Metabolite studies in HIBCH and ECHS1 defects: Implications for screening

Peters, Heidi; Ferdinandusse, Sacha; Ruiter, J. P. N.; Wanders, Ronald J. A.; Boneh, Avihu; Pitt, James

doi:10.1016/j.ymgme.2015.06.008

Cited by 60 publications

(90 citation statements)

References 21 publications

(34 reference statements)

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“…The increased excretion of methacrylyl‐CoA, acryloyl‐CoA adducts, and erythro ‐2,3‐dihydroxy‐2‐methylbutyrate in the two patients quantitated by LC‐MS/MS are consistent with SCEH deficiency; however, they are less than those previously reported in clinically severe cases (James Pitt, unpublished observations; Peters et al, 2014, 2015). 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).…”

Section: Discussionmentioning

confidence: 46%

“…All four patients had increased excretion of erythro ‐2,3‐dihydroxy‐2‐methylbutyrate; this metabolite derived from acryloyl‐CoA was originally described in SCEH deficiency in 2014 by Peters et al Latter patient reports document concentrations of varying magnitude (Bedoyan et al, 2017; Ferdinandusse et al, 2015; Peters et al, 2015) and that levels may be unreliable shortly after birth (Ganetzky et al, 2016) which was the case in Patient 4. Two out of four patients had increased methylmalonic acid which has been reported previously in a patient with SCEH deficiency (Tetreault et al, 2015).…”

Section: Discussionmentioning

confidence: 90%

“…LC‐MS/MS analysis (Peters et al, 2015) of urine from Patients 1 and 4 revealed increased excretion of methacrylyl‐CoA and acryloyl‐CoA related metabolites without significant increases of isoC 4 OH‐carnitine; this metabolic profile was highly suggestive of SCEH deficiency (Table 4). …”

Section: Resultsmentioning

confidence: 99%

“…Analysis was by flow injection tandem mass spectrometry of butyl derivatives as previously described by Peters et al (2015). Quantitation of urine cysteine, cysteamine, glycine, methacrylyl‐CoA and acryloyl‐CoA conjugates and the separation of 3‐hydroxybutyrylcarnitine (C 4 OH‐carnitine), 3‐hydroxyisobutyryl carnitine (isoC 4 OH‐carnitine), and erythro ‐2,3‐dihihydroxy‐2‐methylbutyrate is described by Peters et al (2015). …”

Section: Methodsmentioning

confidence: 99%

“…2,3‐dihydroxy‐2‐methylbutyrate exists as two isomers, erythro and threo . Erythro 2,3‐dihydroxy‐2‐methylbutyrate is elevated in urine of patients with pathogenic ECHS1 and HIBCH variants and propionate defects and clearly segregates when plotted against the threo isomer, while the threo isomer appears to be dietary related (James Pitt, unpublished observation; Peters et al, 2015). …”

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: Discussionmentioning

confidence: 46%

Section: Discussionmentioning

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

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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Metabolite studies in HIBCH and ECHS1 defects: Implications for screening

Cited by 60 publications

References 21 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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