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@ARTICLE{Haack:138289,
      author       = {Haack, Tobias B and Jackson, Christopher B and Murayama,
                      Kei and Kremer, Laura S and Schaller, André and
                      Kotzaeridou, Urania and de Vries, Maaike C and Schottmann,
                      Gudrun and Santra, Saikat and Büchner, Boriana and Wieland,
                      Thomas and Graf, Elisabeth and Freisinger, Peter and
                      Eggimann, Sandra and Ohtake, Akira and Okazaki, Yasushi and
                      Kohda, Masakazu and Kishita, Yoshihito and Tokuzawa, Yoshimi
                      and Sauer, Sascha and Memari, Yasin and Kolb-Kokocinski,
                      Anja and Durbin, Richard and Hasselmann, Oswald and Cremer,
                      Kirsten and Albrecht, Beate and Wieczorek, Dagmar and
                      Engels, Hartmut and Hahn, Dagmar and Zink, Alexander M and
                      Alston, Charlotte L and Taylor, Robert W and Rodenburg,
                      Richard J and Trollmann, Regina and Sperl, Wolfgang and
                      Strom, Tim M and Hoffmann, Georg F and Mayr, Johannes A and
                      Meitinger, Thomas and Bolognini, Ramona and Schuelke, Markus
                      and Nuoffer, Jean-Marc and Kölker, Stefan and Prokisch,
                      Holger and Klopstock, Thomas},
      title        = {{D}eficiency of {ECHS}1 causes mitochondrial encephalopathy
                      with cardiac involvement.},
      journal      = {Annals of Clinical and Translational Neurology},
      volume       = {2},
      number       = {5},
      issn         = {2328-9503},
      address      = {Chichester [u.a.]},
      publisher    = {Wiley},
      reportid     = {DZNE-2020-04611},
      pages        = {492-509},
      year         = {2015},
      abstract     = {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.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.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.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.},
      cin          = {Ext HZM / AG Levin},
      ddc          = {610},
      cid          = {I:(DE-2719)5000050 / I:(DE-2719)1111016},
      pnm          = {342 - Disease Mechanisms and Model Systems (POF3-342) / 344
                      - Clinical and Health Care Research (POF3-344)},
      pid          = {G:(DE-HGF)POF3-342 / G:(DE-HGF)POF3-344},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:26000322},
      pmc          = {pmc:PMC4435704},
      doi          = {10.1002/acn3.189},
      url          = {https://pub.dzne.de/record/138289},
}