ECHS1 mutations in Leigh disease: a new inborn error of metabolism affecting valine metabolism
- 14 August 2014
- journal article
- case report
- Published by Oxford University Press (OUP) in Brain
- Vol. 137 (11), 2903-2908
- https://doi.org/10.1093/brain/awu216
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.This publication has 8 references indexed in Scilit:
- HIBCH mutations can cause Leigh-like disease with combined deficiency of multiple mitochondrial respiratory chain enzymes and pyruvate dehydrogenaseOrphanet Journal of Rare Diseases, 2013
- Exome sequencing reveals a novel Moroccan founder mutation inSLC19A3as a new cause of early-childhood fatal Leigh syndromeBrain, 2013
- Enzymology of the branched‐chain amino acid oxidation disorders: the valine pathwayJournal of Inherited Metabolic Disease, 2010
- Recent Advances in the Genetics of Mitochondrial EncephalopathiesCurrent Neurology and Neuroscience Reports, 2010
- Leigh and Leigh-Like Syndrome in Children and AdultsPediatric Neurology, 2008
- Mutations in the Gene Encoding 3-Hydroxyisobutyryl-CoA Hydrolase Results in Progressive Infantile NeurodegenerationAmerican Journal of Human Genetics, 2007
- β-Hydroxyisobutyryl Coenzyme A Deacylase Deficiency: A Defect in Valine Metabolism Associated with Physical MalformationsPEDIATRICS, 1982
- Two new sulphur-containing amino acids in manJournal of Mass Spectrometry, 1981