Clinical, biochemical and metabolic characterisation of a mild form of human short-chain enoyl-CoA hydratase deficiency: significance of increased N-acetyl-S-(2-carboxypropyl)cysteine excretion

Yamada, Kenichiro; Aiba, Kaori; Kitaura, Yasuyuki; Kondo, Yûsuke; Nomura, Noriko; Nakamura, Yuji; Fukushi, Daisuke; Murayama, Kei; Shimomura, Yoshiharu; Pitt, James; Yamaguchi, Seiji; Yokochi, Kenji; Wakamatsu, Nobuaki

doi:10.1136/jmedgenet-2015-103231

Cited by 64 publications

(89 citation statements)

References 22 publications

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“…Evidence is emerging that metabolite levels may correlate with disease severity, being subtle or normal for some metabolites in clinically milder cases (Haack et al, 2015; Yamada et al, 2015) and retrospective analysis of S ‐(2‐carboxypropyl)cysteamine, S ‐(2‐carboxypropyl)cysteine, and N ‐acetyl‐ S ‐(2‐carboxypropyl) cysteine can be a diagnostic clue in the disease spectrum of ECHS1 deficiency (A Mutairi et al, 2017). SCEH activity in cultured fibroblasts was markedly reduced but not completely deficient, which is in agreement with a milder clinical phenotype considering the age of death when compared to some other published cases (Bedoyan et al, 2017; Haack et al, 2015; Peters et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

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

Fitzsimons

Alston

Bonnen

et al. 2018

American J of Med Genetics Pt A

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Short‐chain enoyl‐CoA hydratase (SCEH or ECHS1) deficiency is a rare inborn error of metabolism caused by biallelic mutations in the gene ECHS1 (OMIM 602292). Clinical presentation includes infantile‐onset severe developmental delay, regression, seizures, elevated lactate, and brain MRI abnormalities consistent with Leigh syndrome (LS). Characteristic abnormal biochemical findings are secondary to dysfunction of valine metabolism. We describe four patients from two consanguineous families (one Pakistani and one Irish Traveler), who presented in infancy with LS. Urine organic acid analysis by GC/MS showed increased levels of erythro‐2,3‐dihydroxy‐2‐methylbutyrate and 3‐methylglutaconate (3‐MGC). Increased urine excretion of methacrylyl‐CoA and acryloyl‐CoA related metabolites analyzed by LC‐MS/MS, were suggestive of SCEH deficiency; this was confirmed in patient fibroblasts. Both families were shown to harbor homozygous pathogenic variants in the ECHS1 gene; a c.476A > G (p.Gln159Arg) ECHS1variant in the Pakistani family and a c.538A > G, p.(Thr180Ala) ECHS1 variant in the Irish Traveler family. The c.538A > G, p.(Thr180Ala) ECHS1 variant was postulated to represent a Canadian founder mutation, but we present SNP genotyping data to support Irish ancestry of this variant with a haplotype common to the previously reported Canadian patients and our Irish Traveler family. The presence of detectable erythro‐2,3‐dihydroxy‐2‐methylbutyrate is a nonspecific marker on urine organic acid analysis but this finding, together with increased excretion of 3‐MGC, elevated plasma lactate, and normal acylcarnitine profile in patients with a Leigh‐like presentation should prompt consideration of a diagnosis of SCEH deficiency and genetic analysis of ECHS1. ECHS1 deficiency can be added to the list of conditions with 3‐MGA.

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Section: Discussionmentioning

confidence: 99%

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

Fitzsimons

Alston

Bonnen

et al. 2018

American J of Med Genetics Pt A

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“…In addition, cardiomyopathy, developmental delay and metabolic acidosis are common, with death mostly under the age of 1 year [120][121][122][123][124] (Table 3). Given the involvement of ECHS1 in both the amino acid and FAO pathways, build-up of intermediates from both pathways are a common feature [120][121][122][123][124][125]. Interestingly, ECHS1 has been demonstrated to be most active in the valine pathway and may be expendable in FAO [122].…”

Section: Disorders Of Fao Enzymesmentioning

confidence: 99%

“…In addition to the OXPHOS defects, pyruvate dehydrogenase activity was reduced in all but one of the ECHS1 deficiencies that was fatal [120][121][122][123][124][125] (Table 3). Interestingly, the pyruvate .…”

