title: ECHS1 mutations in Leigh disease: a new inborn error of metabolism affecting valine metabolism.
abstract: Two siblings with fatal Leigh disease had increased excretion of S-(2-carboxypropyl)cysteine and several other metabolites that are features of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency, a rare defect in the valine catabolic pathway associated with Leigh-like disease. However, this diagnosis was excluded by HIBCH sequencing and normal enzyme activity. In contrast to HIBCH deficiency, the excretion of 3-hydroxyisobutyryl-carnitine was normal in the children, suggesting deficiency of short-chain enoyl-CoA hydratase (ECHS1 gene). This mitochondrial enzyme is active in several metabolic pathways involving fatty acids and amino acids, including valine, and is immediately upstream of HIBCH in the valine pathway. Both children were compound heterozygous for a c.473C > A (p.A158D) missense mutation and a c.414+3G>C splicing mutation in ECHS1. ECHS1 activity was markedly decreased in cultured fibroblasts from both siblings, ECHS1 protein was undetectable by immunoblot analysis and transfection of patient cells with wild-type ECHS1 rescued ECHS1 activity. The highly reactive metabolites methacrylyl-CoA and acryloyl-CoA accumulate in deficiencies of both ECHS1 and HIBCH and are probably responsible for the brain pathology in both disorders. Deficiency of ECHS1 or HIBCH should be considered in children with Leigh disease. Urine metabolite testing can detect and distinguish between these two disorders.
authors.affiliation: 1 Murdoch Childrens Research Institute, Victorian Clinical Genetics Services, Royal Children's Hospital, Parkville, Vic 3052, Australia.
authors.forename: Heidi
authors.initials: H
authors.lastname: Peters
authors.affiliation: 1 Murdoch Childrens Research Institute, Victorian Clinical Genetics Services, Royal Children's Hospital, Parkville, Vic 3052, Australia.
authors.forename: Nicole
authors.initials: N
authors.lastname: Buck
authors.affiliation: 2 University of Amsterdam, Laboratory Genetic Metabolic Diseases, Departments of Paediatrics and Laboratory Medicine, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Ronald
authors.initials: R
authors.lastname: Wanders
authors.affiliation: 2 University of Amsterdam, Laboratory Genetic Metabolic Diseases, Departments of Paediatrics and Laboratory Medicine, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Jos
authors.initials: J
authors.lastname: Ruiter
authors.affiliation: 2 University of Amsterdam, Laboratory Genetic Metabolic Diseases, Departments of Paediatrics and Laboratory Medicine, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Waterham
authors.affiliation: 2 University of Amsterdam, Laboratory Genetic Metabolic Diseases, Departments of Paediatrics and Laboratory Medicine, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Janet
authors.initials: J
authors.lastname: Koster
authors.affiliation: 1 Murdoch Childrens Research Institute, Victorian Clinical Genetics Services, Royal Children's Hospital, Parkville, Vic 3052, Australia.
authors.forename: Joy
authors.initials: J
authors.lastname: Yaplito-Lee
authors.affiliation: 2 University of Amsterdam, Laboratory Genetic Metabolic Diseases, Departments of Paediatrics and Laboratory Medicine, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Sacha
authors.initials: S
authors.lastname: Ferdinandusse
authors.affiliation: 1 Murdoch Childrens Research Institute, Victorian Clinical Genetics Services, Royal Children's Hospital, Parkville, Vic 3052, Australia 3 Department of Paediatrics, University of Melbourne, Parkville, Vic 3052, Australia james.pitt@vcgs.org.au.
authors.forename: James
authors.initials: J
authors.lastname: Pitt
mesh_terms: D004746:Enoyl-CoA Hydratase / Q000172:deficiency / Q000235:genetics*; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007223:Infant; D007888:Leigh Disease / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D035781:Siblings; D013869:Thiolester Hydrolases / Q000172:deficiency / Q000235:genetics; D014633:Valine / Q000378:metabolism*
chemical_list: D013869:Thiolester Hydrolases; C035908:3-hydroxyisobutyryl-CoA hydrolase; D004746:Enoyl-CoA Hydratase; D014633:Valine
keywords: biochemistry; metabolic disease; neurodegeneration