determined the substrate specificity of ECHS1 for five substrates via different metabolic pathways. Results Human ECHS1 catalyses the hydration of five substrates via different metabolic pathways, with the highest specificity for crotonyl-CoA and the lowest specificity for tiglyl-CoA. The patients had relatively high (∼7%) residual ECHS1 enzyme activity for crotonyl-CoA and methacrylyl-CoA caused by the compound heterozygous mutations (c.176A>G, (p.N59S) and c.413C>T, (p.A138V)) with normal mitochondrial complex I–IV activities. Affected patients excrete large amounts of N-acetyl-S-(2-carboxypropyl)cysteine, a metabolite of methacrylyl-CoA. Conclusions Laboratory data and clinical features demonstrated that the patients have a mild form of ECHS1 deficiency harbouring defective valine catabolic and β-oxidation pathways. N-Acetyl-S-(2-carboxypropyl) cysteine level was markedly high in the urine of the patients, and therefore, N-acetyl-S-(2-carboxypropyl)cysteine was regarded as a candidate metabolite for the diagnosis of ECHS1 deficiency. This metabolite is not part of current routine metabolic screening protocols, and its inclusion, therefore, holds immense potential in accurate diagnosis.Keywords
This publication has 18 references indexed in Scilit:
- HIBCH deficiency in a patient with phenotypic characteristics of mitochondrial disordersAmerican Journal of Medical Genetics Part A, 2014
- HIBCH mutations can cause Leigh-like disease with combined deficiency of multiple mitochondrial respiratory chain enzymes and pyruvate dehydrogenaseOrphanet Journal of Rare Diseases, 2013
- Cerebrospinal fluid lactate and pyruvate concentrations and their ratioClinical Biochemistry, 2013
- Enzymology of the branched‐chain amino acid oxidation disorders: the valine pathwayJournal of Inherited Metabolic Disease, 2010
- The enzymology of mitochondrial fatty acid beta‐oxidation and its application to follow‐up analysis of positive neonatal screening resultsJournal of Inherited Metabolic Disease, 2010
- Mutations in the Gene Encoding 3-Hydroxyisobutyryl-CoA Hydrolase Results in Progressive Infantile NeurodegenerationAmerican Journal of Human Genetics, 2007
- Missense and Nonsense Mutations in the Lysosomal α-Mannosidase Gene (MANB) in Severe and Mild Forms of α-MannosidosisAmerican Journal of Human Genetics, 1998
- Purification and Properties of Rat D-3-Hydroxyacyl-CoA Dehydratase: D-3-Hydroxyacyl-CoA Dehydratase/D-3-Hydroxyacyl-CoA Dehydrogenase Bifunctional ProteinThe Journal of Biochemistry, 1996
- [47] Short-chain and long-chain enoyl-CoA hydratases from pig heart muscleMethods in Enzymology, 1981
- ENZYMATIC REACTION OF CROTONYL COENZYME A1Journal of the American Chemical Society, 1953