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

  • Colleen M. CarlstonEmail author
  • Sacha Ferdinandusse
  • Judith A. Hobert
  • Rong Mao
  • Nicola Longo
Research Report
Part of the JIMD Reports book series (JIMD, volume 43)


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.


ECHS1 Exome interpretation Mitochondrial short-chain enoyl-CoA hydratase deficiency Phase determination 



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.


  1. 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. CrossRefPubMedGoogle Scholar
  2. 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. CrossRefGoogle Scholar
  3. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 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):1113–1126CrossRefGoogle Scholar
  7. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 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. Google Scholar
  10. Lek M, Karczewski KJ, Minikel EV et al (2016) Analysis of protein-coding genetic variation in 60,706 humans. Nature 536:285–291. CrossRefPubMedPubMedCentralGoogle Scholar
  11. Li H, Durbin R (2009) Fast and accurate short read alignment with burrows-wheeler transform. Bioinformatics 25:1754–1760. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 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. CrossRefPubMedGoogle Scholar
  13. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 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. CrossRefPubMedGoogle Scholar
  15. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 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. CrossRefPubMedGoogle Scholar
  17. 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. CrossRefPubMedGoogle Scholar
  18. 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. CrossRefPubMedGoogle Scholar
  19. Robinson JT, Thorvaldsdóttir H, Winckler W et al (2011) Integrative genomics viewer. Nat Biotechnol 29:24–26. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 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. CrossRefPubMedGoogle Scholar
  21. Sharpe AJ, McKenzie M (2018) Mitochondrial fatty acid oxidation disorders associated with short-chain enoyl-CoA hydratase (ECHS1) deficiency. Cell 7(6):46. CrossRefGoogle Scholar
  22. 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. CrossRefGoogle Scholar
  23. 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. CrossRefPubMedGoogle Scholar
  24. Tetreault M, Fahiminiya S, Antonicka H et al (2015) Whole-exome sequencing identifies novel ECHS1 mutations in Leigh syndrome. Hum Genet 134:981–991. CrossRefPubMedGoogle Scholar
  25. Thorvaldsdóttir H, Robinson JT, Mesirov JP (2013) Integrative genomics viewer (IGV): high-performance genomics data visualization and exploration. Brief Bioinform 14:178–192. CrossRefPubMedGoogle Scholar
  26. 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. CrossRefPubMedGoogle Scholar
  27. 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. CrossRefPubMedGoogle Scholar

Copyright information

© Society for the Study of Inborn Errors of Metabolism (SSIEM) 2018

Authors and Affiliations

  • Colleen M. Carlston
    • 1
    Email author
  • Sacha Ferdinandusse
    • 2
  • Judith A. Hobert
    • 3
    • 4
  • Rong Mao
    • 3
    • 4
  • Nicola Longo
    • 3
    • 4
    • 5
  1. 1.School of MedicineUniversity of CaliforniaSan FranciscoUSA
  2. 2.Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Academic Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands
  3. 3.Department of PathologyUniversity of Utah School of MedicineSalt Lake CityUSA
  4. 4.ARUP LaboratoriesSalt Lake CityUSA
  5. 5.Department of Pediatrics/Medical GeneticsUniversity of Utah School of MedicineSalt Lake CityUSA

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