Abstract
Loss-of-function and hypomorphic ECHS1 variants are associated with mitochondrial short-chain enoyl-CoA hydratase deficiency, an inborn error of valine metabolism. We report an 8-year-old boy with developmental delay, ataxia, hemiplegia, and hearing loss with abnormalities in the basal ganglia. Biochemical studies were essentially normal except for a persistent mildly elevated CSF alanine. This patient demonstrates an intermediate phenotype between a Leigh-like, early-onset presentation and paroxysmal exercise-induced dyskinesia. Two novel ECHS1 variants (c.79T>G; p.Phe27Val and c.789_790del; p.Phe263fs) were identified via exome sequencing in the proband, and pathogenicity was confirmed by enzyme assay performed on patient fibroblasts. Neither of the ECHS1 variants detected in the child were present in the mother. However, due to nearby polymorphisms, it was possible to determine that p.Phe263fs occurred de novo on the maternal chromosome and that p.Phe27Val likely derived from the paternal chromosome. Nearby polymorphisms can help set phase of variants when only a single parent is available for testing or when an identified variant occurs de novo.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Al Mutairi F, Shamseldin HE, Alfadhel M et al (2017) A lethal neonatal phenotype of mitochondrial short-chain enoyl-CoA hydratase-1 deficiency. Clin Genet 91:629–633. https://doi.org/10.1111/cge.12891
Balasubramaniam S, Riley LG, Bratkovic D et al (2017) Unique presentation of cutis laxa with Leigh-like syndrome due to ECHS1 deficiency. J Inherit Metab Dis. https://doi.org/10.1007/s10545-017-0036-4
Bedoyan JK, Yang SP, Ferdinandusse S et al (2017) Lethal neonatal case and review of primary short-chain enoyl-CoA hydratase (SCEH) deficiency associated with secondary lymphocyte pyruvate dehydrogenase complex (PDC) deficiency. Mol Genet Metab 120:342–349. https://doi.org/10.1016/j.ymgme.2017.02.002
Ferdinandusse S, Friederich MW, Burlina A et al (2015) Clinical and biochemical characterization of four patients with mutations in ECHS1. Orphanet J Rare Dis 10:79. https://doi.org/10.1186/s13023-015-0290-1
Fitzsimons PE, Alston CL, Bonnen PE et al (2018) Clinical, biochemical, and genetic features of four patients with short-chain enoyl-CoA hydratase (ECHS1) deficiency. Am J Med Genet A 176:1115–1127. https://doi.org/10.1002/ajmg.a.38658
Fukasawa Y, Tsuji J, Fu SC et al (2015) MitoFates: improved prediction of mitochondrial targeting sequences and their cleavage sites. Mol Cell Proteomics 14(4):1113–1126
Ganetzky RD, Bloom K, Ahrens-Nicklas R et al (2016) ECHS1 deficiency as a cause of severe neonatal lactic acidosis. JIMD Rep 30:33–37. https://doi.org/10.1007/8904_2016_538
Haack TB, Jackson CB, Murayama K et al (2015) Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement. Ann Clin Transl Neurol 2:492–509. https://doi.org/10.1002/acn3.189
Huffnagel IC, Redeker EJW, Reneman L et al (2017) Mitochondrial encephalopathy and transient 3-methylglutaconic aciduria in ECHS1 deficiency: long-term follow-up. JIMD Rep. https://doi.org/10.1007/8904_2017_48
Lek M, Karczewski KJ, Minikel EV et al (2016) Analysis of protein-coding genetic variation in 60,706 humans. Nature 536:285–291. https://doi.org/10.1038/nature19057
Li H, Durbin R (2009) Fast and accurate short read alignment with burrows-wheeler transform. Bioinformatics 25:1754–1760. https://doi.org/10.1093/bioinformatics/btp324
Mahajan A, Constantinou J, Sidiropoulos C (2017) ECHS1 deficiency-associated paroxysmal exercise-induced dyskinesias: case presentation and initial benefit of intervention. J Neurol 264:185–187. https://doi.org/10.1007/s00415-016-8381-z
McKenna A, Hanna M, Banks E et al (2010) The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 20:1297–1303. https://doi.org/10.1101/gr.107524.110
Nair P, Hamzeh AR, Mohamed M et al (2016) Novel ECHS1 mutation in an Emirati neonate with severe metabolic acidosis. Metab Brain Dis 31:1189–1192. https://doi.org/10.1007/s11011-016-9842-x
Ogawa E, Shimura M, Fushimi T et al (2017) Clinical calidity of biochemical and molecular analysis in diagnosing Leigh syndrome: a study of 106 Japanese patients. J Inherit Metab Dis 40:685–693. https://doi.org/10.1007/s10545-017-0042-6
Olgiati S, Skorvanek M, Quadri M et al (2016) Paroxysmal exercise-induced dystonia within the phenotypic spectrum of ECHS1 deficiency. Mov Disord 31:1041–1048. https://doi.org/10.1002/mds.26610
