Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement

Abstract

ObjectiveShort-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.MethodsUsing 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.ResultsPatients 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.InterpretationIn 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.

Clinical, biochemical, and genetic features of four patients with short‐chain enoyl‐CoA hydratase (ECHS1) deficiency

“…Patient 1 was apparent homozygous for a previously reported c.476A > G, p.(Gln159Arg) variant (Haack et al, 2015) in exon 4 of the ECHS1 gene (GenBank Accession Number: NM_004092.3) corroborating the enzymatic diagnosis of SCEH deficiency. The c.476A > G, p.(Gln159Arg) ECHS1 variant has been previously reported in either the homozygous or compound heterozygous state in clinically affected patients (Haack et al, 2015).…”

“…The c.476A > G, p.(Gln159Arg) ECHS1 variant has been previously reported in either the homozygous or compound heterozygous state in clinically affected patients (Haack et al, 2015). Unfortunately, parental DNA samples were not available to confirm the apparent homozygosity in Patient 1.…”

“…Biallelic mutations in the ECHS1 gene (OMIM 602292) lead to a deficiency of short‐chain enoyl‐CoA hydratase (SCEH/crotonase EC4.2.1.17) resulting in a rare inborn error of valine metabolism (Haack et al, 2015; Peters et al, 2014; Sakai et al, 2015; Tetreault et al, 2015). Clinical presentation includes infantile‐onset of severe developmental delay and regression and seizures, with elevated plasma lactate and brain MRI abnormalities consistent with Leigh syndrome (LS) as described by Denis Leigh in 1951 (Leigh, 1951) and more recently by Baertling et al in 2014 (Baertling, 2014).…”

“…Deficiency of SCEH which converts unsaturated trans ‐2‐enoyl‐CoA species to the corresponding 3( S )‐hydroxyacyl‐CoA (Haack et al, 2015; Peters et al, 2014; Sakai et al, 2015; Tetreault et al, 2015) and deficiency of HIBCH (Brown et al, 1982; Ferdinandusse et al, 2013; Loupatty et al, 2007; Soler‐Alfonso et al, 2015; Stiles et al, 2015) that catalyses the conversion of 3‐OH‐isobutyryl‐CoA to 3‐OH‐isobutyrate, the fourth and fifth steps of valine degradation, respectively, have been associated with LS or Leigh‐like syndrome and deficiencies of multiple mitochondrial respiratory chain enzymes.…”

“…SCEH also catalyzes the second step of the β‐oxidation of short‐chain fatty acids, that is, the hydration of α,β‐unsaturated enoyl‐CoAs to produce β‐hydroxyacyl‐CoAs (Kanazawa et al, 1993). It has been speculated that it is both the β‐oxidation defect and the block in l ‐valine metabolism that contribute to the pathology in SCEH deficiency (Haack et al, 2015). However, Ferdinandusse et al (2013) presented evidence that despite its broad substrate specificity, SCEH appears to be crucial in valine catabolism, but only of limited importance for mitochondrial fatty acid oxidation and may not play a significant role in isoleucine metabolism.…”