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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
  1. Kenichiro Yamada1,
  2. Kaori Aiba2,
  3. Yasuyuki Kitaura3,
  4. Yusuke Kondo3,
  5. Noriko Nomura1,
  6. Yuji Nakamura2,
  7. Daisuke Fukushi1,
  8. Kei Murayama4,
  9. Yoshiharu Shimomura3,
  10. James Pitt5,
  11. Seiji Yamaguchi6,
  12. Kenji Yokochi7,
  13. Nobuaki Wakamatsu1
  1. 1Department of Genetics, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi, Japan
  2. 2Department of Pediatrics, Toyohashi Municipal Hospital, Toyohashi, Aichi, Japan
  3. 3Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Aichi, Japan
  4. 4Department of Metabolism, Chiba Children's Hospital, Chiba, Japan
  5. 5Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, Victoria, Australia
  6. 6Department of Pediatrics, Faculty of Medicine, Shimane University, Izumo, Shimane, Japan
  7. 7Department of Pediatric Neurology, Seirei-Mikatahara General Hospital, Hamamatsu, Shizuoka, Japan
  1. Correspondence to Dr Nobuaki Wakamatsu, Department of Genetics, Institute for Developmental Research, Aichi Human Service Center, 713-8 Kamiya-cho, Kasugai, Aichi 480-0392, Japan; nwaka{at}


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.

  • Metabolic disorders
  • Neurology
  • Genetics

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