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

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.

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

“…Similarly, the p.Gln159Arg mutation appears to correlate with a severe disease phenotype . Two patients homozygous for this mutation both died at 3 years of age , with a heterozygous patient (p.Asn59Ser; p.Gln159Arg) dying at 4 months of age .…”

“…All currently identified ECHS1D patients have mutations in both ECHS1 alleles, indicating autosomal recessive inheritance, with many different mutations identified (Table ). Patients who are homozygous for mutations in ECHS1 have all been offspring of consanguineous relationships, resulting in two copies of the same rare mutation . These mutations can affect the mitochondrial targeting sequence, intro/exon boundaries, splice sites, potential protein–protein interaction sites or encode premature stop codons that lead to non‐sense‐mediated decay of the mRNA .…”

“…Similarly, the p.Gln159Arg mutation appears to correlate with a severe disease phenotype . Two patients homozygous for this mutation both died at 3 years of age , with a heterozygous patient (p.Asn59Ser; p.Gln159Arg) dying at 4 months of age . The p.Gln159Arg mutation is highly conserved in vertebrates, with the resulting substitution from a polar, uncharged residue to a positively charged residue predicted to be ‘possibly damaging’ and disease‐causing .…”

“…Methacrylyl‐CoA and acryloyl‐CoA are the only metabolites identified to accumulate in ECHS1D, suggesting that ECHS1 is essential in valine metabolism, but not isoleucine or leucine metabolism .…”

“…Short‐chain enoyl‐coA hydratase (ECHS1) is a key enzyme involved in mitochondrial fatty acid β‐oxidation (FAO). Since its initial identification in 2014, 46 patients have been described with ECHS1 deficiency (ECHS1D) . Almost all of these patients have been diagnosed with Leigh syndrome (LS), a lethal form of subacute necrotizing encephalomyelopathy.…”