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 2,3dihydroxy-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.

Leigh Syndrome: A Study of 209 Patients at the Beijing Children's Hospital

“…The variable distribution of defects across East Asian and European cohorts suggests that genetic defects may vary based on ethnicity or between populations, such as due to founder mutations as previously described for ECHS1 and GTPBP3 in Chinese patients. 30,31 We, however, found only limited evidence for the contribution of founder variants to disease, with only 5 variants of potential founder status identified in our Chinese LS population. LS was primarily clinically defined in the pregenome area, however, we know today that LS comprises a large heterogeneous group of approximately 100 distinct rare genetic disorders.…”

A Case of ECHS1 Deficiency with Severe Encephalopathy and Status Epilepticus after a Propofol Sedation: Case Report

“…1 Since then 58 patients have been identified with it worldwide. 4,[7][8][9][10][11][12] Here, we presented the 59th case of a patient with ECHS1 deficiency.…”

Exploring triheptanoin as treatment for short chain enoyl CoA hydratase deficiency

“…In contrast, intermediate and mild cases usually have normal laboratory values. A review of the literature 1‐4,6‐29 revealed 67 patients with most suffering the early onset presentation. Average age at death was 28.0 + 43.8 months (range 16 h to 156 months) for 27 early onset patients (age <12 months) for whom age at death was reported.…”