Clinical, biochemical, and genetic features of four patients with short‐chain enoyl‐CoA hydratase (ECHS1) deficiency

American Journal of Medical Genetics, Part A - Tập 176 Số 5 - Trang 1115-1127 - 2018
Patricia Fitzsimons1, Charlotte L. Alston2, Penelope E. Bonnen3, Joanne Hughes4, Ellen Crushell4, Michael T. Geraghty5, Martine Tétreault6, P M O'Reilly4, Eilish Twomey7, Yusra Sheikh7, Richard Walsh1, Hans R. Waterham8, Sacha Ferdinandusse8, Ronald J. A. Wanders8, Robert W. Taylor2, James Pitt9, P D Mayne1
1Department of Paediatric Laboratory Medicine Temple Street Children's University Hospital Dublin Ireland
2Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom
3Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
4National Centre for Inherited Metabolic Disorders, Temple Street Children’s University Hospital, Dublin, Ireland
5Children's Hospital of Eastern Ontario Research Institute, University of Ottawa Ottawa Ontario Canada K1H 8L1
6Department of Human Genetics McGill University Montreal, Québec Canada H3A 1B1
7Department of Radiology Temple Street Children's University Hospital Dublin Ireland
8Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Academic Medical Center, Amsterdam, The Netherlands
9Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, Melbourne, Australia

Tóm tắt

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.

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Tài liệu tham khảo

10.1111/cge.12891

10.1136/jnnp-2012-304426

10.1016/j.ymgme.2017.02.002

10.1016/j.drudis.2013.02.003

10.1016/j.cmet.2015.02.008

10.1016/j.ajhg.2013.07.017

10.1542/peds.70.4.532

10.1093/brain/awl389

10.1186/s13023-015-0290-1

10.1186/1750-1172-8-188

10.1007/8904_2016_538

10.1016/j.ymgme.2015.12.004

10.1038/srep42187

10.1002/acn3.189

Huffnagel I. C., 2017, Mitochondrial encephalopathy and transient 3‐methylglutaconic aciduria in ECHS1 deficiency: Long‐term follow‐up, JIMD Reports, 48, 1

10.1093/jn/113.11.2164

10.1159/000468650

10.1136/jnnp.14.3.216

10.1086/510725

10.1007/s00415-016-8381-z

10.1136/jmedgenet-2016-103922

10.1007/s11011-016-9842-x

10.1007/s10545-016-9977-2

10.1007/s00431-009-1007-z

10.1093/brain/awu216

10.1016/j.ymgme.2015.06.008

10.1002/humu.22730

10.1016/j.ajhg.2014.12.020

10.1186/1750-1172-9-52

10.1016/j.pediatrneurol.2014.10.023

10.1016/j.ymgme.2015.05.008

10.1007/s10545-013-9669-0

10.1007/s00439-015-1577-y

10.1007/s10545-010-9236-x

10.1042/bj2390089

10.1007/s10545-010-9210-7

10.1007/s10545-012-9579-6

10.1016/j.ajhg.2014.12.013

10.1136/jmedgenet-2015-103231

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American Journal of Medical Genetics, Part A

Tập 176 Số 5

1115-1127

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