title: Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement.
abstract: OBJECTIVE
  Short-chain enoyl-CoA hydratase (ECHS1) is a multifunctional mitochondrial matrix enzyme that is involved in the oxidation of fatty acids and essential amino acids such as valine. Here, we describe the broad phenotypic spectrum and pathobiochemistry of individuals with autosomal-recessive ECHS1 deficiency.
  
  
  METHODS
  Using exome sequencing, we identified ten unrelated individuals carrying compound heterozygous or homozygous mutations in ECHS1. Functional investigations in patient-derived fibroblast cell lines included immunoblotting, enzyme activity measurement, and a palmitate loading assay.
  
  
  RESULTS
  Patients showed a heterogeneous phenotype with disease onset in the first year of life and course ranging from neonatal death to survival into adulthood. The most prominent clinical features were encephalopathy (10/10), deafness (9/9), epilepsy (6/9), optic atrophy (6/10), and cardiomyopathy (4/10). Serum lactate was elevated and brain magnetic resonance imaging showed white matter changes or a Leigh-like pattern resembling disorders of mitochondrial energy metabolism. Analysis of patients' fibroblast cell lines (6/10) provided further evidence for the pathogenicity of the respective mutations by showing reduced ECHS1 protein levels and reduced 2-enoyl-CoA hydratase activity. While serum acylcarnitine profiles were largely normal, in vitro palmitate loading of patient fibroblasts revealed increased butyrylcarnitine, unmasking the functional defect in mitochondrial β-oxidation of short-chain fatty acids. Urinary excretion of 2-methyl-2,3-dihydroxybutyrate - a potential derivative of acryloyl-CoA in the valine catabolic pathway - was significantly increased, indicating impaired valine oxidation.
  
