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Ann Clin Transl Neurol. 2015 May;2(5):492-509. doi: 10.1002/acn3.189. Epub 2015 Mar 13.

Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement.

Author information

1
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.
2
Institute of Clinical Chemistry and University Children's Hospital, University of Bern 3010, Bern, Switzerland.
3
Department of Metabolism, Chiba Children's Hospital Chiba, 266-0007, Japan.
4
Division of Human Genetics, Department of Pediatrics, University of Bern 3010, Bern, Switzerland.
5
Divisions of Inherited Metabolic Disease and Neuropediatrics, Department of General Pediatrics, University Hospital Heidelberg D-69120, Heidelberg, Germany.
6
Department of Pediatrics, Nijmegen Center for Mitochondrial Disorders, Radboud University Center 6525 GA, Nijmegen, The Netherlands.
7
Department of Neuropediatrics and NeuroCure Clinical Research Center, Charité Universitätsmedizin Berlin 13353, Berlin, Germany.
8
Department of Pediatrics, Birmingham Children's Hospital Birmingham, B4 6NH, United Kingdom.
9
Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University 80336, Munich, Germany.
10
Department of Pediatrics, Klinikum Reutlingen 72764, Reutlingen, Germany.
11
Department of Pediatrics, Faculty of Medicine, Saitama Medical University Saitama, 350-0495, Japan.
12
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.
13
Division of Translational Research, Research Center for Genomic Medicine, Saitama Medical University Saitama, 350-1241, Japan.
14
Division of Functional Genomics & Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University Saitama, 350-1241, Japan.
15
Max-Planck-Institute for Molecular Genetics, Otto-Warburg Laboratory 14195, Berlin, Germany.
16
Wellcome Trust Sanger Institute Hinxton, Cambridge, CB10 1SA, United Kingdom.
17
Department of Neuropediatrics, Children's Hospital of Eastern Switzerland St.Gallen 9006, St. Gallen, Switzerland.
18
Institute of Human Genetics, University of Bonn 53127, Bonn, Germany.
19
Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen 45122, Essen, Germany.
20
Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University Newcastle upon Tyne, NE2 4HH, United Kingdom.
21
Department of Pediatrics, Friedrich-Alexander-University of Erlangen-Nürnberg 91054, Erlangen, Germany.
22
Department of Pediatrics, Paracelsus Medical University Salzburg 5020, Salzburg, Austria.
23
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.
24
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.

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.

INTERPRETATION:

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.

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