Section: Combined Echs1 Deficiency and Oxphos Complex Defectsmentioning

confidence: 99%

Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

2016

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SynopsisMitochondria provide the main source of energy to eukaryotic cells, oxidizing fats and sugars to generate ATP . Mitochondrial fatty acid β-oxidation (FAO) and oxidative phosphorylation (OXPHOS) are two metabolic pathways which are central to this process. Defects in these pathways can result in diseases of the brain, skeletal muscle, heart and liver, affecting approximately 1 in 5000 live births. There are no effective therapies for these disorders, with quality of life severely reduced for most patients. The pathology underlying many aspects of these diseases is not well understood; for example, it is not clear why some patients with primary FAO deficiencies exhibit secondary OXPHOS defects. However, recent findings suggest that physical interactions exist between FAO and OXPHOS proteins, and that these interactions are critical for both FAO and OXPHOS function. Here, we review our current understanding of the interactions between FAO and OXPHOS proteins and how defects in these two metabolic pathways contribute to mitochondrial disease pathogenesis.Key words: disease, mitochondria, protein complex assembly, protein interactions, supercomplex. MITOCHONDRIAL METABOLISMMitochondria occupy almost all human cell types and are involved in essential metabolic and cellular processes, including calcium and iron homoeostasis, apoptosis, innate immunity and haeme biosynthesis [1]. However, the primary function of mitochondria is the production of energy in the form of ATP [2][3][4]. ATP is the body's energy currency, playing vital roles in cell differentiation, growth and reproduction, thermogenesis and powering the contraction of muscles for movement [1]. In humans, ATP is produced by two different processes; through the breakdown of glucose or other sugars in Abbreviations: ACAD9, acyl-CoA dehydrogenase 9; BN-PAGE, blue native polyacrylamide gel electrophoresis; CACT, carnitine acylcarnitine translocase; CI, oxidative phosphorylation complex I (NADH: ubiquinone oxidoreductase, EC 1.6.5.3); CII, oxidative phosphorylation complex II (succinate: ubiquinone oxidoreductase, EC 1.3.5.1); CIII, oxidative phosphorylation complex III (ubiquinol: ferricytochrome c oxidoreductase, EC 1.10.2.2); CIV, oxidative phosphorylation complex IV (cytochrome c oxidase, EC 1.9.3.1); COPP , complex one phylogenetic profile; CPT1, carnitine O-palmitoyltransferase 1; CPT2, carnitine O-palmitoyltransferase 2; CV, OXPHOS complex V (FoF 1 -ATP synthetase, EC; 3.6.3.14); ECHS1, enoyl-CoA hydratase, short chain 1, mitochondrial; ECI1, enoyl-CoA delta isomerase, 1; ETF, electron transfer flavoprotein; ETFA, electron transfer flavoprotein alpha subunit; ETFB, electron transfer flavoprotein beta subunit; ETF-QO, electron transfer flavoprotein: ubiquinone oxidoreductase; FAD, flavin adenine dinucleotide; FADH 2 , reduced flavin adenine dinucleotide; FAO, fatty acid β-oxidation; H 2 O, water; HADH, hydroxyacyl-CoA dehydrogenase; KAT, 3-ketoacyl-CoA thiolase, mitochondrial; LCAD, long chain acyl-CoA dehydrogenase; LCEH, long chain enoyl-CoA hydra...

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“…SCEH functions to hydrate the double bond between the second and third carbons of enoyl-CoAs in many metabolic pathways, including mitochondrial short- and medium-chain fatty acid β-oxidation and branched-chain amino acid catabolic pathways, as well as in catabolism of ornithine, methionine and threonine [1–7]. Human SCEH has broad substrate specificity for acyl-CoAs, including crotonyl-CoA (from β-oxidation), acryloyl-CoA (from metabolism of various amino acids), 3-methylcrotonyl-CoA (from leucine metabolism), tiglyl-CoA (from isoleucine metabolism), and methacrylyl-CoA (from valine metabolism) [8]. Although SCEH binds tiglyl-CoA, the rate of hydration is relatively low [8].…”

Section: Introductionmentioning

confidence: 99%

“…Human SCEH has broad substrate specificity for acyl-CoAs, including crotonyl-CoA (from β-oxidation), acryloyl-CoA (from metabolism of various amino acids), 3-methylcrotonyl-CoA (from leucine metabolism), tiglyl-CoA (from isoleucine metabolism), and methacrylyl-CoA (from valine metabolism) [8]. Although SCEH binds tiglyl-CoA, the rate of hydration is relatively low [8]. SCEH deficiency was first identified as a disorder of valine metabolism since the main accumulating metabolites are derived from the valine degradation pathway.…”

Section: Introductionmentioning

confidence: 99%

Lethal neonatal case and review of primary short-chain enoyl-CoA hydratase (SCEH) deficiency associated with secondary lymphocyte pyruvate dehydrogenase complex (PDC) deficiency

Bedoyan

Yang

Ferdinandusse

et al. 2017

Molecular Genetics and Metabolism

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Mutations in ECHS1 result in short-chain enoyl-CoA hydratase (SCEH) deficiency which mainly affects the catabolism of various amino acids, particularly valine. We describe a case compound heterozygous for ECHS1 mutations c.836T>C (novel) and c.8C>A identified by whole exome sequencing of proband and parents. SCEH deficiency was confirmed with very low SCEH activity in fibroblasts and nearly absent immunoreactivity of SCEH. The patient had a severe neonatal course with elevated blood and CSF lactate and pyruvate concentrations, high plasma alanine and slightly low plasma cystine. 2-Methyl-2,3-dihydroxybutyric acid was markedly elevated as were metabolites of the three branched-chain ketoacids on urine organic acids analysis. These urine metabolites notably decreased when lactic acidosis decreased in blood. Lymphocyte pyruvate dehydrogenase complex (PDC) activity was deficient, but PDC and α-ketoglutarate dehydrogenase complex activities in cultured fibroblasts were normal. Oxidative phosphorylation analysis on intact digitonin-permeabilized fibroblasts was suggestive of slightly reduced PDC activity relative to control range in mitochondria. We reviewed 16 other cases with mutations in ECHS1 where PDC activity was also assayed in order to determine how common and generalized secondary PDC deficiency is associated with primary SCEH deficiency. For reasons that remain unexplained, we find that about half of cases with primary SCEH deficiency also exhibit secondary PDC deficiency. The patient died on day-of-life 39, prior to establishing his diagnosis, highlighting the importance of early and rapid neonatal diagnosis because of possible adverse effects of certain therapeutic interventions, such as administration of ketogenic diet, in this disorder. There is a need for better understanding of the pathogenic mechanisms and phenotypic variability in this relatively recently discovered disorder.

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Clinical, biochemical and metabolic characterisation of a mild form of human short-chain enoyl-CoA hydratase deficiency: significance of increased N-acetyl-S-(2-carboxypropyl)cysteine excretion

Cited by 64 publications

References 22 publications

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

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

Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

Lethal neonatal case and review of primary short-chain enoyl-CoA hydratase (SCEH) deficiency associated with secondary lymphocyte pyruvate dehydrogenase complex (PDC) deficiency

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