Clinical and biochemical characterization of four patients with mutations in ECHS1
Open Access
- 18 June 2015
- journal article
- case report
- Published by Springer Science and Business Media LLC in Orphanet Journal of Rare Diseases
- Vol. 10 (1), 1-15
- https://doi.org/10.1186/s13023-015-0290-1
Abstract
Short-chain enoyl-CoA hydratase (SCEH, encoded by ECHS1) catalyzes hydration of 2-trans-enoyl-CoAs to 3(S)-hydroxy-acyl-CoAs. SCEH has a broad substrate specificity and is believed to play an important role in mitochondrial fatty acid oxidation and in the metabolism of branched-chain amino acids. Recently, the first patients with SCEH deficiency have been reported revealing only a defect in valine catabolism. We investigated the role of SCEH in fatty acid and branched-chain amino acid metabolism in four newly identified patients. In addition, because of the Leigh-like presentation, we studied enzymes involved in bioenergetics. Metabolite, enzymatic, protein and genetic analyses were performed in four patients, including two siblings. Palmitate loading studies in fibroblasts were performed to study mitochondrial β-oxidation. In addition, enoyl-CoA hydratase activity was measured with crotonyl-CoA, methacrylyl-CoA, tiglyl-CoA and 3-methylcrotonyl-CoA both in fibroblasts and liver to further study the role of SCEH in different metabolic pathways. Analyses of pyruvate dehydrogenase and respiratory chain complexes were performed in multiple tissues of two patients. All patients were either homozygous or compound heterozygous for mutations in the ECHS1 gene, had markedly reduced SCEH enzymatic activity and protein level in fibroblasts. All patients presented with lactic acidosis. The first two patients presented with vacuolating leukoencephalopathy and basal ganglia abnormalities. The third patient showed a slow neurodegenerative condition with global brain atrophy and the fourth patient showed Leigh-like lesions with a single episode of metabolic acidosis. Clinical picture and metabolite analysis were not consistent with a mitochondrial fatty acid oxidation disorder, which was supported by the normal palmitate loading test in fibroblasts. Patient fibroblasts displayed deficient hydratase activity with different substrates tested. Pyruvate dehydrogenase activity was markedly reduced in particular in muscle from the most severely affected patients, which was caused by reduced expression of E2 protein, whereas E2 mRNA was increased. Despite its activity towards substrates from different metabolic pathways, SCEH appears to be only crucial in valine metabolism, but not in isoleucine metabolism, and only of limited importance for mitochondrial fatty acid oxidation. In severely affected patients SCEH deficiency can cause a secondary pyruvate dehydrogenase deficiency contributing to the clinical presentation.Keywords
This publication has 29 references indexed in Scilit:
- Measurement of tissue acyl-CoAs using flow-injection tandem mass spectrometry: acyl-CoA profiles in short-chain fatty acid oxidation defectsMolecular Genetics and Metabolism, 2012
- Enzymology of the branched‐chain amino acid oxidation disorders: the valine pathwayJournal of Inherited Metabolic Disease, 2010
- A general introduction to the biochemistry of mitochondrial fatty acid β‐oxidationJournal of Inherited Metabolic Disease, 2010
- Short-chain acyl-coenzyme A dehydrogenase deficiencyMolecular Genetics and Metabolism, 2008
- Mutations in the Gene Encoding 3-Hydroxyisobutyryl-CoA Hydrolase Results in Progressive Infantile NeurodegenerationAmerican Journal of Human Genetics, 2007
- Inborn errors of isoleucine degradation: A reviewMolecular Genetics and Metabolism, 2006
- Leigh syndrome: Clinical features and biochemical and DNA abnormalitiesAnnals of Neurology, 1996
- Mitochondrial Short-Chain L-3-Hydroxyacl-Coenzyme A Dehydrogenase Deficiency: A New Defect of Fatty Acid OxidationPediatric Research, 1996
- Prenatal diagnosis of nonketotic hyperglycinemia: Enzymatic analysis of the glycine cleavage system in chorionic villiThe Journal of Pediatrics, 1990
- Revised assays for the investigation of congenital lactic acidosis using 14C keto acids, eliminating problems associated with spontaneous decarboxylationClinica Chimica Acta; International Journal of Clinical Chemistry, 1983