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000138289 1001_ $$aHaack, Tobias B$$b0
000138289 245__ $$aDeficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement.
000138289 260__ $$aChichester [u.a.]$$bWiley$$c2015
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000138289 520__ $$aShort-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.
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000138289 542__ $$2Crossref$$i2015-09-01$$uhttp://doi.wiley.com/10.1002/tdm_license_1.1
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000138289 7001_ $$aJackson, Christopher B$$b1
000138289 7001_ $$aMurayama, Kei$$b2
000138289 7001_ $$aKremer, Laura S$$b3
000138289 7001_ $$aSchaller, André$$b4
000138289 7001_ $$aKotzaeridou, Urania$$b5
000138289 7001_ $$ade Vries, Maaike C$$b6
000138289 7001_ $$aSchottmann, Gudrun$$b7
000138289 7001_ $$aSantra, Saikat$$b8
000138289 7001_ $$aBüchner, Boriana$$b9
000138289 7001_ $$aWieland, Thomas$$b10
000138289 7001_ $$aGraf, Elisabeth$$b11
000138289 7001_ $$aFreisinger, Peter$$b12
000138289 7001_ $$aEggimann, Sandra$$b13
000138289 7001_ $$aOhtake, Akira$$b14
000138289 7001_ $$aOkazaki, Yasushi$$b15
000138289 7001_ $$aKohda, Masakazu$$b16
000138289 7001_ $$aKishita, Yoshihito$$b17
000138289 7001_ $$aTokuzawa, Yoshimi$$b18
000138289 7001_ $$aSauer, Sascha$$b19
000138289 7001_ $$aMemari, Yasin$$b20
000138289 7001_ $$aKolb-Kokocinski, Anja$$b21
000138289 7001_ $$aDurbin, Richard$$b22
000138289 7001_ $$aHasselmann, Oswald$$b23
000138289 7001_ $$aCremer, Kirsten$$b24
000138289 7001_ $$aAlbrecht, Beate$$b25
000138289 7001_ $$aWieczorek, Dagmar$$b26
000138289 7001_ $$aEngels, Hartmut$$b27
000138289 7001_ $$aHahn, Dagmar$$b28
000138289 7001_ $$aZink, Alexander M$$b29
000138289 7001_ $$aAlston, Charlotte L$$b30
000138289 7001_ $$aTaylor, Robert W$$b31
000138289 7001_ $$aRodenburg, Richard J$$b32
000138289 7001_ $$aTrollmann, Regina$$b33
000138289 7001_ $$aSperl, Wolfgang$$b34
000138289 7001_ $$aStrom, Tim M$$b35
000138289 7001_ $$aHoffmann, Georg F$$b36
000138289 7001_ $$aMayr, Johannes A$$b37
000138289 7001_ $$0P:(DE-2719)9000207$$aMeitinger, Thomas$$b38$$udzne
000138289 7001_ $$aBolognini, Ramona$$b39
000138289 7001_ $$aSchuelke, Markus$$b40
000138289 7001_ $$aNuoffer, Jean-Marc$$b41
000138289 7001_ $$aKölker, Stefan$$b42
000138289 7001_ $$0P:(DE-HGF)0$$aProkisch, Holger$$b43$$eCorresponding author
000138289 7001_ $$0P:(DE-2719)2810704$$aKlopstock, Thomas$$b44$$eLast author$$udzne
000138289 77318 $$2Crossref$$3journal-article$$a10.1002/acn3.189$$b : Wiley, 2015-03-13$$n5$$p492-509$$tAnnals of Clinical and Translational Neurology$$v2$$x2328-9503$$y2015
000138289 773__ $$0PERI:(DE-600)2740696-9$$a10.1002/acn3.189$$gVol. 2, no. 5, p. 492 - 509$$n5$$p492-509$$q2:5<492 - 509$$tAnnals of Clinical and Translational Neurology$$v2$$x2328-9503$$y2015
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