Deficiency of <scp>ECHS</scp>1 causes mitochondrial encephalopathy with cardiac involvement

Haack, Tobias B.; Jackson, Christopher B.; Murayama, Kei; Kremer, Laura S.; Schaller, André; Kotzaeridou, Urania; Vries, Maaike C. de; Schottmann, Gudrun; Santra, Saikat; Büchner, Boriana; Wieland, Thomas; Graf, Elisabeth; Freisinger, Peter; Eggimann, Seila; 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

doi:10.1002/acn3.189

Cited by 99 publications

(195 citation statements)

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“…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).…”

Section: Resultssupporting

confidence: 56%

“…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.…”

Section: Resultsmentioning

confidence: 91%

“…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).…”

Section: Introductionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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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: Resultssupporting

confidence: 56%

Section: Resultsmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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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Understanding the role of OXPHOS dysfunction in the pathogenesis of ECHS1 deficiency

Burgin

McKenzie

2020

FEBS Letters

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Mitochondria provide the main source of energy for eukaryotic cells, oxidizing fatty acids and sugars to generate ATP. Mitochondrial fatty acid β‐oxidation (FAO) and oxidative phosphorylation (OXPHOS) are two key pathways involved in this process. Disruption of FAO can cause human disease, with patients commonly presenting with liver failure, hypoketotic glycaemia and rhabdomyolysis. However, patients with deficiencies in the FAO enzyme short‐chain enoyl‐CoA hydratase 1 (ECHS1) are typically diagnosed with Leigh syndrome, a lethal form of subacute necrotizing encephalomyelopathy that is normally associated with OXPHOS dysfunction. Furthermore, some ECHS1‐deficient patients also exhibit secondary OXPHOS defects. This sequela of FAO disorders has long been thought to be caused by the accumulation of inhibitory fatty acid intermediates. However, new evidence suggests that the mechanisms involved are more complex, and that disruption of OXPHOS protein complex biogenesis and/or stability is also involved. In this review, we examine the clinical, biochemical and genetic features of all ECHS1‐deficient patients described to date. In particular, we consider the secondary OXPHOS defects associated with ECHS1 deficiency and discuss their possible contribution to disease pathogenesis.

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Dystonia‐ataxia syndrome with permanent torsional nystagmus caused by ECHS1 deficiency

Ronchi

Monfrini

Bonato

et al. 2020

Ann Clin Transl Neurol

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Biallelic mutations in ECHS1, encoding the mitochondrial enoyl-CoA hydratase, have been associated with mitochondrial encephalopathies with basal ganglia involvement. Here, we describe a novel clinical presentation consisting of dystonia-ataxia syndrome with hearing loss and a peculiar torsional nystagmus observed in two adult siblings. The presence of a 0.9-ppm peak at MR spectroscopy analysis suggested the accumulation of branched-chain amino acids. Exome sequencing in index probands identified two ECHS1 mutations, one of which was novel (p.V82L). ECHS1 protein levels and residual activities were reduced in patients' fibroblasts. This paper expands the phenotypic spectrum observed in patients with impaired valine catabolism.

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Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement

Cited by 99 publications

References 26 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

Understanding the role of OXPHOS dysfunction in the pathogenesis of ECHS1 deficiency

Dystonia‐ataxia syndrome with permanent torsional nystagmus caused by ECHS1 deficiency

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