Skip to main content
Log in

Whole-exome sequencing identifies novel ECHS1 mutations in Leigh syndrome

  • Original Investigation
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

Leigh syndrome (LS) is a rare heterogeneous progressive neurodegenerative disorder usually presenting in infancy or early childhood. Clinical presentation is variable and includes psychomotor delay or regression, acute neurological or acidotic episodes, hypotonia, ataxia, spasticity, movement disorders, and corresponding anomalies of the basal ganglia and brain stem on magnetic resonance imaging. To date, 35 genes have been associated with LS, mostly involved in mitochondrial respiratory chain function and encoded in either nuclear or mitochondrial DNA. We used whole-exome sequencing to identify disease-causing variants in four patients with basal ganglia abnormalities and clinical presentations consistent with LS. Compound heterozygote variants in ECHS1, encoding the enzyme enoyl-CoA hydratase were identified. One missense variant (p.Thr180Ala) was common to all four patients and the haplotype surrounding this variant was also shared, suggesting a common ancestor of French-Canadian origin. Rare mutations in ECHS1 as well as in HIBCH, the enzyme downstream in the valine degradation pathway, have been associated with LS or LS-like disorders. A clear clinical overlap is observed between our patients and the reported cases with ECHS1 or HIBCH deficiency. The main clinical features observed in our cohort are T2-hyperintense signal in the globus pallidus and putamen, failure to thrive, developmental delay or regression, and nystagmus. Respiratory chain studies are not strikingly abnormal in our patients: one patient had a mild reduction of complex I and III and another of complex IV. The identification of four additional patients with mutations in ECHS1 highlights the emerging importance of this pathway in LS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Aulbert W, Weigt-Usinger K, Thiels C, Kohler C, Vorgerd M, Schreiner A, Hoffjan S, Rothoeft T, Wortmann SB, Heyer CM, Podskarbi T, Lucke T (2014) Long survival in Leigh syndrome: new cases and review of literature. Neuropediatrics 45:346–353. doi:10.1055/s-0034-1383823

    Article  PubMed  Google Scholar 

  • Bamshad MJ, Ng SB, Bigham AW, Tabor HK, Emond MJ, Nickerson DA, Shendure J (2011) Exome sequencing as a tool for Mendelian disease gene discovery. Nat Rev Genet 12:745–755. doi:10.1038/nrg3031

    Article  CAS  PubMed  Google Scholar 

  • Boycott KM, Vanstone MR, Bulman DE, MacKenzie AE (2013) Rare-disease genetics in the era of next-generation sequencing: discovery to translation. Nat Rev Genet 14:681–691. doi:10.1038/nrg3555

    Article  CAS  PubMed  Google Scholar 

  • Buhas D, Bernard G, Fukao T, Decarie JC, Chouinard S, Mitchell GA (2013) A treatable new cause of chorea: beta-ketothiolase deficiency. Mov Disord 28:1054–1056. doi:10.1002/mds.25538

    Article  PubMed  Google Scholar 

  • Chinnery PF (2000) Mitochondrial disorders overview. In: Pagon RA, Adam MP, Ardinger HH et al (eds) GeneReviews® [Internet]. University of Washington, Seattle, WA, 1993–2015

  • Fahiminiya S, Majewski J, Al-Jallad H, Moffatt P, Mort J, Glorieux FH, Roschger P, Klaushofer K, Rauch F (2014) Osteoporosis caused by mutations in PLS3: clinical and bone tissue characteristics. J Bone Miner Res 29:1805–1814. doi:10.1002/jbmr.2208

    Article  CAS  PubMed  Google Scholar 

  • Ferdinandusse S, Waterham HR, Heales SJ, Brown GK, Hargreaves IP, Taanman JW, Gunny R, Abulhoul L, Wanders RJ, Clayton PT, Leonard JV, Rahman S (2013) HIBCH mutations can cause Leigh-like disease with combined deficiency of multiple mitochondrial respiratory chain enzymes and pyruvate dehydrogenase. Orphanet J Rare Dis 8:188. doi:10.1186/1750-1172-8-188

    Article  PubMed Central  PubMed  Google Scholar 

  • Haack TB, Jackson CB, Murayama K, Kremer LS, Schaller A, Kotzaeridou U, de Vries MC, Schottmann G, Santra S, Buchner B, Wieland T, Graf E, Freisinger P, Eggimann S, Ohtake A, Okazaki Y, Kohda M, Kishita Y, Tokuzawa Y, Sauer S, Memari Y, Kolb-Kokocinski A, Durbin R, Hasselmann O, Cremer K, Albrecht B, Wieczorek D, Engels H, Hahn D, Zink AM, Alston CL, Taylor RW, Rodenburg RJ, Trollmann R, Sperl W, Strom TM, Hoffmann GF, Mayr JA, Meitinger T, Bolognini R, Schuelke M, Nuoffer JM, Kolker S, Prokisch H, Klopstock T (2015) Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement. Ann Clin Transl Neurol 2:492–509. doi:10.1002/acn3.189

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Jellinger K, Seitelberger F (1970) Subacute necrotizing encephalomyelopathy (LEIGH). Ergeb Inn Med Kinderheilkd 29:155–219

