Clinical, biochemical and metabolic characterization of patients with short-chain enoyl-CoA hydratase(ECHS1) deficiency: two case reports and the review of the literature

Abstract

Background: Short-chain enoyl-CoA hydratase (SCEH or ECHS1) deficiency is a rare congenital metabolic disorder caused by biallelic mutations in the ECHS gene. Clinical phenotype includes severe developmental delay, regression, dystonia, seizures, elevated lactate, and brain MRI abnormalities consistent with Leigh syndrome (LS). SCEH is most notably involved in valine catabolism. There is no effective treatment for the disease, patients may respond to dietary restriction of valine and supplementation of N-acetylcysteine. Case presentation: We describe two patients who presented in infancy or early childhood with SCEH deficiency. Both patients were shown to harbor heterozygous or homozygous variants in the ECHS1 gene, and developmental retardation or regression as the onset manifestation. Brain MRI showed abnormal signals of bilateral pallidus. Urine metabolic examination showed increased levels of 2,3-dihydroxy-2-methylbutyric acid and S-(2-carboxypropyl) cysteamine S-(2-carboxypropoxypropyl) cysteamine (SCPCM). A valine restricted diet and combined of Nacetylcysteine supplementation were utilized in the two patients. Conclusions: In clinical practice, The elevated urinary 2,3-dihydroxy-2-methylbutyrate, S-(2-carboxypropyl) cysteine, S-(2-carboxypropyl) cysteine and N-acetyl-S-(2-carboxypropyl) cysteine levels might be clues for diagnosis of SCEH deficiency which can be confirmed throughGenetic sequencing of ECHS1 gene. Early cocktail therapy, valine restrictied diet and N-acetylcysteine supplementation could improve the prognosis of patients.

Cinical, Metabolic, and Genetic Analysis and Follow-Up of Eight Patients With HIBCH Mutations Presenting With Leigh/Leigh-Like Syndrome

“…In the valine pathway, it is originated from acryloyl-CoA, but the exact mechanism is not clear. 23DH2MB abnormalities were also identified in a few Leigh syndrome patients with ECHS1 mutations ( Peters et al, 2014 ; Yang and Yu, 2020 ). There was only 2 reported patient with an HIBCH mutation with elevated urinary 23DH2MB excretion ( Ferdinandusse et al, 2013 ; Marti-Sanchez et al, 2020 ).…”

Delineating the neurological phenotype in children with defects in the ECHS1 or HIBCH gene

“…To date, 63 SCEH patients are described, all presenting between 0 and 18 years of age. 2,4,[26][27][28][29][30][31][32][33][34][35]8,36,[10][11][12][13]22,24,25,59 Three distinct clinical phenotypes are reported: LS (79%), paroxysmal dystonia (10%), and fatal neonatal lactic acidosis (11%) ( Table S1). Kaplan-Meier survival curves showed that half of the patients died before 10 years of age.…”

“…This metabolite was found in 75% of HIBCH cases in our study and in previous series. 4,9,26,27,40,41,45,54 Forty-three different ECHS1 mutations in 63 SCEH patients from 54 families have been described 2,4,[26][27][28][29][30][31][32][33][34][35]8,36,[10][11][12][13]22,24,25,59 ( Figure S2). Overall, 73% of the variants were present exclusively in one or two alleles, confirming the wide genetic heterogeneity of ECHS1.…”

“…Forty‐three different ECHS1 mutations in 63 SCEH patients from 54 families have been described 2,4,26‐35,8,36,10‐13,22,24,25,59 (Figure S2). Overall, 73% of the variants were present exclusively in one or two alleles, confirming the wide genetic heterogeneity of ECHS1 .…”

ECHS1 disease in two unrelated families of Samoan descent: Common variant ‐ rare disorder

“…Most patients present with developmental delay, regression, dystonia, feeding difficulties, cardiomyopathy, and brain MRI changes consistent with Leigh syndrome. Since Sharpe et al, reviewed the mutational, clinical, and biochemical spectrum of 42 patients from 33 families with ECHS1 disease, an additional nine new cases have been reported, none of which are due to synonymous mutations (Aretini et al, 2018;Carlston, Ferdinandusse, Hobert, Mao, & Longo, 2019;Pajares et al, 2020;Ronchi et al, 2020;Sharpe & McKenzie, 2018;Uchino et al, 2019;Wu et al, 2020;Yang & Yu, 2020). Here we report clinical, biochemical, molecular, and functional data on four patients from two unrelated families, presenting with two novel mutations in ECHS1.…”