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| Item Type: | Article |
|---|---|
| Title: | Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement |
| Creators Name: | Haack, T.B. and Jackson, C.B. and Murayama, K. and Kremer, L.S. and Schaller, A. and Kotzaeridou, U. and de Vries, M.C. and Schottmann, G. and Santra, S. and Büchner, B. and Wieland, T. and Graf, E. and Freisinger, P. and Eggimann, S. and Ohtake, A. and Okazaki, Y. and Kohda, M. and Kishita, Y. and Tokuzawa, Y. and Sauer, S. and Memari, Y. and Kolb-Kokocinski, A. and Durbin, R. and Hasselmann, O. and Cremer, K. and Albrecht, B. and Wieczorek, D. and Engels, H. and Hahn, D. and Zink, A.M. and Alston, C.L. and Taylor, R.W. and Rodenburg, R.J. and Trollmann, R. and Sperl, W. and Strom, T.M. and Hoffmann, G.F. and Mayr, J.A. and Meitinger, T. and Bolognini, R. and Schuelke, M. and Nuoffer, J.M. and Kölker, S. and Prokisch, H. and Klopstock, T. |
| 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. |
| Source: | Annals of Clinical and Translational Neurology |
| ISSN: | 2328-9503 |
| Publisher: | Wiley |
| Volume: | 2 |
| Number: | 5 |
| Page Range: | 492-509 |
| Date: | May 2015 |
| Official Publication: | https://doi.org/10.1002/acn3.189 |
| PubMed: | View item in PubMed |
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