Date Published: March 25, 2018
Publisher: John Wiley and Sons Inc.
Author(s): Patricia E. Fitzsimons, Charlotte L. Alston, Penelope E. Bonnen, Joanne Hughes, Ellen Crushell, Michael T. Geraghty, Martine Tetreault, Peter O’Reilly, Eilish Twomey, Yusra Sheikh, Richard Walsh, Hans R. Waterham, Sacha Ferdinandusse, Ronald J. A. Wanders, Robert W. Taylor, James J. Pitt, Philip D. Mayne.
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.
Biallelic mutations in the ECHS1 gene (OMIM 602292) lead to a deficiency of short‐chain enoyl‐CoA hydratase (SCEH/crotonase EC18.104.22.168) 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). Genetic diagnosis of SCEH deficiency can be complicated by the clinical, radiological, and biochemical overlap with mitochondrial encephalopathic disorders; often occurring with respiratory chain complex deficiencies (Ferdinandusse et al., 2015; Sakai et al., 2015) or pyruvate dehydrogenase (PDH) deficiency (Bedoyan et al., 2017; Ferdinandusse et al., 2015; Peters et al., 2014).
This case series was part of a retrospective study performed following the publication that the presence of erythro‐2,3‐dihydroxy‐2‐methylbutyrate in urine had been identified in some patients with SCEH and HIBCH deficiency. This review involves four patients from two families where no definitive cause of death was made at the time of death in two of the index cases in each family.
The presence of detectable erythro‐2,3‐dihydroxy‐2‐methylbutyrate in urine is a nonspecific biochemical finding. 3MGA is not a discriminative feature but a minor finding in the biochemical phenotype of ECHS1 deficiency; however, in combination with increased excretion of erythro‐2,3‐dihydroxy‐2‐methylbutyrate, elevated plasma lactate and normal acylcarnitine profile in a patient with LS should prompt consideration of SCEH deficiency.
The author(s) declare that there is no conflict of interest regarding the publication of this article.