Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement.
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Haack Tobias B, Jackson Christopher B, 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 Sandra, Ohtake Akira, Okazaki Yasushi, Kohda Masakazu, Kishita Yoshihito, Tokuzawa Yoshimi, Sauer Sascha, Memari Yasin, Kolb-Kokocinski Anja, Durbin Richard, Hasselmann Oswald, Cremer Kirsten, Albrecht Beate, Wieczorek Dagmar, Engels Hartmut, Hahn Dagmar, Zink Alexander M, Alston Charlotte L, Taylor Robert W, Rodenburg Richard J, Trollmann Regina, Sperl Wolfgang, Strom Tim M, Hoffmann Georg F, Mayr Johannes A, Meitinger Thomas, Bolognini Ramona, Schuelke Markus, Nuoffer Jean-Marc, Kölker Stefan, Prokisch Holger, Klopstock Thomas
Аннотация
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.