Novel ECHS1 mutations in Leigh syndrome identified by whole-exome sequencing in five Chinese families: case report

Dan Sun,Liang Song,Yuanyuan Zhu,Yongchu Liu,Xianbo Deng,Fang Fang,Fang Fang,Zhisheng Liu,Miaojuan Wu,Chunhua Zhang,Zhimei Liu,Zhimei Liu,Kei Murayama

doi:10.1186/s12881-020-01083-1

Abstract

BackgroundShort-chain enoyl-CoA hydratase deficiency (ECHS1D), also known as ECHS1 deficiency, is a rare inborn metabolic disorder with clinical presentations characterized by Leigh syndrome (LS). Thirty-four different pathogenic mutations have been identified from over 40 patients to date.Case presentationHere, we report five Chinese patients with clinical syndromes typified as LS. Despite different initial symptoms, all patients presented developmental regression, dystonia, common radiological features such as symmetrical bilateral brain abnormalities, and similar metabolic results such as elevated plasma lactate and 2,3-dihydroxy-2-methylbutyrate. Utilizing whole-exome sequencing (WES), we identified eight distinct variants in ECHS1, with six novel variants, and the remaining two variants have been previously reported. Interestingly, one of the six novel variants, c.463G > A (p.Gly155Ser), was detected in three patients from unrelated families, suggesting a potential founder effect already described for a few mutations in LS. Incorporating both genetic analysis and medical results, including magnetic resonance imaging (MRI), electroencephalography (EEG), and biochemical testing, our study enriched the mutation spectrum of the ECHS1 gene and confirmed the phenotypic presentations of LS.ConclusionsThe severity of ECHS1 deficiency seems to vary. It was affected by both genetics and external environmental factors that lead to increased metabolism. Our study enriched the mutation spectrum of the ECHS1 gene, confirmed the phenotypic presentations, and highlighted the importance of the valine catabolic pathway in Leigh syndrome. Further studies are required to examine the potential founder mutation c.463G > A (p.Gly155Ser) and the role of ECHS1 in relevant pathways.

Highlights

Short-chain enoyl-CoA hydratase deficiency (ECHS1D), known as ECHS1 deficiency, is a rare inborn metabolic disorder with clinical presentations characterized by Leigh syndrome (LS)
The severity of ECHS1 deficiency seems to vary. It was affected by both genetics and external environmental factors that lead to increased metabolism
Brain magnetic resonance imaging (MRI) examinations, and biochemical investigations The studied patients were from five different and unrelated Chinese families with healthy and nonconsanguineous parents. Their ages of onset ranged from birth to 21 months, with diverse initial symptoms

Summary

Introduction

Short-chain enoyl-CoA hydratase deficiency (ECHS1D), known as ECHS1 deficiency, is a rare inborn metabolic disorder with clinical presentations characterized by Leigh syndrome (LS). One of the six novel variants, c.463G > A (p.Gly155Ser), was detected in three patients from unrelated families, suggesting a potential founder effect already described for a few mutations in LS Incorporating both genetic analysis and medical results, including magnetic resonance imaging (MRI), electroencephalography (EEG), and biochemical testing, our study enriched the mutation spectrum of the ECHS1 gene and confirmed the phenotypic presentations of LS. Mitochondrial short-chain enoyl-CoA hydratase-1 deficiency, known as ECHS1 deficiency, is an autosomal recessive inborn metabolic disorder commonly presenting after birth or early in life. It is typically characterized by developmental delay, regression, high levels of lactic acid, and abnormalities in the basal ganglia of the brain [1]. The deficiency of ECHS1 leads to the accumulation of methacrylyl-CoA and acryloyl-CoA, two toxic intermediates that are highly reactive with sulfhydryl groups that are suspected to cause brain pathology and the relevant biochemical patterns [5]

Results

Discussion

Conclusion