JIMD Reports, Volume 32

Nafisinia, Michael, Guo, Yiran, Dang, Xiao, Li, Jiankang, Chen, Yulan, Zhang, Jianguo, Lake, Nicole J, Gold, Wendy A, Riley, Lisa G, Thorburn, David R, Keating, Brendan, Xu, Xun, Hakonarson, Hakon, Christodoulou, John, Lake, Nicole J., Gold, Wendy A., Riley, Lisa G., Thorburn, David R., Michael Nafisinia, Yiran Guo, Xiao Dang, Jiankang Li, Yulan Chen, Jianguo Zhang, Nicole J. Lake, Wendy A. Gold, Lisa G. Riley, David R. Thorburn, Brendan Keating, Xun Xu, Hakon Hakonarson, John Christodoulou

Eva Morava, Matthias Baumgartner, Marc Patterson, Shamima Rahman, Johannes Zschocke, Verena Peters

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.