Peters H, Buck N, Wanders R et al (2014) ECHS1 mutations in Leigh disease: a new inborn error of metabolism affecting valine metabolism. Brain 137:2903–2908. https://doi.org/10.1093/brain/awu216
Peters H, Ferdinandusse S, Ruiter JP et al (2015) Metabolite studies in HIBCH and ECHS1 defects: implications for screening. Mol Genet Metab 115:168–173. https://doi.org/10.1016/j.ymgme.2015.06.008
Robinson JT, Thorvaldsdóttir H, Winckler W et al (2011) Integrative genomics viewer. Nat Biotechnol 29:24–26. https://doi.org/10.1038/nbt.1754
Sakai C, Yamaguchi S, Sasaki M et al (2015) ECHS1 mutations cause combined respiratory chain deficiency resulting in Leigh syndrome. Hum Mutat 36:232–239. https://doi.org/10.1002/humu.22730
Sharpe AJ, McKenzie M (2018) Mitochondrial fatty acid oxidation disorders associated with short-chain enoyl-CoA hydratase (ECHS1) deficiency. Cell 7(6):46. https://doi.org/10.3390/cells7060046
Singh R, Jamdar SN, Goyal VD et al (2017) Structure of the human Aminopeptidase XPNPEP3 and comparison of its in-vitro activity with Icp55 orthologs: insights into diverse cellular processes. J Biol Chem. https://doi.org/10.1074/jbc.M117.783357
Stark Z, Tan TY, Chong B et al (2016) A prospective evaluation of whole-exome sequencing as a first-tier molecular test in infants with suspected monogenic disorders. Genet Med 18:1090–1096. https://doi.org/10.1038/gim.2016.1
Tetreault M, Fahiminiya S, Antonicka H et al (2015) Whole-exome sequencing identifies novel ECHS1 mutations in Leigh syndrome. Hum Genet 134:981–991. https://doi.org/10.1007/s00439-015-1577-y
Thorvaldsdóttir H, Robinson JT, Mesirov JP (2013) Integrative genomics viewer (IGV): high-performance genomics data visualization and exploration. Brief Bioinform 14:178–192. https://doi.org/10.1093/bib/bbs017
Vögtle F-N, Wortelkamp S, Zahedi RP et al (2009) Global analysis of the mitochondrial N-proteome identifies a processing peptidase critical for protein stability. Cell 139:428–439. https://doi.org/10.1016/j.cell.2009.07.045
Yamada K, Aiba K, Kitaura Y et al (2015) Clinical, biochemical and metabolic characterisation of a mild form of human short-chain enoyl-CoA hydratase deficiency: significance of increased N-acetyl-S-(2-carboxypropyl)cysteine excretion. J Med Genet 52:691–698. https://doi.org/10.1136/jmedgenet-2015-103231
Acknowledgments
We are grateful to the family for their willingness to share this case with the medical community. We also would like to thank the members of Genomics Lab and Genetic Sequencing Lab at ARUP laboratories for performing testing on the individuals included in this study.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Additional information
Communicated by: Manuel Schiff
Appendices
Author Contributions
Colleen M. Carlston: exome data interpretation, study design, and writing manuscript.
Dr. Ferdinandusse: metabolite analysis (ECHS1 testing), data analysis, and interpretation.
Dr. Hobert: metabolite analysis (previous metabolic testing), data analysis and interpretation, and critical revision of manuscript.
Dr. Mao: exome lab director, exome data interpretation, and STR interpretation.
Dr. Longo: study concept, design and supervision, patient care, and critical revision of manuscript.
Compliance with Ethics Guidelines
Colleen Carlston, Sacha Ferdinandusse, Judith Hobert, Rong Mao, and Nicola Longo declare that they have no conflicts of interest.
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from the family included in the study and is available upon request.
Take-Home Message
During exome analysis performed without both biological parents and/or when a de novo variant is suspected, the use of nearby polymorphisms can help set phase of variants as in this case of a boy with biochemically confirmed ECHS1 deficiency caused by two novel ECHS1 variants.
Rights and permissions
Copyright information
© 2018 Society for the Study of Inborn Errors of Metabolism (SSIEM)
About this chapter
Cite this chapter
Carlston, C.M., Ferdinandusse, S., Hobert, J.A., Mao, R., Longo, N. (2018). Extrapolation of Variant Phase in Mitochondrial Short-Chain Enoyl-CoA Hydratase (ECHS1) Deficiency. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 43. JIMD Reports, vol 43. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2018_111
Download citation
DOI: https://doi.org/10.1007/8904_2018_111
Received:
Revised:
Accepted:
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-662-58613-6
Online ISBN: 978-3-662-58614-3
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)