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

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...

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Veröffentlicht in:EBioMedicine 2018-04, Vol.30, p.86-93
Hauptverfasser: 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 G.J., 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 D.S., McFarland, Robert, Gorman, Gráinne S.
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Zusammenfassung: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. •The m.13094T>C mutation in MT-ND5 is associated with severe, variable neurological manifestations.•Whole mtDNA genome sequencing should be considered in patients with undiagnosed complex neurological disorders.•Biochemical analysis of muscle maybe normal in more than half of all cases. The m.13094T>C mutation in MT-ND5 was considered a rare cause of mitochondrial disease that had been previously reported in association with Leigh Syndrome only. This study revealed that the m.13094T>C mutation is associated with severe, variable neurological features, with a more extensive phenotypic spectrum of disease, frequently manifesting at lower mutant heteroplasmy levels compared to many other primary mitochondrial DNA mutations. The work described here proposes that an unexplained central nervous system disorder should raise clinical suspicion of a mitochondrial disorder, and full mtDNA genome sequencing should be considered even with normal muscle biopsy findings.
ISSN:2352-3964
2352-3964
DOI:10.1016/j.ebiom.2018.02.010