MT-ND5 Mutation Exhibits Highly Variable Neurological Manifestations at Low Mutant Load.

TitleMT-ND5 Mutation Exhibits Highly Variable Neurological Manifestations at Low Mutant Load.
Publication TypeJournal Article
Year of Publication2018
AuthorsNg, 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
JournalEBioMedicine
Volume30
Pagination86-93
Date Published2018 Apr
ISSN2352-3964
KeywordsAdolescent, 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.

DOI10.1016/j.ebiom.2018.02.010
Alternate JournalEBioMedicine
Citation Key10.1016/j.ebiom.2018.02.010
PubMed ID29506874
PubMed Central IDPMC5952215
Grant ListG1100540 / / 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