MT-ND5 Mutation Exhibits Highly Variable Neurological Manifestations at Low Mutant Load.
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Authors
Ng, Yi Shiau
Lax, Nichola Z
Maddison, Paul
Alston, Charlotte L
Blakely, Emma L
Hepplewhite, Philippa D
Riordan, Gillian
Meldau, Surita
Chinnery, Patrick F
Pierre, Germaine
Chronopoulou, Efstathia
Du, Ailian
Hughes, Imelda
Morris, Andrew A
Kamakari, Smaragda
Chrousos, Georgia
Rodenburg, Richard J
Saris, Christiaan GJ
Feeney, Catherine
Hardy, Steven A
Sakakibara, Takafumi
Sudo, Akira
Okazaki, Yasushi
Murayama, Kei
Mundy, Helen
Hanna, Michael G
Ohtake, Akira
Schaefer, Andrew M
Champion, Mike P
Turnbull, Doug M
Taylor, Robert W
Pitceathly, Robert DS
McFarland, Robert
Gorman, Gráinne S
Publication Date
2018-04Journal Title
EBioMedicine
ISSN
2352-3964
Publisher
Elsevier BV
Volume
30
Pages
86-93
Language
eng
Type
Article
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Ng, Y. S., Lax, N. Z., Maddison, P., Alston, C. L., Blakely, E. L., Hepplewhite, P. D., Riordan, G., et al. (2018). MT-ND5 Mutation Exhibits Highly Variable Neurological Manifestations at Low Mutant Load.. EBioMedicine, 30 86-93. https://doi.org/10.1016/j.ebiom.2018.02.010
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.
Keywords
Brain, Humans, Syndrome, Electron Transport Complex I, Mitochondrial Proteins, Magnetic Resonance Imaging, Cohort Studies, Mutation, Adolescent, Adult, Child, Female, Male, Young Adult
Sponsorship
Department of Health (via National Institute for Health Research (NIHR)) (unknown)
Wellcome Trust (101876/Z/13/Z)
Cambridge University Hospitals NHS Foundation Trust (CUH) (3819-1617-17)
Department of Health (via Newcastle University) (BH091682-RG81903)
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Identifiers
External DOI: https://doi.org/10.1016/j.ebiom.2018.02.010
This record's URL: https://www.repository.cam.ac.uk/handle/1810/283380
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