Title | MT-ND5 Mutation Exhibits Highly Variable Neurological Manifestations at Low Mutant Load. |
Publication Type | Journal Article |
Year of Publication | 2018 |
Authors | Ng, YShiau, Lax, NZ, Maddison, P, Alston, CL, Blakely, EL, Hepplewhite, PD, Riordan, G, Meldau, S, Chinnery, PF, Pierre, G, Chronopoulou, E, Du, A, Hughes, I, Morris, AA, Kamakari, S, Chrousos, G, Rodenburg, RJ, Saris, CGJ, Feeney, C, Hardy, SA, Sakakibara, T, Sudo, A, Okazaki, Y, Murayama, K, Mundy, H, Hanna, MG, Ohtake, A, Schaefer, AM, Champion, MP, Turnbull, DM, Taylor, RW, Pitceathly, RDS, McFarland, R, Gorman, GS |
Journal | EBioMedicine |
Volume | 30 |
Pagination | 86-93 |
Date Published | 2018 Apr |
ISSN | 2352-3964 |
Keywords | Adolescent, Adult, Brain, Child, Cohort Studies, Electron Transport Complex I, Female, Humans, Magnetic Resonance Imaging, Male, Mitochondrial Proteins, Mutation, Syndrome, Young Adult |
Abstract | Mutations in the m.13094T>C MT-ND5 gene have been previously described in three cases of Leigh Syndrome (LS). In this retrospective, international cohort study we identified 20 clinically affected individuals (13 families) and four asymptomatic carriers. Ten patients were deceased at the time of analysis (median age of death was 10years (range: 5·4months-37years, IQR=17·9years). Nine patients manifested with LS, one with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), and one with Leber hereditary optic neuropathy. The remaining nine patients presented with either overlapping syndromes or isolated neurological symptoms. Mitochondrial respiratory chain activity analysis was normal in five out of ten muscle biopsies. We confirmed maternal inheritance in six families, and demonstrated marked variability in tissue segregation, and phenotypic expression at relatively low blood mutant loads. Neuropathological studies of two patients manifesting with LS/MELAS showed prominent capillary proliferation, microvacuolation and severe neuronal cell loss in the brainstem and cerebellum, with conspicuous absence of basal ganglia involvement. These findings suggest that whole mtDNA genome sequencing should be considered in patients with suspected mitochondrial disease presenting with complex neurological manifestations, which would identify over 300 known pathogenic variants including the m.13094T>C. |
DOI | 10.1016/j.ebiom.2018.02.010 |
Alternate Journal | EBioMedicine |
Citation Key | 10.1016/j.ebiom.2018.02.010 |
PubMed ID | 29506874 |
PubMed Central ID | PMC5952215 |
Grant List | G1100540 / / Medical Research Council / United Kingdom MR/K000608/1 / / Medical Research Council / United Kingdom MC_UP_1501/2 / / Medical Research Council / United Kingdom G0900652 / / Medical Research Council / United Kingdom G0502157 / / Medical Research Council / United Kingdom G0400074 / / Medical Research Council / United Kingdom NIHR-HCS-D12-03-04 / / Department of Health / United Kingdom MR/L016354/1 / / Medical Research Council / United Kingdom G0601943 / / Medical Research Council / United Kingdom |