title: Whole Exome Sequencing Identifies the Genetic Basis of Late-Onset Leigh Syndrome in a Patient with MRI but Little Biochemical Evidence of a Mitochondrial Disorder.
abstract: Leigh syndrome is a subacute necrotising encephalomyopathy proven by post-mortem analysis of brain tissue showing spongiform lesions with vacuolation of the neuropil followed by demyelination, gliosis and capillary proliferation caused by mutations in one of over 75 different genes, including nuclear- and mitochondrial-encoded genes, most of which are associated with mitochondrial respiratory chain function. In this study, we report a patient with suspected Leigh syndrome presenting with seizures, ptosis, scoliosis, dystonia, symmetrical putaminal abnormalities and a lactate peak on brain MRS, but showing normal MRC enzymology in muscle and liver, thereby complicating the diagnosis. Whole exome sequencing uncovered compound heterozygous mutations in NADH dehydrogenase (ubiquinone) flavoprotein 1 gene (NDUFV1), c.1162+4A>C (NM_007103.3), resulting in skipping of exon 8, and c.640G>A, causing the amino acid substitution p.Glu214Lys, both of which have previously been reported in a patient with complex I deficiency. Patient fibroblasts showed a significant reduction in NDUFV1 protein expression, decreased complex CI and complex IV assembly and consequential reductions in the enzymatic activities of both complexes by 38% and 67%, respectively. The pathogenic effect of these variations was further confirmed by immunoblot analysis of subunits for MRC enzyme complexes in patient muscle, liver and fibroblast where we observed 90%, 60% and 95% reduction in complex CI, respectively. Together these studies highlight the importance of a comprehensive, multipronged approach to the laboratory evaluation of patients with suspected Leigh syndrome.
authors.affiliation: Genetic Metabolic Disorders Research Unit, Western Sydney Genetics Program, The Children's Hospital at Westmead, Locked Bag 4001, Sydney, NSW, 2145, Australia.|Discipline of Paediatrics and Child Health, Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Nafisinia
authors.affiliation: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
authors.forename: Yiran
authors.initials: Y
authors.lastname: Guo
authors.affiliation: BGI Education Center, University of Chinese Academy of Sciences, Shenzhen, 518083, China.|Shenzen Key Laboratory of Neurogenomics, BGI-Shenzen, Shenzhen, 518083, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Dang
authors.affiliation: Shenzen Key Laboratory of Neurogenomics, BGI-Shenzen, Shenzhen, 518083, China.
authors.forename: Jiankang
authors.initials: J
authors.lastname: Li
authors.affiliation: Shenzen Key Laboratory of Neurogenomics, BGI-Shenzen, Shenzhen, 518083, China.
authors.forename: Yulan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Shenzen Key Laboratory of Neurogenomics, BGI-Shenzen, Shenzhen, 518083, China.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Murdoch Childrens Research Institute and Victorian Clinical Genetics Services, Royal Children's Hospital, Melbourne, VIC, Australia.|Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Nicole J
authors.initials: NJ
authors.lastname: Lake
authors.affiliation: Genetic Metabolic Disorders Research Unit, Western Sydney Genetics Program, The Children's Hospital at Westmead, Locked Bag 4001, Sydney, NSW, 2145, Australia.|Discipline of Paediatrics and Child Health, Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Gold
authors.affiliation: Genetic Metabolic Disorders Research Unit, Western Sydney Genetics Program, The Children's Hospital at Westmead, Locked Bag 4001, Sydney, NSW, 2145, Australia.|Discipline of Paediatrics and Child Health, Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
authors.forename: Lisa G
authors.initials: LG
authors.lastname: Riley
authors.affiliation: Murdoch Childrens Research Institute and Victorian Clinical Genetics Services, Royal Children's Hospital, Melbourne, VIC, Australia.|Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.
authors.forename: David R
authors.initials: DR
authors.lastname: Thorburn
authors.affiliation: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
authors.forename: Brendan
authors.initials: B
authors.lastname: Keating
authors.affiliation: Shenzen Key Laboratory of Neurogenomics, BGI-Shenzen, Shenzhen, 518083, China.
authors.forename: Xun
authors.initials: X
authors.lastname: Xu
authors.affiliation: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.affiliation: Genetic Metabolic Disorders Research Unit, Western Sydney Genetics Program, The Children's Hospital at Westmead, Locked Bag 4001, Sydney, NSW, 2145, Australia. john.christodoulou@health.nsw.gov.au.|Discipline of Paediatrics and Child Health, Sydney Medical School, University of Sydney, Sydney, NSW, Australia. john.christodoulou@health.nsw.gov.au.|Discipline of Genetic Medicine, Sydney Medical School, University of Sydney, Sydney, NSW, Australia. john.christodoulou@health.nsw.gov.au.
authors.forename: John
authors.initials: J
authors.lastname: Christodoulou
keywords: Leigh syndrome; Mitochondrial respiratory chain complexes; Mutation; NDUFV1; Whole exome sequencing