    Article  CAS  PubMed  Google Scholar 

  • Jordan DM, Ramensky VE, Sunyaev SR (2010) Human allelic variation: perspective from protein function, structure, and evolution. Curr Opin Struct Biol 20:342–350. doi:10.1016/j.sbi.2010.03.006

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Loupatty FJ, Clayton PT, Ruiter JP, Ofman R, Ijlst L, Brown GK, Thorburn DR, Harris RA, Duran M, Desousa C, Krywawych S, Heales SJ, Wanders RJ (2007) Mutations in the gene encoding 3-hydroxyisobutyryl-CoA hydrolase results in progressive infantile neurodegeneration. Am J Hum Genet 80:195–199. doi:10.1086/510725

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • McKelvie P, Infeld B, Marotta R, Chin J, Thorburn D, Collins S (2012) Late-adult onset Leigh syndrome. J Clin Neurosci 19:195–202. doi:10.1016/j.jocn.2011.09.009

    Article  PubMed  Google Scholar 

  • Mitchell GA, Gauthier N, Lesimple A, Wang SP, Mamer O, Qureshi I (2008) Hereditary and acquired diseases of acyl-coenzyme A metabolism. Mol Genet Metab 94:4–15. doi:10.1016/j.ymgme.2007.12.005

    Article  CAS  PubMed  Google Scholar 

  • Perelman DLN (2000) Requirements for branched chain amino acids and their interactions in the nematode Caenorhabditis elegans. Nematology 2:6

    Article  Google Scholar 

  • Peters H, Buck N, Wanders R, Ruiter J, Waterham H, Koster J, Yaplito-Lee J, Ferdinandusse S, Pitt J (2014) ECHS1 mutations in Leigh disease: a new inborn error of metabolism affecting valine metabolism. Brain 137:2903–2908. doi:10.1093/brain/awu216

    Article  PubMed  Google Scholar 

  • Reuter MS, Sass JO, Leis T, Kohler J, Mayr JA, Feichtinger RG, Rauh M, Schanze I, Bahr L, Trollmann R, Uebe S, Ekici AB, Reis A (2014) HIBCH deficiency in a patient with phenotypic characteristics of mitochondrial disorders. Am J Med Genet A 164:3162–3169. doi:10.1002/ajmg.a.36766

    Article  CAS  Google Scholar 

  • Ruhoy IS, Saneto RP (2014) The genetics of Leigh syndrome and its implications for clinical practice and risk management. Appl Clin Genet 7:221–234. doi:10.2147/TACG.S46176

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sakai C, Yamaguchi S, Sasaki M, Miyamoto Y, Matsushima Y, Goto YI (2014) ECHS1 mutations cause combined respiratory chain deficiency resulting in Leigh syndrome. Hum Mutat. doi:10.1002/humu.22730

    Google Scholar 

  • Shrikhande DY, Kalakoti P, Syed MM, Ahya K, Singh G (2010) A rare mitochondrial disorder: Leigh syndrome—a case report. Ital J Pediatr 36:62. doi:10.1186/1824-7288-36-62

    Article  PubMed Central  PubMed  Google Scholar 

  • Thorburn DR, Rahman S (2003) Mitochondrial DNA-associated Leigh syndrome and NARP. In: Pagon RA, Adam MP, Ardinger HH et al (eds) GeneReviews® [Internet]. University of Washington, Seattle, WA, 1993–2015

  • Wanders RJ, Duran M, Loupatty FJ (2012) Enzymology of the branched-chain amino acid oxidation disorders: the valine pathway. J Inherit Metab Dis 35:5–12. doi:10.1007/s10545-010-9236-x

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

We would like to thank the families who participated in this study. We would also like to thank Pierre Lepage and his team at the Genome Quebec Innovation Centre for Sanger validation. This work was funded in part by a Grant (MT_15460) from the CIHR to EAS and performed under the Care4Rare Canada Consortium (Enhanced Care for Rare Genetic Diseases in Canada) funded by Genome Canada, the Canadian Institutes of Health Research, the Ontario Genomics Institute, Ontario Research Fund, Genome Quebec, and Children’s Hospital of Eastern Ontario Foundation. The project was selected for analysis by the Care4Rare Consortium Gene Discovery Steering Committee consisting of Kym Boycott (lead; University of Ottawa), Alex MacKenzie (co-lead; University of Ottawa), Jacek Majewski (McGill University), Michael Brudno (University of Toronto), Dennis Bulman (University of Ottawa), David Dyment (University of Ottawa). The authors wish to acknowledge the contribution of the high throughput-sequencing platform of the McGill University and Génome Québec Innovation Centre, Montréal, Canada. MT received a post-doctoral fellowship from the Réseau de Médecine Génique Appliquée (RMGA) and the Fond de Recherche du Québec en Santé. SF received a post-doctoral fellowship from RMGA. URL: MuPro: http://mupro.proteomics.ics.uci.edu, Auto-Mute: http://proteins.gmu.edu.

Author information

Authors and Affiliations

Authors

Consortia

Corresponding author

Correspondence to Martine Tetreault.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tetreault, M., Fahiminiya, S., Antonicka, H. et al. Whole-exome sequencing identifies novel ECHS1 mutations in Leigh syndrome. Hum Genet 134, 981–991 (2015). https://doi.org/10.1007/s00439-015-1577-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-015-1577-y

Keywords

Navigation