Clinical and biochemical characterization of four patients with mutations in ECHS1

Orphanet Journal of Rare Diseases

Ronald J. A. Wanders²  Johan L. K. Van Hove⁹  Orly Elpeleg³  Michael J. Bennett⁴  Kaitlyn Bloom⁴  Kathryn Chatfield¹  Katherine Gowan⁶  Hans R. Waterham²  Frédéric M. Vaz²  Jirair K. Bedoyan⁷  Renata C. Gallagher⁹  Megan K. Dishop⁸  Curtis R. Coughlin⁹  Jos P. N. Ruiter²  Alberto Burlina⁵  Marisa W. Friederich⁹  Sacha Ferdinandusse² 

[1] Department of Pediatrics, Section of Pediatric Cardiology, University of Colorado, Aurora 80045, CO, USA;Departments of Clinical Chemistry and Pediatrics, Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam 1105, AZ, The Netherlands;Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel;Department of Pathology & Laboratory Medicine, Children’s Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia U74SA, PA, USA;Department of Paediatrics, Division of Metabolic Diseases, University Hospital of Padua, Padua, Italy;Department of Biochemistry and Molecular Genetics, University of Colorado, Aurora 80045, CO, USA;Departments of Genetics and Pediatrics, Case Western Reserve University, Cleveland 44106, OH, USA;Department of Pathology, University of Colorado, Aurora 80045, CO, USA;Department of Pediatrics, Section of Genetics, University of Colorado, Aurora 80045, CO, USA

关键词: Pyruvate dehydrogenase complex;    Leigh disease;    Mitochondrial fatty acid oxidation;    Branched-chain amino acid metabolism;    Crotonase;   

Others  :  1219120
DOI  :  10.1186/s13023-015-0290-1

 received in 2015-03-25, accepted in 2015-05-29,  发布年份 2015

【 摘 要 】

Background

Short-chain enoyl-CoA hydratase (SCEH, encoded by ECHS1) catalyzes hydration of 2-trans-enoyl-CoAs to 3(S)-hydroxy-acyl-CoAs. SCEH has a broad substrate specificity and is believed to play an important role in mitochondrial fatty acid oxidation and in the metabolism of branched-chain amino acids. Recently, the first patients with SCEH deficiency have been reported revealing only a defect in valine catabolism. We investigated the role of SCEH in fatty acid and branched-chain amino acid metabolism in four newly identified patients. In addition, because of the Leigh-like presentation, we studied enzymes involved in bioenergetics.

Methods

Metabolite, enzymatic, protein and genetic analyses were performed in four patients, including two siblings. Palmitate loading studies in fibroblasts were performed to study mitochondrial β-oxidation. In addition, enoyl-CoA hydratase activity was measured with crotonyl-CoA, methacrylyl-CoA, tiglyl-CoA and 3-methylcrotonyl-CoA both in fibroblasts and liver to further study the role of SCEH in different metabolic pathways. Analyses of pyruvate dehydrogenase and respiratory chain complexes were performed in multiple tissues of two patients.

Results

All patients were either homozygous or compound heterozygous for mutations in the ECHS1 gene, had markedly reduced SCEH enzymatic activity and protein level in fibroblasts. All patients presented with lactic acidosis. The first two patients presented with vacuolating leukoencephalopathy and basal ganglia abnormalities. The third patient showed a slow neurodegenerative condition with global brain atrophy and the fourth patient showed Leigh-like lesions with a single episode of metabolic acidosis. Clinical picture and metabolite analysis were not consistent with a mitochondrial fatty acid oxidation disorder, which was supported by the normal palmitate loading test in fibroblasts. Patient fibroblasts displayed deficient hydratase activity with different substrates tested. Pyruvate dehydrogenase activity was markedly reduced in particular in muscle from the most severely affected patients, which was caused by reduced expression of E2 protein, whereas E2 mRNA was increased.

Conclusions

Despite its activity towards substrates from different metabolic pathways, SCEH appears to be only crucial in valine metabolism, but not in isoleucine metabolism, and only of limited importance for mitochondrial fatty acid oxidation. In severely affected patients SCEH deficiency can cause a secondary pyruvate dehydrogenase deficiency contributing to the clinical presentation.

【 授权许可】

   
2015 Ferdinandusse et al.

【 图 表 】

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