دورية أكاديمية
Clinical, biochemical, and genetic features of four patients with short-chain enoyl-CoA hydratase (ECHS1) deficiency.
| العنوان: | Clinical, biochemical, and genetic features of four patients with short-chain enoyl-CoA hydratase (ECHS1) deficiency. |
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| المؤلفون: | Fitzsimons PE; Department of Paediatric Laboratory Medicine, Temple Street Children's University Hospital, Dublin, Ireland., Alston CL; Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, NE2 4HH, United Kingdom., Bonnen PE; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas., Hughes J; National Centre for Inherited Metabolic Disorders, Temple Street Children's University Hospital, Dublin, Ireland., Crushell E; National Centre for Inherited Metabolic Disorders, Temple Street Children's University Hospital, Dublin, Ireland., Geraghty MT; Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada K1H 8L1., Tetreault M; Department of Human Genetics, McGill University, Montreal, Québec, Canada H3A 1B1., O'Reilly P; National Centre for Inherited Metabolic Disorders, Temple Street Children's University Hospital, Dublin, Ireland., Twomey E; Department of Radiology, Temple Street Children's University Hospital, Dublin, Ireland., Sheikh Y; Department of Radiology, Temple Street Children's University Hospital, Dublin, Ireland., Walsh R; Department of Paediatric Laboratory Medicine, Temple Street Children's University Hospital, Dublin, Ireland., Waterham HR; Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Academic Medical Center, Amsterdam, The Netherlands., Ferdinandusse S; Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Academic Medical Center, Amsterdam, The Netherlands., Wanders RJA; Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Academic Medical Center, Amsterdam, The Netherlands., Taylor RW; Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, NE2 4HH, United Kingdom., Pitt JJ; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Australia., Mayne PD; Department of Paediatric Laboratory Medicine, Temple Street Children's University Hospital, Dublin, Ireland. |
| المصدر: | American journal of medical genetics. Part A [Am J Med Genet A] 2018 May; Vol. 176 (5), pp. 1115-1127. Date of Electronic Publication: 2018 Mar 25. |
| نوع المنشور: | Case Reports; Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Wiley-Blackwell Country of Publication: United States NLM ID: 101235741 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1552-4833 (Electronic) Linking ISSN: 15524825 NLM ISO Abbreviation: Am J Med Genet A Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Hoboken, N.J. : Wiley-Blackwell Original Publication: Hoboken, N.J. : Wiley-Liss, c2003- |
| مواضيع طبية MeSH: | Biomarkers* , Genetic Association Studies*/methods , Genetic Predisposition to Disease* , Phenotype*, Enoyl-CoA Hydratase/*deficiency, Amino Acid Sequence ; Brain/abnormalities ; Brain/diagnostic imaging ; Chromatography, Liquid ; DNA Mutational Analysis ; Enoyl-CoA Hydratase/genetics ; Enoyl-CoA Hydratase/metabolism ; Enzyme Activation ; Female ; Humans ; Infant ; Infant, Newborn ; Magnetic Resonance Imaging ; Male ; Metabolic Networks and Pathways ; Metabolome ; Metabolomics/methods ; Pedigree ; Tandem Mass Spectrometry ; Valine/metabolism |
| مستخلص: | Short-chain enoyl-CoA hydratase (SCEH or ECHS1) deficiency is a rare inborn error of metabolism caused by biallelic mutations in the gene ECHS1 (OMIM 602292). Clinical presentation includes infantile-onset severe developmental delay, regression, seizures, elevated lactate, and brain MRI abnormalities consistent with Leigh syndrome (LS). Characteristic abnormal biochemical findings are secondary to dysfunction of valine metabolism. We describe four patients from two consanguineous families (one Pakistani and one Irish Traveler), who presented in infancy with LS. Urine organic acid analysis by GC/MS showed increased levels of erythro-2,3-dihydroxy-2-methylbutyrate and 3-methylglutaconate (3-MGC). Increased urine excretion of methacrylyl-CoA and acryloyl-CoA related metabolites analyzed by LC-MS/MS, were suggestive of SCEH deficiency; this was confirmed in patient fibroblasts. Both families were shown to harbor homozygous pathogenic variants in the ECHS1 gene; a c.476A > G (p.Gln159Arg) ECHS1variant in the Pakistani family and a c.538A > G, p.(Thr180Ala) ECHS1 variant in the Irish Traveler family. The c.538A > G, p.(Thr180Ala) ECHS1 variant was postulated to represent a Canadian founder mutation, but we present SNP genotyping data to support Irish ancestry of this variant with a haplotype common to the previously reported Canadian patients and our Irish Traveler family. The presence of detectable erythro-2,3-dihydroxy-2-methylbutyrate is a nonspecific marker on urine organic acid analysis but this finding, together with increased excretion of 3-MGC, elevated plasma lactate, and normal acylcarnitine profile in patients with a Leigh-like presentation should prompt consideration of a diagnosis of SCEH deficiency and genetic analysis of ECHS1. ECHS1 deficiency can be added to the list of conditions with 3-MGA. (© 2018 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.) |
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| معلومات مُعتمدة: | G0601943 United Kingdom MRC_ Medical Research Council; NIHR-HCS-D12-03-04 United Kingdom DH_ Department of Health; R01 NS083726 United States NS NINDS NIH HHS |
| فهرسة مساهمة: | Keywords: 3-methylglutaconate; ECHS1; Leigh syndrome; SCEH deficiency; Valine |
| المشرفين على المادة: | 0 (Biomarkers) EC 4.2.1.17 (ECHS1 protein, human) EC 4.2.1.17 (Enoyl-CoA Hydratase) HG18B9YRS7 (Valine) |
| تواريخ الأحداث: | Date Created: 20180326 Date Completed: 20190520 Latest Revision: 20220129 |
| رمز التحديث: | 20240628 |
| مُعرف محوري في PubMed: | PMC5947294 |
| DOI: | 10.1002/ajmg.a.38658 |
| PMID: | 29575569 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1552-4833 |
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| DOI: | 10.1002/ajmg.a.38658 |