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