title: Whole-exome sequencing identifies novel ECHS1 mutations in Leigh syndrome.
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.
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC, H3A 1B1, Canada, Martine.tetreault@mcgill.ca.
authors.forename: Martine
authors.initials: M
authors.lastname: Tetreault
authors.forename: Somayyeh
authors.initials: S
authors.lastname: Fahiminiya
authors.forename: Hana
authors.initials: H
authors.lastname: Antonicka
authors.forename: Grant A
authors.initials: GA
authors.lastname: Mitchell
authors.forename: Michael T
authors.initials: MT
authors.lastname: Geraghty
authors.forename: Matthew
authors.initials: M
authors.lastname: Lines
authors.forename: Kym M
authors.initials: KM
authors.lastname: Boycott
authors.forename: Eric A
authors.initials: EA
authors.lastname: Shoubridge
authors.forename: John J
authors.initials: JJ
authors.lastname: Mitchell
authors.forename: Jacques L
authors.initials: JL
authors.lastname: Michaud
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
mesh_terms: D000015:Abnormalities, Multiple / Q000097:blood; D000592:Amino Acid Metabolism, Inborn Errors / Q000097:blood; D002170:Canada; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004746:Enoyl-CoA Hydratase / Q000235:genetics*; D059472:Exome; D005260:Female; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007888:Leigh Disease / Q000175:diagnosis / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation; D010375:Pedigree; D013869:Thiolester Hydrolases / Q000097:blood / Q000172:deficiency
chemical_list: D013869:Thiolester Hydrolases; C000600529:ECHS1 protein, human; D004746:Enoyl-CoA Hydratase