Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement

Autor: Georg F. Hoffmann, Charlotte L. Alston, André Schaller, Richard J. Rodenburg, Holger Prokisch, Yoshihito Kishita, Markus Schuelke, Sascha Sauer, Yasin Memari, Thomas Meitinger, Regina Trollmann, Urania Kotzaeridou, Kei Murayama, Wolfgang Sperl, Thomas Wieland, Stefan Kölker, Saikat Santra, Tobias B. Haack, Hartmut Engels, Gudrun Schottmann, Boriana Büchner, Yasushi Okazaki, Johannes A. Mayr, Masakazu Kohda, Christopher B. Jackson, Yoshimi Tokuzawa, Jean-Marc Nuoffer, Richard Durbin, Beate Albrecht, Peter Freisinger, Robert W. Taylor, Ramona Bolognini, Dagmar Hahn, Tim M. Strom, Dagmar Wieczorek, Oswald Hasselmann, Laura S. Kremer, Kirsten Cremer, Elisabeth Graf, Akira Ohtake, Maaike de Vries, Anja Kolb-Kokocinski, Alexander M. Zink, Thomas Klopstock, Seila Eggimann
Rok vydání: 2015
Předmět:
Zdroj: Annals of Clinical and Translational Neurology, 2, 492-509
Haack, Tobias B; Jackson, Christopher; Murayama, Kei; Kremer, Laura S; Schaller, André; Kotzaeridou, Urania; de Vries, Maaike C; Schottmann, Gudrun; Santra, Saikat; Büchner, Boriana; Wieland, Thomas; Graf, Elisabeth; Freisinger, Peter; Eggimann, Seila; Ohtake, Akira; Okazaki, Yasushi; Kohda, Masakazu; Kishita, Yoshihito; Tokuzawa, Yoshimi; Sauer, Sascha; ... (2015). Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement. Annals of Clinical and Translational Neurology, 2(5), pp. 492-509. Wiley 10.1002/acn3.189
Annals of Clinical and Translational Neurology 2(5), 492-509 (2015). doi:10.1002/acn3.189
Ann. Clin. Transl. Neurol. 2, 492-509 (2015)
Annals of Clinical and Translational Neurology
Annals of Clinical and Translational Neurology, 2, 5, pp. 492-509
ISSN: 2328-9503
DOI: 10.1002/acn3.189
Popis: 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, invitro 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.
Databáze: OpenAIRE
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