Whole-exome sequencing identifies novel ECHS1 mutations in Leigh syndrome
- 23 June 2015
- journal article
- Published by Springer Science and Business Media LLC in Human Genetics
- Vol. 134 (9), 981-991
- https://doi.org/10.1007/s00439-015-1577-y
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.Funding Information
- CIHR (MT_15460)
- Genome Canada
- Ontario Genomics Institute
- Ontario Research Fund
- Génome Québec
- Children Hospital of Eastern Ontario Foundation
- Reseau de medecine genique appliquee
- Fonds de Recherche du Québec - Santé
- Reseau de medecine genique appliquee
This publication has 18 references indexed in Scilit:
- Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvementAnnals of Clinical and Translational Neurology, 2015
- ECHS1 Mutations Cause Combined Respiratory Chain Deficiency Resulting in Leigh SyndromeHuman Mutation, 2014
- The genetics of Leigh syndrome and its implications for clinical practice and risk managementThe Application of Clinical Genetics, 2014
- HIBCH deficiency in a patient with phenotypic characteristics of mitochondrial disordersAmerican Journal of Medical Genetics Part A, 2014
- ECHS1 mutations in Leigh disease: a new inborn error of metabolism affecting valine metabolismBrain, 2014
- Osteoporosis Caused by Mutations in PLS3: Clinical and Bone Tissue CharacteristicsJournal of Bone and Mineral Research, 2014
- A treatable new cause of chorea: Beta-ketothiolase deficiencyMovement Disorders, 2013
- Late-adult onset Leigh syndromeJournal of Clinical Neuroscience, 2012
- Human allelic variation: perspective from protein function, structure, and evolutionCurrent Opinion in Structural Biology, 2010
- Subacute Necrotizing Encephalomyelopathy (LEIGH)Published by Springer Science and Business Media LLC ,1970