  
  CONCLUSIONS
  In conclusion, we define the phenotypic spectrum of a new syndrome caused by ECHS1 deficiency. We speculate that both the β-oxidation defect and the block in l-valine metabolism, with accumulation of toxic methacrylyl-CoA and acryloyl-CoA, contribute to the disorder that may be amenable to metabolic treatment approaches.
authors.affiliation: Institute of Human Genetics, Technische Universität München 81675, Munich, Germany ; Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health 85764, Neuherberg, Germany.
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Haack
authors.affiliation: Institute of Clinical Chemistry and University Children's Hospital, University of Bern 3010, Bern, Switzerland.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Jackson
authors.affiliation: Department of Metabolism, Chiba Children's Hospital Chiba, 266-0007, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Murayama
authors.affiliation: Institute of Human Genetics, Technische Universität München 81675, Munich, Germany ; Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health 85764, Neuherberg, Germany.
authors.forename: Laura S
authors.initials: LS
authors.lastname: Kremer
authors.affiliation: Division of Human Genetics, Department of Pediatrics, University of Bern 3010, Bern, Switzerland.
authors.forename: André
authors.initials: A
authors.lastname: Schaller
authors.affiliation: Divisions of Inherited Metabolic Disease and Neuropediatrics, Department of General Pediatrics, University Hospital Heidelberg D-69120, Heidelberg, Germany.
authors.forename: Urania
authors.initials: U
authors.lastname: Kotzaeridou
authors.affiliation: Department of Pediatrics, Nijmegen Center for Mitochondrial Disorders, Radboud University Center 6525 GA, Nijmegen, The Netherlands.
authors.forename: Maaike C
authors.initials: MC
authors.lastname: de Vries
authors.affiliation: Department of Neuropediatrics and NeuroCure Clinical Research Center, Charité Universitätsmedizin Berlin 13353, Berlin, Germany.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Schottmann
authors.affiliation: Department of Pediatrics, Birmingham Children's Hospital Birmingham, B4 6NH, United Kingdom.
authors.forename: Saikat
authors.initials: S
authors.lastname: Santra
authors.affiliation: Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University 80336, Munich, Germany.
authors.forename: Boriana
authors.initials: B
authors.lastname: Büchner
authors.affiliation: Institute of Human Genetics, Technische Universität München 81675, Munich, Germany ; Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health 85764, Neuherberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieland
authors.affiliation: Institute of Human Genetics, Technische Universität München 81675, Munich, Germany ; Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health 85764, Neuherberg, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Graf
authors.affiliation: Department of Pediatrics, Klinikum Reutlingen 72764, Reutlingen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Freisinger
authors.affiliation: Institute of Clinical Chemistry and University Children's Hospital, University of Bern 3010, Bern, Switzerland.
authors.forename: Sandra
authors.initials: S
authors.lastname: Eggimann
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Saitama Medical University Saitama, 350-0495, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Ohtake
authors.affiliation: Division of Translational Research, Research Center for Genomic Medicine, Saitama Medical University Saitama, 350-1241, Japan ; Division of Functional Genomics & Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University Saitama, 350-1241, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Okazaki
authors.affiliation: Division of Translational Research, Research Center for Genomic Medicine, Saitama Medical University Saitama, 350-1241, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kohda
authors.affiliation: Division of Functional Genomics & Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University Saitama, 350-1241, Japan.
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Kishita
authors.affiliation: Division of Functional Genomics & Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University Saitama, 350-1241, Japan.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Tokuzawa
authors.affiliation: Max-Planck-Institute for Molecular Genetics, Otto-Warburg Laboratory 14195, Berlin, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Sauer
authors.affiliation: Wellcome Trust Sanger Institute Hinxton, Cambridge, CB10 1SA, United Kingdom.
authors.forename: Yasin
authors.initials: Y
authors.lastname: Memari
authors.affiliation: Wellcome Trust Sanger Institute Hinxton, Cambridge, CB10 1SA, United Kingdom.
authors.forename: Anja
authors.initials: A
authors.lastname: Kolb-Kokocinski
authors.affiliation: Wellcome Trust Sanger Institute Hinxton, Cambridge, CB10 1SA, United Kingdom.
authors.forename: Richard
authors.initials: R
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authors.affiliation: Department of Neuropediatrics, Children's Hospital of Eastern Switzerland St.Gallen 9006, St. Gallen, Switzerland.
authors.forename: Oswald
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authors.affiliation: Institute of Human Genetics, University of Bonn 53127, Bonn, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Cremer
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen 45122, Essen, Germany.
authors.forename: Beate
authors.initials: B
authors.lastname: Albrecht
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen 45122, Essen, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wieczorek
authors.affiliation: Institute of Human Genetics, University of Bonn 53127, Bonn, Germany.
authors.forename: Hartmut
authors.initials: H
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authors.affiliation: Institute of Clinical Chemistry and University Children's Hospital, University of Bern 3010, Bern, Switzerland.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Hahn
authors.affiliation: Institute of Human Genetics, University of Bonn 53127, Bonn, Germany.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Zink
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University Newcastle upon Tyne, NE2 4HH, United Kingdom.
authors.forename: Charlotte L
authors.initials: CL
authors.lastname: Alston
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University Newcastle upon Tyne, NE2 4HH, United Kingdom.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.affiliation: Department of Pediatrics, Nijmegen Center for Mitochondrial Disorders, Radboud University Center 6525 GA, Nijmegen, The Netherlands.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Rodenburg
authors.affiliation: Department of Pediatrics, Friedrich-Alexander-University of Erlangen-Nürnberg 91054, Erlangen, Germany.
authors.forename: Regina
authors.initials: R
authors.lastname: Trollmann
authors.affiliation: Department of Pediatrics, Paracelsus Medical University Salzburg 5020, Salzburg, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sperl
authors.affiliation: Institute of Human Genetics, Technische Universität München 81675, Munich, Germany ; Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health 85764, Neuherberg, Germany.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.affiliation: Divisions of Inherited Metabolic Disease and Neuropediatrics, Department of General Pediatrics, University Hospital Heidelberg D-69120, Heidelberg, Germany.
authors.forename: Georg F
authors.initials: GF
authors.lastname: Hoffmann
authors.affiliation: Department of Pediatrics, Paracelsus Medical University Salzburg 5020, Salzburg, Austria.
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Mayr
authors.affiliation: Institute of Human Genetics, Technische Universität München 81675, Munich, Germany ; Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health 85764, Neuherberg, Germany ; Munich Cluster for Systems Neurology (SyNergy) 80336, Munich, Germany ; DZNE - German Center for Neurodegenerative Diseases 80336, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.affiliation: Division of Human Genetics, Department of Pediatrics, University of Bern 3010, Bern, Switzerland.
authors.forename: Ramona
authors.initials: R
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authors.affiliation: Department of Neuropediatrics and NeuroCure Clinical Research Center, Charité Universitätsmedizin Berlin 13353, Berlin, Germany.
authors.forename: Markus
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authors.lastname: Schuelke
authors.affiliation: Institute of Clinical Chemistry and University Children's Hospital, University of Bern 3010, Bern, Switzerland.
authors.forename: Jean-Marc
authors.initials: JM
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authors.affiliation: Divisions of Inherited Metabolic Disease and Neuropediatrics, Department of General Pediatrics, University Hospital Heidelberg D-69120, Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kölker
authors.affiliation: Institute of Human Genetics, Technische Universität München 81675, Munich, Germany ; Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health 85764, Neuherberg, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.affiliation: Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University 80336, Munich, Germany ; Munich Cluster for Systems Neurology (SyNergy) 80336, Munich, Germany ; DZNE - German Center for Neurodegenerative Diseases 80336, Munich, Germany.
authors.forename: Thomas
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authors.lastname: Klopstock