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.
Highlights
Short-chain enoyl-CoA hydratase (ECHS1, synonym: crotonase, EC 4.2.1.17), encoded by ECHS1, is a mitochondrial matrix enzyme that catalyzes the second step of the b-oxidation spiral of fatty acids, that is, the hydration of chain-shortened a,b-unsaturated enoyl-CoA thioesters to produce b-hydroxyacyl-CoA.[1]
We applied whole exome sequencing in a cohort of 435 individuals with a suspected disorder of mitochondrial energy metabolism and identified six unrelated affected individuals carrying two heterozygous or homozygous rare variants in ECHS1 (Fig. 2)
(deafness, seizures, hypotonia, ataxia, and developmental delay) are very well compatible with a mitochondrial disorder. It remains unclear whether the dysmorphic signs in this patient are related to the ECHS1 deficiency as dysmorphism is rather uncommon in mitochondrial diseases and was not found in any of the other ECHS1-deficient patients
Summary
Short-chain enoyl-CoA hydratase (ECHS1, synonym: crotonase, EC 4.2.1.17), encoded by ECHS1 (cytogenetic location: 10q26.3; GenBank accession number: NM_004092.3; OMIM*602292), is a mitochondrial matrix enzyme that catalyzes the second step of the b-oxidation spiral of fatty acids, that is, the hydration of chain-shortened a,b-unsaturated enoyl-CoA thioesters to produce b-hydroxyacyl-CoA.[1]. Decreased formation of acetyl-CoA may hamper posttranslational acetylation of mitochondrial proteins, a mechanism that is emerging as a critical regulator of mitochondrial function.[2] Evidence is increasing that ECHS1 has a wide substrate specificity and plays an important role in amino acid catabolism, in particular of valine, where it converts methacrylyl-CoA to (S)-3-hydroxyisobutyryl-CoA and acryloyl-CoA to 3-hydroxypropionyl-CoA (Fig. 1), the fourth step of valine oxidation.[3] Accumulation of toxic methacrylyl-CoA and acryloyl-CoA, two highly reactive intermediates that spontaneously react with sulfhydryl groups of, for example, cysteine and cysteamine, is suspected to cause brain pathology and biochemical phenotype in b-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency, a disorder of the fifth step of valine oxidation with a Leigh-like phenotype and deficiency of multiple mitochondrial enzymes.[4,5] Very recently, ECHS1 mutations were reported in two siblings with Leigh disease and remarkable clinical and biochemical similarities to HIBCH deficiency.[6] Both presented soon after birth with generalized hypotonia, poor feeding, respiratory insufficiency, and developmental delay. They suffered a severe clinical course and died at the age of 4 and 8 months
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