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

Patricia E Fitzsimons,Eilish Twomey,Michael T Geraghty,Yusra Sheikh,Ellen Crushell,Martine Tetreault,James J Pitt,Charlotte L Alston,Peter O'Reilly,Penelope E Bonnen,Joanne Hughes,Robert W Taylor,Sacha Ferdinandusse,Hans R Waterham,Richard Walsh,Ronald J A Wanders,Philip D Mayne

doi:10.1002/ajmg.a.38658

Abstract

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.

Highlights

IntroductionBiallelic 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)
Five enzymes are involved in the mitochondrial degradation of valine to propionyl-CoA: isobutyryl-CoA dehydrogenase, short-chain enoyl-CoA hydratase (SCEH), 3-OH-isobutyryl-CoA hydrolase (HIBCH), 3-hydroxyisobutyric acid dehydrogenase (HIBADH), and methylmalonate semialdehyde dehydrogenase (Figure 1); defects in these enzymes cause inborn errors of valine degradation (Peters et al, 2014; Wanders, Duran, & Loupatty, 2012)
Deficiency of SCEH which converts unsaturated trans-2-enoylCoA 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 Leigh syndrome (LS) or Leigh-like syndrome and deficiencies of multiple mitochondrial respiratory chain enzymes

Summary

Introduction

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). Deficiency of SCEH which converts unsaturated trans-2-enoylCoA 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. 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

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