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

Abstract

Background: Short-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 presentation: Here, 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.

Conclusions: The 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.

Keywords: Case report; ECHS1; Leigh syndrome; Whole-exome sequencing.

Fig. 1

MRI and MRS of patient P4. Images (a1) and (a2) are T2-weighted images, with green arrows showing abnormal areas. (b1) and (b2) are T2-FLAIR images

Fig. 2

MRI images of patient P5 with green arrows showing abnormal areas. Images (a1–4) and (b1–4) are T2-weighted and T2-FLAIR images, respectively. Images (a1–2) and (b1–2) are the results of the first MRI, which show symmetric abnormal signals of the bilateral basal ganglia. Images (a3–4) and (b3–4) show the results of the second MRI, which were similar to the first MRI

Fig. 3

Genograms with Sanger confirmation results for the five studied families

Fig. 4

Summary of the variants and amino acid alterations of ECHS1 gene related to Leigh syndrome. (A) The previously reported variants (below the bar with dashed lines) and the newly identified variants (above the bar with solid lines); (B) The previously reported amino acid alterations (below the bar with dashed lines) and the newly identified amino acid alterations (above the bar with solid lines)