Extrapolation of Variant Phase in Mitochondrial Short-Chain Enoyl-CoA Hydratase (ECHS1) Deficiency

Carlston, Colleen M.; Ferdinandusse, Sacha; Hobert, Judith A.; Mao, Rong; Longo, Nicola

doi:10.1007/8904_2018_111

Cited by 13 publications

(22 citation statements)

References 27 publications

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“…Some experts suggest that the combined approach of N-acetylcysteine supplementation and a restricted diet can be safely utilized in SCEH deficiency patients. In addition, there are literatures on ketogenic diet for SCEH deficiency [11,16,17], but the efficacy and safety of it remains yet to be studied. In this study, two patients were treated with cocktail therapy, low valine diet and rehabilitation therapy.…”

Section: Discussionmentioning

confidence: 99%

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

Yang

2020

BMC Pediatr

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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.

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Section: Discussionmentioning

confidence: 99%

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

Yang

2020

BMC Pediatr

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“…Sharpe and McKenzie performed a comprehensive review of ECHS1D and collected all reported ECHS1 mutations up to then in 2018 [2]. Carlston and colleagues updated the reported mutations in their case report of ECHS1D [21]. To date, 34 pathogenic ECHS1 mutations have been identified, with 29 missense, 2 splicing, 2 frameshift and 1 nonsense [2,21].…”

Section: Discussionmentioning

confidence: 99%

“…Carlston and colleagues updated the reported mutations in their case report of ECHS1D [21]. To date, 34 pathogenic ECHS1 mutations have been identified, with 29 missense, 2 splicing, 2 frameshift and 1 nonsense [2,21]. We summarized the currently reported mutation spectrum of the ECHS1 gene in Fig.…”

Section: Discussionmentioning

confidence: 99%

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

Sun

Liu

Yong-chu³

et al. 2020

BMC Med Genet

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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.

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“…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 .…”

Section: Echs1 Deficiencymentioning

confidence: 99%

“…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.…”

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confidence: 99%

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

Burgin

McKenzie

2020

FEBS Letters

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Mitochondria provide the main source of energy for eukaryotic cells, oxidizing fatty acids and sugars to generate ATP. Mitochondrial fatty acid β‐oxidation (FAO) and oxidative phosphorylation (OXPHOS) are two key pathways involved in this process. Disruption of FAO can cause human disease, with patients commonly presenting with liver failure, hypoketotic glycaemia and rhabdomyolysis. However, patients with deficiencies in the FAO enzyme short‐chain enoyl‐CoA hydratase 1 (ECHS1) are typically diagnosed with Leigh syndrome, a lethal form of subacute necrotizing encephalomyelopathy that is normally associated with OXPHOS dysfunction. Furthermore, some ECHS1‐deficient patients also exhibit secondary OXPHOS defects. This sequela of FAO disorders has long been thought to be caused by the accumulation of inhibitory fatty acid intermediates. However, new evidence suggests that the mechanisms involved are more complex, and that disruption of OXPHOS protein complex biogenesis and/or stability is also involved. In this review, we examine the clinical, biochemical and genetic features of all ECHS1‐deficient patients described to date. In particular, we consider the secondary OXPHOS defects associated with ECHS1 deficiency and discuss their possible contribution to disease pathogenesis.

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Extrapolation of Variant Phase in Mitochondrial Short-Chain Enoyl-CoA Hydratase (ECHS1) Deficiency

Cited by 13 publications

References 27 publications

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

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

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

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

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